Novel bicyclic heterocyclyl compounds and their uses

Abstract

The present invention relates to an SOS1 inhibitor, which is a compound represented by Chemical Formula 1, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition containing the same as an active ingredient. The compound, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition containing the same as an active ingredient can be effectively used for the prevention, amelioration, or treatment of diseases associated with SOS1 activity. TIFF2025533170000208.tif77170

Description

[Technical Field]

[0001] The present invention relates to bicyclic heterocyclyl compounds that exhibit SOS1 inhibitory activity, and more particularly to novel bicyclic heterocyclyl compounds that exhibit preventive, ameliorative or therapeutic activity against various cancers due to their excellent SOS1 inhibitory activity, their optical isomers, their stereoisomers, their solvates, their isotope-modified forms, their tautomers, or pharmaceutically acceptable salts thereof, their uses, and pharmaceutical compositions containing them. [Background technology]

[0002] The RAS (renin angiotensin system) family of proteins, including KRAS, NRAS, and HRAS, are small GTPases that exist in GTP- or GDP-bound states within cells. RAS family proteins inherently exhibit weak GTPase activity and slow nucleotide exchange rates. Binding of guanine nucleotide exchange factors (GEFs), such as SOS1 (Son of Sevenless 1), promotes GDP release from RAS proteins, allowing them to bind GTP. RAS family proteins are activated in their GTP-bound state and associate with effector proteins, such as C-RAF and PI3K. These pathways affect various cellular processes, including proliferation, survival, metabolism, motility, angiogenesis, immunity, and growth. Cancer-related mutations in RAS family proteins inhibit GAP-induced GTPase activity, increasing GTP-bound / active RAS family proteins. This leads to the continuous activation of downstream effector pathways of RAS family proteins, such as the MEK / ERK, PI3K / AKT / mTOR, and RalGDS pathways. KRAS mutations (e.g., amino acids G12, G13, Q61, A146) are found in a variety of human cancers, including lung, colorectal, and pancreatic cancers.

[0003] SOS1 (Son of Sevenless 1) is the human homolog of the first Drosophila protein, SOS. SOS1 has two binding sites for RAS family proteins: a catalytic site for GDP-bound RAS family proteins and an allosteric site for GTP-bound RAS family proteins. SOS1 deficiency reduces the growth rate and viability of tumor cells with KRAS mutations, but not KRAS wild-type cell lines. Furthermore, alterations in SOS1 are associated with cancer. SOS1 mutations are found in embryonic rhabdomyosarcoma, Sertoli cell tumor, granular cell tumor of the skin, and lung adenocarcinoma. SOS1 overexpression, on the other hand, is found in bladder and prostate cancers. In addition to cancer, inherited SOS1 mutations have been implicated in the pathogenesis of RASopathy, including Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC), and hereditary gingival fibromatosis type 1.

[0004] To date, several efforts have been made to discover and optimize conjugates targeting the effector binding site of RAS or the catalytic binding site of SOS1 in relation to SOS1 inhibition (Lu et al., ChemMedChem. 2016, 11(8):814-21), but these have not met expectations. Recently, small activating molecules have been discovered that bind to a hydrophobic pocket in SOS1, close to the RAS-binding site (Burns et al., Proc. Natl. Acad. Sci. 2014, 111(9):3401-6). However, binding of these molecules appears to activate RAS rather than inactivate it by increasing nucleotide exchange. Stabilizes the protein-protein interaction between RAS family proteins and SOS1, and inhibits GTP Attempts to prevent reloading of bound RAS family proteins have been made, and several fragment molecules have been discovered (Winter et al., J. Med. Chem. 2015, 58(5):2265-74). However, reversible binding of the fragment molecules to SOS1 did not translate into a measurable effect on nucleotide exchange, and only a weak effect was observed with small molecules covalently bound to RAS. More recently, rational design and screening platforms have been combined to develop small molecule inhibitors of SOS1 (Evelyn et al., Chem. Biol. 2014, 21(12):1618-28; Evelyn et al., J. Biol. Chem. 2015, 290(20):12879-98; Zheng et al., WO2016 / 077793). Although compounds with modest inhibitory effects on SOS1 have been identified, their effects on guanine nucleotide exchange and cell signaling regulation (e.g., ERK phosphorylation) are weak. Therefore, there is a need for new SOS1 inhibitors that can effectively inhibit SOS1. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Patent Publication No. WO2016 / 077793 [Non-patent literature]

[0006] [Non-Patent Document 1] Lu et al.,ChemMedChem.2016.11(8):814-21 [Non-patent document 2] Burns et al.,Proc.Natl.Acad.Sci.2014.111(9):3401-6 [Non-patent document 3] Winter et al.,J.Med.Chem.2015.58(5):2265-74 [Non-patent document 4] Evelyn et al.,Chem.Biol.2014.21(12):1618-28 [Non-Patent Document 5] Evelyn et al.,J.Biol.Chem.2015.290(20):12879-98 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention aims to provide novel bicyclic heterocyclyl compounds having excellent SOS1 inhibitory activity, their optical isomers, their stereoisomers, their solvates, their isotope-modified derivatives, their tautomers, or pharmaceutically acceptable salts thereof. Another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, the bicyclic heterocyclyl compound, its optical isomer, its stereoisomer, its solvate, its isotope-modified derivative, its tautomer, or a pharmaceutically acceptable salt thereof. Another object of the present invention is to provide a pharmaceutical composition containing the bicyclic heterocyclyl compound, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof as an active ingredient, for preventing, ameliorating, or treating various diseases caused by SOS1 activity. Another object of the present invention is to provide use of the bicyclic heterocyclyl compound, its optical isomer, its stereoisomer, its solvate, its isotopically modified product, its tautomer, or a pharmaceutically acceptable salt thereof for the prevention, amelioration, or treatment of various diseases caused by SOS1 activity. Another object of the present invention is to provide a method for the preparation of a medicament for preventing, ameliorating, or treating various diseases caused by SOS1 activity, comprising administering to a subject a bicyclic heterocyclyl compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopically modified product thereof, a tautomer thereof, or a mixture thereof. The present invention also provides uses of these pharmaceutically acceptable salts. Another object of the present invention is to provide a method for preventing, ameliorating, or treating various diseases caused by SOS1 activity by administering the bicyclic heterocyclyl compound, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. [Means for solving the problem]

[0008] The present invention will be described in more detail below. All combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the following specific description should not be construed as limiting the scope of the present invention.

[0009] This research was supported by the Korea Drug Development Fund funded by the Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (Project ID: RS-2023-00217674, Republic of Korea). The project ID may be used in conjunction with "1711198230."

[0010] Compound represented by chemical formula 1 (1) The present invention provides a compound represented by the following chemical formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotope-modified product thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0011] [ka]

[0012] In the above Chemical Formula 1, A is C 3-8 Cycloalkyl, C 3-8 cycloalkenyl, 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, C 6-12 a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring;

[0013] [ka] and;

[0014] n is 0, 1, 2, 3, or 4; R1 is C 1-6 Alkyl, C 6-12 aryl, -CF2H, -CF3, -CN, -OH, -NH2, or halogen (wherein, when n is 2 or more, n R1s are each independent of one another); C of R1 1-6 Alkyl, C 6-12 One or more H in aryl, -CFH, and -OH are each independently C 1-6 Alkyl (wherein C 1-6 One or more H in the alkyl may each independently be -OH, -OC 1-6 Alkyl, or -NR a R b optionally substituted with ), or optionally substituted with halogen; X1 is CH or N, X2 is CR2, and X3 is CH; R2 is H, C 1-6 Alkyl, -CF3, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -OH, -OCF3, -NR C R d or a halogen; L1 is a single bond, -(C=O)-, -(C=O)O-, -O-, or -(C=O)NR e -, -NR e -, -NR e (C=O)-, -NR e SO2- or -NR e (C=O)NR f - and; R3 is H, -OH, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-12 aryl, 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; C 3-8 cycloalkenyl, a 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring,

[0015] [ka]

[0016] (wherein m is 0 or 1, and Y1 is CH2, NR j or O and R ja , R jb , R jc , and R jd are each independently H or C 1-5 alkyl, and R ja , R jb , R jc , and R jd selected two of which may be bonded to form CH2 or CH2-CH2) or

[0017] [ka]

[0018] wherein o and p are each independently 1 or 2, q and r are each independently 0, 1 or 2, and Y and Y are each independently CH, NR k or O), R3 is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S in the ring, or

[0019] [ka]

[0020] one or more -CH2- may be replaced by -(C=O)-, -SO- or -SO2-; C of R3 3-8 One or more -CH2- of the cycloalkyl may be replaced by -SO2-; One or more H in R3 are each independently selected from C 1-6 optionally substituted with alkyl, -OH, halogen, or -L2-R4; L2 is a single bond, C 1-6 Alkylene, -O-, -(C=O)-, -SO2-, -(C=O)NR g -or-NR g (C=O)-; R4 is H, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; C 6-12 aryl, a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; -NR h R i , -CF3, -CF2H, -OH or halogen; One or more H in R4 are each independently selected from C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -NR m R nor may be substituted with halogen; R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R m and R n are each independently H or C 1-6 It is alkyl.

[0021] In the present invention, the resonance structure of the compound represented by Chemical Formula 1 may be considered to be the same as the structures represented by Chemical Formula 1a and Chemical Formula 1b below.

[0022] [ka]

[0023] [ka]

[0024] The above is merely an example of the resonance structure defined in Chemical Formula 1, and is not intended to be limiting.

[0025] In one embodiment, in the above Chemical Formula 1, n may be 0, 1, 2, 3, or 4, and preferably 1, 2, or 3.

[0026] In one embodiment, when n is 2 or more, n R1 may be independent of each other. That is, n R1 may be the same or different substituents. For example, when n is 2, one R1 may be C 1-6 Alkyl, C 6-12 aryl, -CF2H, -CF3, -CN, -OH and halogen, and the other R1 may also be C1-6 Alkyl, C 6-12 It may be a selected one of aryl, -CF2H, -CF3, -CN, -OH and halogen.

[0027] In one embodiment, when A is aryl, n may be 2 or more, preferably 2, and when A is heteroaryl, n may be 1 or more, preferably 1, but is not limited thereto.

[0028] In one embodiment, L is a linker, and when L is a single bond, [ka]

[0029] In other words, in the present invention, "L1 is a single bond" can mean that -L1-R3 is substantially -R3. In the present specification, "L1 is a single bond" can be expressed as L1 being "absent" or "null".

[0030] In one embodiment, one or more H in R3 may each independently be replaced by L2-R4, where L2 is a linker, and when L2 is a single bond, R4 may be substituted with one or more H in R3 and may represent a structure directly linked to R3.

[0031] In one embodiment, in Chemical Formula 1, when A is aryl, n may be 2, and R3 may be N-containing heterocycloalkyl or N-containing heterocycloalkenyl. In this case, the N-containing heterocycloalkyl or N-containing heterocycloalkenyl may or may not further contain one or more heteroatoms.

[0032] In one embodiment, when A in Chemical Formula 1 is heteroaryl, n may be 1, and R3 may be N-containing heterocycloalkyl or N-containing heterocycloalkenyl. In this case, the N-containing heterocycloalkyl or N-containing heterocycloalkenyl may or may not further contain one or more heteroatoms.

[0033] In one embodiment,

[0034] [ka] For example,

[0035] [ka]

[0036] However, the present invention is not limited to these. [ka] teeth,

[0037] [ka]

[0038] In this case, R j is H or C 1-6 It may also be alkyl.

[0039] In one embodiment, [ka] For example,

[0040] [ka]

[0041] However, the present invention is not limited to these. [ka] teeth,

[0042] [ka]

[0043] In this case, R k is H or C 1-6 It may also be alkyl.

[0044] In one embodiment, R3 is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, or

[0045] [ka]

[0046] may be substituted with -(C=O)-, -SO-, or -SO-. The structure in which one or more -CH- are substituted with -(C=O)- includes, for example,

[0047] [ka]

[0048] Furthermore, the structure in which one or more -CH2- are replaced with -SO- or -SO2- may be, but is not limited to,

[0049] [ka] It may be, but is not limited to these.

[0050] In one embodiment, C in R 3-8 One or more -CH2- of the cycloalkyl may be replaced by -SO2-, and C in said R3 3-8 One or more -CH2- of the cycloalkyl may be replaced with -SO2- to form a cyclic compound containing a heteroatom. For example, C in the R3 3-8 The structure in which one or more -CH2- of cycloalkyl is replaced with -SO2- is

[0051] [ka] It may be, but is not limited to this.

[0052] (2) In one embodiment, in the above (1), in the above Chemical Formula 1, A is C 6-12 a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of aryl, N, O, and S in the ring;

[0053] [ka] and;

[0054] n is 1, 2 or 3; R1 is C 1-6 Alkyl, C 6-12 aryl, -CF2H, -CF3, -CN, or halogen (wherein, when n is 2 or more, n R1s are each independent of one another); C of R1 1-6 Alkyl, C 6-12 One or more H in aryl and -CFH are each independently C 1-6 Alkyl (where C 1-6 One or more H in the alkyl may each independently be -OH, -OC 1-6 Alkyl or -NR a R boptionally substituted with) or halogen; X1 and X3 are each CH; X2 is CR2; where R2, R3, R4, L1, L2, Y1, Y2, Y3, m, o, p, q, r, R ja , R jb , R jc , R jd , R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R m and R n are the same as those defined in (1) above. (3) In one embodiment, in the above (1) or (2), in the above Chemical Formula 1, A is C 6-12 is aryl; n is 1 or 2; R1 is independently C 1-6 alkyl, -CF2H, -CF3, -CN or halogen; X1, X2 and X3 are each CH; L1 is a single bond or -NR e - and; R3 is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; C 3-8 cycloalkenyl, a 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, wherein the heterocycloalkyl is

[0055] [ka]

[0056] wherein Y is O and each Y is independently CH, NR k or O, One or more H in R3 are each independently selected from C 1-6 optionally substituted with alkyl, -OH, halogen, or -L2-R4; L2 is a single bond, C 1-6 Alkylene, -O-, -(C=O)-, -(C=O)NR g -or-NR g (C=O)-; R4 is H, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, -NR h R i or a halogen, One or more H in R4 may each independently be replaced with -OH; where R e、 R g , R h , R i and R k are the same as those defined in (1) above.

[0057] (4) In one embodiment, in any one of (1) to (3), in Chemical Formula 1, A is C 6-12 is aryl; n is 2; R1 is independently C 1-6 alkyl, -CF2H, -CF3, -CN or halogen; X1, X2 and X3 are each CH; L1 is a single bond or -NR e - and; R3 is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, or a 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, wherein the heterocycloalkyl is

[0058] [ka]

[0059] wherein Y1 is O and each Y3 is independently CH2; One or more H in R3 are each independently selected from C 1-6 optionally substituted with alkyl, -OH, or -L2-R4; L2 is a single bond, -(C=O)- or -NR g (C=O)-; R4 is H, -OH, C 1-6 Alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, or -NR h R i and One or more H in R4 may each independently be replaced with -OH; where R e、 R g , R h and R i are the same as those defined in (1) above.

[0060] In one embodiment, in the above (1) to (4), the heterocycloalkyl or heterocycloalkenyl in R3 may contain N. In this case, the heterocycloalkyl or heterocycloalkenyl may be a heterocycloalkyl or heterocycloalkenyl in which the atom connecting to the core structure is N, or may be a heterocycloalkyl or heterocycloalkenyl containing N in the ring. In this case, the heterocycloalkyl or heterocycloalkenyl may contain one or more N in the ring, or may be a heterocycloalkyl or heterocycloalkenyl containing 0 to 2 other heteroatoms (S or O) in addition to N in the ring, but is not limited to these.

[0061] In the present invention, "Cm-Cn" (where m and n are each independently an integer of 1 or more) refers to the number of carbon atoms, for example, "C1-C5 alkyl" refers to alkyl having 1 to 5 carbon atoms.

[0062] In the present invention, "alkyl" refers to a linear or branched saturated hydrocarbon group. In the present invention, the number of carbon atoms in the alkyl may be 1 to 5. In one embodiment, the number of carbon atoms in the alkyl may be 1 to 3. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, sec-pentyl, tert-pentyl, isopentyl, sec-isopentyl, and neo-pentyl. In the present invention, alkyl may refer to an unsubstituted alkyl or an alkyl in which one or more H atoms are optionally substituted. The substituent that can replace one or more H atoms in the alkyl may include any functional group that can replace one or more H atoms in the alkyl, without any particular limitation. For example, the substituent may be one defined in the compound represented by Chemical Formula 1 of the present invention, but is not necessarily limited thereto.

[0063] In the present invention, "cycloalkyl" refers to a saturated hydrocarbon ring having three or more carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic structures. The polycyclic structure may include multiple ring structures such as spiro, bridged, and fused ring structures. The cycloalkyl may be a saturated hydrocarbon ring having 3 to 12 carbon atoms. Examples of cycloalkyl include, but are not limited to, one or more selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In the present invention, the cycloalkyl may be unsubstituted or may refer to a cycloalkyl in which one or more H atoms are optionally substituted. The substituent that can replace one or more H atoms in the cycloalkyl may be any functional group that can replace one or more H atoms in the cycloalkyl, without any particular limitation. For example, the substituent may be one defined in the compound represented by Chemical Formula 1 of the present invention, but is not necessarily limited thereto.

[0064] In the present invention, "cycloalkenyl" refers to an unsaturated hydrocarbon ring having three or more carbon atoms and containing one or more double bonds, and the hydrocarbon ring includes both monocyclic and polycyclic structures. That is, in the present invention, cycloalkenyl may refer to a ring structure containing one or more carbon-carbon double bonds in a cycloalkyl ring. In the present invention, cycloalkenyl may be an unsaturated hydrocarbon ring having 3 to 12 carbon atoms. Examples of cycloalkenyl include, but are not limited to, one or more selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. In the present invention, cycloalkenyl may refer to an unsubstituted cycloalkenyl or a cycloalkenyl in which one or more H atoms are optionally substituted. The substituent that can be substituted with one or more H atoms of the cycloalkenyl may include, without particular limitation, any functional group that can be substituted with one or more H atoms of the cycloalkenyl. For example, the substituents may be those defined in the compound represented by Chemical Formula 1 of the present invention, but are not necessarily limited thereto.

[0065] In the present invention, the term "heterocycloalkyl" refers to a cyclic functional group in which at least one carbon atom constituting the ring is replaced with a heteroatom. Examples of the heteroatom include nitrogen (N), oxygen (O), and sulfur (S). In this case, the heteroatom contained in the heterocycloalkyl ring may be one or more types, may contain one or more types of heteroatom, or may contain at least one of each of two or more types of heteroatoms. In the present invention, the atom connected to the core structure of the heterocycloalkyl may be a carbon atom, and the ring may contain a heteroatom, or the atom connected to the core structure may be a heteroatom (in this case, when there are two or more heteroatoms, the ring may also contain heteroatoms). The heterocycloalkyl may be a 3- to 12-membered ring. The heterocycloalkyl includes both monocyclic and polycyclic structures. Examples of heterocycloalkyl include, but are not limited to, oxiranyl, oxetanyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, azepanyl, etc. In the present invention, heterocycloalkyl may mean unsubstituted or heterocycloalkyl in which one or more H atoms are optionally substituted. The substituent that can replace one or more H atoms of the heterocycloalkyl may include, without limitation, any functional group that can replace one or more H atoms of the heterocycloalkyl. For example, the substituent may be one defined in the compound represented by Chemical Formula 1 of the present invention, but is not necessarily limited thereto.

[0066] In the present invention, polycyclic structures may include multiple ring structures such as spiro, bridged and fused ring structures. A spiro ring structure means a ring structure in which two rings are formed by one common atom. In the compounds of the present invention, the structure of a spiro heterocycloalkyl ring is, for example,

[0067] [ka]

[0068] wherein o and p are each independently 1 or 2, q and r are each independently 0, 1 or 2, and Y and Y are each independently CH, NR k or O). Specifically, the structure of the spiroheterocycloalkyl ring may be, but is not limited to,

[0069] [ka] It may be, but is not limited to these.

[0070] A bridged ring structure refers to a hydrocarbon ring structure in which two or more rings share one or more pairs of carbon atoms. Examples of bridged heterocycloalkyl ring structures in the compounds of the present invention include:

[0071] [ka]

[0072] (where m is 0 or 1, and Y1 is NR J or O and R ja , R jb , R jc and R jd are each independently H or C 1-5 alkyl, and R ja , R jb , R jc and R jdmay be linked to form CH2 or CH2-CH2), but is not limited thereto. Specifically, in the present invention, the bridged ring structure may be

[0073] [ka] It may be, but is not limited to these.

[0074] The fused ring structure is, for example, [ka] The structure may be, but is not limited to, the following.

[0075] In the present invention, "heterocycloalkenyl" refers to a cyclic functional group in which at least one or more carbon atoms constituting a cycloalkenyl ring are substituted with a heteroatom. Examples of the heteroatom include nitrogen (N), oxygen (O), and sulfur (S). In this case, the heteroatom contained in the heterocycloalkenyl ring may be one or two or more types, and may contain one or two or more types of heteroatom, or may contain at least one or more types of each of two or more types of heteroatoms. In the present invention, the atom connected to the core structure of the heterocycloalkenyl may be a carbon atom, and the ring may contain a heteroatom, or the atom connected to the core structure may be a heteroatom (in this case, when there are two or more heteroatoms, the ring may also contain a heteroatom). The heterocycloalkenyl may be a 3- to 12-membered ring. Examples of heterocycloalkenyl include:

[0076] [ka] These include, but are not limited to:

[0077] In the present invention, heterocycloalkenyl may mean unsubstituted or one in which one or more H of the heterocycloalkenyl are optionally substituted. The substituent that can replace one or more H of the heterocycloalkenyl may include, without particular limitation, any functional group that can replace one or more H of the heterocycloalkenyl. For example, the substituent may be one defined in the compound represented by Chemical Formula 1 of the present invention, but is not necessarily limited thereto.

[0078] In the present invention, "aryl" refers to an aromatic hydrocarbon having 6 or more carbon atoms, including a monocyclic aromatic or polycyclic aromatic. The number of carbon atoms in the aryl may be 6 to 20. For example, the aryl may be phenyl, biphenyl, naphthalenyl, etc. In the present invention, the aryl may be unsubstituted or may refer to an aryl in which one or more H atoms are optionally substituted. The substituent that can be substituted with one or more H atoms in the aryl may be any functional group that can be substituted with one or more H atoms in the aryl, and is not particularly limited thereto. For example, the substituent may be one defined in the compound represented by Chemical Formula 1 of the present invention, but is not necessarily limited thereto.

[0079] In the present invention, the term "heteroaryl" refers to a monocyclic or polycyclic heterocycle in which at least one carbon atom in the aryl is replaced with a heteroatom, such as nitrogen (N), oxygen (O), or sulfur (S). For example, the heteroaryl in the present invention may be 5- to 12-membered, but is not limited thereto. When the heteroaryl contains two or more heteroatoms, the heteroatoms may be the same or different. For example, when the heteroaryl contains two or more heteroatoms selected from nitrogen, oxygen, and sulfur, it refers to various combinations such as containing two nitrogen atoms, containing one nitrogen and one oxygen atom, or containing two oxygen atoms and one nitrogen atom. Furthermore, in the present invention, the heteroaryl may have a carbon atom connected to the core structure and contain a heteroatom within the ring, or the atom connected to the core structure may be a heteroatom (in this case, when there are two or more heteroatoms, the heteroatom may also be contained within the ring). For example, heteroaryl may include pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, chromenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolopyridinyl, triazinyl, triazolopyrimidinyl, triazolopyridinyl, triazolopyridazinyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl, and isomers thereof, and the like. In the present invention, heteroaryl may mean unsubstituted or heteroaryl in which one or more H's are optionally substituted. The substituent that can be substituted with one or more H's of the heteroaryl may include, without particular limitation, any functional group that can be substituted with one or more H's of the heteroaryl.For example, the substituents may be those defined in the compound represented by Chemical Formula 1 of the present invention, but are not necessarily limited thereto.

[0080] In the present invention, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl refer to both monovalent and divalent or higher polyvalent substituents in the chemical structure according to the respective definitions. For example, "alkyl" may include monovalent alkyl or divalent alkyl (alkylene), and "aryl" may include monovalent aryl or divalent aryl (arylene).

[0081] In the present invention, in the definition of each of alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl, "can be substituted" means that each of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl may be unsubstituted or substituted. Specifically, "can be substituted" of alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl means that the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl are unsubstituted, or one or more H in the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl may be independently substituted with a substituent, and the substituent is not particularly limited as long as it is a functional group that can be substituted with one or more H. For example, in each of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl of the present invention, the substituent may be a substituent defined in the definition of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl of the compound represented by Chemical Formula 1 of the present invention, but is not necessarily limited thereto. In the present invention, "halogen" may be F, Cl, Br or I.

[0082] The compound according to the present invention, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof may be a compound listed in Table 1 below.

[0083] [Table 1-1]

[0084] [Table 1-2]

[0085]

Table 1-3

[0086]

Table 1-4

[0087]

Table 1-5

[0088]

Table 1-6

[0089]

Table 1-7

[0090]

Table 1-8

[0091]

Table 1-9

[0092]

Table 1-10

[0093]

Table 1-11

[0094]

Table 1-12

[0095] [Table 1-13]

[0096] [Table 1-14]

[0097] [Table 1-15]

[0098] [Table 1-16]

[0099] [Table 1-17]

[0100] [Table 1-18]

[0101] [Table 1-19]

[0102] [Table 1-20]

[0103] Furthermore, the compound according to the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof may be a compound listed in Table 2 or Table 3 below.

[0104] [Table 2-1]

[0105]

Table 2-2

[0106]

Table 3-1

[0107]

Table 3-2

[0108]

Table 3-3

[0109]

Table 3-4

[0110]

Table 3-5

[0111]

Table 3-6

[0112]

Table 3-7

[0113]

Table 3-8

[0114]

Table 3-9

[0115]

Table 3-10

[0116]

Table 3-11

[0117]

Table 3-12

[0118]

Table 3-13

[0119]

Table 3-14

[0120]

Table 3-15

[0121]

Table 3-16

[0122]

Table 3-17

[0123]

Table 3-18

[0124]

Table 3-19

[0125]

Table 3-20

[0126]

Table 3-21

[0127]

Table 3-22

[0128]

Table 3-23

[0129]

Table 3-24

[0130]

Table 3-25

[0131]

Table 3-26

[0132]

Table 3-27

[0133]

Table 3-28

[0134]

Table 3-29

[0135]

Table 3-30

[0136]

Table 3-31

[0137]

Table 3-32

[0138]

Table 3-33

[0139]

Table 3-34

[0140]

Table 3-35

[0141]

Table 3-36

[0142]

Table 3-37

[0143]

Table 3-38

[0144]

Table 3-39

[0145]

Table 3-40

[0146] [Table 3-41]

[0147] [Table 3-42]

[0148] [Table 3-43]

[0149] [Table 3-44]

[0150] In the present invention, the term "pharmaceutically acceptable salt" means a salt commonly used in the pharmaceutical industry. and can be prepared by conventional methods known to those of ordinary skill in the art.

[0151] In the present invention, pharmaceutically acceptable salts include, for example, inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, etc.; acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, and ascorbic acid. Examples of suitable salts include organic acid salts prepared from, for example, carbonic acid, vanillic acid, or hydroiodic acid; sulfonates prepared from, for example, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid; amino acid salts prepared from, for example, glycine, arginine, or lysine; and amine salts prepared from, for example, trimethylamine, triethylamine, ammonia, pyridine, or picoline. However, the types of salts referred to in the present invention are not limited to these listed salts. In one embodiment of the present invention, the salt may be a hydrochloride salt.

[0152] In the present invention, the term "stereoisomer" includes partial stereoisomers and optical isomers, and optical isomers include not only enantiomers but also mixtures of enantiomers and racemates. These isomers can be separated by conventional techniques, such as column chromatography or HPLC. Alternatively, each stereoisomer of the compound represented by Formula 1 can be stereospecifically synthesized using optically pure starting materials and / or reagents of known sequence.

[0153] In the present invention, "prevention" means any action of suppressing or delaying the onset of a disease by administering the compound represented by Chemical Formula 1 of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0154] In the present invention, "treatment" means any action in which the symptoms of a subject suspected of or affected by a disease are improved or beneficially altered by administering a compound represented by Chemical Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0155] In the present invention, "SOS1" is meant to include nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or heterologous SOS1 molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, variants and active fragments thereof.

[0156] The compound represented by Chemical Formula 1 of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof can be effectively used for the prevention, amelioration, or treatment of any disease associated with SOS1 activity caused by SOS1 activity. The compound represented by Chemical Formula 1 of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof can suppress / inhibit SOS1, disable the RAS pathway, and inhibit cell growth and proliferation in various diseases caused by SOS1 activity, particularly cancer (tumor), and therefore can exhibit excellent preventive, ameliorative, or therapeutic effects on various diseases caused by SOS1 activity, particularly cancer (tumor). The compound represented by Chemical Formula 1 of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof is capable of inhibiting SOS1 activity at a level similar to, or substantially the same as, or superior to, a conventionally known drug for preventing, ameliorating, or treating a disease associated with SOS1 activity. It may be effective in preventing, improving or treating sexually related diseases.

[0157] A composition comprising a compound represented by chemical formula 1 The present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound represented by Chemical Formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopically modified product thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof. Furthermore, the present invention provides a pharmaceutical composition for preventing, ameliorating, or treating a disease associated with SOS1 activity, comprising, as an active ingredient, a compound represented by Chemical Formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopically modified product thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof. That is, a pharmaceutical composition comprising, as an active ingredient, the compound represented by Chemical Formula 1 of the present invention, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof, can be effectively used for the prevention, amelioration, or treatment of diseases associated with SOS1 activity.

[0158] The diseases associated with SOS1 activity include various diseases caused by SOS1 mutation, overexpression of SOS1, and SOS1 activity, and may include, for example, cancer (tumor). Cancers include lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, blood cancer, leukemia including acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), adrenal cancer, anal cancer, basal squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, uterine cancer, esophageal cancer, Ewing's sarcoma family tumors, eye cancer, gallbladder cancer, gastrointestinal neuroendocrine tumors, and gastrointestinal stromal tumors. tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, hypopharyngeal cancer, liver cancer, lung and breast carcinoma, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymic cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, cutaneous granular cell tumor, lung adenocarcinoma, etc. The diseases associated with SOS1 activity may also include RAS diseases such as neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML) (also known as LEOPARD syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facio-cutaneous (CFC) syndrome, Legius syndrome (also known as NF1-like syndrome), and hereditary gingival fibromatosis type 1.

[0159] The pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable carriers in addition to the compound represented by Chemical Formula 1, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable carriers include those commonly used in the art, specifically, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidine, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, minerals, or oils, but are not limited thereto. In addition to the above-mentioned ingredients, the pharmaceutical composition of the present invention may further contain lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, dispersing agents, stabilizers, etc. Furthermore, the pharmaceutical composition of the present invention can be formulated using pharmaceutically acceptable carriers and excipients into oral preparations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, oral solutions, emulsions, syrups, external preparations, suppositories, or sterile injectable solutions, and can be manufactured in unit dose forms or in multi-dose containers. Preparations can be manufactured using conventional methods used in the art or methods disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and can be formulated into various preparations depending on the disease or ingredient. Non-limiting examples of oral administration formulations using the pharmaceutical composition of the present invention include tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, and elixirs. To formulate the pharmaceutical composition of the present invention for oral administration, binders such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose, or gelatin; excipients such as dibasic calcium phosphate; disintegrants such as corn starch or sweet potato starch; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax may be used, as well as sweeteners, flavorings, syrups, and the like. Furthermore, in the case of capsules, liquid carriers such as oils or fats may be used in addition to the above-mentioned substances.

[0160] Non-limiting examples of parenteral formulations using the pharmaceutical composition of the present invention include injections, suppositories, powders for inhalation, aerosols for spraying, ointments, powders for application, oils, creams, etc. To formulate the pharmaceutical composition of the present invention for parenteral administration, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, topical preparations, etc. may be used, and examples of the non-aqueous solvents and suspensions that may be used include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0161] The present invention provides a method for preventing, ameliorating, or treating a disease associated with SOS1 activity, comprising the step of administering to a subject (in need thereof) a compound represented by Chemical Formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopically modified product thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a composition containing any of them.

[0162] In the present invention, "administration" means introducing a given substance into a subject by an appropriate method. In the present invention, the term "subject" refers to any animal, including humans, such as mice, rats, livestock, etc., that has or may develop a disease associated with SOS1 activity, and may specifically be a mammal, including humans, but is not limited to these.

[0163] The method for preventing, ameliorating, or treating a disease associated with SOS1 activity of the present invention may comprise administering a therapeutically effective amount of a compound represented by Chemical Formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotope-modified product thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0164] In the present invention, the term "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment and not to cause side effects, which may be determined by a person skilled in the art depending on factors including the patient's sex, age, weight, health condition, type and severity of the disease, drug activity, drug sensitivity, administration method, administration time, administration route, excretion rate, treatment period, co-administered or concomitant drugs, and other factors well known in the medical field. A specific therapeutically effective amount for a particular patient will depend on the type of response to be achieved and It is preferable to apply it differently depending on various factors such as the dosage and intensity, the specific composition including, in some cases, whether a different formulation is used, the age, weight, general health condition, sex and diet of the patient, the time of administration, the route of administration and excretion rate of the composition, the duration of treatment, drugs used in conjunction with or simultaneously with the specific composition, and similar factors well known in the pharmaceutical arts.

[0165] The present invention provides use of a compound represented by Chemical Formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopically modified product thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a composition containing the same, for the prevention, amelioration, or treatment of a disease associated with SOS1 activity. The present invention provides use of the compound represented by Chemical Formula 1, its optical isomer, its stereoisomer, its solvate, its isotope-modified derivative, its tautomer, or a pharmaceutically acceptable salt thereof, or a composition containing the same, for the manufacture of a medicament for preventing, ameliorating, or treating a disease associated with SOS1 activity. For the prevention, amelioration, or treatment of diseases associated with SOS1 activity, or for the manufacture of a medicament therefor, the compound represented by Chemical Formula 1, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof may be mixed with a pharmaceutically acceptable adjuvant, diluent, carrier, etc., and may be manufactured as a combined preparation together with other active agents to produce a synergistic effect.

[0166] The contents of the compounds, pharmaceutical compositions, methods of treatment and uses of the present invention are equally applicable unless they contradict each other. [Effects of the Invention]

[0167] The compound represented by Chemical Formula 1 of the present invention, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition containing the same as an active ingredient, can be effectively used for the prevention, amelioration, or treatment of diseases associated with SOS1 activity. DETAILED DESCRIPTION OF THE INVENTION

[0168] The present invention will be described in more detail below with reference to the following embodiments. It will be obvious to those skilled in the art that these embodiments are for illustrative purposes only and should not be construed as limiting the scope of the present invention.

[0169] Preparation of the compound represented by formula 1 The compounds of the present invention represented by Formula 1 can be prepared by the methods described below. Unless otherwise specified, the starting materials are commercially available or can be prepared by known methods. The use of any examples or exemplary language provided herein is merely intended to further illustrate the present invention and does not limit the scope of the claims.

[0170] <Intermediate> Intermediate IA [ka]

[0171] Step 1 [ka] 1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethanone

[0172] To a pressure flask containing a solution of 1-(benzyloxy)-3-bromo-5-(difluoromethyl)benzene (1.17 mg, 3.74 mmol) in dioxane (11 mL) was added tributyl(1-ethoxyvinyl)tin (1.3 mL, 3.9 mmol) and PdCl2(PPh3)2 (262 mg, 0.37 mmol) at room temperature, followed by stirring at 80 °C for 16 hours. After cooling to room temperature, 1N aqueous HCl was added, stirred for 1 hour, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give 1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethanone (1.03 g, 100%) as a yellow solid.

[0173] Step 2 [ka] (R,E)-N-(1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide

[0174] To a solution of 1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethanone (1 g, 3.62 mmol) in tetrahydrofuran (10 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (658 mg, 5.43 mmol) and Ti(OEt) (1.5 mL, 7.24 mmol) at room temperature, followed by stirring at 80 °C for 16 hours. After cooling to room temperature, the precipitated solid was filtered by adding cold water, then dissolved in ethyl acetate and filtered through a Celite pad. The filtrate was concentrated under vacuum without column purification to give (R,E)-N-(1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1 g, 98%) as a yellow liquid. MS(ESI+)m / z380(M+H) +

[0175] Step 3 [ka] N-((R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

[0176] To a solution of (R,E)-N-(1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (1 g, 3.60 mmol) in tetrahydrofuran (10 ml) was added NaBH (164 mg, 4.34 mmol) at 0 °C and stirred at room temperature for 5 hours. After confirming the completion of the reaction, HO was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give (R)-N-((R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (830 mg, 58%) as a white solid. MS(ESI+)m / z382(M+H)+

[0177] Step 4 [ka] (R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethanamine hydrochloride

[0178] To a solution of N-((R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (873 mg, 2.28 mmol) in dioxane (7 mL), 4 M HCl solution in dioxane (1.71 mL, 6.84 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated to give (R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethanamine hydrochloride (682 mg, 100%) as a white solid. MS(ESI+)m / z278(M+H) +

[0179] <Synthesis Methods and Examples> Synthesis method A [ka]

[0180] The general synthesis of compound A-3 is exemplified in Synthesis Method A. A-2, which has an amine group introduced therein, was synthesized using A-1 and diisopropylethylamine, and the final compound A-3 was obtained by Suzuki-Miyaura coupling reaction.

[0181] Example 1 [ka] (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone

[0182] Step 1 [ka] (R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0183] To 6-bromo-4-chlorocinnoline (Intermediate A-1) (150 mg, 0.62 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine (0.15 ml, 0.92 mmol) and diisopropylethylamine (0.15 ml, 1.83 mmol) were added dropwise, and the mixture was stirred at 130° C. for 4 hours. After the reaction was completed, the mixture was concentrated and purified by CombiFlash to obtain (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine (220 mg, 90%) as a brown solid. MS(ESI+) m / z 396, 398(M+H) +

[0184] Step 2 [ka] (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone

[0185] To a solution of (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine (80 mg, 0.20 mmol) in dioxane (4 mL), 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid, pinacol ester (120 mg, 0.30 mmol), Pd(dppf)Cl·DCM (40 mg, 0.02 mmol), KCO (160 mg, 0.60 mmol), and HO (4 mL) were added and stirred at 90 °C for 6 h and then at room temperature for 12 h. The reaction mixture was cooled to room temperature, diluted with distilled water, and extracted with DCM. The combined organic extracts were dried over sodium sulfate and concentrated. The concentrated residue was purified by CombiFlash to give (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (18 mg, 14%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.34( s,1H),8.08(d,J=8.8Hz,1H),7.96(t,J=6.8Hz,1H),7.80-7.76(m,1H),7.64(t,J=7.2Hz,1H),7.55(t,J=7.2Hz,1H),7.32-7.27(m,2H) ),6.49(d,J=3.6Hz,1H),5.29(t,J=6.8Hz,1H),4.21(d,J=2.0Hz,2H),3.75-3.71(m,2H),2.10(d,J=16.8Hz,3H),1.27(d,J=6.8Hz,3H) MS(ESI+)m / z441(M+H) +

[0186] Example 2 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- 6-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine

[0187] As described in Example 1, compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-1-dimethylethyl ester-1-(2H)-pyridinecarboxylic acid in a manner substantially similar to the synthesis method of Example 1 to obtain (R)-tert-butyl-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (50 mg, 67%). To a solution of (R)-tert-butyl-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.10 mmol) in dichloromethane (1 mL) was added 4N hydrochloric acid solution in 1,4-dioxane (0.40 mL, 1.0 mmol) at 0° C. and stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated and extracted with aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine (6 mg, 15%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.33( s,1H),8.06(d,J=8.8Hz,1H),7.95(dd,J=2.0Hz,7.2Hz,1H),7.81(d,J=6 .8Hz,1H),7.64(t,J=7.2Hz,1H),7.55(t,J=7.2Hz,1H),7.41(s,0.5H),7. 32-7.34(m,2H),7.14(s,0.5H),6.53(s,1H),5.28(t,J=6.8Hz,1H),3.56( d,H=2.4Hz,2H),3.10(t,J=5.6Hz,2H),2.64(s,2H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z399(M+H) +

[0188] Example 3 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine

[0189] As described in Example 1, compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by the synthesis of 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester. The title compound (26 mg, 31%) was obtained in substantially the same manner as in Example 1 using the same synthetic method. 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.31( s,1H),8.06(d,J=8.8Hz,1H),7.95(dd,J=2.0Hz,8.8Hz,1H),7.82(d,J=7.2Hz,1H),7.64(t,J=7.2Hz,1H),7.55(t,J=7.2Hz,1H),7 .42-7.12(m,2H),6.53(s,1H),5.28(quint,J=6.8Hz,1H),3.23-3.11(m,2H),2.76-2.63(m,4H),2.38(s,3H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z413(M+H) +

[0190] Example 4 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)cinnolin-4-amine

[0191] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then 1,2,3,6-tetrahydropyran-4-boronic acid pinacol ester was used to obtain the title compound (28 mg, 35%) in a manner substantially similar to the synthesis method of Example 1. 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.33( s,1H),8.06(d,J=8.8Hz,1H),7.98(dd,J=2.0Hz,8.8Hz,1H),7.83(d,J=7.2Hz,1H),7.64(t,J=7.2Hz,1H),7.55(t,J=7.2Hz,1H),7.42- 7.14(m,2H),6.59(s,1H),5.29(quint,J=6.8Hz,1H),4.36-4.32(m,2H),3.92(t,J=5.6Hz,2H),2.72-2.63(m,2H),1.70(d,J=6.8Hz,3H) MS(ESI+) m / z 400(M+H)+

[0192] Synthesis method B [ka]

[0193] The general synthesis of compound B-1 is exemplified in Synthetic Method B. The bromine of intermediate A-2 is displaced with an amine using a Buchwald-Hartwig reaction to give the final compound B-1.

[0194] Example 5 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-methylpiperazin-1-yl)cinnolin-4-amine

[0195] A solution of (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine (Intermediate A-2) (230 mg, 0.58 mmol) in tetrahydrofuran (4 mL) was dissolved in N-methylpiperazine (0.23 mL, 1.16 mmol), Pd2(dba)3 (160 mg, 0.058 mmol), and Xphos (160 mg, 0.116 mmol), and 1N LiHMDS in THF (2 mL, 2.9 mmol) was added and heated with stirring at 100 °C for 1 h. Upon completion of the reaction, the mixture was cooled to room temperature, diluted with distilled water, and extracted with DCM. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by CombiFlash to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-methylpiperazin-1-yl)cinnolin-4-amine (100 mg, 42%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.95( d,J=9.6Hz,1H),7.64(dd,J=2.4Hz,6.8Hz,1H),7.59(t,J=7.2Hz,1H),7.54(t,J=7.2Hz,1H),7. 47(d,J=2.4Hz,1H),7.41(s,0.5H),7.32-7.27(m,3H),7.14(s,0.5H),3.44(s,4H),2.53(s,4H),2.27(s,3H),1.68(d,J=6.8Hz,3H) MS(ESI+)m / z416(M+H) +

[0196] Example 6 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-(dimethylamino)piperidin-1-yl)cinnolin-4-amine

[0197] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that N,N-dimethylpiperidin-4-amine was used, to obtain the title compound (8 mg, 16%). 1 H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.93( d,J=9.6Hz,1H),7.64-7.59(m,2H),7.48(s,1H),7.32(t,J=6.8Hz,1H),7.28(d,J=4.0Hz,1H),5.25-5.18(m,1H),4.07(d ,J=10.0Hz,2H),2.91-2.90(m,2H),2.50-2.50(m,2H),2.23(s,3H),1.91(s,3H),1.68(d,J=6.8Hz,3H),1.55-1.52(m,2H) MS(ESI+)m / z444(M+H) +

[0198] Example 7 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- 6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)cinnolin-4-amine

[0199] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 2-methyl-2,6-diazaspiro[3.3]heptane was used, to obtain the title compound (33 mg, 38%). 1 H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.93( d,J=9.6Hz,1H),7.60-7.52(m,2H),7.41-7.14(m,3H),7.07-7.04(m,2H),5.19(q,J= 7.2Hz,1H),4.13-4.08(m,4H),3.40-3.30(m,4H),2.21(s,3H),1.68(d,J=6.8Hz,3H) MS(ESI+)m / z428(M+H) +

[0200] Example 8 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-(oxetan-3-yl)piperazin-1-yl)cinnolin-4-amine

[0201] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 1-(oxetan-3-yl)piperazine was used, to obtain the title compound (33 mg, 36%). 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96( d,J=9.6Hz,1H),7.66(dd,J=9.6,2.4Hz,1H),7.62-7.49(m,2H),7.49(d,J=2.4Hz,1H),7.41-7.14(m,3H),5.21(q,J= 7.2Hz,1H),4.61(t,J=6.4Hz,2H),4.52(t,J=6.0Hz,2H),3.55-3.46(m,5H),3.40-3.30(m,4H),1.69(d,J=6.8Hz,3H) MS(ESI+)m / z458(M+H) +

[0202] Example 9 [ka] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)cinnolin-4-amine

[0203] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (S)-octahydropyrazino[2,1-c][1,4]oxazine was used, to obtain the title compound (17 mg, 25%). 1 H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.96( d,J=9.2Hz,1H),7.72(dd,J=2.4Hz,6.8Hz,1H),7.59(t,J=7.2Hz,1H),7.54(t,J=7.2Hz,1H),7.46(d,J= 2.4Hz,1H),7.42(s,0.25H),7.34(s,0.25H),7.31(d,J=3.2Hz,1H),7.28(d,J=4.0Hz,1H),7.27(s,0.25 H),7.14(s,0.25H),5.25-5.18(m,1H),4.02(d,J=11.6Hz,1H),3.85-3.79(m,3H),3.61-3.55(m,1H),3. 25(t,J=10.4Hz,2H),3.00-2.92(m,2H),2.74(d,J=11.2Hz,1H),2.41-2.24(m,3H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z458(M+H) +

[0204] Example 10 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-morpholinocinnoline-4-amine

[0205] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that morpholine was used, to obtain the title compound (50 mg, 62%). 1 H NMR(400MHz,DMSO-d6)δ8.12(s,1H),7.98( d,J=9.2Hz,1H),7.65(dd,J=2.4Hz,7.2Hz,1H),7.60(t,J=7.2Hz,1H),7.54(t,J=6.8Hz,1H),7.50(d,J=2.4Hz,1H),7. 41(s,0.5H),7.35-7.19(m,3H),7.14(s,0.5H),5.22(t,J=6.8Hz,1H),3.82(s,4H),3.41(s,4H),1.69(d,J=6.8Hz,3H) MS(ESI+)m / z403(M+H) +

[0206] Example 11 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)cinnolin-4-amine

[0207] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 2-oxa-6-azaspiro[3.3]heptane was used to obtain the title compound (16 mg, 20%). 1 H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.94( d,J=8.8Hz,1H),7.59-7.52(m,2H),7.41(s,0.5H),7.30-7.26(m,1H),7.21(d,J=6.8Hz,1H),7.14( s,0.5H),7.09-7.06(m,2H),5.19(t,J=6.8Hz,1H),4.79(s,4H),4.22(s,4H),1.68(d,J=6.8Hz,3H) MS(ESI+) m / z 415(M+H) +

[0208] Example 12 [ka] 6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0209] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used, to obtain the title compound (913 mg, 50%). 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),8.03( d,J=9.6Hz,1H),7.60(t,J=7.4Hz,1H),7.54(t,J=7.8Hz,1H),7.51(d,J=9.6Hz,1H),7.42-7.15(m,4H),5.23(t,J=6.8Hz,1H),4.8 3(d,J=6.8Hz,2H),3.80(t,J=12.8Hz,2H),3.65(t,J=13.4Hz,2H),3.23-3.18(m,1H),1.99(d,J=8.8Hz,1H),1.70(d,J=6.4Hz,3H) MS(ESI+) m / z 415(M+H) +

[0210] Example 13 [ka] 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0211] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used, to obtain the title compound (32 mg, 39%). 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.95( d,J=9.2Hz,1H),7.56(dd,J=8.0Hz,15.9Hz,2H),7.41-7.10(m,5H),5.19(t,J=6.8Hz,1H),4.90(s,1H),4.75(s,1H),3.88(d ,J=6.0Hz,1H),3.74(d,J=7.2Hz,1H),3.65(d,J=8.4Hz,1H),3.32-3.25(m,1H),1.99(q,J=10.8Hz,2H),1.68(d,J=6.8Hz,3H) MS(ESI+) m / z 415(M+H) +

[0212] Example 14 [ka] 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0213] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used, to obtain the title compound (30 mg, 36%). 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.95( d,J=9.2Hz,1H),7.59(t,J=7.4Hz,1H),7.54(t,J=6.2Hz,1H),7.41-7.27(m,3H),7.16-7.12(m,2H),5.20(t,J=6.8Hz,1H),4.92(s,1H),4.76 (s,1H),3.87(d,J=6.4Hz,1H),3.71(d,J=7.2Hz,1H),3.64(d,J=9.6Hz,1H),3.32-3.25(m,1H),1.97(q,J=11.6Hz,2H),1.68(d,J=6.8Hz,3H) MS(ESI+) m / z 415(M+H) +

[0214] Example 15 [ka] 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0215] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride was used, to obtain the title compound (45 mg, 45%). 1 H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.96( d,J=9.2Hz,1H),7.55-7.52(m,3H),7.42-7.14(m,4H),5.20(t,J=6.8Hz,1H),4.52(s,2H),3.77(d,J =7.6Hz,1H),3.76(d,J=7.6Hz,1H),3.58(d,J=10.8Hz,2H),2.09-2.01(m,4H),1.68(d,J=6.8Hz,3H) MS(ESI+)m / z429(M+H) +

[0216] Example 16 [ka] 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0217] Intermediate A-1 and (R)-1-(3-(difluoromethyl)methyl)-2-(2-methyl-2-propanol)-2-one were prepared as described in Example 1. Compound A-2 was synthesized using (methyl)-2-fluorophenyl)ethanamine, and then the title compound (27 mg, 25%) was obtained in substantially the same manner as described in Example 5, except that 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride was used. 1 H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.96( d,J=9.6Hz,1H),7.61-7.52(m,3H),7.42-7.14(m,4H),5.21(t,J=6.8Hz,1H),4.54( s,2H),3.73(d,J=10.4Hz,2H),3.05-3.00(m,2H),1.89(s,4H),1.68(d,J=6.8Hz,3H) MS(ESI+)m / z429(M+H) +

[0218] Example 17 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-thiomorpholinocinnolin-4-amine

[0219] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that thiomorpholine was used, to obtain the title compound (24 mg, 40%). 1 H NMR(400MHz,DMSO-d6)δ8.19(s,1H),7.96( d,J=9.2Hz,1H),7.62(d,J=2.4Hz,1H),7.60-7.54(m,2H),7.47(d,J=2.4Hz,1H),7.42(s,0.25H),7.34(s,0.25H),7.32(d,J=2.8Hz,1H) ,7.29(d,J=3.6Hz,1H),7.27(s,0.25H),7.15(s,0.25H),5.23-5.19(m,1H),3.86-3.83(m,4H),2.77-2.75(m,4H),1.69(d,J=6.8Hz,3H) MS(ESI+)m / z419(M+H) +

[0220] Example 18 [ka] (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)piperidin-4-ol

[0221] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 4-hydroxypiperidine was used, to obtain the title compound (30 mg, 36%). 1 H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.93( d,J=9.6Hz,1H),7.64-7.52(m,3H),7.47(d,J=2.4Hz,1H),7.41-7.14(m,3H),5.21(q,J=7.2Hz,1H),4.76(d,J=4.0Hz,1 H),3.91-3.82(m,2H),3.78-3.71(m,1H),3.16-3.09(m,2H),1.93-1.89(m,2H),1.70(d,J=6.8Hz,3H),1.58-1.50(m,2H) MS(ESI+)m / z417(M+H) +

[0222] Example 19 [ka] (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)-4-methylpiperidin-4-ol

[0223] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 4-methyl-4-piperidinol was used, to obtain the title compound (29 mg, 33%). 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.92( d,J=9.2Hz,1H),7.65-7.52(m,3H),7.46(d,J=2.4Hz,1H),7.41-7.14(m,3H),5.21(q,J=7.2Hz,1H),4. 41(s,1H),3.69-3.65(m,2H),3.40-3.35(m,2H),1.70(d,J=6.8Hz,3H),1.65-1.63(m,4H),1.20(s,3H) MS(ESI+)m / z431(M+H) +

[0224] Example 20 [ka] (R)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)piperidin-3-ol

[0225] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (R)-3-hydroxypiperidine was used, to obtain the title compound (40 mg, 48%). 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.92( d,J=9.2Hz,1H),7.62-7.52(m,3H),7.46(d,J=2.0Hz,1H),7.43-7.14(m,3H),5 .21(q,J=7.2Hz,1H),4.90(d,J=4.8Hz,1H),3.95-3.91(m,1H),3.81-3.78(m,1 H),3.70-3.63(m,1H),2.99-2.92(m,1H),2.83-2.78(m,1H),1.97-1.94(m,1H) ,1.88-1.83(m,1H),1.70(d,J=6.8Hz,3H),1.64-1.54(m,1H),1.44-1.36(m,1H) MS(ESI+)m / z417(M+H) +

[0226] Example 21 [ka] (S)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)piperidin-3-ol

[0227] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (S)-3-hydroxypiperidine was used, to obtain the title compound (13 mg, 15%). 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.92( d,J=9.6Hz,1H),7.62-7.52(m,3H),7.47-7.43(m,2H),7.43-7.14(m,2H),5.2 1(q,J=7.2Hz,1H),5.00(d,J=4.8Hz,1H),3.94-3.90(m,1H),3.83-3.80(m,1H) ,3.68-3.63(m,1H),2.98-2.91(m,1H),2.84-2.79(m,1H),1.98-1.94(m,1H), 1.88-1.83(m,1H),1.70(d,J=6.8Hz,3H),1.64-1.55(m,1H),1.45-1.36(m,1H) MS(ESI+)m / z417(M+H) +

[0228] Example 22 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-methoxypiperidin-1-yl)cinnolin-4-amine

[0229] Intermediate A-1 and (R)-1-(3-(difluoromethyl)methyl)-2-(2-methyl-2-propanol)-2-one were prepared as described in Example 1. Compound A-2 was synthesized using (methyl)-2-fluorophenyl)ethanamine, followed by a procedure substantially similar to that described in Example 5, except that 4-methoxypiperidine was used, to obtain the title compound (13 mg, 15%). 1 H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.94( d,J=9.6Hz,1H),7.65-7.52(m,3H),7.48(d,J=2.4Hz,1H),7.41-7.14(m,3H),5.22(q,J=7.2Hz,1H),3.81-3.76(m, 2H),3.49-3.43(m,1H),3.33(s,3H),3.22-3.14(m,2H),2.03-1.99(m,2H),1.69(d,J=6.8Hz,3H),1.65-1.56(m,2H) MS(ESI+)m / z431(M+H) +

[0230] Example 23 [ka] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((R)-3-methoxypiperidin-1-yl)cinnolin-4-amine

[0231] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (R)-3-methoxypiperidine was used, to obtain the title compound (22 mg, 25%). 1 H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.93( d,J=9.6Hz,1H),7.65-7.52(m,3H),7.46(d,J=2.4Hz,1H),7.41-7.14(m,3H),5.21(q,J=7.2Hz,1H),3.92-3.88(m,1H),3.71-3.67(m, 1H),3.43-3.37(m,1H),3.33(s,3H),3.17-3.02(m,2H),2.10-1.99(m,1H),1.91-1.85(m,1H),1.69(d,J=6.8Hz,3H),1.65-1.43(m,2H) MS(ESI+)m / z431(M+H) +

[0232] Example 24 [ka] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((S)-3-methoxypiperidin-1-yl)cinnolin-4-amine

[0233] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (S)-3-methoxypiperidine was used, to obtain the title compound (6 mg, 7%). 1 H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.93( d,J=9.6Hz,1H),7.65-7.52(m,3H),7.46(d,J=2.4Hz,1H),7.41-7.14(m,3H),5.20(q,J=7.2Hz,1H),3.91-3.88(m,1H),3.73-3.70(m, 1H),3.43-3.37(m,1H),3.33(s,3H),3.14-3.02(m,2H),2.10-1.99(m,1H),1.91-1.85(m,1H),1.69(d,J=6.8Hz,3H),1.65-1.45(m,2H) MS(ESI+)m / z431(M+H) +

[0234] Example 25 [ka] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((R)-3-fluoropyrrolidin-1-yl)cinnolin-4-amine

[0235] As described in Example 1, compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by ( The title compound (11 mg, 14%) was obtained by carrying out a synthetic method essentially similar to that described in Example 5, except that R)-3-fluoropyrrolidine hydrochloride was used. 1 H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.97( d,J=9.2Hz,1H),7.60-7.52(m,2H),7.41-7.10(m,5H),5.63-5.50(m,1H),5.2 1(q,J=7.2Hz,1H),3.79-3.54(m,4H),2.39-2.23(m,2H),1.69(d,J=6.8Hz,3H) MS(ESI+) m / z 405(M+H) +

[0236] Example 26 [ka] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((S)-3-fluoropyrrolidin-1-yl)cinnolin-4-amine

[0237] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (S)-3-fluoropyrrolidine hydrochloride was used, to obtain the title compound (21 mg, 27%). 1 H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.97( d,J=9.2Hz,1H),7.60-7.52(m,2H),7.41-7.10(m,5H),5.64-5.50(m,1H),5.21(q,J=7. 2Hz,1H),3.79-3.67(m,3H),3.57-3.50(m,1H),2.38-2.19(m,2H),1.69(d,J=6.8Hz,3H) MS(ESI+) m / z 405(M+H) +

[0238] Example 27 [ka] (R)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)pyrrolidin-3-ol

[0239] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (R)-pyrrolidin-3-ol was used, to obtain the title compound (5 mg, 6%). 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.93( d,J=9.2Hz,1H),7.59(t,J=7.6Hz,1H),7.54(t,J=7.2Hz,1H),7.41-7.05(m,6H),5.24(q,J=7.2Hz,1H),5.11 (d,J=3.6Hz,1H),4.49(s,1H),3.64-3.42(m,4H),2.17-2.08(m,1H),2.02-1.95(m,1H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z403(M+H) +

[0240] Example 28 [ka] (S)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)pyrrolidin-3-ol

[0241] As described in Example 1, compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by ( A synthetic method essentially similar to that described in Example 5 was carried out, except that S)-pyrrolidin-3-ol was used, to give the title compound (9 mg, 11%). 1 H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.94( d,J=9.6Hz,1H),7.59(t,J=7.6Hz,1H),7.54(t,J=7.2Hz,1H),7.41-7.14(m,5H),7.04(d,J=2.0Hz,1H),5.23(q,J=7.2Hz,1H),5.0 9(d,J=3.6Hz,1H),4.50(s,1H),3.61-3.53(m,3H),3.39-3.36(m,1H),2.16-2.10(m,1H),2.01-1.95(m,1H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z403(M+H) +

[0242] Example 29 [ka] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cinnolin-4-amine

[0243] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the title compound (70 mg, 32%) was obtained in substantially the same manner as described in Example 5, except that (3aS,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride was used. 1 H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.82( d,J=9.2Hz,1H),7.47-7.39(m,2H),7.28-7.00(m,5H),5.08(q,J=7.2Hz,1H),3.79-3.7 6(m,2H),3.53-3.46(m,4H),3.35-3.25(m,2H),3.02-2.95(m,2H),1.55(d,J=6.8Hz,3H) MS(ESI+)m / z429(M+H) +

[0244] Example 30 [ka] (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)azetidin-3-ol

[0245] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis method was carried out in substantially the same manner as described in Example 5, except that azetidin-3-ol hydrochloride was used, to obtain the title compound (3 mg, 3%). 1 H NMR(400MHz,MeOD)δ8.03(s,1H),7.97(d,J =9.2Hz,1H),7.56(q,J=8.7Hz,2H),7.26(t,J=7.8Hz,1H),7.21-6.93(m,3H),5.27(q,J=6.9Hz ,1H),4.83-4.79(m,1H),4.42-4.38(m,2H),3.92(x,J=4.1Hz,8.3Hz,2H),1.78(d,J=6.8Hz,3H) MS(ESI+)m / z389(M+H) +

[0246] Example 31 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3-methoxyazetidin-1-yl)cinnolin-4-amine

[0247] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 3-methoxyazetidine hydrochloride was used, to obtain the title compound (3 mg, 3%). 1 H NMR(400MHz,MeOD)δ8.03(s,1H),7.97(d,J =9.2Hz,1H),7.57-7.52(m,2H),7.26(t,J=7.8H z,1H),7.21-6.93(m,3H),5.27(q,J=7.6Hz,1H),4.50-4.47(m,1H),4.38-4 .34(m,2H),3.96(x,J=4.1Hz,8.3Hz,2H),3.42(s,3H),1.78(d,J=6.8Hz,3H) MS(ESI+)m / z403(M+H) +

[0248] Example 32 [ka] (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)-3-methylazetidin-3-ol

[0249] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 3-methylazetidin-3-ol hydrochloride was used, to obtain the title compound (40 mg, 40%). 1 H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.94( d,J=9.2Hz,1H),7.56(dd,J=9.6Hz,16.1Hz,2H),7.41-7.07(m,5H),5.68(s,1H),5.19(t,J= 6.8Hz,1H),3.97(t,J=6.8Hz,2H),3.87(t,J=8.6Hz,2H),1.68(d,J=6.8Hz,3H),1.51(s,3H) MS(ESI+)m / z403(M+H) +

[0250] Example 33 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3-methoxy-3-methylazetidin-1-yl)cinnolin-4-amine

[0251] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 3-methoxy-3-methylazetidine hydrochloride was used, to obtain the title compound (24 mg, 29%). 1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.95( d,J=9.6Hz,1H),7.59(t,J=7.0Hz,1H),7.53(t,J=6.4Hz,1H),7.41-7.09(m,5H),5.19(t,J=6.8H z,1H),3.98(t,J=7.8Hz,2H),3.92-3.88(m,2H),3.25(s,3H),1.68(d,J=6.8Hz,3H),1.54(s,3H) MS(ESI+)m / z417(M+H) +

[0252] Example 34 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(6-methoxy-2-azaspiro[3.3]heptan-2-yl)cinnolin-4-amine

[0253] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the title compound (32 mg, 36%) was obtained in substantially the same manner as in Example 5, except that 6-methoxy-2-azaspiro[3.3]heptane hydrochloride was used. 1 H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.93( d,J=9.6Hz,1H),7.60-7.52(m,2H),7.41-7.14(m,3H),7.07-7.04(m,2H),5.21(q,J=7.2Hz,1H),4.11-3. 95(m,4H),3.83(q,J=6.8Hz,1H),3.16(s,3H),2.57-2.52(m,2H),2.15-2.10(m,2H),1.67(d,J=6.8Hz,3H) MS(ESI+)m / z443(M+H) +

[0254] Example 35 [ka] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((R)-tetrahydrofuran-3-yl)cinnoline-4,6-diamine

[0255] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (3R)-tetrahydro-3-furanamine was used, to obtain the title compound (10 mg, 17%). 1 H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.82( d,J=9.2Hz,1H),7.59(t,J=7.2Hz,1H),7.54(t,J=6.8Hz,1H),7.42(s,0.25H),7.31(s,0.25H), 7.29(d,J=5.6Hz,1H),7.22(dd,J=2.4Hz,6.8Hz,1H),7.14(s,0.25H),7.06(s,0.25H),7.03(d, J=2.0Hz,1H),6.80(d,J=7.2Hz,1H),5.20-5.17(m,1H),4.32-4.29(m,1H),4.13-4.09(m,1H),3 .92-3.80(m,2H),3.60-3.57(m,1H),2.83-2.33(m,1H),1.88-1.81(m,1H),1.54(d,J=6.8Hz,3H) MS(ESI+)m / z403(M+H) +

[0256] Example 36 [ka] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((S)-tetrahydrofuran-3-yl)cinnoline-4,6-diamine

[0257] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (3S)-tetrahydro-3-furanamine was used, to obtain the title compound (24 mg, 40%). 1 H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.82( d,J=9.2Hz,1H),7.59(t,J=7.2Hz,1H),7.54(t,J=6.8Hz,1H),7.41(s,0.25H),7.31(s,0.25H), 7.29(d,J=6.4Hz,1H),7.22(dd,J=2.4Hz,6.8Hz,1H),7.14(s,0.25H),7.06(s,0.25H),7.03(d, J=2.0Hz,1H),6.80(d,J=7.2Hz,1H),5.20-5.17(m,1H),4.32-4.29(m,1H),4.11-4.07(m,1H),3 .92-3.82(m,2H),3.57-3.54(m,1H),2.83-2.33(m,1H),1.88-1.81(m,1H),1.69(d,J=6.8Hz,3H) MS(ESI+)m / z403(M+H) +

[0258] Example 37 [ka] (R)-N4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-(tetrahydro-2H-pyran-4-yl)cinnoline-4,6-diamine

[0259] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 4-aminotetrahydropyran was used, to obtain the title compound (27 mg, 43%). 1 H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.83( d,J=9.2Hz,1H),7.60-7.52(m,2H),7.41(s,0.25H),7.30-7.26(m,2.50H),7.23( dd,J=2.0Hz,7.2Hz,1H),7.14(s,0.25H),7.03(d,J=2.0Hz,1H),6.95(d,J=7.2Hz, 1H),6.49(d,J=8.0Hz,1H),5.19-5.16(m,1H),3.98-3.91(m,2H),3.83-3.80(m,1 H),3.87-3.49(m,2H),2.03-1.99(m,2H),1.68(d,J=6.8Hz,3H),1.51-1.48(m,1H) MS(ESI+)m / z417(M+H) +

[0260] Example 38 [ka] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((R)-1-methylpyrrolidin-3-yl)cinnoline-4,6-diamine

[0261] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (3R)-1-methyl-3-pyrrolidinamine was used, to obtain the title compound (6 mg, 10%). 1H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.80( d,J=9.2Hz,1H),7.60-7.52(m,2H),7.42(s,0.25H),7.31(s,0.25H),7.29-7.28(m, 2.50H),7.21(dd,J=2.4Hz,6.8Hz,1H),7.15(s,0.25H),7.06(d,J=7.2Hz,1H),6.98( d,J=2.0Hz,1H),6.74(d,J=7.6Hz,1H),5.20-5.15(m,1H),4.23-4.22(m,1H),3.00-2 .97(m,1H),2.63-2.31(m,4H),2.31(s,1H),1.68(d,J=6.8Hz,3H),1.58-1.49(m,1H) MS(ESI+)m / z416(M+H) +

[0262] Example 39 [ka] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((R)-pyrrolidin-3-yl)cinnoline-4,6-diamine

[0263] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then a method substantially similar to the synthesis method described in Example 5 was carried out, except that (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate was used, to obtain (R)-tert-butyl 3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylate (57 mg, 57%). To a solution of (R)-tert-butyl 3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylate (57 mg, 0.11 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid solution in 1,4-dioxane (0.40 mL, 1.0 mmol) at 0°C and stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated and extracted with aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to give N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N-((R)-pyrrolidin-3-yl)cinnoline-4,6-diamine (6 mg, 13%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ7.98(s,1H),7.80( d,J=9.2Hz,1H),7.60-7.52(m,2H),7.42(s,0.25H),7.31(s,0.25H),7.29-7.28(m,1.25H),7.54-7.02(m,3.25H),6.78-6.62(m,1H),5 .20-5.15(m,1H),4.23-4.08(m,1H),3.78-2.70(m,1H),2.99-2.83(m,1H),2.22-2.13(m,1H),1.89-1.82(m,1H),1.68(d,J=6.8Hz,3H) MS(ESI+)m / z402(M+H) +

[0264] Example 40 [ka] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((S)-pyrrolidin-3-yl)cinnoline-4,6-diamine

[0265] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then a method substantially similar to that described in Example 5 was carried out, except that (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate was used, to obtain (S)-tert-butyl 3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylate (40 mg, 40%). To a solution of (S)-tert-butyl 3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylate (40 mg, 0.11 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid solution in 1,4-dioxane (0.40 mL, 1.0 mmol) at 0° C. and stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated and extracted with aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to give N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N-((S)-pyrrolidin-3-yl)cinnoline-4,6-diamine (17 mg, 60%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ7.99(s,1H),7.80( d,J=9.2Hz,1H),7.59(t,J=7.6Hz,1H),7.53(t,J=7..2Hz,1H),7.42(s,0. 25H),7.31-7.27(m,1.50H),7.20-7.02(m,3.25H),6.78-6.62(m,1H),5.19 -5.16(m,1H),4.23-4.14(m,1H),3.75-2.72(m,1H),3.23-3.20(m,1H),2.9 0-2.79(m,2H),2.32-2.15(m,1H),1.98-1.89(m,1H),1.68(d,J=6.8Hz,3H) MS(ESI+)m / z402(M+H) +

[0266] Example 41 [ka] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)(oxetan-3-yl)methanone

[0267] Step 1 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnolin-4-amine hydrochloride

[0268] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then a method substantially similar to that described in Example 5 was carried out, except that tert-butoxycarbonylpiperazine was used, to obtain (R)-tert-butyl 4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazine-1-carboxylate (60 mg, 60%). To a solution of (R)-tert-butyl 4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid solution in 1,4-dioxane (0.40 mL, 1.0 mmol) at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnolin-4-amine hydrochloride (40 mg, 90%) as a brown solid. MS(ESI+)m / z402(M+H) +

[0269] Step 2 [ka] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)(oxetan-3-yl)methanone

[0270] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnolin-4-amine hydrochloride (40 mg, 0.09 mmol), oxetane-3-carboxylic acid (11 mg, 0.11 mmol), HATU (60 mg, 0.27 mmol), and N,N-diisopropylethylamine (0.06 ml, 0.54 mmol) were added to dimethyl sulfoxide (1.5 ml), and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. After the combined organic extracts were dried over sodium sulfate and concentrated, the residue was purified by column chromatography to give (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)(oxetan-3-yl)methanone (7 mg, 16%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),8.19( s,1H),7.94(d,J=9.2Hz,1H),7.81(d,J=2.0Hz,1H),7.69-7.55(m,3H), 7.42-7.12(m,2H),5.45-5.42(m,1H),4.76-4.68(m,4H),4.26-4.18(m, 1H),3.71-3.65(m,2H),3.50-3.49(m,2H),1.73(d,J=6.8Hz,3H) MS(ESI+)m / z486(M+H) +

[0271] Example 42 [ka] 6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)cinnolin-4-amine

[0272] Compound A-2a was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethanamine as described in Example 1, followed by a procedure essentially similar to that described in Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used, to obtain the title compound (3 mg, 4%). 1 H NMR(400MHz,DMSO-d6)δ8.15(s,1H),8.01( d,J=9.2Hz,1H),7.68-7.65(m,2H),7.50-7.43(m,3H),7.26-7.25(m,2H),7.02(t,J=55.8Hz,1H),5.02(t,J=6.8Hz,1H),4.83(d, J=6.4Hz,2H),3.80(t,J=13.4Hz,2H),3.64(t,J=14.0Hz,2H),3.20(q,J=7.3Hz,1H),2.00(d,J=8.8Hz,1H),1.65(d,J=6.8Hz,3H) MS(ESI+)m / z397(M+H) +

[0273] Example 43 [ka] (R)-1-(4-((1-(3-(difluoromethyl)phenyl)ethyl)amino) Cinnolin-6-yl)-4-methylpiperidin-4-ol

[0274] Compound A-2a was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethanamine as described in Example 1, and then the title compound (56 mg, 54%) was obtained in substantially the same manner as described in Example 5, except that 4-methyl-4-piperidinol was used. 1 H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.91( d,J=9.2Hz,1H),7.68-7.60(m,3H),7.52-7.45(m,3H),7.31(d,J=7.2Hz,1H),7.02(t,J=55.8Hz,1H),5.0 2(t,J=6.8Hz,1H),4.43(s,1H),4.68-3.64(m,2H),3.35-3.24(m,2H),1.64(d,J=6.8Hz,7H),1.20(s,3H) MS(ESI+)m / z413(M+H) +

[0275] Example 44 [ka] 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)cinnolin-4-amine

[0276] Compound A-2a was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used to obtain the title compound (60 mg, 58%). 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.93( d,J=9.6Hz,1H),7.67-7.63(m,2H),7.51-7.43(m,2H),7.34(d,J=9.2Hz,1H),7.16-6.88(m,3H),5.01(t,J=6.8Hz,1H),4.90(s,1H),4.75(s, 1H),3.88(d,J=6.0Hz,1H),3.74(d,J=7.2Hz,1H),3.65(d,J=8.4Hz,1H),3.25(d,J=10.0Hz,1H),1.99(q,J=11.3Hz,2H),1.64(d,J=6.8Hz,3H) MS(ESI+)m / z397(M+H) +

[0277] Example 45 [ka] (R)-1-(4-((1-(3-(difluoromethyl)phenyl)ethyl)amino)cinnolin-6-yl)-3-methylazetidin-3-ol

[0278] Compound A-2a was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethanamine as described in Example 1, and then the title compound (45 mg, 45%) was obtained in a manner substantially similar to that described in Example 5, except that 3-methylazetidin-3-ol was used instead. 1 H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.92( d,J=10.0Hz,1H),7.67-7.63(m,2H),7.51-7.43(m,2H),7.18-6.88(m,4H),5.68(s,1H),5.00(t ,J=7.0Hz,1H),3.97(t,J=7.0Hz,2H),3.87(d,J=9.2Hz,2H),1.63(d,J=6.8Hz,3H),1.51(s,3H) MS(ESI+)m / z385(M+H) +

[0279] Example 46 [ka] N4-((R)-1-(3-(difluoromethyl)phenyl)ethyl)-N6-((R)-tetrahydrofuran-3-yl)cinnoline-4,6-diamine

[0280] Compound A-2a was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethanamine as described in Example 1, and then the title compound (25 mg, 33%) was obtained in substantially the same manner as described in Example 5, except that (3R)-tetrahydro-3-furanamine was used. 1 H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.80( d,J=9.2Hz,1H),7.67-7.63(m,2H),7.51-7.43( m,2H),7.20(dd,J=2.4Hz,9.2Hz,1H),7.19-6.88(m,3H),6.78(d,J=7.2Hz,1H),5.00(t,J=7.0Hz,1H),4.31-4.29(m,1H),4 .11(q,J=4.9Hz,1H),3.92-3.80(m,2H),3.58(q,J=4.4Hz,1H),2.36-2.34(m,1H),1.88-1.82(m,1H),1.64(d,J=6.8Hz,3H) MS(ESI+)m / z385(M+H) +

[0281] Example 47 [ka] 6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)cinnolin-4-amine

[0282] Compound A-2b was synthesized using intermediate A-1 and (R)-1-(3-(trifluoromethyl)phenyl)ethanamine as described in Example 1, followed by a procedure essentially similar to that described in Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used, to obtain the title compound (278 mg, 40%). 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.02( d,J=9.2Hz,1H),7.87(s,1H),7.80(d,J=6.8Hz,1H),7.63-7.51(m,2H),7.49(dd,J=2.8Hz,9.2Hz,1H),7.33-7.21(m,2H),5.10(quint,J=6. 8Hz,1H),4.82(d,J=6.4Hz,2H),3.80(t,J=12.4Hz,2H),3.66(t,J=12.4Hz,2H),3.26-3.18(m,1H),2.07-1.98(m,1H),1.66(d,J=6.8Hz,3H) MS(ESI+) m / z 415(M+H) +

[0283] Example 48 [ka] 6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)cinnolin-4-amine

[0284] Compound A-2c was synthesized using intermediate A-1 and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethanamine as described in Example 1, followed by a procedure essentially similar to that described in Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used, to obtain the title compound (45 mg, 54%). 1 H NMR(400MHz,DMSO-d6)δ8.02(d,J=9.6Hz,1 H),7.89(s,1H),7.64(d,J=8Hz,1H),7.58(d,J=7.6Hz,1H),7.51(d,J=2.4Hz,1H),7. 48(d,J=2.4Hz,1H),7.34-7.29(m,3H),5.20(q,J=7.2Hz,1H),4.83(d,J=6.4Hz,2H),3 .82(d,J=15.6Hz,1H),3.79(d,J=15.6Hz,1H),3.66(d,J=16.4Hz,1H),3.63(d,J=16. 4Hz,1H),3.23-3.18(m,1H),2.61(s,3H),1.99(d,J=8.8Hz,1H),1.63(d,J=6.8Hz,3H) MS(ESI+)m / z429(M+H) +

[0285] Example 49 [ka] (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)cinnolin-4-amine

[0286] Compound A-2c was synthesized using intermediate A-1 and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethanamine as described in Example 1, followed by a procedure substantially similar to that described in Example 5, except that 2-methyl-2,6-diazaspiro[3.3]heptane was used, to obtain the title compound (46 mg, 54%). 1 H NMR(400MHz,DMSO-d6)δ7.97(d,J=9.2Hz,1 H),7.91(s,1H),7.67(d,J=8Hz,1H),7.63(d,J=7.6Hz,1H),7.36(t,J=7.6Hz,1H),7.25(d,J=6.8Hz,1H),7.15(d,J=2.4Hz,1H), 7.12-7.09(m,1H),5.21(q,J=7.2Hz,1H),4.18-4.13(m,4H),3.40-3.30(m,4H),2.65(s,3H),2.27(s,3H),1.66(d,J=6.8Hz,3H) MS(ESI+)m / z442(M+H) +

[0287] Example 50 [ka] 3-((1R)-1-((6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cinnolin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0288] Compound A-2d was synthesized using intermediate A-1 and 3-[(1R)-1-aminoethyl]-2-methylbenzonitrile as described in Example 1, and then the title compound (13 mg, 21%) was obtained in substantially the same manner as described in Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used. 1 H NMR(400MHz,DMSO-d6)δ8.02(d,J=9.2Hz,1 H),7.90(s,1H),7.69-7.63(m,2H),7.50(dd,J=2.8Hz,6.8Hz,1H),7.34-7.26(m,3H),5.15-5.12(m,1H),4.83(d,J=6.4H) z,2H),3.84-3.77(m,2H),3.68-3.61(m,2H),3.23-3.18(m,1H),2.71(s,3H),1.99(d,J=8.8Hz,1H),1.62(d,J=6.8Hz,3H) MS(ESI+)m / z386(M+H) +

[0289] Example 51 [ka] (R)-3-(1-((6-(4-hydroxy-4-methylpiperidin-1-yl)cinnolin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0290] Compound A-2d was synthesized using intermediate A-1 and 3-[(1R)-1-aminoethyl]-2-methylbenzonitrile as described in Example 1, and then the title compound (17 mg, 27%) was obtained in substantially the same manner as described in Example 5, except that 4-methyl-4-piperidinol was used instead. 1 H NMR(400MHz,DMSO-d6)δ7.92-7.89(m,2H), 7.69(d,J=7.6Hz,1H),7.65-7.62(m,2H),7.49-7.48(m,1H),7.37(d,J=6.4Hz,1H),7.33(t,J=7.6Hz,1H ),5.14-5.11(m,1H),4.44(s,1H),3.70-3.65(m,2H),2.70(s,3H),1.64-1.59(m,5H),1.20-1.19(m,5H) MS(ESI+)m / z402(M+H) +

[0291] Example 52 [ka] (R)-2-Methyl-3-(1-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-ylamino)ethyl)benzonitrile

[0292] Compound A-2d was synthesized using intermediate A-1 and 3-[(1R)-1-aminoethyl]-2-methylbenzonitrile as described in Example 1, followed by 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester to give the title compound (16 mg, 17%). 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.12( s,1H),8.05-7.95(m,2H),7.83(d,J=6.4Hz,1H) ,7.71-7.64(m,2H),7.33(t,J=8.0Hz,1H),6.49-6.48(m,1H),5.19-5.17(m, 1H),3.14-3.12(m,2H),2.73-2.65(m,7H),2.33(s,3H),1.62(d,J=6.8Hz,3H) MS(ESI+)m / z384(M+H) +

[0293] Example 53 [ka] (R)-3-(1-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-ylamino)ethyl)benzonitrile

[0294] Compound A-2e was synthesized using intermediate A-1 and 3-[(1R)-1-aminoethyl]benzonitrile as described in Example 1, followed by 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester to give the title compound (16 mg, 17%). 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.38( s,1H),8.05-7.94(m,3H),7.83(d,J=8.0Hz,1H),7.79(d,J=7.2Hz,1H),7.75-7.72(m,1H),7.57(t,J=7.6Hz,1H) ,6.50-6.48(m,1H),5.12-5.09(m,1H),3.14-3.12(m,2H),2.73-2.66(m,4H),2.33(s,3H),1.65(d,J=6.8Hz,3H) MS(ESI+)m / z370(M+H) +

[0295] Example 54 [ka] 3-((R)-1-(6-((R)-pyrrolidin-3-ylamino)cinnoline-4- (I)ylamino)ethyl)benzonitrile

[0296] Compound A-2e was synthesized using intermediate A-1 and 3-[(1R)-1-aminoethyl]benzonitrile as described in Example 1, followed by a procedure substantially similar to that described in Example 5, except that (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate was used to obtain (R)-tert-butyl 3-(4-((R)-1-(3-cyanophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylate (50 mg, 64%). To a solution of (R)-tert-butyl 3-(4-((R)-1-(3-cyanophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylate (50 mg, 0.11 mmol) in dichloromethane (3 mL) was added 4N hydrochloric acid solution in 1,4-dioxane (0.40 mL, 1.0 mmol) at 0°C and stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated and extracted with aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to give 3-((R)-1-(6-((R)-pyrrolidin-3-ylamino)cinnolin-4-ylamino)ethyl)benzonitrile (13 mg, 33%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.95( s,1H),7.81-7.78(m,2H),7.72(d,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H) ,7.19-7.16(m,1H),7.04(d,J=7.2Hz,1H),6.98(s,1H),6.64(d,J=7.2H z,1H),5.02-4.98(m,1H),4.32-4.11(m,2H),3.24-3.18(m,1H),2.98-2 .81(m,2H),2.71-2.65(m,2H),2.19-2.12(m,1H),1.63(d,J=6.8Hz,3H) MS(ESI+)m / z359(M+H) +

[0297] Example 55 [ka] 3-((1R)-1-((6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cinnolin-4-yl)amino)ethyl)-5-(difluoromethyl)phenol

[0298] Step 1 [ka] N-((R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cinnolin-4-amine

[0299] Compound A-2f was synthesized using Intermediate A-1 and Intermediate IA as described in Example 1, followed by a procedure substantially similar to that described in Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used, to obtain N-((R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cinnolin-4-amine (40 mg, 32%). MS(ESI+)m / z503(M+H) +

[0300] Step 2 [ka] 3-((1R)-1-((6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cinnolin-4-yl)amino)ethyl)-5-(difluoromethyl)phenol

[0301] To a solution of N-((R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cinnolin-4-amine (20 mg, 0.04 mmol) in methanol (1 mL) was added 10% Pd / C (4 mg, 20 wt%), and the reaction vessel was charged with hydrogen gas and stirred at 1 atmosphere. The reaction mixture was filtered through a pad of Celite and then concentrated. This gave 3-((1R)-1-((6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)cinnolin-4-yl)amino)ethyl)-5-(difluoromethyl)phenol (8 mg, 51%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),8.12( s,1H),8.01(d,J=9.6Hz,1H),7.49(dd,J=9.6,2.4Hz,1H),7.26-7.23(m,2H),7.10(s,1H),7.06-6.78(m,3H),4.92(q,J=7.2Hz, 1H),4.82(d,J=6.4Hz,2H),3.83-3.76(m,2H),3.67-3.60(m,2H),3.22-3.18(m,1H),1.98(d,J=8.8Hz,1H),1.69(d,J=6.8Hz,3H) MS(ESI+)m / z413(M+H) +

[0302] Example 56 [ka] 6-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-N-((R)-1-(2,3-difluorophenyl)ethyl)cinnolin-4-amine

[0303] Compound A-2g was synthesized using intermediate A-1 and (aR)-2,3-difluoro-a-methylbenzenemethanamine as described in Example 1, and then the title compound (15 mg, 20%) was obtained in substantially the same manner as described in Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used. 1 H NMR(400MHz,DMSO-d6)δ8.08(s,1H),8.02( d,J=9.2Hz,1H),7.51-7.49(m,1H),7.36-7.12(m,5H),5.21(q,J=7.2Hz,1H),4.82(d,J=6.4Hz,2H), 3.82-3.76(m,2H),3.67-3.60(m,2H),3.22-3.17(m,1H),1.97(d,J=8.8Hz,1H),1.69(d,J=6.8Hz,3H) MS(ESI+)m / z383(M+H) +

[0304] Example 57 [ka] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((R)-2-methylmorpholino)cinnolin-4-amine

[0305] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (R)-2-methylmorpholine was used, to obtain the title compound (20 mg, 24%). 1 H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.98( d,J=9.2Hz,1H),7.67(dd,J=2.4Hz,9.6Hz,1H),7.62-7.7.53(m,2H),7.48(s,1H),7.42-7.15(m,3H),5.22(t,J=6.6Hz,1H),4.03(d,J=11. 6Hz,1H),3.90(q,J=11.7Hz,2H),3.74-3.69(m,2H),2.87(t,J=12.0Hz,1H),2.59-2.56(m,1H),1.70(d,J=6.8Hz,3H),1.24(d,J=6.4Hz,3H) MS(ESI+)m / z417(M+H) +

[0306] Example 58 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(furan-3-yl)cinnolin-4-amine

[0307] As described in Example 1, compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, followed by 3 -Furanboronic acid pinacol ester was used to give the title compound (40 mg, 42%). 1 H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.44( s,1H),8.34(s,1H),8.11-8.10(m,2H),7.89(s,1H),7.72(d,J=7.2Hz,1H),7.66(t,J=7.8Hz ,1H),7.56(t,J=7.8Hz,1H),7.42-7.15(m,3H),5.30(t,J=6.8Hz,1H),1.73(d,J=6.8Hz,3H) MS(ESI+)m / z484(M+H) +

[0308] Example 59 [ka] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((S)-2-methylmorpholino)cinnolin-4-amine

[0309] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that (S)-2-methylmorpholine was used, to obtain the title compound (41 mg, 49%). 1 H NMR(400MHz,DMSO-d6)δ8.11(s,1H),7.98( d,J=9.2Hz,1H),7.67(dd,J=2.4Hz,9.2Hz,1H),7.57(dd,J=9.4Hz,15.8Hz,2H) ,7.48(s,1H),7.42-7.14(m,3H),5.22(t,J=6.6Hz,1H),4.02(dd,J=2.2Hz,11. 8Hz,1H),3.94(d,J=11.6Hz,1H),3.84(d,J=12.0Hz,1H),3.74-3.67(m,2H),2. 91-2.85(m,1H),2.58-2.56(m,1H),1.69(d,J=6.8Hz,3H),1.23(d,J=6.4Hz,3H) MS(ESI+)m / z417(M+H) +

[0310] Example 60 [ka] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)(oxetan-3-yl)methanone

[0311] Step 1 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine hydrochloride

[0312] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, followed by the use of 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-1-dimethylethyl ester-1-(2H)-pyridinecarboxylic acid to give (R)-tert-butyl-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.33 g, 67%). To a solution of (R)-tert-butyl-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.33 g, 2.67 mmol) in dichloromethane (10 mL), a 4N solution of hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol) was added at 0°C and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine hydrochloride (1.15 g, 99%) as a brown solid. MS(ESI+)m / z399(M+H) +

[0313] Step 2 [ka] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)(oxetan-3-yl)methanone

[0314] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine hydrochloride (50 mg, 0.12 mmol), oxetane-3-carboxylic acid (23 mg, 0.23 mmol), HATU (153 mg, 0.40 mmol), and N,N-diisopropylethylamine (0.1 ml, 0.58 mmol) were added to dimethyl sulfoxide (1 ml), and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. After the combined organic extracts were dried over sodium sulfate and concentrated, the residue was purified by column chromatography to give (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)(oxetan-3-yl)methanone (16 mg, 29%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.33( s,1H),8.06(d,J=8.8Hz,1H),7.99-7.92(m,1H),7.88-7.81(m,1H),7.66-7.59(m,1H),7.58-7.53(m,1H),7.43-7.12(m,2H),6.54-6 .42(m,1H),5.31(q,J=6.8Hz,1H),4.82-4.61(m,4H),4.33-4.21(m,2H),4.03-3.99(m,1H),3.83-3.79(m,1H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z483(M+H) +

[0315] Example 61 [ka] (R)-Cyclopropyl(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)methanone

[0316] As described in Example 60, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine hydrochloride was synthesized using Intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then cyclopropanecarboxylic acid was used to obtain the title compound (26 mg, 48%) in a manner substantially similar to the synthesis method of Example 60. 1 H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.33( s,1H),8.08(d,J=9.2Hz,1H),8.04-7.94(m,1H),7.89-7.81(m,1H),7.63( t,J=7.2Hz,1H),7.55(t,J=6.8Hz,1H),7.43-7.13(m,2H),6.54-6.48(m,1H ),5.29(q,J=6.8Hz,1H),4.50(s,1H),4.23(s,1H),4.04-3.97(m,1H),3.8 4-3.68(m,1H),2.24-1.98(m,1H),1.70(d,J=6.8Hz,3H),0.83-0.71(m,4H) MS(ESI+)m / z467(M+H) +

[0317] Example 62 [ka] (R)-Cyclopropyl(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)methanone

[0318] As described in Example 41, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnolin-4-amine hydrochloride was synthesized using Intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then cyclopropanecarboxylic acid was used to obtain the title compound (26 mg, 23%) in a manner substantially similar to the synthesis method of Example 41. 1 H NMR(400MHz,MeOD)δ8.11(s,1H),8.03(d,J =9.6Hz,1H),7.74(dd,J=2.6Hz,9.4Hz,1H),7.60-7.54(m,3H),7.27(t,J=7.6Hz,1H),7.08(t,J=54.8Hz,1H),5.30(q,J=7 .6Hz,1H),4.04(m,2H),3.87(m,2H),3.63(m,2H),3.54(m,2H),2.10-2.06(m,1H),1.80(d,J=6.8Hz,3H),0.98-0.88(m,4H) MS(ESI+)m / z470(M+H) +

[0319] Example 63 [ka] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone

[0320] As described in Example 41, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnolin-4-amine hydrochloride was synthesized using Intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then tetrahydro-2H-pyran-4-carboxylic acid was used to obtain the title compound (60 mg, 56%) in a manner substantially similar to the synthesis method of Example 41. 1 H NMR(400MHz,MeOD)δ8.11(s,1H),8.03(d,J =9.2Hz,1H),7.74(dd,J=2.6Hz,9.4Hz,1H),7.60-7.54(m,3H),7.27(t,J=7.8Hz,1H),7.08(t,J=54.8Hz,1H),5.30(q,J=7.6 Hz,1H),4.03-4.00(m,2H),3.89-3.84(m,4H),3.60-3.50(m,6H),3.12-3.04(m,4H),1.92-1.69(m,4H),1.80(d,J=6.8Hz,3H) MS(ESI+)m / z514(M+H) +

[0321] Example 64 [ka] (4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)((R)-tetrahydrofuran-3-yl)methanone

[0322] As described in Example 41, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnolin-4-amine hydrochloride was synthesized using Intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then (3R)-tetrahydro-3-furancarboxylic acid was used to obtain the title compound (55 mg, 52%) in substantially the same manner as the synthesis method of Example 41. 1 H NMR(400MHz,MeOD)δ8.18(s,1H),7.99(d,J =9.6Hz,1H),7.81(dd,J=2.6Hz,9.4Hz,1H),7.63-7.56(m,3H),7.30(t,J=7.6Hz,1H),7.07(t,J=54.6Hz,1H),5.40(q,J=6.7Hz) ,1H),4.04(t,J=8.2Hz,1H),3.96-3.93(m,1H),3.91-3.83(m,6H),3.62-3.55(m,5H),2.24-2.15(m,2H),1.82(d,J=6.8Hz,3H) MS(ESI+)m / z500(M+H) +

[0323] Example 65 [ka] (4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)((S)-tetrahydrofuran-3-yl)methanone

[0324] As described in Example 41, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnolin-4-amine hydrochloride was synthesized using Intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then (3S)-tetrahydro-3-furancarboxylic acid was used to obtain the title compound (15 mg, 14%) in substantially the same manner as the synthesis method of Example 41. 1 H NMR(400MHz,MeOD)δ8.11(s,1H),8.03(d,J =9.6Hz,1H),7.74(dd,J=2.8Hz,9.6Hz,1H),7.60-7.54(m,3H),7.27(t,J=7.6Hz,1H),7.08(t,J=54.8Hz,1H),5.30(q,J=6.7Hz ,1H),4.04(t,J=8.0Hz,1H),3.97-3.93(m,2H),3.91-3.83(m,5H),3.59-3.53(m,5H),2.25-2.15(m,2H),1.80(d,J=6.8Hz,3H) MS(ESI+)m / z500(M+H) +

[0325] Example 66 [ka] (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)-2-hydroxyethanone

[0326] As described in Example 41, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnolin-4-amine hydrochloride was synthesized using Intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then glycolic acid was used to obtain the title compound (20 mg, 21%) in substantially the same manner as the synthesis method of Example 41. 1 H NMR(400MHz,MeOD)δ8.11(s,1H),8.03(d,J =9.2Hz,1H),7.73(dd,J=2.6Hz,9.4Hz,1H),7.60-7.54(m,3H),7.27(t,J=7.8Hz,1H),7.08(t,J=54.8Hz,1H),5.29(q ,J=6.8Hz,1H),4.35(s,2H),3.86(t,J=5.2Hz,2H),3.69(t,J=4.8Hz,2H),3.57(q,J=5.6Hz,4H),1.80(d,J=6.8Hz,3H) MS(ESI+) m / z 460(M+H) +

[0327] Example 67 [ka] (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)ethanone

[0328] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that 1-acetylpiperazine was used, to obtain the title compound (24 mg, 22%). 1 H NMR(400MHz,MeOD)δ8.11(s,1H),8.03(d,J =9.6Hz,1H),7.73(dd,J=2.8Hz,9.6Hz,1H),7.60-7.54(m,3H),7.27(t,J=7.6Hz,1H),7.08(t,J=54.8Hz,1H),5.29(q,J=6.8Hz,1 H),3.85(t,J=5.4Hz,2H),3.80(t,J=5.2Hz,2H),3.60(t,J=5.2Hz,2H),3.54(t,J=5.4Hz,2H),2.21(s,3H),1.80(d,J=6.8Hz,3H) MS(ESI+)m / z444(M+H) +

[0329] Example 68 [ka] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(isoxazol-4-yl)cinnolin-4-amine

[0330] As described in Example 1, compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then the compound A-2 was synthesized using 4-isoxazoleboronic acid pinacol ester in the same manner as in Example 1. In a similar manner, the title compound (29 mg, 29%) was obtained. 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),9.30( s,1H),8.79(s,1H),8.39(s,1H),8.16(q,J=10.5Hz,2H),7.68(t,J=8.0Hz,2H),7.57(t,J=7.2Hz ,1H),7.31(t,J=7.8Hz,1H),7.28(t,J=54.2Hz,1H),5.32(t,J=6.8Hz,1H),1.73(d,J=6.8Hz,3H) MS(ESI+)m / z385(M+H) +

[0331] Example 69 [ka] (R)-N-(1-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperidin-4-yl)oxetane-3-carboxamide

[0332] Step 1 [ka] N-(piperidin-4-yl)oxetane-3-carboxamide

[0333] 1-Benzyloxycarbonyl-4-aminopiperidine (1.9 g, 8.5 mmol), oxetane-3-carboxylic acid (790 mg, 7.7 mmol), HATU (3.8 g, 10 mmol), and N,N-diisopropylethylamine (2.7 mL, 15.4 mmol) were added to dimethyl sulfoxide (20 mL) and stirred at room temperature for 16 hours. After confirming the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give 4-(oxetane-3-carboxamido)piperidine-1-carboxylate (120 mg, 6%) as a clear liquid. To a solution of 4-(oxetane-3-carboxamide)piperidine-1-carboxylate (140 mg, 0.44 mmol) in ethyl acetate / methanol (3:1, 4 mL) was added 10% Pd / C (30 mg, 20 wt%), and the reaction vessel was charged with hydrogen gas and stirred at 1 atmosphere. The reaction mixture was filtered through a pad of Celite and concentrated to give N-(piperidin-4-yl)oxetane-3-carboxamide (38 mg, 21%) as a yellow liquid.

[0334] Step 2 [ka] (R)-N-(1-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperidin-4-yl)oxetane-3-carboxamide

[0335] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, and then the synthesis was carried out in substantially the same manner as described in Example 5, except that N-(piperidin-4-yl)oxetane-3-carboxamide was used to obtain the title compound (15 mg, 18%). 1 H NMR(400MHz,MeOD-d4)δ7.95(s,1H),7.85( d,J=9.6Hz,1H),7.57(dd,J=9.6Hz,2.4Hz,1H),7.47-7.40(m,3H),7.14(t ,J=8.0Hz,1H),7.09-6.81(t,J=54.8Hz,1H),5.15(q,J=6.8Hz,1H),4.74- 7.64(m,4H),4.05-3.95(m,2H),3.92-3.84(m,1H),3.77-3.70(m,1H),3.0 3-2.97(m,2H),1.97-1.92(m,2H),1.66(d,J=6.8Hz,3H),1.60-1.49(m,2H) MS(ESI+)m / z500(M+H) +

[0336] Example 70 [ka] (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-1-methylpiperidin-4-ol

[0337] A solution of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine (100 mg, 0.24 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedionate)manganese(III) (7 mg, 0.23 mmol) in isopropyl alcohol and dichloromethane (4 mL / 0.5 mL) was stirred for 5 minutes under air bubbling. Phenylsilane (50 mg, 0.47 mmol) was then added and stirred for 2 hours at room temperature under air bubbling. After completion of the reaction, saturated sodium thiosulfate solution was added and stirred for 1 hour. 1N hydrochloric acid was added to the reaction solution and washed with dichloromethane. The resulting aqueous layer was basified to pH 14 with aqueous sodium bicarbonate and extracted three times with dichloromethane. After the combined organic layers were dried over sodium sulfate and concentrated, the residue was purified by column chromatography to give (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-1-methylpiperidin-4-ol (11 mg, 11%) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.31( s,1H),8.12-7.99(m,2H),7.71(s,1H),7.54-7.52(m,1H),7.42-7.15(m,3H),5.46(s, 1H),5.27(s,1H),3.15-2.85(m,4H),2.56-2.52(m,2H),1.84-1.82(m,2H),1.72(s,3H) MS(ESI+)m / z431(M+H) +

[0338] Example 71 [ka] Methyl 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)cyclohex-3-enecarboxylate

[0339] As described in Example 1, compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then the title compound (332 mg, 60%) was obtained in substantially the same manner as in Example 1 using 1,3,2-dioxaborolane and 3-cyclohexene-1-carboxylic acid. 1 H NMR(400MHz,DMSO-d6)δ8.40(s,1H),8.31( d,J=2.4Hz,1H),8.05-8.03(m,1H),7.96-7.92(m,1H),7.85(d,J=6.0Hz,1H),7.6 3(t,J=7.2Hz,1H),7.55(t,J=6.8Hz,1H),7.42(s,0.25H),7.32-7.28(m,1.50H),7 .15(s,0.5H),6.50-6.49(m,1H),5.30-5.26(m,1H),3.67(s,3H),2.75-2.69(m,2 H),2.65-2.58(m,2H),2.20-2.16(m,1H),1.86-1.80(m,1H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z456(M+H) +

[0340] Example 72 [ka] 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)cyclohex-3-enecarboxylic acid

[0341] To a solution of 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)cyclohex-3-enecarboxylic acid (250 mg, 0.65 mmol) in tetrahydrofuran and HO (3 mL / 0.6 mL), LiOH (125 mg, 6.5 mmol) was added and stirred at room temperature for 16 h. After confirming the reaction was complete, 1N HCl was added to adjust the pH to 4-5 and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated to give 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)cyclohex-3-enecarboxylic acid (190 mg, 66%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ12.35(s,1H),9.94 (s,1H),8.65(d,J=2.8Hz,2H),8.27-8.24)(m,1H),7.96(d,J=9.2Hz,1H),7.81(t,J=7.2Hz,1H),7.64(t,J=6.8Hz,1H),7.40(t ,J=8.8Hz,1H),7.26-7.12(m,1H),6.57(s,1H),5.80-5.77(m,1H),2.67-2.60(m,4H),2.16-2.13(m,1H),1.80(d,J=6.8Hz,4H) MS(ESI+)m / z442(M+H) +

[0342] Example 73 [ka] 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-N-(oxetan-3-yl)cyclohex-3-enecarboxamide

[0343] 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)cyclohex-3-enecarboxylic acid (60 mg, 0.13 mmol), oxetane-3-carboxylic acid (21 mg, 0.15 mmol), HATU (100 mg, 0.40 mmol), and N,N-diisopropylethylamine (0.20 ml, 0.40 mmol) were added to dimethyl sulfoxide (1 ml), and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. After the combined organic extracts were dried over sodium sulfate and concentrated, the residue was purified by column chromatography to give 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-N-(oxetan-3-yl)cyclohex-3-enecarboxamide (24 mg, 37%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.70(d,J=6.8Hz,1 H),8.40(s,1H),8.31(d,J=2.0Hz,1H),8.05-8.03(m,1H),7.96-7.93(m,1H),7.84(t,J=6 .8Hz,1H),7.63(t,J=7.2Hz,1H),7.55(t,J=7.2Hz,1H),7.42-7.15(m,2H),6.51(s,1H),5 .30-5.26(m,1H),4.85-4.81(m,1H),4.74(t,J=6.8Hz,2H),4.45(t,J=7.2Hz,2H),2.80-2 .67(m,1H),2.49-2.42(m,3H),2.08-2.04(m,1H),1.80-1.79(m,1H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z497(M+H) +

[0344] Example 74 [ka] 6-Oxa-3-azabicyclo[3.1.1]heptan-3-yl(4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)cyclohex-3-enyl)methanone

[0345] The title compound (45 mg, 66%) was obtained in a synthetic manner essentially similar to that described in Example 73, using 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride. 1 H NMR(400MHz,DMSO-d6)δ8.43-8.42(m,1H), 8.33(d,J=4.8Hz,1H),8.06-8.03(m,1H),7.98-7.92(m,2H),7.64(d,J= 7.6Hz,1H),7.56(t,J=6.8Hz,1H),7.42-7.14(m,2H),6.55(s,1H),5.32 -5.29(m,1H),4.62(d,J=6.4Hz,2H),3.88-3.85(m,2H),3.71-3.67(m,1 H),3.47-3.43(m,2H),3.12-3.06(m,1H),2.91-2.67(m,3H),2.10-2.07 (m,1H),1.82-1.74(m,2H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z523(M+H) +

[0346] Example 75 [ka] ((R)-3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidin-1-yl)(oxetan-3-yl)methanone

[0347] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((R)-pyrrolidin-3-yl)cinnoline-4,6-diamine (150 mg, 0.37 mmol), oxetane-3-carboxylic acid (50 mg, 0.44 mmol), HATU (200 mg, 0.44 mmol), and N,N-diisopropylethylamine (0.50 mL, 1.11 mmol) were added to dimethyl sulfoxide (1 mL) and stirred at room temperature for 1 hour. After confirming the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. After the combined organic extracts were dried over sodium sulfate and concentrated, the residue was purified by column chromatography to give ((R)-3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidin-1-yl)(oxetan-3-yl)methanone (90 mg, 50%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ8.05(d,J=16.4Hz, 1H),7.83(dd,J=2.0Hz,7.2Hz,1H),7.63-7.53(m,2H),7.42-7.7.07(m,5H),6.87(d,J=6.4Hz,1H),5.25-5.20(m,1H),4.75-4. 63(m,4H),4.34-4.26(m,1H),4.11-4.04(m,1H),3.81-3.73(m,1H),3.53-3.36(m,4H),2.33-2.23(m,1H),1.70(d,J=6.8Hz,3H) MS(ESI+)m / z486(M+H) +

[0348] Example 76 [ka] 6-(3-oxabicyclo[4.1.0]heptan-6-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0349] As described in Example 1, compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine, and then the title compound (4 mg, 4%) was obtained in substantially the same manner as in Example 1 using 4,4,5,5-tetramethyl-2-[3-oxabicyclo[4.1.0]heptan-6-yl]1,3,2-dioxaborolane. 1 H NMR(400MHz,MeOD)δ8.24(s,1H),8.15(s,1 H),7.97(d,J=8.8Hz,1H),7.74(dd,J=2.0Hz,8.8Hz,1H),7.57(ddd,J=7.4Hz,7.4Hz,15.2H z,2H),7.16(t,J=7.8Hz,1H),6.96(t,J=54.8Hz,1H),5.21(q,J=6.8Hz,1H),4.06(dd,J=4. 4Hz,11.2Hz,1H),3.90(d,J=11.2Hz,1H),3.59-3.54(m,2H),3.49-3.42(m,1H),2.22-2.14 (m,1H),2.10-2.04(m,1H),1.69(d,J=6.8Hz,3H),1.54-1.47(m,1H),0.97(t,J=5.4Hz,1H) MS(ESI+)m / z414(M+H) +

[0350] <Experimental Example> Experimental Example 1: Biochemical Test KRAS::SOS1 HTRF binding assay The effectiveness of the compounds according to the examples of the present invention in inhibiting the protein-protein interaction between SOS1 and KRAS G12C was confirmed, thereby confirming the effectiveness of the compounds according to the examples of the present invention in inhibiting SOS1. Specifically, a KRAS G12C / SOS1 binding kit (64KRASG12PEG, Cisbio, France) was purchased and used. 2 μl of Tag1-KRAS G12C and 2 μl of GTP were premixed and dispensed into each well of a 384-well plate (6007290, PerkinElmer, USA). After adding 2 μl of compound and 4 μl of Tag2-SOS1, 10 μl of premixed Anti-Tag1 XL665 antibody and Anti-Tag2 Tb cryptate antibody was dispensed into each well. The plate was sealed and incubated at room temperature for 1 hour and 40 minutes. Measurements were then taken at wavelengths of 665 nm and 620 nm using an HTRF®-compatible reader (Synergy H4, BioTek, USA). The ratio of the acceptor and donor emission signals in each well was calculated as 665 nm / 620 nm × 10. 4 was calculated. The above-described methods demonstrate the molecular mechanism of action of the compounds, and high inhibition rates in the above-described assay environments indicate high efficacy of SOS1 inhibitor compounds. The calculation results are shown in Table 4 below. (+++: Over 70 to 100% inhibition, ++: Over 40 to 70% inhibition, +: 0 to 40% inhibition)

[0351] [Table 4]

[0352] As shown in Table 4 above, it can be confirmed that the compounds according to the examples of the present invention can inhibit SOS1 at a concentration of 0.1 uM, and that the majority of the compounds according to the present invention exhibit very high SOS1 inhibition rates. That is, it can be confirmed that the compound according to the present invention exhibits high efficacy in inhibiting SOS1.

[0353] EGFR kinase inhibition assay The EGFR kinase inhibitory effect of the compounds according to the examples of the present invention was confirmed. Specifically, the ADP-Glo™ Enzyme Assay System (V3831, Promega) We purchased and used EGFR (Epidermal Growth Factor Receptor) kinase (phosphorylation enzyme) from Corning Corporation, USA. 5x Kinase Reaction Buffer was diluted to 1.5x to prepare EGFR (Epidermal Growth Factor Receptor) kinase (phosphorylation enzyme) and ATP. 6 ng of EGFR and 25 M ATP were prepared using 1.5x Kinase Reaction Buffer. Then, 1 μl of compound, 2 μl of EGFR kinase, and 2 μl of the substrate / ATP mixture were mixed in a 384-well plate (REF4513, Corning, USA) and incubated at room temperature for 60 minutes. 5 μl of ADP-Glo™ Reagent was added to each well and incubated at room temperature for 40 minutes to terminate the EGFR kinase reaction and scavenge unused ATP. 10 μl of Kinase Detection Reagent was added and incubated at room temperature for 30 minutes to convert ADP to ATP, which was then detected using luciferase and luciferin. Detection was performed using luminescence from an ELISA reader (Synergy H4, BioTek, USA). The aforementioned method demonstrates the compound's selective molecular mechanism of action on EGFR kinase, resulting in high IC in the aforementioned analytical environment. 50 The values ​​indicate no EGFR kinase inhibitory effect. The assay results are shown in Table 5 below.

[0354] [Table 5]

[0355] As shown in Table 5 above, the compounds of the present invention are confirmed to have no EGFR kinase inhibitory effect compared to the control substance EGFR kinase inhibitor (Gefitinib), confirming that they have high selectivity for SOS1. In other words, the compounds of the present invention not only exhibit high selectivity for SOS1 but also exhibit high efficacy in inhibiting SOS1, and therefore can be effectively used in the treatment of diseases associated with SOS1 activity. Although the present invention has been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the true scope of the present invention is to be defined by the appended claims and their equivalents.

Claims

1. A compound represented by Chemical Formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopically modified product thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the above Chemical Formula 1, A is C ３－８ Cycloalkyl, C ３－８ cycloalkenyl, 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, C ６－１２ a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of aryl, N, O and S; 【Chemistry 2】 and n is 0, 1, 2, 3, or 4; R １ is C １－６ Alkyl, C ６－１２ Aryl, —CF ２ H, -CF ３ , -CN, -OH, -NH ２ or halogen (wherein, when n is 2 or more, n R １ are independent of each other), The R １ C １－６ Alkyl, C ６－１２ Aryl, —CF ２ One or more H of H and —OH are each independently C １－６ Alkyl (where C １－６ One or more H in the alkyl are each independently —OH, —O—C １－６ alkyl, or —NR ａ R ｂ substituted with ), or halogen; X １ is CH or N, and X ２ is CR ２ and X ３ is CH; R ２ is H, C １－６ Alkyl, —CF ３ , —O—C １－６ Alkyl, C ３－６ Cycloalkyl, —O—C ３－６ Cycloalkyl, —OH, —OCF ３ , -NR Ｃ R ｄ or a halogen; L １ represents a single bond, —(C═O)—, —(C═O)O—, —O—, or —(C═O)NR ｅ - , -NR ｅ -, -NR ｅ (C=O)-, -NR ｅ SO ２ -or-NR ｅ (C=O)NR ｆ - and; R ３ is H, -OH, C １－６ Alkyl, C ３－８ Cycloalkyl, C ６－１２ aryl, 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; C ３－８ cycloalkenyl, a 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, 【Chemistry 3】 (where m is 0 or 1, and Y １ is CH ２ , N.R. ｊ or O, and R ｊａ , R ｊｂ , R ｊｃ , and R ｊｄ are each independently H or C １－５ alkyl, and R ｊａ , R ｊｂ , R ｊｃ , and R ｊｄ Two selected from the group are bonded to form CH ２ or CH ２ -CH ２ or 【Chemistry 4】 (wherein o and p are each independently 1 or 2, q and r are each independently 0, 1 or 2, and Y ２ and Y ３ are each independently CH ２ , N.R. ｋ or O), The R ３ or a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, O and S; 【Chemistry 5】 one or more -CH ２ - is -(C=O)-, -SO- or -SO ２ may be substituted with -, The R ３ C ３－８ One or more —CH ２ - is -SO ２ - is replaced by It is okay to The R ３ One or more H's are each independently selected from C １－６ Alkyl, —OH, halogen, or —L ２ -R ４ may be substituted with; L ２ is a single bond, C １－６ Alkylene, —O—, —(C═O)—, —SO ２ -, -(C=O)NR ｇ -or-NR ｇ (C═O)—; R ４ is H, C １－６ Alkyl, —O—C １－６ Alkyl, C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; C ６－１２ aryl, a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; -NR ｈ R ｉ , -CF ３ , -CF ２ H, —OH or halogen; The R ４ One or more H's are each independently selected from C １－６ Alkyl, —OH, —O—C １－６ Alkyl, —NR ｍ R ｎ or may be substituted with halogen; R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ , R ｋ , R ｍ and R ｎ are each independently H or C １－６ It is alkyl.

2. In the above Chemical Formula 1, A is C ６－１２ a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of aryl, N, O and S; 【Chemistry 6】 and n is 1, 2 or 3; R １ is C １－６ Alkyl, C ６－１２ Aryl, —CF ２ H, -CF ３ , —CN or halogen (wherein, when n is 2 or more, n R １ are independent of each other), The R １ C １－６ Alkyl, C ６－１２ Aryl and —CF ２ One or more of H are each independently C １－６ Alkyl (where C １－６ One or more H in the alkyl are each independently —OH, —O—C １－６ Alkyl or -NR ａ R ｂ substituted with ), or halogen; X １ and X ３ are each CH; X ２ is CR ２ and R ２ , R ３ , R ４ , L １ , L ２ , Y １ , Y ２ , Y ３ , m, o, p, q, r, R ｊａ , R ｊｂ , R ｊｃ , R ｊｄ , R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ , R ｋ , R ｍ and R ｎ are each as defined in claim 1, A compound represented by chemical formula 1 according to claim 1, its optical isomer, its stereoisomer, its solvate, its isotope modified product, its tautomer, or a pharmaceutically acceptable salt thereof.

3. In the above Chemical Formula 1, A is C ６－１２ is aryl; n is 1 or 2; R １ are each independently C １－６ Alkyl, —CF ２ H, -CF ３ , —CN or halogen; X １ , X ２ and X ３ are each CH; L １ is a single bond or -NR ｅ - and; R ３ is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring; C ３－８ cycloalkenyl, a 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, wherein said heterocycloalkyl is 【Chemistry 7】 where Y １ is O and Y ３ are each independently CH ２ , N.R. ｋ or O, The R ３ One or more H's are each independently selected from C １－６ Alkyl, —OH, halogen, or —L ２ -R ４ may be substituted with; L ２ is a single bond, C １－６ Alkylene, —O—, —(C═O)—, —(C═O)NR ｇ -or-NR ｇ (C═O)—; R ４ is H, -OH, C １－６ Alkyl, —O—C １－６ Alkyl, C ３－８ cycloalkyl, a 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, -NR ｈ R ｉ or a halogen, The R ４ one or more H may each independently be replaced with —OH; R ｅ , R ｇ , R ｈ , R ｉ and R ｋ are each independently H or C １－６ is alkyl, A compound represented by chemical formula 1 according to claim 1, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or its pharmaceutically acceptable salt.

4. In the above Chemical Formula 1, A is C ６－１２ is aryl; n is 2; R １ are each independently C １－６ Alkyl, —CF ２ H, -CF ３ , —CN or halogen; X １ , X ２ and X ３ are each CH; L １ is a single bond or -NR ｅ - and; R ３ is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, or a 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, wherein said heterocycloalkyl is 【Chemistry 8】 where Y １ is O and Y ３ are each independently CH ２ and The R ３ One or more H's are each independently selected from C １－６ Alkyl, —OH, or —L ２ -R ４ may be substituted with; L ２ represents a single bond, —(C═O)—, or —NR ｇ (C═O)—; R ４ is H, -OH, C １－６ Alkyl, C ３－８ cycloalkyl, a 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S in the ring, or —NR ｈ R ｉ and The R ４ one or more H may each independently be replaced with —OH; R ｅ , R ｇ , R ｈ and R ｉ are each independently H or C １－６ is alkyl, A compound represented by chemical formula 1 according to claim 1, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or its pharmaceutically acceptable salt.

5. The compounds set forth in the table below, their optical isomers, their stereoisomers, their solvates, their isotopically modified forms, their tautomers, or pharmaceutically acceptable salts thereof. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】

6. The compound according to any one of claims 1 to 5, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing, ameliorating or treating a disease associated with SOS1 activity.

7. The pharmaceutical composition of claim 6 , wherein the disease associated with SOS1 activity includes cancer.

8. The cancers include lung cancer, pancreatic cancer, gastric cancer, myelodysplastic syndrome, blood cancer, leukemia including acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), adrenal cancer, anal cancer, basal squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, uterine cancer, esophageal cancer, Ewing's sarcoma family tumors, eye cancer, gallbladder cancer, gastrointestinal neuroendocrine tumors, gastrointestinal stromal tumors, and tumor (GIST), gestational trophoblastic disease, glioma, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, hypopharyngeal cancer, liver cancer, lung and breast carcinoma, lymphoma including cutaneous T-cell lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary gland tumors, including one or more diseases selected from prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymic cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, cutaneous granular cell tumor, and lung adenocarcinoma, The pharmaceutical composition of claim 7.

9. Administering to a subject in need thereof the compound according to any one of claims 1 to 5, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. A method for preventing, ameliorating or treating a disease associated with SOS1 activity.

10. The method for preventing, ameliorating, or treating a disease associated with SOS1 activity according to claim 9 , wherein the disease associated with SOS1 activity includes cancer.

11. Use of the compound according to any one of claims 1 to 5, its optical isomer, its stereoisomer, its solvate, its isotopically modified form, its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the prevention, amelioration, or treatment of a disease associated with SOS1 activity.

12. Use of the compound according to any one of claims 1 to 5, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopically modified product thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the manufacture of a medicament for the prevention, amelioration, or treatment of a disease associated with SOS1 activity.

13. The use according to claim 11 or 12, wherein the disease associated with SOS1 activity comprises cancer.

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