Novel bicyclic heterocyclyl compounds and uses thereof

Abstract

The present invention relates to a compound represented by Chemical Formula 1 as an SOS1 inhibitor, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and to a pharmaceutical composition containing the same as an active ingredient. The compound, the optical isomer thereof, the stereoisomer thereof, the solvate thereof, the isotope variant thereof, the tautomer thereof or the pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient can be effectively used for preventing, improving or treating diseases associated with SOS1 activity. [Formula 1] # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a bicyclic heterocyclic compound showing SOS1 inhibitory activity, and more specifically to a novel bicyclic heterocyclic compound, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt, its use, and a pharmaceutical composition comprising the same. The bicyclic heterocyclic compound shows preventive, ameliorative or therapeutic activity against various cancers due to its excellent SOS1 inhibitory activity. Background Art

[0002] Renin angiotensin system (RAS) family proteins include KRAS, NRAS and HRAS, and their mutations are small GTPases present in cells in GTP-bound or GDP-bound states. RAS family proteins have weak intrinsic GTPase activity and slow nucleotide exchange rate. The binding of guanine nucleotide exchange factors (GEFs) such as Son of Sevenless1 (SOS1) promotes GDP to be released from RAS proteins and enables GTP to bind. RAS family proteins are active in the GTP-bound state and are associated with effector proteins such as C-RAF and PI3K. These pathways affect a variety of cellular processes, such as proliferation, survival, metabolism, motility, angiogenesis, immunity and growth. Cancer-related mutations in RAS family proteins inhibit GAP-induced GTPase activity to increase GTP-bound / active RAS family proteins. It leads to sustained activation of effector pathways (e.g., MEK / ERK, PI3K / AKT / mTOR, RalGDS pathways) downstream of RAS family proteins. KRAS mutations (eg, amino acids G12, G13, Q61, A146) are found in a variety of human cancers, including lung, colorectal, and pancreatic cancers.

[0003] SOS1 is the human homolog of the originally discovered fruit fly protein Son of Sevenless (SOS). SOS1 has two sites that bind to RAS family proteins, which are the catalytic site that binds to GDP-bound RAS family proteins and the allosteric site that binds to GTP-bound RAS family proteins. It was found that the loss of SOS1 reduced the proliferation rate and survival of tumor cells with KRAS mutations, and no effect was observed on KRAS wild-type cell lines. In addition, SOS1 modification is associated with cancer. SOS1 mutations are found in embryonic rhabdomyosarcoma, Sertoli cell testicular tumor, cutaneous granular cell tumor, and lung adenocarcinoma. At the same time, overexpression of SOS1 has been found in bladder cancer and prostate cancer. In addition to cancer, hereditary SOS1 mutations are also associated with the pathogenesis of RAS diseases (RASopathy), such as Noonan syndrome (NS), cardio-facial-cutaneous (CFC) syndrome, and hereditary gingival fibromatosis type 1.

[0004] Regarding SOS1 inhibition, many efforts have been made to date to discover and optimize complexes targeting the effector binding site of RAS or the catalytic binding site of SOS1 (Lu et al., ChemMedChem. 2016, 11(8):814-21), but have failed to meet expectations.

[0005] Meanwhile, small activating molecules have recently been discovered that bind to the lipophilic pocket of SOS1 near the RAS binding site (Burns et al., Proc. Natl. Acad. Sci. 2014, 111(9):3401-6). However, the binding of these molecules appears to increase nucleotide exchange, thereby activating RAS rather than inactivating it.

[0006] Many fragmented molecules have been found in an effort to stabilize the protein-protein interaction between RAS family proteins and SOS1 and to prevent the reloading of GTP-bound RAS family proteins (Winter et al., J. Med. Chem. 2015, 58(5): 2265-74). However, the reversible binding of fragmented molecules to SOS1 was not interpreted as a measurable effect in nucleotide exchange, and only weak effects were identified by small molecules covalently bound to RAS.

[0007] In addition, in recent years, research has been conducted to develop small molecule inhibitors of SOS1 by combining rational design and screening platforms (Evelyn et al., Chem. Biol. 2014, 21(12): 1618-28; Evelyn et al., J. Biol. Chem. 2015, 290(20): 12879-98; Zheng et al., WO 2016 / 077793). Although compounds with only slight inhibitory effects on SOS1 have been identified, they have only weak effects on guanine nucleotide exchange and regulation of cell signaling (e.g., ERK phosphorylation).

[0008] Therefore, new SOS1 inhibitors that can effectively inhibit SOS1 are needed.

[0009] Related technical references

[0010] Patent Literature

[0011] (Patent Document 1) International Publication WO 2016 / 077793

[0012] Non-patent literature

[0013] (Non-patent document 1) Lu et al., ChemMedChem. 2016, 11(8): 814-21

[0014] (Non-patent document 2) Burns et al., Proc. Natl. Acad. Sci. 2014, 111(9): 3401-6

[0015] (Non-patent document 3) Winter et al., J. Med. Chem. 2015, 58(5): 2265-74

[0016] (Non-patent document 4) Evelyn et al., Chem. Biol. 2014, 21(12): 1618-28

[0017] (Non-patent document 5) Evelyn et al., J. Biol. Chem. 2015, 290(20): 12879-98 DETAILED DESCRIPTION

[0018] Technical issues

[0019] An object of the present invention is to provide a novel bicyclic heterocyclic group-based compound having excellent SOS1 inhibitory activity, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0020] Furthermore, another object of the present invention is to provide a pharmaceutical composition comprising a bicyclic heterocyclic group-based compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0021] Another object of the present invention is to provide a pharmaceutical composition comprising a bicyclic heterocyclic group-based compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient for preventing, improving or treating various diseases caused by SOS1 activity.

[0022] Another object of the present invention is to provide a bicyclic heterocyclic group-based compound, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt for preventing, improving or treating various diseases caused by SOS1 activity.

[0023] Another object of the present invention is to provide a bicyclic heterocyclic group-based compound, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt for use in the preparation of drugs for preventing, improving or treating various diseases caused by SOS1 activity.

[0024] Another object of the present invention is to provide a method for preventing, improving or treating various diseases caused by SOS1 activity, by administering a bicyclic heterocyclic group-based compound, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

[0025] Technical Solution

[0026] Hereinafter, the present invention will be described in more detail. All combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited to the following specific description.

[0027] This research was carried out with the support of the Korea Drug Development Fund funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare of South Korea (mission identification number: RS-2023-00217674). The mission identification number can be used in combination as "1711198230".

[0028] The compound represented by formula 1

[0029] (1) The present invention provides a compound represented by the following Formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0030] [Formula 1]

[0031]

[0032] In the above formula 1,

[0033] A is for C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, C 6-12 Aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring,

[0034] n is 0, 1, 2, 3, or 4;

[0035] R1 is C 1-6 Alkyl, C 6-12 Aryl, -CF2H, -CF3, -CN, -OH, -NH2 or halogen (wherein when n is 2 or greater, the n R1 are each independent of each other),

[0036] R1 C 1-6 Alkyl, C 6-12 At least one of the H groups of the aryl group, -CF2H and -OH group may be independently replaced by C 1-6 Alkyl (where C 1-6 At least one H in the alkyl group can be replaced independently by -OH, -OC 1-6 Alkyl or -NR a R b substituted) or halogen substituted;

[0037] X1 is CH or N, X2 is CR2, and X3 is CH;

[0038] 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 halogen;

[0039] L1 is a single bond, -(C=O)-, -(C=O)O-, -O-, -(C=O)NR e -、-NRe -、-NR e (C=O)-、-NR e SO2-, or -NR e (C=O)NR f -;

[0040] 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 N, O and S in the ring, C 3-8 Cycloalkenyl, 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, (where m is 0 or 1, Y1 is CH2, NR j or O, and R ja , R jb , R jc and R jd Each independently is H or C 1-5 Alkyl, provided that it is selected from R ja , R jb , R jc and R jd Two of them can be connected to form CH2 or CH2-CH2), or (wherein o and p are each independently 1 or 2, q and r are each independently 0, 1 or 2, and Y2 and Y3 are each independently CH2, NR k or O),

[0041] In R3, a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, or At least one -CH2- in the compound may be substituted by -(C=O)-, -SO- or -SO2-,

[0042] R3 C 3-8 At least one -CH2- of the cycloalkyl group may be substituted with -SO2-,

[0043] At least one H of R3 may be independently replaced by C 1-6 Alkyl, -OH, halogen or -L2-R4 substitution;

[0044] L2 is a single bond, C 1-6 Alkylene, -O-, -(C=O)-, -SO2-, -(C=O)NR g -or-NR g (C=O)-;

[0045] R4 is H, C1-6 alkyl, -OC 1-6 Alkyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, C 6-12 Aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, -NR h R i , -CF3, -CF2H, -OH or halogen,

[0046] At least one H of R4 may be independently replaced by C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -NR m R n or halogen substituted; and

[0047] 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 Each independently is H or C 1-6 alkyl.

[0048] In the present invention, the resonance structure of the compound represented by Formula 1 may be considered to be the same as the structures represented by the following Formulas 1a and 1b:

[0049] [Formula 1a]

[0050]

[0051] [Formula 1b]

[0052]

[0053] In the above, the resonance structure defined in Formula 1 has been exemplarily described, but is not limited thereto.

[0054] In one embodiment, in the above Formula 1, n may be 0, 1, 2, 3 or 4, and preferably 1, 2 or 3.

[0055] In one embodiment, when n is 2 or greater, the n R1s may be independent of each other. In other words, the n R1s may be the same substituent or different substituents. For example, when n is 2, one R1 may be selected from C 1-6Alkyl, C 6-12 aryl, -CF2H, -CF3, -CN, -OH and halogen, and the other R1 can be selected from C 1-6 Alkyl, C 6-12 One of aryl, -CF2H, -CF3, -CN, -OH and halogen.

[0056] In one embodiment, when A is an aryl group, n may be 2 or more, preferably 2. When A is a heteroaryl group, n may be 1 or more, preferably 1, but is not limited thereto.

[0057] In one embodiment, when L1 is a linker and L1 is a single bond, it may refer to a structure in which R3 is directly connected to the parent core structure, for example In other words, in the present invention, when L1 is a single bond, it may mean that -L1-R3 is substantially -R3. In the present specification, when L1 is a single bond, L1 may be represented as absent or zero.

[0058] In one embodiment, at least one H of R3 may be substituted by L2-R4 independently, wherein when L2 is a linker and L2 is a single bond, R4 may be substituted by at least one H of R3, thus referring to a structure directly connected to R3.

[0059] In one embodiment, in the above Formula 1, when A is an aryl group, n may be 2, and R3 may be a heterocycloalkyl group containing N or a heterocycloalkenyl group containing N. In this case, the heterocycloalkyl group containing N or the heterocycloalkenyl group containing N may further contain one or more heteroatoms, and may not further contain the same heteroatoms.

[0060] In one embodiment, in the above Formula 1, when A is a heteroaryl group, n may be 1, and R3 may be a heterocycloalkyl group containing N or a heterocycloalkenyl group containing N. In this case, the heterocycloalkyl group containing N or the heterocycloalkenyl group containing N may further contain one or more heteroatoms, and may not further contain the same heteroatoms.

[0061] In one embodiment, It can be, for example But not limited to this. Specifically, Can be But not limited to this. In this case, R j Is H or C 1-6 alkyl.

[0062] In one embodiment, It can be, for example But not limited to this. Specifically, Can be

[0063] But not limited to this. In this case, R k Is H or C 1-6 alkyl.

[0064] In one embodiment, in R3, a 3- to 12-membered heterocycloalkyl ring containing 1 to 3 heteroatoms independently selected from N, O and S, or At least one -CH2- in the structure may be substituted by -(C=O)-, -SO- or -SO2-, and the structure in which at least one -CH2- is substituted by -(C=O)- may be, for example But not limited to this. In addition, the structure in which at least one -CH2- is replaced by -SO- or -SO2- can be But it is not limited to this.

[0065] In one embodiment, R3 C 3-8 At least one -CH2- of the cycloalkyl group may be substituted with -SO2-, and the C 3-8 At least one -CH2- of the cycloalkyl group may be substituted with -SO2- to form a cyclic compound containing a heteroatom. 3-8 The structure in which at least one -CH2- of the cycloalkyl group is replaced by -SO2- can be But it is not limited to this.

[0066] (2) In one embodiment, in the above (1), it can be provided that in the above formula 1,

[0067] A is for C 6-12 Aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring,

[0068] n is 1, 2, or 3;

[0069] R1 is C 1-6 Alkyl, C 6-12 Aryl, -CF2H, -CF3, -CN or halogen (wherein when n is 2 or greater, the n R1 are each independent of each other),

[0070] R1 C 1-6 Alkyl, C 6-12 At least one of the H in the aryl group and -CF2H can be independently replaced by C 1-6 Alkyl (where C 1-6 At least one H in the alkyl group can be replaced independently by -OH, -OC1-6 Alkyl or -NR a R b substituted) or halogen substituted;

[0071] X1 and X3 are each CH; and

[0072] X2 is CR2;

[0073] Among them, 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 Each is the same as defined in (1) above.

[0074] (3) In one embodiment, in the above (1) or (2), it can be provided that in the above formula 1,

[0075] A is for C 6-12 Aryl;

[0076] n is 1 or 2;

[0077] R1 is each independently C 1-6 Alkyl, -CF2H, -CF3, -CN or halogen;

[0078] X1, X2 and X3 are each CH;

[0079] L1 is a single bond or -NR e -;

[0080] R3 is a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, C 3-8 Cycloalkenyl, 3 to 8 membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, or 5 to 12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, wherein the heterocycloalkyl group includes wherein Y1 is O, and Y3 are each independently CH2, NR k or O,

[0081] At least one H of R3 may be independently replaced by C 1-6 Alkyl, -OH, halogen or -L2-R4 substitution;

[0082] L2 is a single bond, C 1-6 Alkylene, -O-, -(C=O)-, -(C=O)NR g -or-NR g (C=O)-;

[0083] 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 N, O and S in the ring, -NR h R i or halogen,

[0084] At least one H of R4 may be independently substituted by -OH;

[0085] Where R e , R g , R h , R i and R k Each is the same as defined in (1) above.

[0086] (4) In one embodiment, in any one of the above (1) to (3), it can be provided that in the above formula 1, A is C 6-12 Aryl;

[0087] n is 2;

[0088] R1 is each independently C 1-6 Alkyl, -CF2H, -CF3, -CN or halogen;

[0089] X1, X2 and X3 are each CH;

[0090] L1 is a single bond or -NR e -;

[0091] R3 is a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, or a 3- to 8-membered heterocycloalkenyl group containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, wherein the heterocycloalkyl group includes wherein Y1 is O, and Y3 are each independently CH2,

[0092] At least one H of R3 may be independently replaced by C 1-6 Alkyl, -OH or -L2-R4 substitution;

[0093] L2 is a single bond, -(C=O)- or -NR g (C=O)-;

[0094] 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 N, O and S in the ring, or -NR h R i ,

[0095] At least one H of R4 may be independently substituted by -OH;

[0096] Where R e , R g , R h , and R i Each is the same as defined in (1) above.

[0097] In one embodiment, in the above (1) to (4), the heterocycloalkyl or heterocycloalkenyl of R3 may contain N. In this case, the heterocycloalkyl or heterocycloalkenyl may be a heterocycloalkyl or heterocycloalkenyl in which the atom connected to the parent core structure is N, or may be a heterocycloalkyl or heterocycloalkenyl containing N in the ring. At this time, the heterocycloalkyl or heterocycloalkenyl may contain at least one N in the ring, and may be a heterocycloalkyl or heterocycloalkenyl containing 0 to 2 heteroatoms (S or O) other than N in the ring, but is not limited thereto.

[0098] In the present invention, “Cm-Cn” (wherein m and n are each independently an integer of 1 or more) may refer to the number of carbons, and, for example, “C1-C5 alkyl” may represent an alkyl group having 1 to 5 carbon atoms.

[0099] In the present invention, "alkyl" may refer to a saturated hydrocarbon group of a straight chain or branched chain. In the present invention, the alkyl group may have 1 to 5 carbon atoms. In one embodiment, the alkyl group may have 1 to 3 carbon atoms. Examples of alkyl groups may include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, sec-pentyl, tert-pentyl, isopentyl, sec-isopentyl, neopentyl, etc. In the present invention, the alkyl group may refer to unsubstituted, or may refer to at least one H of the alkyl group being optionally substituted. The substituent in which at least one H of the alkyl group may be substituted may include, but is not limited to, a functional group, as long as at least one H of the alkyl group is substitutable. For example, the substituent may be a substituent defined in a compound represented by Formula 1 of the present invention, but is not necessarily limited thereto.

[0100] In the present invention, "cycloalkyl" may refer to a saturated hydrocarbon ring having 3 or more carbon atoms, and the saturated hydrocarbon ring may include a monocyclic and polycyclic structure. The polycyclic structure may include a polycyclic structure such as a spirocyclic ring, a bridged ring, and a condensed ring structure. The cycloalkyl may be a saturated hydrocarbon ring having 3 to 12 carbon atoms. Examples of cycloalkyl may include at least one selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., but are not limited thereto. In the present invention, the cycloalkyl may refer to unsubstituted, or may refer to at least one H of the cycloalkyl being optionally substituted. The substituent in which at least one H of the cycloalkyl may be substituted may include, but is not limited to, a functional group, as long as at least one H of the cycloalkyl is substitutable. For example, the substituent may be a substituent defined in a compound represented by Formula 1 of the present invention, but is not necessarily limited thereto.

[0101] In the present invention, "cycloalkenyl" may refer to an unsaturated hydrocarbon ring having 3 or more carbon atoms, which includes one or more double bonds, and the hydrocarbon ring may include monocyclic and polycyclic structures. In other words, in the present invention, cycloalkenyl may refer to a ring structure including 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 may include at least one selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc., but are not limited thereto. In the present invention, cycloalkenyl may refer to unsubstituted, or may refer to at least one H in the cycloalkenyl group being optionally substituted. The substituent in which at least one H of the cycloalkenyl group may be substituted may include but is not limited to a functional group, as long as at least one H of the cycloalkenyl group is substitutable. For example, the substituent may be a substituent defined in a compound represented by Formula 1 of the present invention, but is not necessarily limited thereto.

[0102] In the present invention, "heterocycloalkyl" may refer to a cyclic functional group in which at least one or more carbon atoms constituting the ring are replaced by heteroatoms. Examples of the heteroatoms may include nitrogen (N), oxygen (O) or sulfur (S). In this case, the heteroatoms contained in the ring of heterocycloalkyl may be one type or two or more types, one or two or more of the heteroatoms of one type may be included therein respectively, and at least one or more of the heteroatoms of two or more types may be included therein respectively. In the present invention, in heterocycloalkyl, the atom connected to the parent core structure may be a carbon atom, and the heteroatom may be included in the ring, or the atom connected to the parent core structure may be a heteroatom (wherein, when there are two or more heteroatoms, the heteroatom may also be included in the ring). Heterocycloalkyl may be a 3 to 12 ring. Heterocycloalkyl may include monocyclic and polycyclic structures. Examples of heterocycloalkyl groups may include oxirane, oxetane, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, azepanyl, etc., but are not limited thereto. In the present invention, heterocycloalkyl groups may refer to unsubstituted, or may refer to at least one H of heterocycloalkyl groups being optionally substituted. Substituents in which at least one H of heterocycloalkyl groups may be substituted may include but are not limited to functional groups, as long as at least one H of the heterocycloalkyl groups is substitutable. For example, the substituents may be substituents defined in the compounds represented by Formula 1 of the present invention, but are not necessarily limited thereto.

[0103] In the present invention, the polycyclic structure may include polycyclic structures such as spiro ring, bridged ring and condensed ring structures.

[0104] A spirocyclic structure may refer to a ring structure in which two rings consist of one common atom. In the compounds of the present invention, a spiroheterocycloalkyl ring structure may be, for example (wherein o and p are each independently 1 or 2, q and r are each independently 0, 1 or 2, and Y2 and Y3 are each independently CH2, NR k or O), but is not limited thereto. Specifically, the spiro heterocycloalkyl ring structure can be But it is not limited to this.

[0105] A bridged ring structure may refer to a hydrocarbon ring structure in which two or more rings share one or more pairs of carbon atoms. In the compounds of the present invention, a bridged heterocycloalkyl ring structure may be, for example, (where m is 0 or 1, Y1 is NR j or O, and R ja , R jb , R jc and R jd Each independently is H or C 1-5Alkyl, provided that it is selected from R ja , R jb , R jc and R jd Two of them can be connected to form CH2 or CH2-CH2), but are not limited thereto. Specifically, in the present invention, the bridge ring structure can be But it is not limited to this.

[0106] The fused ring structure may be, for example, etc., but not limited thereto.

[0107] In the present invention, "heterocycloalkenyl" may refer to a cyclic functional group in which at least one or more carbon atoms constituting the cycloalkenyl ring are substituted by a heteroatom. Examples of the heteroatom may include nitrogen (N), oxygen (O) or sulfur (S). In this case, the heteroatoms contained in the ring of the heterocycloalkenyl may be one type or two or more types, one or two or more of one type of heteroatoms may be included therein, and at least one or more of two or more types of heteroatoms may be included therein, respectively. In the present invention, in the heterocycloalkenyl, the atom connected to the parent core structure may be a carbon atom, and the heteroatom may be contained in the ring, or the atom connected to the parent core structure may be a heteroatom (wherein, when there are two or more heteroatoms, the heteroatom may also be contained in the ring). The heterocycloalkenyl group may be a 3 to 12 membered ring. Examples of heterocycloalkyl may include But not limited thereto. In the present invention, heterocycloalkenyl may refer to unsubstituted, or may refer to at least one H of heterocycloalkenyl is optionally substituted. The substituent in which at least one H of heterocycloalkenyl may be substituted may include but is not limited to a functional group, as long as at least one H of the heterocycloalkenyl is substitutable. For example, the substituent may be a substituent defined in the compound represented by Formula 1 of the present invention, but is not necessarily limited thereto.

[0108] In the present invention, "aryl" may include monocyclic aromatics or polycyclic aromatics, and refers to aromatic hydrocarbons having 6 or more carbon atoms. The aryl group may have 6 to 20 carbon atoms. For example, the aryl group may be phenyl, biphenyl, naphthyl, etc. In the present invention, the aryl group may refer to unsubstituted, or may refer to at least one H of the aryl group being optionally substituted. The substituent in which at least one H of the aryl group may be substituted may include, but is not limited to, a functional group, as long as at least one H of the aryl group is substitutable. For example, the substituent group may be a substituent group defined in the compound represented by Formula 1 of the present invention, but is not necessarily limited thereto.

[0109] In the present invention, "heteroaryl" may refer to a monocyclic or polycyclic heterocycle, wherein at least one or more carbon atoms in the aryl are replaced by nitrogen (N), oxygen (O) or sulfur (S) as heteroatoms. As an example, in the present invention, heteroaryl may be a 5 to 12-membered ring, but is not limited thereto. When the heteroaryl contains two or more heteroatoms, the types of heteroatoms may be the same or different from each other. For example, the case where the heteroaryl contains two or more heteroatoms selected from nitrogen, oxygen and sulfur may refer to various combinations, such as the case where two nitrogen atoms are included, the case where one nitrogen atom and one oxygen atom are included, the case where two oxygen atoms and one nitrogen atom are included, etc. In addition, in the present invention, in the heteroaryl, the atom connected to the parent core structure may be a carbon atom, and the heteroatom may be contained in the ring, or the atom connected to the parent core structure may be a heteroatom (wherein, when there are two or more heteroatoms, the heteroatom may also be contained in the ring). For instance, examples of heteroaryl groups can include pyridyl, thienyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolyl, benzoxazolyl, benzimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, chromenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolopyridinyl, triazinyl, triazolopyrimidinyl, triazolopyridinyl, triazolopyridazinyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazole, isomers thereof, and the like. In the present invention, heteroaryl may refer to unsubstituted, or may refer to at least one H of heteroaryl is optionally substituted. The substituent in which at least one H of heteroaryl may be substituted may include, but is not limited to, a functional group, as long as at least one H of the heteroaryl is substitutable. For example, the substituent may be a substituent defined in the compound represented by Formula 1 of the present invention, but is not necessarily limited thereto.

[0110] In the present invention, alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl may refer to a divalent or higher valent monovalent substituent or a polyvalent substituent having a chemical structure according to each definition. For example, "alkyl" may include a monovalent alkyl or a divalent alkyl (alkylene), and "aryl" may include a monovalent aryl or a divalent aryl (arylene).

[0111] In the present invention, in each definition of alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl, "may be substituted" may mean that each of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl may be unsubstituted or substituted. Specifically, when alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl may be substituted, it may mean that alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl may be unsubstituted, or at least one H in alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl may be substituted independently by a substituent, and the substituent may be available without limitation, as long as the substituent is a functional group capable of replacing at least one H. For example, in each of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl groups of the present invention, the substituent may be a substituent defined in the definition of the alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl and heterocycloalkenyl groups of the compound represented by Formula 1 of the present invention, but is not necessarily limited thereto.

[0112] In the present invention, "halogen" may be F, Cl, Br or I.

[0113] The compound according to the present invention, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt may be a compound as shown in Table 1 below.

[0114]

Table 1

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131] Furthermore, the compound according to the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof may be a compound shown in Table 2 or 3 below.

[0132]

Table 2

[0133]

[0134]

[0135]

[0136]

Table 3

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] In the present invention, "pharmaceutically acceptable salt" may refer to a salt conventionally used in the pharmaceutical industry and may be prepared by a conventional method known to those skilled in the art.

[0176] In the present invention, pharmaceutically acceptable salts may 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.; organic acid salts prepared from 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, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonates prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; or other analogs, but the types of salts referred to in the present invention are not limited to those listed. In one embodiment of the present invention, the salt may be a hydrochloride.

[0177] In the present invention, "stereoisomers" may include diastereomers and optical isomers (enantiomers), wherein optical isomers may include not only enantiomers, but also mixtures of enantiomers, and even racemates. Such isomers may be separated by splitting according to relevant techniques (e.g., column chromatography, HPLC, etc.). Alternatively, stereoisomers of each of the compounds represented by Formula 1 may be synthesized stereospecifically using a known series of optically pure starting materials and / or reagents.

[0178] In the present invention, "prevention" may refer to all actions of inhibiting or delaying the occurrence of a disease by administering the compound represented by Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0179] In the present invention, "treatment" may refer to all actions that make the symptoms of an individual who may develop or suffer from a disease better or improve by administering the compound represented by Formula 1 of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof.

[0180] In the present invention, "SOS1" may include nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous SOS1 molecules, their isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, other species and active fragments.

[0181] The compound represented by Formula 1 of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof can be advantageously used for preventing, improving or treating various diseases associated with SOS1 activity caused by SOS1 activity.

[0182] The compound represented by Formula 1 of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof can inhibit / suppress SOS1, and can neutralize the RAS pathway to inhibit the growth and proliferation of cells in various diseases caused by SOS1 activity, especially cancer (tumor). Therefore, they can show excellent effects of preventing, improving or treating various diseases caused by SOS1 activity, especially cancer (tumor).

[0183] The compound represented by Formula 1 of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof can show the effect of preventing, improving or treating diseases associated with SOS1 activity at a level similar to, substantially the same as or higher than that of conventionally known drugs for preventing, alleviating or treating diseases associated with SOS1 activity.

[0184] Compositions comprising a compound represented by Formula 1

[0185] The present invention provides a pharmaceutical composition comprising a compound represented by the above Formula 1, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0186] In addition, the present invention provides a pharmaceutical composition for preventing, alleviating or treating a disease associated with SOS1 activity, comprising a compound represented by the above Formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

[0187] In other words, the pharmaceutical composition comprising the compound represented by Formula 1 of the present invention, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt as an active ingredient can be advantageously used to prevent, alleviate or treat diseases associated with SOS1 activity.

[0188] Diseases associated with SOS1 activity may include various diseases caused by SOS1 mutation, SOS1 overexpression, and SOS1 activity, and may include, for example, cancer (tumor).

[0189] Cancers may 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, cerebrospinal fluid tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational choriocarcinoma, glioma, Hodgkin lymphoma, Kaposi's sarcoma, kidney cancer, hypopharyngeal Cancer, liver cancer, lung cancer, lymphoma (including cutaneous T-cell lymphoma), malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach 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 tumor, cutaneous granular cell tumor and lung adenocarcinoma, etc.

[0190] In addition, diseases associated with SOS1 activity can include RAS diseases, such as neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with lentigines (NSML) (also known as LEOPARD syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-cutaneous (CFC) syndrome, Legius syndrome (also known as NF1-like syndrome) and hereditary gingival fibromatosis type 1.

[0191] In addition to the compound represented by the above formula 1, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt, the pharmaceutical composition of the present invention can also include at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carrier can be the conventional carrier used in this area, specifically including but not limited to lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidine, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral or oil. In addition to the above-mentioned ingredients, the pharmaceutical composition of the present invention can also include lubricant, wetting agent, sweetener, flavoring agent, emulsifier, suspending agent, preservative, dispersant, stabilizer etc. In addition, the pharmaceutical composition of the present invention can be formulated into oral dosage forms, such as tablets, powders, granules, pills, capsules, suspensions, emulsions, internal liquids, emulsions, syrups, etc., as well as external dosage forms, suppositories and sterile solutions for injection, by using pharmaceutically acceptable carriers and excipients, and thus can be prepared into unit dosage forms or prepared by inserting into multi-dose containers. The preparation can be prepared according to conventional methods used in the art for preparations or the methods disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and can be prepared into various preparations according to each disease or ingredient.

[0192] Non-limiting examples of preparations for oral administration using the pharmaceutical composition of the present invention may include tablets, lozenges, troches, water-soluble suspensions, oil suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, elixirs, etc. In order to formulate the pharmaceutical composition of the present invention into a preparation for oral administration, the following substances may be used: binders such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose, gelatin, etc.; excipients such as dicalcium phosphate, etc.; disintegrants such as corn starch, sweet potato starch, etc.; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol wax, etc.; etc., wherein sweeteners, flavorings, syrups, etc. may also be used. In addition, in the case of capsules, in addition to the above materials, liquid carriers such as fatty oils, etc. may also be used.

[0193] Non-limiting examples of parenteral preparations using the pharmaceutical composition of the present invention may include injectable solutions, suppositories, powders for respiratory inhalation, aerosols for spraying, ointments, powders for application, oils, creams, etc. In order to formulate the pharmaceutical composition of the present invention into a preparation for parenteral administration, the following may be used: sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, external preparations, etc. As the non-aqueous solvents and suspensions, the following substances may be used, but are not limited thereto: propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), injectable esters (such as ethyl oleate), etc. The present invention provides a method for preventing, improving or treating a disease associated with SOS1 activity, the method comprising administering a compound represented by the above formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a composition comprising them to an individual (an individual in need thereof).

[0194] In the present invention, "administration" means introducing a predetermined substance into an individual by an appropriate method.

[0195] In the present invention, "individual" refers to all animals that have developed or may develop a disease associated with SOS1 activity, such as rats, mice, livestock, etc., including humans, and specifically may refer to mammals including humans, but is not limited thereto.

[0196] The method for preventing, improving or treating a disease associated with SOS1 activity of the present invention may comprise administering a therapeutically effective amount of a compound represented by the above Formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0197] In the present invention, the term "therapeutically effective amount" refers to an amount sufficient to treat a disease at a reasonable risk / benefit ratio applicable to medical treatment and without causing side effects, and can be determined by those skilled in the art based on factors including the patient's sex, age, weight and health status, disease type, severity, drug activity, sensitivity to drugs, administration method, administration time, administration route, excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the pharmaceutical field. It is preferred to administer a specific therapeutically effective amount differently to a certain patient, depending on various factors, including the type and degree of response to be achieved, a specific composition including the presence of other preparations used in some cases, the patient's age, weight, general health status, sex and diet, administration time, administration route, secretion rate of the composition, treatment time, and drugs used together with or simultaneously with the specific composition, as well as other similar factors well known in the pharmaceutical field.

[0198] The present invention provides a compound represented by the above formula 1, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt, or a composition comprising them for preventing, improving or treating diseases associated with SOS1 activity.

[0199] The present invention provides a compound represented by the above formula 1, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt, or a composition comprising them for use in preparing a medicament for preventing, improving or treating a disease associated with SOS1 activity.

[0200] In the preparation of drugs for preventing, improving or treating diseases associated with SOS1 activity, the compound represented by the above formula 1, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt can be mixed with a pharmaceutically acceptable adjuvant, diluent, carrier, etc., and can be prepared into a composite preparation together with other active agents to provide a synergistic effect.

[0201] The matters mentioned in the compounds, pharmaceutical compositions, methods of treatment and uses of the present invention may be identically applied if not contradictory to each other.

[0202] Beneficial Effects

[0203] The compound represented by Formula 1 of the present invention, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt; and the pharmaceutical composition comprising the same as an active ingredient can be advantageously used for preventing, improving or treating diseases associated with SOS1 activity.

[0204] Invention method

[0205] Hereinafter, the present invention will be described in more detail by exemplary embodiments. These exemplary embodiments are provided only for the purpose of illustrating the present invention, and therefore it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.

[0206] Preparation of the compound represented by Formula 1

[0207] The compound represented by Formula 1 of the present invention can be prepared by the following method. The raw materials can be commercially available or can be prepared by known methods, unless otherwise specified. The use of all embodiments or exemplary language provided herein is only intended to better illustrate the present invention, without limiting the scope of the claimed invention.

[0208] <Intermediate>

[0209] Intermediate IA

[0210]

[0211] Step 1

[0212]

[0213] 1-(3-(Benzyloxy)-5-(difluoromethyl)phenyl)ethanone

[0214] 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 and stirred for 16 hours while heating to 80°C. After cooling to room temperature, 1N HCl aqueous solution was added and stirred for 1 hour, then 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.

[0215] Step 2

[0216]

[0217] (R,E)-N-(1-(3-(Benzyloxy)-5-(difluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfenamide

[0218] To a solution of 1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethanone (1 g, 3.62 mmol) in tetrahydrofuran (10 ml) at room temperature were added (R)-(+)-2-methyl-2-propanesulfenamide (658 mg, 5.43 mmol) and Ti(OEt)4 (1.5 ml, 7.24 mmol) and stirred for 16 hours while heating to 80°C. After cooling to room temperature, the solid precipitated upon addition of cold water was filtered off, dissolved in ethyl acetate, and then filtered through a pad of celite. The filtrate was concentrated under vacuum without column purification to give (R,E)-N-(1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfenamide (1 g, 98%) as a yellow liquid.

[0219] MS (ESI+) m / z 380 (M+H) +

[0220] Step 3

[0221]

[0222] N-((R)-1-(3-(Benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide

[0223] To a solution of (R,E)-N-(1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfenamide (1 g, 3.60 mmol) in tetrahydrofuran (10 ml) was added NaBH4 (164 mg, 4.34 mmol) at 0°C and stirred at room temperature for 5 hours. After confirming the completion of the reaction, H2O was added 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 (R)-N-((R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (830 mg, 58%) as a white solid.

[0224] MS (ESI+) m / z 382 (M+H) +

[0225] Step 4

[0226]

[0227] (R)-1-(3-(Benzyloxy)-5-(difluoromethyl)phenyl)ethylamine hydrochloride

[0228] To a solution of N-((R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfenamide (873 mg, 2.28 mmol) in dioxane (7 ml) was added a 4M solution of HCl (1.71 ml, 6.84 mmol) in dioxane and stirred at room temperature for 1 hour. After the reaction was complete, the resulting mixture was concentrated to give (R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethylamine hydrochloride (682 mg, 100%) as a white solid.

[0229] MS (ESI+) m / z 278 (M+H) +

[0230] <Synthesis Method and Examples>

[0231] Synthesis Method A

[0232]

[0233] The general synthesis of compound A-3 is described in Synthesis Method A. Regarding A-1, diisopropylethylamine is used to synthesize A-2 into which an amine is introduced, and then Suzuki coupling reaction is performed to obtain the final compound A-3.

[0234] Example 1

[0235]

[0236] (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone Step 1

[0237]

[0238] (R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0239] To 6-bromo-4-chlorocinnoline (Intermediate A-1) (150 mg, 0.62 mmol) were added (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine (0.15 ml, 0.92 mmol) and diisopropylethylamine (0.15 ml, 1.83 mmol) dropwise, and the resulting mixture was stirred at 130° C. for 4 hours. After completion of the reaction, the reaction mixture was concentrated and then purified by combi flash to give (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnoline-4-amine (220 mg, 90%) as a brown solid.

[0240] MS (ESI+) m / z 396,398 (M+H) +

[0241] Step 2

[0242]

[0243] (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone

[0244] To a solution in which (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine (80 mg, 0.20 mmol) was dissolved in dioxane (4 ml), 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (120 mg, 0.30 mmol), Pd(dppf)2Cl2·DCM (40 mg, 0.02 mmol), K2CO3 (160 mg, 0.60 mmol) and H2O (4 ml) were added and stirred at 90°C for 6 hours and then at room temperature for 12 hours. 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 then concentrated. The concentrated residue was purified by combi flash 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.

[0245] 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)

[0246] MS (ESI+) m / z 441 (M+H) +

[0247] Example 2

[0248]

[0249] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine

[0250] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-1-dimethylethyl ester-1-(2H)-picolinic acid was used in a manner essentially the same as the synthesis method of Example 1 to obtain (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (50 mg, 67%).

[0251] To a solution in which (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) was dissolved in dichloromethane (1 ml) was added 4N hydrochloric acid (0.40 ml, 1.0 mmol) in 1,4-dioxane at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting mixture was concentrated and extracted with aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts were dried over sodium sulfate and then 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.

[0252] 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,1 H),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)

[0253] MS (ESI+) m / z 399 (M+H) +

[0254] Example 3

[0255]

[0256] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine

[0257] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester was used in a manner essentially the same as the synthesis method of Example 1 to obtain the title compound (26 mg, 31%).

[0258] 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,1 H),3.23-3.11(m,2H),2.76-2.63(m,4H),2.38(s,3H),1.70(d,J=6.8Hz,3H)

[0259] MS (ESI+) m / z 413 (M+H) +

[0260] Example 4

[0261]

[0262] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)cinnolin-4-amine

[0263] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then 1,2,3,6-tetrahydropyran-4-boronic acid pinacol ester was used in a manner essentially the same as the synthesis method of Example 1 to obtain the title compound (28 mg, 35%).

[0264] 1H 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),4.3 6-4.32(m,2H),3.92(t,J=5.6Hz,2H),2.72-2.63(m,2H),1.70(d,J=6.8Hz,3H)

[0265] MS (ESI+) m / z 400 (M+H) +

[0266] Synthesis Method B

[0267]

[0268] The general synthesis of compound B-1 is illustrated in Synthesis Method B. The bromine of intermediate A-2 is replaced with an amine by using a Buchwald reaction to give the final compound B-1.

[0269] Example 5

[0270]

[0271] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-methylpiperazin-1-yl)cinnolin-4-amine

[0272] Into a solution in which (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnoline-4-amine (intermediate A-2) (230 mg, 0.58 mmol) was dissolved in tetrahydrofuran (4 ml), N-methylpiperazine (0.23 ml, 1.16 mmol), Pd2(dba)3 (160 mg, 0.058 mmol) and Xphos (160 mg, 0.116 mmol) were dissolved, and 1N LiHMDS THF solution (2 ml, 2.9 mmol) was added to the resulting solution, which was then stirred for 1 hour while heating to 100°C. After completion of the reaction, the resulting 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 combi flash 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.

[0273] 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)

[0274] MS (ESI+) m / z 416 (M+H) +

[0275] Example 6

[0276]

[0277] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-(dimethylamino)piperidin-1-yl)cinnolin-4-amine

[0278] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (8 mg, 16%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that N,N-dimethylpiperidin-4-amine was used.

[0279] 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)

[0280] MS (ESI+) m / z 444 (M+H) +

[0281] Example 7

[0282]

[0283] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)cinnolin-4-amine

[0284] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (33 mg, 38%) was obtained in essentially the same manner as described in the synthetic method of Example 5, except that 2-methyl-2,6-diazaspiro[3.3]heptane was used.

[0285] 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)

[0286] MS (ESI+) m / z 428 (M+H) +

[0287] Example 8

[0288]

[0289] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-(oxetan-3-yl)piperazin-1-yl)cinnolin-4-amine

[0290] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (33 mg, 36%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 1-(oxetane-3-yl)piperazine was used.

[0291] 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)

[0292] MS (ESI+) m / z 458 (M+H) +

[0293] Example 9

[0294]

[0295] N-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-6-((S)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)cinnolin-4-amine

[0296] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then the title compound (17 mg, 25%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (S)-octahydropyrazino[2,1-c][1,4]oxazine was used.

[0297] 1H 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=4.0 Hz,1H),7.27(s,0.25H),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)

[0298] MS (ESI+) m / z 458 (M+H) +

[0299] Example 10

[0300]

[0301] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-morpholinoquinolin-4-amine

[0302] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (50 mg, 62%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that morpholine was used.

[0303] 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),7.5 0(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)

[0304] MS (ESI+) m / z 403 (M+H) +

[0305] Embodiment 11

[0306]

[0307] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)cinnolin-4-amine

[0308] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (16 mg, 20%) was obtained in essentially the same manner as described in the synthetic method of Example 5, except that 2-oxa-6-azaspiro[3.3]heptane was used.

[0309] 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)

[0310] MS (ESI+) m / z 415 (M+H) +

[0311] Example 12

[0312]

[0313] 6-(6-Oxa-3-azabicyclo[3.1.1]heptane-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0314] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (913 mg, 50%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used.

[0315] 1H NMR (400MHz, DMSO-d6) δ8.07(s,1H),8.03(d,J=9.6Hz,1H),7.60(t,J=7.4H z,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),4.83(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)

[0316] MS (ESI+) m / z 415 (M+H) +

[0317] Embodiment 13

[0318]

[0319] 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0320] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (32 mg, 39%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (1R, 4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used.

[0321] 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)

[0322] MS (ESI+) m / z 415 (M+H) +

[0323] Embodiment 14

[0324]

[0325] 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0326] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (30 mg, 36%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used.

[0327] 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,1 H),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)

[0328] MS (ESI+) m / z 415 (M+H) +

[0329] Embodiment 15

[0330]

[0331] 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0332] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (45 mg, 45%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride was used.

[0333] 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)

[0334] MS (ESI+) m / z 429 (M+H) +

[0335] Example 16

[0336]

[0337] 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0338] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (27 mg, 25%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride was used.

[0339] 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)

[0340] MS (ESI+) m / z 429 (M+H) +

[0341] Embodiment 17

[0342]

[0343] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-thiomorpholino-4-amine

[0344] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (24 mg, 40%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that thiomorpholine was used.

[0345] 1H NMR (400MHz, DMSO-d6) δ8.19(s,1H),7.96(d,J=9.2Hz,1H),7.62(d,J=2.4Hz,1 H),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)

[0346] MS (ESI+) m / z 419 (M+H) +

[0347] Embodiment 18

[0348]

[0349] (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)piperidin-4-ol

[0350] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (30 mg, 36%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 4-hydroxypiperidine was used.

[0351] 1H 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,1H),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)

[0352] MS (ESI+) m / z 417 (M+H) +

[0353] Embodiment 19

[0354]

[0355] (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)-4-methylpiperidin-4-ol

[0356] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (29 mg, 33%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 4-methyl-4-piperidinol was used.

[0357] 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),5.2 1(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)

[0358] MS (ESI+) m / z 431 (M+H) +

[0359] Embodiment 20

[0360]

[0361] (R)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)piperidin-3-ol

[0362] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (40 mg, 48%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (R)-3-hydroxypiperidine was used.

[0363] 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,1H),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)

[0364] MS (ESI+) m / z 417 (M+H) +

[0365] Embodiment 21

[0366]

[0367] (S)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)piperidin-3-ol

[0368] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (13 mg, 15%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (S)-3-hydroxypiperidine was used.

[0369] 1H NMR (400MHz, DMSO-d6) δ8.07 (s, 1H), 7.92 (d, J = 9.6Hz, 1H), 7.62-7.52 (m, 3H), 7.47-7.4 3(m,2H),7.43-7.14(m,2H),5.21(q,J=7.2Hz,1H),5.00(d,J=4.8Hz,1H),3.94-3.90(m,1 H),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)

[0370] MS (ESI+) m / z 417 (M+H) +

[0371] Embodiment 22

[0372]

[0373] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(4-methoxypiperidin-1-yl)cinnolin-4-amine

[0374] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (13 mg, 15%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 4-methoxypiperidine was used.

[0375] 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=7.2H z,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)

[0376] MS (ESI+) m / z 431 (M+H) +

[0377] Embodiment 23

[0378]

[0379] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((R)-3-methoxypiperidin-1-yl)cinnolin-4-amine

[0380] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (22 mg, 25%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (R)-3-methoxypiperidine was used.

[0381] 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)

[0382] MS (ESI+) m / z 431 (M+H) +

[0383] Embodiment 24

[0384]

[0385] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((S)-3-methoxypiperidin-1-yl)cinnolin-4-amine

[0386] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (6 mg, 7%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (S)-3-methoxypiperidine was used.

[0387] 1H 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)

[0388] MS (ESI+) m / z 431 (M+H) +

[0389] Embodiment 25

[0390]

[0391] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((R)-3-fluoropyrrolidin-1-yl)cinnolin-4-amine

[0392] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then the title compound (11 mg, 14%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (R)-3-fluoropyrrolidine hydrochloride was used.

[0393] 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),5.21(q,J=7.2Hz,1H),3.79-3.54(m,4H),2.39-2.23(m,2H),1.69(d,J=6.8Hz,3H)

[0394] MS (ESI+) m / z 405 (M+H) +

[0395] Embodiment 26

[0396]

[0397] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((S)-3-fluoropyrrolidin-1-yl)cinnolin-4-amine

[0398] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then the title compound (21 mg, 27%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (S)-3-fluoropyrrolidine hydrochloride was used.

[0399] 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)

[0400] MS (ESI+) m / z 405 (M+H) +

[0401] Embodiment 27

[0402]

[0403] (R)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)pyrrolidin-3-ol

[0404] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then the title compound (5 mg, 6%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (R)-pyrrolidin-3-ol was used.

[0405] 1H 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)

[0406] MS (ESI+) m / z 403 (M+H) +

[0407] Embodiment 28

[0408]

[0409] (S)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)pyrrolidin-3-ol

[0410] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then the title compound (9 mg, 11%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (S)-pyrrolidin-3-ol was used.

[0411] 1 H NMR(400MHz, DMSO-d6)δ8.03(s,1H),7.94(d,J=9.6Hz,1H),7.59(t,J=7.6H z,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),5.09(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)

[0412] MS (ESI+) m / z 403 (M+H) +

[0413] Embodiment 29

[0414]

[0415] N-((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-6-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cinnolin-4-amine

[0416] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (70 mg, 32%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (3aS, 6aS)-hexahydro-1H-furano[3,4-c]pyrrole hydrochloride was used.

[0417] 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),3.79-3.76(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)

[0418] MS (ESI+) m / z 429 (M+H) +

[0419] Embodiment 30

[0420]

[0421] (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)azetidin-3-ol

[0422] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then the title compound (3 mg, 3%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that azetidine-3-ol hydrochloride was used.

[0423] 1H 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)

[0424] MS (ESI+) m / z 389 (M+H) +

[0425] Embodiment 31

[0426]

[0427] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3-methoxyazetidin-1-yl)cinnolin-4-amine

[0428] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then the title compound (3 mg, 3%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 3-methoxyazetidine hydrochloride was used.

[0429] 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=7.8Hz,1H),7.21-6.93(m,3H),5.2 7(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)

[0430] MS (ESI+) m / z 403 (M+H) +

[0431] Embodiment 32

[0432]

[0433] (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)cinnolin-6-yl)-3-methylazetidin-3-ol

[0434] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then the title compound (40 mg, 40%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 3-methylazetidine-3-ol hydrochloride was used.

[0435] 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)

[0436] MS (ESI+) m / z 403 (M+H) +

[0437] Embodiment 33

[0438]

[0439] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3-methoxy-3-methylazetidin-1-yl)cinnolin-4-amine

[0440] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (24 mg, 29%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 3-methoxy-3-methylazetidine hydrochloride was used.

[0441] 1 H 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=6.8Hz,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)

[0442] MS (ESI+) m / z 417 (M+H) +

[0443] Embodiment 34

[0444]

[0445] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(6-methoxy-2-azaspiro[3.3]heptane-2-yl)cinnolin-4-amine

[0446] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (32 mg, 36%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 6-methoxy-2-azaspiro[3.3]heptane hydrochloride was used.

[0447] 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)

[0448] MS (ESI+) m / z 443 (M+H) +

[0449] Embodiment 35

[0450]

[0451] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((R)-tetrahydrofuran-3-yl)cinnoline-4,6-diamine

[0452] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (10 mg, 17%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (3R)-tetrahydro-3-furanamine was used.

[0453] 1H 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),7.0 6(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),4.13-4.0 9(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)

[0454] MS (ESI+) m / z 403 (M+H) +

[0455] Embodiment 36

[0456]

[0457] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((S)-tetrahydrofuran-3-yl)cinnoline-4,6-diamine

[0458] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (24 mg, 40%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (3S)-tetrahydro-3-furanamine was used.

[0459] 1H 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),7.0 6(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),4.11-4.0 7(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)

[0460] MS (ESI+) m / z 403 (M+H) +

[0461] Embodiment 37

[0462]

[0463] (R)-N4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-(tetrahydro-2H-pyran-4-yl)cinnoline-4,6-diamine

[0464] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (27 mg, 43%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 4-aminotetrahydropyran was used.

[0465] 1H NMR (400MHz, DMSO-d6) δ7.98 (s, 1H), 7.83 (d, J = 9.2Hz, 1H), 7.60-7.52 (m, 2H), 7.41 (s, 0.25 H),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,1 H),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,1H),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)

[0466] MS (ESI+) m / z 417 (M+H) +

[0467] Embodiment 38

[0468]

[0469] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((R)-1-methylpyrrolidin-3-yl)cinnoline-4,6-diamine

[0470] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (6 mg, 10%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (3R)-1-methyl-3-aminopyrrolidine was used.

[0471] 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,1 H),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)

[0472] MS (ESI+) m / z 416 (M+H) +

[0473] Embodiment 39

[0474]

[0475] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((R)-pyrrolidin-3-yl)cinnoline-4,6-diamine

[0476] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then (R)-3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (57 mg, 57%) was obtained in a manner essentially the same as described in the synthesis method of Example 5, except that (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester was used.

[0477] To a solution in which tert-butyl (R)-3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnoline-6-ylamino)pyrrolidine-1-carboxylate (57 mg, 0.11 mmol) was dissolved in dichloromethane (3 ml) was added a solution of 4N hydrochloric acid (0.40 ml, 1.0 mmol) in 1,4-dioxane at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting mixture was concentrated, extracted with aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated to give N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((R)-pyrrolidin-3-yl)cinnoline-4,6-diamine (6 mg, 13%) as a yellow solid.

[0478] 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,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)

[0479] MS (ESI+) m / z 402 (M+H) +

[0480] Embodiment 40

[0481]

[0482] N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((S)-pyrrolidin-3-yl)cinnoline-4,6-diamine

[0483] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then (S)-3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 40%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester was used.

[0484] To a solution in which tert-butyl (S)-3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnoline-6-ylamino)pyrrolidine-1-carboxylate (40 mg, 0.11 mmol) was dissolved in dichloromethane (3 ml) was added a solution of 4N hydrochloric acid (0.40 ml, 1.0 mmol) in 1,4-dioxane at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting mixture was concentrated, extracted with aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated to give N4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6-((S)-pyrrolidin-3-yl)cinnoline-4,6-diamine (17 mg, 60%) as a yellow solid.

[0485] 1H 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),2.90-2.79(m,2H),2.32-2.15(m,1H),1.98-1.89(m,1H),1.68(d,J=6.8Hz,3H)

[0486] MS (ESI+) m / z 402 (M+H) +

[0487] Embodiment 41

[0488]

[0489] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)(oxetan-3-yl)methanone

[0490] Step 1

[0491]

[0492] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnolin-4-amine hydrochloride

[0493] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazine-1-carboxylic acid tert-butyl ester (60 mg, 60%) was obtained in a manner essentially the same as described in the synthesis method of Example 5, except that tert-butyloxycarbonylpiperazine was used.

[0494] To a solution in which (R)-tert-butyl 4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazine-1-carboxylate (60 mg, 0.11 mmol) was dissolved in dichloromethane (3 ml) was added a solution of 4N hydrochloric acid (0.40 ml, 1.0 mmol) in 1,4-dioxane at 0°C, followed by stirring at room temperature for 2 hours. After the reaction was completed, the resulting 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.

[0495] MS (ESI+) m / z 402 (M+H) +

[0496] Step 2

[0497]

[0498] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)(oxetan-3-yl)methanone

[0499] After adding (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazin-1-yl)cinnoline-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) in dimethyl sulfoxide (1.5 ml), the resulting mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, water was added and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated, and the residue was then purified by column chromatography to give (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnoline-6-yl)piperazin-1-yl)(oxetane-3-yl)methanone (7 mg, 16%) as a yellow solid.

[0500] 1H 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)

[0501] MS (ESI+) m / z 486 (M+H) +

[0502] Embodiment 42

[0503]

[0504] 6-(6-Oxa-3-azabicyclo[3.1.1]heptane-3-yl)-N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)cinnolin-4-amine

[0505] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethylamine were used to synthesize compound A-2a, and then the title compound (3 mg, 4%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used.

[0506] 1 H NMR (400MHz, DMSO-d6) δ8.15 (s, 1H), 8.01 (d, J = 9.2Hz, 1H), 7.68-7.65 (m, 2 H),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=14.0 Hz,2H),3.20(q,J=7.3Hz,1H),2.00(d,J=8.8Hz,1H),1.65(d,J=6.8Hz,3H)

[0507] MS (ESI+) m / z 397 (M+H) +

[0508] Embodiment 43

[0509]

[0510] (R)-1-(4-((1-(3-(difluoromethyl)phenyl)ethyl)amino)cinnolin-6-yl)-4-methylpiperidin-4-ol

[0511] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethylamine were used to synthesize compound A-2a, and then the title compound (56 mg, 54%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 4-methyl-4-piperidinol was used.

[0512] 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),5.02(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)

[0513] MS (ESI+) m / z 413 (M+H) +

[0514] Embodiment 44

[0515]

[0516] 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-N-((R)-1-(3-(difluoromethyl)phenyl)ethyl)cinnolin-4-amine

[0517] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethylamine were used to synthesize compound A-2a, and then the title compound (60 mg, 58%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was used.

[0518] 1H 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)

[0519] MS (ESI+) m / z 397 (M+H) +

[0520] Embodiment 45

[0521]

[0522] (R)-1-(4-((1-(3-(difluoromethyl)phenyl)ethyl)amino)cinnolin-6-yl)-3-methylazetidin-3-ol

[0523] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethylamine were used to synthesize compound A-2a, and then the title compound (45 mg, 45%) was obtained in essentially the same manner as described in the synthetic method of Example 5, except that 3-methylazetidine-3-ol was used.

[0524] 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)

[0525] MS (ESI+) m / z 385 (M+H) +

[0526] Embodiment 46

[0527]

[0528] N4-((R)-1-(3-(difluoromethyl)phenyl)ethyl)-N6-((R)-tetrahydrofuran-3-yl)cinnoline-4,6-diamine

[0529] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)phenyl)ethylamine were used to synthesize compound A-2a, and then the title compound (25 mg, 33%) was obtained in essentially the same manner as described in the synthetic method of Example 5, except that (3R)-tetrahydro-3-furanamine was used.

[0530] 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)

[0531] MS (ESI+) m / z 385 (M+H) +

[0532] Embodiment 47

[0533]

[0534] 6-(6-Oxa-3-azabicyclo[3.1.1]heptane-3-yl)-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)cinnolin-4-amine

[0535] As described in Example 1, intermediate A-1 and (R)-1-(3-(trifluoromethyl)phenyl)ethylamine were used to synthesize compound A-2b, and then the title compound (278 mg, 40%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used.

[0536] 1H 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,2 H),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)

[0537] MS (ESI+) m / z 415 (M+H) +

[0538] Embodiment 48

[0539]

[0540] 6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)cinnolin-4-amine

[0541] As described in Example 1, intermediate A-1 and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethylamine were used to synthesize compound A-2c, and then the title compound (45 mg, 54%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used.

[0542] 1H NMR (400MHz, DMSO-d6) δ8.02(d,J=9.6Hz,1H),7.89(s,1H),7.64(d,J=8Hz,1H),7.58(d,J=7.6H z,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),3.6 3(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)

[0543] MS (ESI+) m / z 429 (M+H) +

[0544] Embodiment 49

[0545]

[0546] (R)-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-6-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)cinnolin-4-amine

[0547] As described in Example 1, intermediate A-1 and (R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethylamine were used to synthesize compound A-2c, and then the title compound (46 mg, 54%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 2-methyl-2,6-diazaspiro[3.3]heptane was used.

[0548] 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=9.2Hz,1H),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)

[0549] MS (ESI+) m / z 442 (M+H) +

[0550] Embodiment 50

[0551]

[0552] 3-((1R)-1-((6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)cinnolin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0553] As described in Example 1, compound A-2d was synthesized using intermediate A-1 and 3-[(1R)-1-aminoethyl]-2-methylbenzonitrile, and then the title compound (13 mg, 21%) was obtained in essentially the same manner as described in the synthetic method of Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used.

[0554] 1H NMR (400MHz, DMSO-d6) δ8.02(d,J=9.2Hz,1H),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=6.4Hz,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)

[0555] MS (ESI+) m / z 386 (M+H) +

[0556] Embodiment 51

[0557]

[0558] (R)-3-(1-((6-(4-hydroxy-4-methylpiperidin-1-yl)cinnolin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0559] As described in Example 1, compound A-2d was synthesized using intermediate A-1 and 3-[(1R)-1-aminoethyl]-2-methylbenzonitrile, and then the title compound (17 mg, 27%) was obtained in essentially the same manner as described in the synthetic method of Example 5, except that 4-methyl-4-piperidinol was used.

[0560] 1H 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)

[0561] MS (ESI+) m / z 402 (M+H) +

[0562] Embodiment 52

[0563]

[0564] (R)-2-Methyl-3-(1-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-ylamino)ethyl)benzonitrile

[0565] Compound A-2d was synthesized as described in Example 1 using intermediate A-1 and 3-[(1R)-1-aminoethyl]-2-methylbenzonitrile, followed by 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester to give the title compound (16 mg, 17%).

[0566] 1H 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)

[0567] MS (ESI+) m / z 384 (M+H) +

[0568] Embodiment 53

[0569]

[0570] (R)-3-(1-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-ylamino)ethyl)benzonitrile

[0571] Compound A-2e was synthesized as described in Example 1 using intermediate A-1 and 3-[(1R)-1-aminoethyl]benzonitrile, followed by 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester to give the title compound (16 mg, 17%).

[0572] 1H 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)

[0573] MS (ESI+) m / z 370 (M+H) +

[0574] Embodiment 54

[0575]

[0576] 3-((R)-1-(6-((R)-Pyrrolidin-3-ylamino)cinnolin-4-ylamino)ethyl)benzonitrile

[0577] As described in Example 1, compound A-2e was synthesized using intermediate A-1 and 3-[(1R)-1-aminoethyl]benzonitrile, and then (R)-3-(4-((R)-1-(3-cyanophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 64%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester was used.

[0578] To a solution in which tert-butyl (R)-3-(4-((R)-1-(3-cyanophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidine-1-carboxylate (50 mg, 0.11 mmol) was dissolved in dichloromethane (3 ml) was added a solution of 4N hydrochloric acid (0.40 ml, 1.0 mmol) in 1,4-dioxane at 0°C, followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting mixture was concentrated and extracted with aqueous sodium bicarbonate and ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated to give 3-((R)-1-(6-((R)-pyrrolidin-3-ylamino)cinnolin-4-ylamino)ethyl)benzonitrile (13 mg, 33%) as a yellow solid.

[0579] 1H 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=7.2Hz,1H),5.02-4.98(m,1H),4.32-4.11(m,2H),3.24-3.18(m,1 H),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)

[0580] MS (ESI+) m / z 359 (M+H) +

[0581] Embodiment 55

[0582]

[0583] 3-((1R)-1-((6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)cinnolin-4-yl)amino)ethyl)-5-(difluoromethyl)phenol

[0584] Step 1

[0585]

[0586] N-((R)-1-(3-(Benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)cinnolin-4-amine

[0587] As described in Example 1, compound A-2f was synthesized using intermediate A-1 and intermediate IA, and then N-(R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)cinnoline-4-amine (40 mg, 32%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used.

[0588] Step 2

[0589]

[0590] 3-((1R)-1-((6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)cinnolin-4-yl)amino)ethyl)-5-(difluoromethyl)phenol

[0591] To a solution of N-((R)-1-(3-(benzyloxy)-5-(difluoromethyl)phenyl)ethyl)-6-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)cinnolin-4-amine (20 mg, 0.04 mmol) in methanol (1 ml) was added 10% Pd / C (4 mg, 20% wt), then hydrogen was added to the reaction vessel and stirred at 1 atmosphere. The reaction mixture was filtered through a pad of celite and then concentrated to give 3-((1R)-1-((6-(oxa-3-azabicyclo[3.1.1]heptane-3-yl)cinnolin-4-yl)amino)ethyl)-5-(difluoromethyl)phenol (8 mg, 51%) as a yellow solid.

[0592] 1 H 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,3 H),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)

[0593] MS (ESI+) m / z 413 (M+H) +

[0594] Embodiment 56

[0595]

[0596] 6-(6-Oxa-3-azabicyclo[3.1.1]heptane-3-yl)-N-((R)-1-(2,3-difluorophenyl)ethyl)cinnolin-4-amine

[0597] As described in Example 1, compound A-2g was synthesized using intermediate A-1 and (aR)-2,3-difluoro-a-methylbenzylamine, and then the title compound (15 mg, 20%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used.

[0598] 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)

[0599] MS (ESI+) m / z 383 (M+H) +

[0600] Embodiment 57

[0601]

[0602] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((R)-2-methylmorpholino)cinnolin-4-amine

[0603] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (20 mg, 24%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (R)-2-methylmorpholine was used.

[0604] 1H 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=6.6H z,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)

[0605] MS (ESI+) m / z 417 (M+H) +

[0606] Embodiment 58

[0607]

[0608] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(furan-3-yl)cinnolin-4-amine

[0609] Compound A-2 was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine as described in Example 1, followed by 3-furanboronic acid pinacol ester to give the title compound (40 mg, 42%).

[0610] 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)

[0611] MS (ESI+) m / z 484 (M+H) +

[0612] Embodiment 59

[0613]

[0614] N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((S)-2-methylmorpholino)cinnolin-4-amine

[0615] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (41 mg, 49%) was obtained in essentially the same manner as described in the synthesis method of Example 5, except that (S)-2-methylmorpholine was used.

[0616] 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)

[0617] MS (ESI+) m / z 417 (M+H) +

[0618] Embodiment 60

[0619]

[0620] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)(oxetan-3-yl)methanone

[0621] Step 1

[0622]

[0623] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnolin-4-amine hydrochloride

[0624] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-1-dimethylethyl ester-1-(2H)-picolinic acid was used to provide (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.33 g, 67%).

[0625] To a solution in which tert-butyl (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.33 g, 2.67 mmol) was dissolved in dichloromethane (10 ml) was added a solution of 4N hydrochloric acid (10 ml, 40 mmol) in 1,4-dioxane at 0°C, followed by stirring at room temperature for 2 hours. After the reaction was completed, the resulting 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.

[0626] MS (ESI+) m / z 399 (M+H) +

[0627] Step 2

[0628]

[0629] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)(oxetan-3-yl)methanone

[0630] After adding (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) to dimethyl sulfoxide (1 ml), the resulting mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, water was added and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated, and 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.

[0631] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.33(s,1H),8.06(d,J=8.8Hz,1H),7.9 9-7.92(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)

[0632] MS (ESI+) m / z 483 (M+H) +

[0633] Embodiment 61

[0634]

[0635] (R)-Cyclopropyl(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-5,6-dihydropyridin-1(2H)-yl)methanone

[0636] As described in Example 60, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline-4-amine hydrochloride was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)cinnoline-4-amine hydrochloride, and then cyclopropanecarboxylic acid was used in essentially the same manner as the synthesis method of Example 60 to give the title compound (26 mg, 48%).

[0637] 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),3.84-3.68(m,1H),2.24-1.98(m,1H),1.70(d,J=6.8Hz,3H),0.83-0.71(m,4H)

[0638] MS (ESI+) m / z 467 (M+H) +

[0639] Embodiment 62

[0640]

[0641] (R)-Cyclopropyl(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)methanone

[0642] As described in Example 41, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazine-1-yl)cinnoline-4-amine hydrochloride were synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazine-1-yl)cinnoline-4-amine hydrochloride, and cyclopropanecarboxylic acid was then used in essentially the same manner as in the synthesis method of Example 41 to give the title compound (26 mg, 23%).

[0643] 1H 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)

[0644] MS (ESI+) m / z 470 (M+H) +

[0645] Embodiment 63

[0646]

[0647] (R)-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone

[0648] As described in Example 41, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazine-1-yl)cinnoline-4-amine hydrochloride was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazine-1-yl)cinnoline-4-amine hydrochloride, and then tetrahydro-2H-pyran-4-carboxylic acid was used in essentially the same manner as in the synthesis method of Example 41 to give the title compound (60 mg, 56%).

[0649] 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=54.8H z,1H),5.30(q,J=7.6Hz,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)

[0650] MS (ESI+) m / z 514 (M+H) +

[0651] Embodiment 64

[0652]

[0653] (4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)((R)-tetrahydrofuran-3-yl)methanone

[0654] As described in Example 41, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazine-1-yl)cinnoline-4-amine hydrochloride was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazine-1-yl)cinnoline-4-amine hydrochloride, and then (3R)-tetrahydro-3-furancarboxylic acid was used in a manner essentially the same as the synthesis method of Example 41 to give the title compound (55 mg, 52%).

[0655] 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)

[0656] MS (ESI+) m / z 500 (M+H) +

[0657] Embodiment 65

[0658]

[0659] (4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)((S)-tetrahydrofuran-3-yl)methanone

[0660] As described in Example 41, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazine-1-yl)cinnoline-4-amine hydrochloride was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazine-1-yl)cinnoline-4-amine hydrochloride, and then (3S)-tetrahydro-3-furancarboxylic acid was used in essentially the same manner as the synthesis method of Example 41 to give the title compound (15 mg, 14%).

[0661] 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)

[0662] MS (ESI+) m / z 500 (M+H) +

[0663] Embodiment 66

[0664]

[0665] (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)-2-hydroxyethanone

[0666] As described in Example 41, (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(piperazine-1-yl)cinnoline-4-amine hydrochloride was synthesized using intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine, and then ethanolic acid was used in essentially the same manner as the synthesis method of Example 41 to give the title compound (20 mg, 21%).

[0667] 1H 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)

[0668] MS (ESI+) m / z 460 (M+H) +

[0669] Embodiment 67

[0670]

[0671] (R)-1-(4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperazin-1-yl)ethanone

[0672] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then the title compound (24 mg, 22%) was obtained in a manner essentially the same as the synthesis method of Example 5, except that 1-acetylpiperazine was used.

[0673] 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,1H),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)

[0674] MS (ESI+) m / z 444 (M+H) +

[0675] Embodiment 68

[0676]

[0677] (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(isoxazol-4-yl)cinnolin-4-amine

[0678] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then 4-isoxazole boronic acid pinacol ester was used in a manner essentially the same as the synthesis method of Example 1 to obtain the title compound (29 mg, 29%).

[0679] 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)

[0680] MS (ESI+) m / z 385 (M+H) +

[0681] Embodiment 69

[0682]

[0683] (R)-N-(1-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperidin-4-yl)oxetane-3-carboxamide

[0684] Step 1

[0685]

[0686] N-(Piperidin-4-yl)oxetane-3-carboxamide

[0687] After adding 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) in dimethyl sulfoxide (20 ml), the resulting mixture was stirred at room temperature for 16 hours. After confirming that the reaction was complete, water was added and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated, and the residue was then purified by column chromatography to obtain 4-(oxetane-3-carboxamido)piperidine-1-carboxylic acid benzyl ester (120 mg, 6%) as a clear liquid.

[0688] 10% Pd / C (30 mg, 20% wt) was added to a solution of 4-(oxetane-3-carboxamido)piperidine-1-carboxylic acid benzyl ester (140 mg, 0.44 mmol) in ethyl acetate / methanol (3:1, 4 ml), and then hydrogen was charged into the reaction vessel and stirred at 1 atmosphere. The reaction mixture was filtered through a celite pad and then concentrated to give N-(piperidin-4-yl)oxetane-3-carboxamide (38 mg, 21%) as a yellow liquid.

[0689] Step 2

[0690]

[0691] (R)-N-(1-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)piperidin-4-yl)oxetane-3-carboxamide

[0692] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine were used to synthesize compound A-2, and then the title compound (15 mg, 18%) was obtained in a manner essentially the same as the synthesis method of Example 5, except that N-(piperidin-4-yl)oxetane-3-carboxamide was used.

[0693] 1H 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),3.03-2.97(m,2H),1.97-1.92(m,2H),1.66(d,J=6.8Hz,3H),1.60-1.49(m,2H)

[0694] MS (ESI+) m / z 500 (M+H) +

[0695] Embodiment 70

[0696]

[0697] (R)-4-(4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-1-methylpiperidin-4-ol

[0698] A solution of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)cinnoline-4-amine (100 mg, 0.24 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedione)manganese(III) (7 mg, 0.23 mmol) dissolved in isopropanol and dichloromethane (4 ml / 0.5 ml) was stirred for 5 minutes under air bubbling. Then, phenylsilane (50 mg, 0.47 mmol) was added and stirred at room temperature for 2 hours under air bubbling. After the reaction was completed, a saturated sodium thiosulfate solution was added and then stirred for 1 hour. 1N hydrochloric acid was added to the reaction solution, which was then washed with dichloromethane. The resulting water layer was alkalized to pH 14 by adding sodium bicarbonate aqueous solution and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated, and 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.

[0699] 1H 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)

[0700] MS (ESI+) m / z 431 (M+H) +

[0701] Embodiment 71

[0702]

[0703] Methyl 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)cyclohex-3-enecarboxylate

[0704] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then 1,3,2-dioxaborolane and 3-cyclohexene-1-carboxylic acid were used in a manner essentially the same as the synthesis method of Example 1 to obtain the title compound (332 mg, 60%).

[0705] 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),7.63(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,2H),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)

[0706] MS (ESI+) m / z 456 (M+H) +

[0707] Embodiment 72

[0708]

[0709] 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)cyclohex-3-enecarboxylic acid

[0710] To a solution of methyl 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnoline-6-yl)cyclohex-3-enecarboxylate (250 mg, 0.65 mmol) in tetrahydrofuran and H2O (3 ml / 0.6 ml) was added LiOH (125 mg, 6.5 mmol) and stirred at room temperature for 16 hours. After confirming that the reaction was complete, 1N HCl was added to reach pH 4 to 5, followed by extraction with ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated to give 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnoline-6-yl)cyclohex-3-enecarboxylic acid (190 mg, 66%) as a yellow solid.

[0711] 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)

[0712] MS (ESI+) m / z 442 (M+H) +

[0713] Embodiment 73

[0714]

[0715] 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-N-(oxetan-3-yl)cyclohex-3-enecarboxamide

[0716] After adding 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) in dimethyl sulfoxide (1 ml), the resulting mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, water was added and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated, and the residue was then purified by column chromatography to give 4-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-yl)-N-(oxetane-3-yl)cyclohex-3-enecarboxamide (24 mg, 37%) as a yellow solid.

[0717] 1 H NMR(400MHz, DMSO-d6)δ8.70(d,J=6.8Hz,1H),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,2 H),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)

[0718] MS (ESI+) m / z 497 (M+H) +

[0719] Embodiment 74

[0720]

[0721] 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

[0722] The title compound (45 mg, 66%) was obtained using 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride in substantially the same manner as in the synthesis method of Example 73.

[0723] 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),7.98-7.9 2(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,1H),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)

[0724] MS (ESI+) m / z 523 (M+H) +

[0725] Embodiment 75

[0726]

[0727] ((R)-3-(4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamino)cinnolin-6-ylamino)pyrrolidin-1-yl)(oxetan-3-yl)methanone

[0728] After adding 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) to dimethyl sulfoxide (1 ml), the resulting mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction, water was added and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated, and the residue was then 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.

[0729] 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),3.8 1-3.73(m,1H),3.53-3.36(m,4H),2.33-2.23(m,1H),1.70(d,J=6.8Hz,3H)

[0730] MS (ESI+) m / z 486 (M+H) +

[0731] Embodiment 76

[0732]

[0733] 6-(3-oxabicyclo[4.1.0]heptane-6-yl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)cinnolin-4-amine

[0734] As described in Example 1, intermediate A-1 and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethylamine were used to synthesize compound A-2, and then 4,4,5,5-tetramethyl-2-[3-oxabicyclo[4.1.0]hept-6-yl]1,3,2-dioxaborolane was used in a manner essentially the same as the synthesis method of Example 1 to give the title compound (4 mg, 4%).

[0735] 1H NMR (400MHz, MeOD) δ8.24(s,1H),8.15(s,1H),7.97(d,J=8.8Hz,1H),7.74(dd,J=2.0Hz,8.8Hz,1H),7 .57(ddd,J=7.4Hz,7.4Hz,15.2Hz,2H),7.16(t,J=7.8Hz,1H),6.96(t,J=54.8Hz,1H),5.21(q,J=6.8H z,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)

[0736] MS (ESI+) m / z 414 (M+H) +

[0737] <Experimental Example>

[0738] Experimental Example 1. Biochemical Test

[0739] 1-1. KRAS::SOS1 HTRF binding analysis

[0740] The SOS1 inhibitory ability of the compounds of the examples of the present invention was confirmed by identifying the effect of the compounds of the examples of the present invention on inhibiting the protein-protein interaction between SOS1 and KRAS G12C.

[0741] 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 4 μl was dispensed into a 384-well plate (6007290, PerkinElmer, USA). 2 μl of compound and 4 μl of Tag2-SOS1 were placed, and then 10 μl of premixed anti-Tag1 XL665 antibody and anti-Tag2 Tb cryptate antibody were dispensed into each well. The plate was sealed and allowed to react at room temperature for 1 hour and 40 minutes, and then used A compatible reader (Synergy H4, BioTeK, USA) measured the wavelengths of 665 nm and 620 nm, and the ratio of the acceptor and donor emission signals for each well was calculated as 665 nm / 620 nm × 10 4 .

[0742] This approach demonstrates the molecular mode of action of the compounds, and the high inhibition rates in the context of this assay indicate high potency of the SOS1 inhibitor compounds.

[0743] The results are listed in Table 4.

[0744] (+++: greater than 70 to 100% inhibition, ++: greater than 40 to 70% inhibition, +: 0 to 40% inhibition)

[0745]

Table 4

[0746]

[0747]

[0748] 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 μM, and it can be confirmed that most of the compounds of the present invention exhibit very high SOS1 inhibition rates.

[0749] In other words, it could be confirmed that the compounds according to the present invention could exhibit high SOS1 inhibitory efficacy.

[0750] 1-2. EGFR kinase inhibition analysis

[0751] The EGFR kinase inhibitory efficacy of the compounds according to the examples of the present invention was confirmed.

[0752] Specifically, purchase and use ADP-Glo TM Enzyme assay system (V3831, Promega Corporation, USA). 5x kinase reaction buffer (phosphorylase reaction buffer) was diluted to 1.5x and prepared, and then 6ng of epidermal growth factor receptor (EGFR) and 25M of ATP were prepared in EGFR kinase (phosphorylase) and ATP using 1.5x kinase reaction buffer, and then 2μl of EGFR kinase and 2μl of substrate / 2μl of ATP mixture were mixed with 1μl of compound 1 in a 384-well plate (REF4513, Corning, USA) and reacted at room temperature for 60 minutes. ADP-Glo ​​was added in an amount of 5μl / well TM Reagent, and make it react at room temperature for 40 minutes to stop EGFR kinase reaction and remove unused ATP.Add 10 μ l of kinase detection reagent (phosphorylase detection reagent), and react at room temperature for 30 minutes, to convert ADP into ATP, and use luciferase and luciferin to show ATP.Use the luminescence of ELISA reader (Synergy H4, BioTek, USA) to detect.

[0753] This method demonstrates the EGFR kinase-selective molecular mode of action of the compounds, with high IC 50 values, indicating no EGFR kinase inhibitory efficacy.

[0754] The results are listed in Table 5.

[0755]

Table 5

[0756] Compound <![CDATA[IC 50 (nM)]]> Gefitinib 13.90 Example 2 >10,000 Example 5 >10,000

[0757] As can be seen from Table 5 above, compared with the control EGFR kinase inhibitor (Gefitinib), it is found that the compounds of the present invention have no EGFR kinase inhibitory effect, indicating that the compounds of the present invention have high selectivity for SOS1.

[0758] In other words, the compounds of the present invention may exhibit high selectivity for SOS1 and high SOS1 inhibitory potency, and thus the compounds of the present invention may be advantageously used for treating diseases associated with SOS1 activity.

[0759] Although the present invention has been described in detail above, it is obvious to those skilled in the art that such detailed description is only for illustrating exemplary embodiments and should not be interpreted as limiting the scope of the present invention. Therefore, it should be understood that the essential scope of the present invention is limited by the appended claims and their equivalents.

Claims

1. A compound represented by the following formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof: [Formula 1] In the above formula 1, A is for C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, 3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, C 6-12 Aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, n is 0, 1, 2, 3, or 4; R1 is C 1-6 Alkyl, C 6-12 Aryl, -CF2H, -CF 3、 -CN, -OH, -NH2 or halogen (wherein when n is 2 or greater, the n R1 are each independent of each other), R1 C 1-6 Alkyl, C 6-12 At least one of the H groups of the aryl group, -CF2H and -OH is independently replaced by C 1-6 Alkyl (where C 1-6 At least one H in the alkyl group is independently replaced by -OH, -OC 1-6 Alkyl or -NR a R b substituted) or halogen substituted; 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 halogen; L1 is a single bond, -(C=O)-, -(C=O)O-, -O-, -(C=O)NR e -、-NR e -、-NR e (C=O)-、-NR e SO2-, or -NR e (C=O)NR f -; 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 N, O and S in the ring, C 3-8 Cycloalkenyl, 3- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, (where m is 0 or 1, Y1 is CH2, NR j or O, and R ja , R jb , R jc and R jd Each independently is H or C 1-5 Alkyl, provided that it is selected from R ja , R jb , R jc and R jd two of which are connected to form CH2 or CH2-CH2), or (wherein o and p are each independently 1 or 2, q and r are each independently 0, 1 or 2, and Y2 and Y3 are each independently CH2, NR k or O), In R3, a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, or At least one -CH2- of the compound is replaced by -(C=O)-, -SO- or -SO2-, R3 C 3-8 At least one -CH2- of the cycloalkyl group is replaced by -SO2-, At least one H of R3 is independently replaced by C 1-6 Alkyl, -OH, halogen or -L2-R4 substitution; 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 N, O and S in the ring, C 6-12 Aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, -NR h R i , -CF3, -CF2H, -OH or halogen, At least one H of R4 is independently replaced by C 1-6 Alkyl, -OH, -OC 1-6 Alkyl, -NR m R n or halogen substituted; and 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 Each independently is H or C 1-6 alkyl.

2. The compound represented by Formula 1 according to claim 1, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer, or its pharmaceutically acceptable salt, In the above formula 1, A is for C 6-12 Aryl, 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, 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 greater, the n R1 are each independent of each other), R1 C 1-6 Alkyl, C 6-12 The aryl group and at least one of the H groups in -CF2H are each independently replaced by a C 1-6 Alkyl (where C 1-6 At least one H in the alkyl group is independently replaced by -OH, -OC 1-6 Alkyl or -NR a R b substituted) or halogen substituted; X1 and X3 are each CH; X2 is CR2; and 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 Each is the same as defined in claim 1.

3. The compound represented by Formula 1 according to claim 1, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer, or its pharmaceutically acceptable salt, In the above formula 1, A is for C 6-12 Aryl; n is 1 or 2; R1 is each 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 -; R3 is a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, C 3-8 Cycloalkenyl, 3 to 8 membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, or 5 to 12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, wherein the heterocycloalkyl group includes wherein Y1 is O, and Y3 are each independently CH2, NR k or O, At least one H of R3 is independently replaced by C 1-6 Alkyl, -OH, halogen or -L2-R4 substitution; 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 N, O and S in the ring, -NR h R i or halogen, At least one H of R4 is each independently substituted with -OH; and R e , R g , R h , R i and R k Each independently is H or C 1-6 alkyl.

4. The compound represented by Formula 1 according to claim 1, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer, or its pharmaceutically acceptable salt, In the above formula 1, A is for C 6-12 Aryl; n is 2; R1 is each 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 -; R3 is a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, or a 3- to 8-membered heterocycloalkenyl group containing 1 to 3 heteroatoms independently selected from N, O and S in the ring, wherein the heterocycloalkyl group includes wherein Y1 is O, and Y3 are each independently CH2, At least one H of R3 is independently replaced by C 1-6 Alkyl, -OH or -L2-R4 substitution; 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 N, O and S in the ring, or -NR h R i , At least one H of R4 is each independently substituted with -OH; and R e , R g , R h and R i Each independently is H or C 1-6 alkyl.

5. A compound described in the following table, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer, or its pharmaceutically acceptable salt:

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or a pharmaceutically acceptable salt thereof, for preventing, improving or treating a disease associated with SOS1 activity.

7. The pharmaceutical composition according to claim 6, wherein the disease associated with SOS1 activity comprises cancer.

8. The pharmaceutical composition according to claim 7, wherein the cancer comprises at least one disease selected from the group consisting of 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, cerebrospinal fluid tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, Ewing family tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational choriocarcinoma, glioma, Hodgkin's Lymphoma, Kaposi's sarcoma, kidney cancer, hypopharyngeal cancer, liver cancer, lung cancer, lymphoma (including cutaneous T-cell lymphoma), malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal and paranasal cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach 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 tumor, granular cell tumor of the skin, and lung adenocarcinoma.

9. A method for preventing, ameliorating or treating a disease associated with SOS1 activity, the method comprising administering to an individual in need thereof a compound according to any one of claims 1 to 5, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

10. The method of claim 9, wherein the disease associated with SOS1 activity comprises cancer.

11. Use of the compound according to any one of claims 1 to 5, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising them for preventing, improving or treating a disease associated with SOS1 activity.

12. Use of the compound according to any one of claims 1 to 5, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising them in the preparation of a medicament for preventing, improving or treating 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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