Pharmaceutical composition for treating cancer comprising an SOS1 inhibitor and an anticancer drug

Abstract

A pharmaceutical composition for preventing or treating cancer is provided, which comprises a novel compound having SOS1 inhibitory activity and an anticancer agent as active ingredients. The novel compound according to the present invention inhibits the interaction between SOS1 and RAS family proteins or between SOS1 and RAC1, thereby exhibiting synergistic anticancer activity when combined with other anticancer agents. Therefore, a pharmaceutical composition for treating cancer, which comprises the novel compound and an anticancer agent as active ingredients, can be useful for preventing or treating cancer.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to a pharmaceutical composition for preventing or treating cancer, which comprises a novel compound having SOS1 inhibitory activity, a solvate, stereoisomer or pharmaceutically acceptable salt thereof, and an anticancer agent as active ingredients, and to medical uses thereof.

[0002] [Background technology] Mutations in the RAS gene are a major oncogene with a high incidence in human cancers, and are observed in 20-30% of human cancers, particularly in lung, colon, rectal, and pancreatic cancers. RAS family proteins include KRAS, NRAS, and HRAS.

[0003] RAS proteins are small GTPases that exist in cells in either a GTP- or GDP-bound state and are molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state. Mutations in RAS genes reduce the ability of RAS GTPases to hydrolyze GTP, leaving this molecular switch in a constitutively active GTP-bound conformation, thereby inducing oncogenic downstream signaling (e.g., the RAF-MEK-ERK pathway or the PI3K-PDK1-AKT pathway).

[0004] On the one hand, the binding of GTPase-activating proteins (GAPs), such as NF1, downregulates active RAS by accelerating the weak intrinsic GTPase activity of the RAS protein, returning it to its inactive form, whereas the binding of guanine nucleotide exchange factors (GEFs), such as SOS1, promotes the release of GDP from the RAS protein, increasing its GTP-bound active state.

[0005] Various studies on direct or indirect RAS inhibition have been conducted in the prior art. However, direct RAS inhibition has proven extremely difficult due to the picomolar-level affinity of GTP for the binding site, the lack of other well-defined pockets, and the fact that RAS interacts with GEFs, GAPs, and effectors through a broad and flat protein-protein interaction surface, making the application of small molecule drugs difficult. In addition, attempts have been made to indirectly inhibit RAS by targeting farnesyltransferase, but no approved drugs have yet been prepared. Given that RAS cannot be inhibited directly or indirectly, it has generally been considered difficult to develop drugs targeting RAS.

[0006] Under these circumstances, a method of inhibiting RAS by blocking the interaction between RAS and GEFs to prevent GTP reloading has emerged.

[0007] SOS1 (Son of Sevenless 1) is a guanine nucleotide exchange factor (GEF) that regulates RAS family protein signaling by promoting GDP release from RAS family proteins, allowing them to bind GTP. SOS proteins exist in two isoforms, SOS1 and SOS2, and only SOS1 is phosphorylated by ERK. Growth factor-induced phosphorylation of SOS1 is primarily mediated by ERK, which phosphorylates at least four serine residues in the C-terminal region of SOS1. This suggests that SOS1 plays an important role in negative feedback regulation of the KRAS pathway. The SOS1 protein consists of 1,333 amino acids (150 kDa). SOS1 is a multidomain protein with two tandem N-terminal histone domains (HD), followed by a Dbl homology domain (DH), a pleckstrin homology domain (PH), a helical linker (HL), a RAS exchange motif (REM), a CDC25 homology domain, and a C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins: a catalytic site that binds GDP-bound RAS family proteins and promotes guanine nucleotide exchange, and an allosteric site that binds GTP-bound RAS family proteins and upregulates the activity of the SOS1 catalytic site (J. Med. Chem. 2021, 64, 10, 6569-6580). Selective pharmacological inhibition of the binding of the SOS1 catalytic site to RAS family proteins is expected to suppress SOS1-mediated activation of RAS family proteins in their GTP-bound form.

[0008] Therefore, SOS1 inhibitor compounds are expected to inhibit intracellular signaling downstream of RAS family proteins (e.g., ERK phosphorylation), and novel SOS1 inhibitor compounds that bind to the SOS1 catalytic site and suppress the binding and activation of RAS family proteins are currently under development.

[0009] It has been reported that SOS1 is critically involved in mutant KRAS activation and oncogenic signaling in cancer (Current Opinion in Chemical Biology, 2021, 62:109-118). Depletion of SOS1 levels reduced the survival of tumor cells harboring KRAS mutations, but this effect was not observed in KRAS wild-type cell lines. The depletion effect of SOS1 was due to the impaired catalytic site of SOS1. F929A Mutations or SOS1 mutations defective in GTP-KRAS binding at the allosteric site (SOS1 L687E / R688A ), suggesting that targeting the catalytic or allosteric sites of SOS1 may be an effective option for the treatment of KRAS-mutated cancers.

[0010] In addition, SOS1 is critically involved in the activation of RAS family protein signaling in cancer through mechanisms other than mutations in RAS family proteins. SOS1 interacts with the adaptor protein Grb2 to form the SOS1 / Grb2 complex. This complex binds to activated / phosphorylated receptor tyrosine kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3, and AXL). Additionally, SOS1 has been reported to localize to other phosphorylated cell surface receptors, such as T cell receptor (TCR), B cell receptor (BCR), and monocyte colony-stimulating factor receptor (MCFR), resulting in the activation of RAS family proteins.

[0011] Furthermore, SOS1 is a GEF for the activation of the GTPase RAC1 (Ras-related C3 botulinum toxin substrate 1). RAC1, like RAS family proteins, is known to be involved in the pathogenesis of various cancers and other diseases.

[0012] Currently, BI3406, BI1701963, MRTX0902, etc. are being developed as inhibitors of SOS1 activity, but are still in the early stages of development. Therefore, there remains a need in the art for the development of novel compounds and pharmaceutical compositions containing the same that treat cancer by inhibiting SOS1.

[0013] [Detailed Description of the Invention] [Technical issue] It is an object of the present invention to provide a pharmaceutical composition comprising a compound of formula I, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, and an anti-cancer agent.

[0014] An object of the present invention is to provide the use of a pharmaceutical composition comprising a compound of formula I, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, and an anti-cancer agent for the prevention or treatment of cancer.

[0015] It is an object of the present invention to provide a method for preventing or treating cancer by administering a pharmaceutical composition comprising a compound of formula I, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, and an anti-cancer agent.

[0016] An object of the present invention is to provide the use of a pharmaceutical composition comprising a compound of formula I, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, and an anti-cancer agent for the manufacture of a medicament for the prevention or treatment of cancer.

[0017] [Problem Solution] Each description and embodiment disclosed herein may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of this application. In addition, the scope of this application should not be construed as being limited by the specific description provided below.

[0018] In one embodiment of the present invention, a compound of formula 1: [ka] [In formula 1, [ka] is a single or double bond; E is O or S; X is O or S; Z 1 is N or CH, and Z 2 are N, NH, and CR 1 or CHR 1 and Z 3 is CR 1 or CHR 1 where Z 1 , Z 2 and Z 3 at most one of is N or NH, Each R 1 H, halogen, OH, CN, NR b R c , C1-C6 alkyl optionally interrupted and / or optionally substituted with 1 to 3 oxygen or nitrogen atoms, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 acylamino, optionally substituted (C1-C6 alkyl)sulfonylamino 、 Optionally substituted C3-C6 cycloalkyl, optionally substituted 4-7 membered heterocycloalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C-C 10 Aryloxy, optionally substituted (C6-C 10 aryl)-(C1-C6 alkyl)oxy-, optionally substituted (C6-C 10 independently selected from the group consisting of (aryl)amino and optionally substituted 5-10 membered heteroaryl; or Z 1 If is N, then [ka] is a double bond, and Z 2 and Z 3 are all CR 1 In this case, two R 1 are optionally concatenated together to form two R 1 together with the carbon atom to which it is attached form a 5-membered heteroaryl containing one N, O or S; R' and R" are each independently H or C1-C3 alkyl, or R' and R" attached to the same carbon or adjacent carbons may together with the carbon atom to which R' and R" are attached form a C3-C4 cycloalkyl, wherein the C1-C3 alkyl and C3-C4 cycloalkyl are selected from the group consisting of at least one halogen, OH, CN, C1-C3 alkoxy, or NR b R c may be optionally substituted with; m is an integer from 1 to 3; A is Cy1 or Cy1-Y-Cy2; Y is NR d , C.R. d R e , O, S, or a direct bond; Cy1 and Cy2 each independently represent a C6-C cycloalkyl group optionally fused to a C3-C8 cycloalkyl group. 10 aryl or 5-10 membered heteroaryl; The Cy1 and Cy2 each have 1 to 3 R 2 may be optionally substituted with; R 2 H, halogen, OH, CN, oxo, amino, -NR b R C , -N=S(O)R b , -N=S(O)NR b R c , -SF5, -Si(C1-C3 alkyl)3, -SO2R b , -C(O)R b , C1-C6 alkyl optionally interrupted and / or optionally substituted with 1 to 3 oxygen or nitrogen atoms, optionally substituted C1-C6 alkoxy, and optionally substituted C3-C6 cycloalkyl; B is H, optionally substituted C1-C6 alkyl, -(CH2) o -Cy3 or -(CH2) o -Cy3-W-Cy4; o is an integer from 0 to 3; W is NR d , C.R. d R e , C(O), O, S, or a direct bond; Cy3 and Cy4 are each a C3-C6 monocyclic cycloalkyl or a C3-C6 monocyclic cycloalkenyl optionally fused with a 5-10 membered heterocycloalkyl or a 5-10 membered heteroaryl; a bicyclic, tricyclic, or tetracyclic bridged, fused, or spiro C5-C 20 Cycloalkyl or C5-C 20 Cycloalkenyl; C6-C optionally fused with 5- to 10-membered heterocycloalkyl 10 independently selected from the group consisting of aryl; 5-10 membered monocyclic heteroaryl optionally fused to C3-C6 cycloalkyl; 5-10 membered bicyclic heteroaryl; 4-10 membered saturated or partially unsaturated monocyclic heterocycloalkyl optionally fused to C3-C6 cycloalkyl; and 5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl; Cy3 and Cy4 each independently represent 1 to 3 R 3 may be optionally substituted with; R 3 H, deuterium, halogen, OH, CN, oxo, -NR b R c , -N=S(O)R b , -N=S(O)NR b R c , -SO2R b , -C(O)R b , -C(O)OR b , -CONR b R c , -NR b COR c , -NR b C(O)OR c , -NR b SO2R c, -NHCO-(C3-C6 cycloalkyl), optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C3-C6 cycloalkyl; R b and R c are each independently H or optionally substituted C1-C6 alkyl; and R d and R e are each independently H or optionally substituted C1-C6 alkyl. or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof; and an anticancer agent as active ingredients, for preventing or treating cancer.

[0019] In this disclosure, "optionally substituted" as used in the definition of a substituent means that the structure is unsubstituted or is one of the following: (i) halogen, OH, CN, oxo, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; (ii) C1-C3 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen, OH, CN, oxo, NH2, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2; (iii) C1-C3 alkoxy optionally substituted with at least one substituent selected from the group consisting of halogen, OH, CN, oxo, NH2, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2; and (iv) C3-C6 cycloalkyl optionally substituted with at least one substituent selected from the group consisting of halogen, OH, CN, oxo, NH2, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2 It can mean that the group is substituted with at least one substituent selected from the group consisting of:

[0020] In one embodiment, optionally substituted moieties may be substituted with one or more of the same or different substituents selected from the group consisting of halogen, OH, CN, NH, NH(C1-C6 alkyl), N(C1-C6 alkyl) and C1-C3 alkoxy.

[0021] In one embodiment, an "optionally substituted" group may be unsubstituted or substituted with at least one substituent selected from the group consisting of deuterium, halogen, OH, CN, oxo, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, and C1-C6 alkoxy. In this case, two or more substituents may be substituted on the same atom or different atoms. For example, 1-fluoro-2-oxopropyl is an alkyl group substituted with oxo and fluoro, respectively, on different carbon atoms of the propyl group, and is encompassed by "optionally substituted alkyl" in the present disclosure. As used herein, when two or more substituents are substituted on the same moiety, the two or more substituents may be substituted on the same atom or different atoms of the moiety.

[0022] In the above formula 1, E may be O or S. For example, E may be O.

[0023] In formula 1, X may be O or S. For example, X may be O.

[0024] In equation 1, Z 1 may be N or CH, Z 2 are N, NH, and CR 1 or CHR 1 Z may be 3 is CR 1 or CHR 1 may be.

[0025] [ka] may be a single bond or a double bond. 1 , Z 2 and Z 3 At most one of is N or NH.

[0026] Alternatively, Z 1 If is N, then [ka] is a double bond, and Z 2 and Z 3 are all CR 1 In this case, two R 1 are optionally concatenated together to form two R 1 may be taken together with the carbon atom to which it is attached to form a 5-membered heteroaryl ring containing one N, O or S.

[0027] In the above formula 1, m may be an integer of 1 to 3. For example, m may be 1 or 2. In one embodiment, m may be 1. When m is 2 or 3, R' bonded to each carbon atom in the alkylene chain may be the same as or different from each other. When m is 2 or 3, R'' bonded to each carbon atom in the alkylene chain may be the same as or different from each other.

[0028] In one embodiment, R′ and R″ are each independently H or C 1~3 It may be alkyl, such as -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2. The C1-C3 alkyl may be at least one of halogen, OH, CN, C1-C3 alkoxy or NR b R c In this case, R b and R c may each independently be H or an optionally substituted C1-C3 alkyl. In one embodiment, R' and R'' are both C 1~3In one embodiment, R' and R" may both be H. In one embodiment, one of R' and R" may be H and the other may be C. 1~3 For example, one of R' and R'' may be H and the other may be methyl, ethyl, difluoromethyl, fluoromethyl, hydroxymethyl, aminomethyl, etc., but is not limited to these.

[0029] In some embodiments, R' and R" attached to the same carbon or adjacent carbons may be taken together with the carbon atom to which R' and R' are attached to form a cyclopropyl or cyclobutyl ring. The cyclopropyl or cyclobutyl ring may contain at least one halogen, OH, CN, C1-C3 alkoxy, or NR b R c In this case, R b and R c may each independently be H or an optionally substituted C1-C3 alkyl. For example, R' and R" together with the alkylene chain to which they are attached may form, but are not limited to, the following structure: [ka] may be formed.

[0030] In the above formula 1, R 1 H, halogen, OH, CN, NR b R c , C1-C6 alkyl optionally interrupted by 1 to 3 oxygen or nitrogen atoms, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 acylamino, optionally substituted (C1-C6 alkyl)sulfonylamino, or C3-C6 cycloalkyl. In one embodiment, R 1may be H, OH, CH3, -CH=CH2, -C≡CH, CN, or optionally substituted cyclopropyl.

[0031] In one embodiment, R 1 may be an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, or an optionally substituted C2-C6 alkynyl, preferably an optionally substituted C1-C3 alkyl. In this case, the optionally substituted C1-C6 alkyl or C1-C3 alkyl, the optionally substituted C2-C6 alkenyl, or the optionally substituted C2-C6 alkynyl may be substituted with at least one substituent selected from the group consisting of the above substituents (i) to (iv). In this case, the at least one substituent may be a combination of two or more substituents selected from any one of (i), (ii), (iii), and (iv), or a combination of two or more substituents each selected from two or more of (i), (ii), (iii), and (iv), or a combination thereof. When two or more substituents are present, the substituents may be the same or different. For example, an optionally substituted C1-C6 alkyl or C1-C3 alkyl may be substituted with 1 to 5, 1 to 4, 1 to 3, 1, 2, or 3 substituents. For example, optionally substituted C1-C6 alkyl or C1-C3 alkyl includes -CF2CH2OH substituted with two F and one OH, -CF3 substituted with three F, and the like.

[0032] The C1-C6 alkyl may be optionally interrupted by 1 to 3 oxygen atoms or nitrogen atoms, and examples of the C1-C6 alkyl include, but are not limited to, methoxymethyl, methoxymethoxymethyl, ethoxymethyl, ethoxyethoxymethyl, methylaminomethyl, methylaminoethyl, dimethylaminomethyl, and dimethylaminoethyl.

[0033] In some embodiments, R 1is an optionally substituted 4- to 7-membered heterocycloalkyl, optionally substituted C-C 10 Aryl, optionally substituted C-C 10 Aryloxy, optionally substituted (C6-C 10 aryl)-(C1-C6 alkyl)oxy-, optionally substituted (C6-C 10 In one embodiment, R may be a 5- to 10-membered heteroaryl (aryl) amino or an optionally substituted 5- to 10-membered heteroaryl, in which case the optional substituents are as described above. 1 may be a 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, and S, such as, but not limited to, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, or piperazinyl. 1 Examples of R include, but are not limited to, 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N, O, and S, such as indolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, imidazolyl, or triazolyl. 1 may be phenyl or naphthyl.

[0034] In the formula 1 of the present invention, A may be Cy1 or Cy1-Y-Cy2, in which case Y is NR d , C.R. d R e , O, S or a direct bond. d and R e may each be H or optionally substituted C1-C6 alkyl, preferably H or optionally substituted C1-C3 alkyl, in which case the optional substituents are as defined above.

[0035] In A of the above formula 1, Cy1 and Cy2 each independently represent C6 to C 10C6-C fused with aryl, C3-C8 cycloalkyl 10 It may be aryl or 5- to 10-membered heteroaryl.

[0036] In one embodiment, Cy1 is C6 to C 10 It may be aryl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S. In one embodiment, Cy1 is C6-C 10 In another embodiment, Cy1 may be a 5- to 6-membered heteroaryl containing one or two N or S. For example, Cy1 may be phenyl, naphthalenyl, thiazolyl, thiophenyl, or pyrazolyl.

[0037] In one embodiment, Cy2 is a C6-C cycloalkyl fused to a C3-C6 cycloalkyl. 10 Aryl, C6-C 10 It may be aryl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S. In one embodiment, Cy2 is a C6-C cycloalkyl fused to a C3-C5 cycloalkyl. 10 Aryl or C6-C 10 In another embodiment, Cy2 may be a 5- or 6-membered heteroaryl containing one or two N or S atoms. For example, Cy2 may be phenyl, 2,3-dihydroindenyl, bicyclo[4.2.0]octa-1,3,5-trienyl, pyrazolyl, thiophenyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, or pyrrolyl.

[0038] In some embodiments, A can be Cy1, where Cy1 is C6-C 10 In some embodiments, A may be Cy1, where Cy1 is a 5-10 membered heteroaryl. In some embodiments, A may be Cy1-Y-Cy2, where Cy1 and Cy2 are each C6-C 10aryl, and Y may be O. For example, A may be phenyl-O-phenyl. In some embodiments, A may be Cy1-Y-Cy2, where Cy1 is C6-C 10 In some embodiments, A may be Cy1-Y-Cy2, where Cy1 may be a 5-10 membered heteroaryl and Cy2 may be a C6-C 10 It is aryl.

[0039] In some specific embodiments, the 5- to 10-membered heteroaryl of Cy1 or Cy2 may be, but is not limited to, indolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, imidazolyl, or triazolyl.

[0040] In addition, each of Cy1 and Cy2 has 1 to 3 R 2 R 2 is halogen, OH, CN, oxo, amino, -NR b R C , -N=S(O)R b , -N=S(O)NR b R c , -SF5, -Si(C1-C3 alkyl)3, -SO2R b , -C(O)R b , C1-C6 alkyl optionally interrupted by 1 to 3 oxygen or nitrogen atoms, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C3-C6 cycloalkyl. In this case, the optionally substituted substituents are as described above. In addition, R 2 Particular substituents of are as set forth in Formula I below.

[0041] In the formula 1 of the present invention, when A is Cy1-Y-Cy2, Cy 1 is 1 to 3 R 2aand optionally substituted with Cy 2 is 1 to 3 R 2b R 2a and R 2b is as set forth in Formula I below.

[0042] In the formula 1 of the present invention, B is H, optionally substituted C1-C6 alkyl, -(CH2) o -Cy3 or -(CH2) o -Cy3-W-Cy4, in which o may be an integer of 0 to 3. In addition, o may be 0 or 1.

[0043] In some embodiments, B is —(CH) o In some embodiments, B may be -Cy3. o -Cy3-W-Cy4, where W is NR d , C.R. d R e , O, S or a direct bond, d and R e may each be H or optionally substituted C1-C6 alkyl, preferably H or optionally substituted C1-C3 alkyl, in which case the optional substituents are as defined above.

[0044] In Formula 1 of the present invention, Cy3 and Cy4 are each independently a C3-C6 monocyclic cycloalkyl or a C3-C6 monocyclic cycloalkenyl, and the cycloalkyl or cycloalkenyl may be optionally fused with a 5- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl. In one embodiment, Cy3 and Cy4 are each independently cyclopropyl; cyclobutyl, cyclopentyl, cyclohexyl; cyclobutenyl; cyclopentenyl, cyclohexenyl; or cyclohexyl or cyclopentyl fused with pyrazole, piperazine, or tetrahydropyran. In one embodiment, the 5- to 10-membered heteroaryl fused with a cycloalkyl or cycloalkenyl may include, but is not limited to, indolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, imidazolyl, or triazolyl. In one embodiment, the 5-10 membered heterocycloalkyl fused to a cycloalkyl or cycloalkenyl can include, but is not limited to, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, or tetrahydro-2H-thiopyranyl.

[0045] In some embodiments, Cy3 and Cy4 are each independently a bicyclic, tricyclic, or tetracyclic bridged, fused, or spiro C5-C 20 Cycloalkyl or C5-C 20 In one embodiment, Cy3 and Cy4 each independently represent a bicyclic or tricyclic bridged or fused C5-C 15 Cycloalkyl or C5-C 15 In one embodiment, Cy3 is a bicyclic or tricyclic bridged C5-C 10 Cycloalkyl or C5-C 10In one embodiment, Cy3 can be, but is not limited to, bicyclo[2.2.2]octanyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, or bicyclo[1.1.1]pentanyl.

[0046] In some embodiments, Cy3 and Cy4 are each independently C6 to C 10 It may be aryl. In one embodiment, Cy3 may be phenyl or naphthyl.

[0047] In some embodiments, Cy3 and Cy4 can each independently be a 5-10-membered monocyclic or bicyclic heteroaryl, a 5-10-membered monocyclic heterocycloalkyl, or a 5-10-membered bicyclic bridged, fused, or spiroheterocycloalkyl, where the 5-10-membered monocyclic heteroaryl and the 5-10-membered monocyclic heterocycloalkyl are optionally fused to a C3-C6 cycloalkyl. In one embodiment, the 5-10-membered heteroaryl can contain one or two heteroatoms selected from N, O, or S, and the 5-10-membered heterocycloalkyl can be a 5- or 6-membered heterocycloalkyl containing one heteroatom selected from N, O, or S. In one embodiment, the 5-10-membered heteroaryl can include, but is not limited to, indolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, isothiazolyl, imidazolyl, or triazolyl. In one embodiment, the 5- or 6-membered heterocycloalkyl may include, but is not limited to, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, or tetrahydro-2H-thiopyranyl. In one embodiment, the 5- to 10-membered heteroaryl or 5- to 10-membered heterocycloalkyl may be optionally fused with a C3-C6 cycloalkyl or a C3-C6 cycloalkenyl, such as to form a pyrazolyl, piperazine, or tetrahydropyran fused with cyclohexyl. In one embodiment, the 5- to 10-membered heterocycloalkyl may be a bicyclic bridged, fused, or spiro heterocycloalkyl, such as, but not limited to, 3-oxabicyclo[2.1.1]hexanyl or 2-oxabicyclo[2.1.1]hexanyl. In one embodiment, Cy3 may be phenyl, naphthyl, pyridinyl, thiophenyl, tetrahydropyranyl, or piperidinyl.

[0048] In some embodiments, B is —(CH) o-Cy3-W-Cy4, where Cy3 and W are as described above and Cy4 can be phenyl or naphthyl. In one embodiment, Cy3 and Cy4 can each be phenyl and W can be a direct bond.

[0049] In one embodiment, B is —(CH) o -Cy3-W-Cy4, wherein Cy3 is a C3-C6 cycloalkyl, a C3-C6 cycloalkenyl, a 5- or 6-membered saturated or partially unsaturated heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, or S, a bridged bicyclic C 5~10 C6-C optionally fused to a 5- or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from cycloalkyl, N, O, or S 10 aryl and 5- or 6-membered monocyclic heteroaryl or 5- to 10-membered bicyclic heteroaryl containing 1 or 2 heteroatoms selected from N, O, or S. In this case, W may be NH, C(O), or a direct bond. Additionally, Cy4 may be a saturated or partially unsaturated 4- to 10-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, or S, C6-C 10 It may be selected from the group consisting of aryl and 5- or 6-membered monocyclic heteroaryl containing 1-4 heteroatoms selected from N, O, or S.

[0050] In B of formula 1 of the present invention, Cy3 and Cy4 each independently represent 1 to 3 R 3 R 3 is halogen, OH, CN, oxo, amino, -NR b R c , -N=S(O)R b , -N=S(O)NR b R c , -SO2R b , -C(O)R b , -CONR b R c , -NR b COR c , N.R. b SO2Rc , optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C3-C6 cycloalkyl; R b and R c may be H or optionally substituted C1-C6 alkyl, preferably optionally substituted C1-C3 alkyl, in which case the optional substituents are as defined above.

[0051] In the formula 1 of the present invention, when B is —(CH)—Cy—W—Cy, 3 is 1 to 3 R 3a and optionally substituted with Cy 4 is 1 to 3 R 3b R 3a and R 3b is as set forth in Formula I below.

[0052] The limitations on each structure and substituent of Formula 1 above, where applicable, can be equally applied to Formula I below. Similarly, the limitations on each structure and substituent of Formula I below, where applicable, can be equally applied to Formula 1 above.

[0053] In one embodiment of the present invention, a compound of formula I: [ka] [In formula I, [ka] is a single or double bond; Z 1 is N or CH; Z 1 If N, then Z 2 and Z 3 are both CHR 1 and [ka] is a single bond, or Z 2 and Z 3 are all CR 1 and [ka] is a double bond; Z 1 If is CH, then Z 2 is N or CR 1 and Z 3 is CR 1 and [ka] is a double bond; or Z 1 If N, then Z 2 and Z 3 are all CR 1 and [ka] is a double bond, in which case two R 1 are optionally concatenated together to form two R 1 may be taken together with the carbon atom to which it is attached to form a thiophene or pyrrole ring; Each R 1 H, halogen, CN, OH, NR b R c , C1-C6 alkoxy, C1-C6 acylamino, C1-C6 alkylsulfonylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C6-C 10 Aryloxy, (C6-C 10 aryl)-(C1-C6 alkyl)oxy and C6-C 10 independently selected from the group consisting of arylamino; R' and R'' are each independently H or C1-C3 alkyl, or R' and R'' together with the carbon atom to which they are attached may form a C3-C4 cycloalkyl, wherein the C1-C3 alkyl and C3-C4 cycloalkyl are substituted with at least one of halogen, OH, CN, C1-C3 alkoxy, or NR b R c may be optionally substituted with; A is Cy1 or Cy1-Y-Cy2; Y is O, S or a direct bond; Cy1 is C6 to C 10 aryl or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S; Cy1 has 1 to 3 R 2a may be optionally substituted with; R 2a H, halogen, OH, CN, oxo, SF5, NR b R c , -Si(C 1~3 Alkyl)3, -SO2R b , -C(O)R b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and [ka] selected from the group consisting of: R 21 H, halogen, OH, NR b R c , C1-C6 alkoxy or C1-C6 acyloxy, and R 22 and R 23 are each independently H, halogen, or C1-C2 alkyl; Cy2 is C6~C 10 aryl, phenyl fused with C3-C6 cycloalkyl, or 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S; Cy2 has 1 to 3 R 2bmay be optionally substituted with; R 2b H, halogen, OH, CN, oxo, NR b R c ;C1-C6 alkyl;Halogen, CN, OH, NR b R c or C1-C6 alkyl substituted with C1-C6 alkoxy; C1-C6 alkyl optionally interrupted with 1 to 3 oxygen atoms and / or nitrogen atoms; and C1-C6 alkyl substituted with hydroxy-(C1-C6 alkyl)amino-; B is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, NR b R c C1-C6 alkyl substituted with -(CH2) o -Cy3 or -(CH2) o -Cy3-W-Cy4; W is NH, C(O) or a direct bond; o is an integer of 0 or 1; Cy3 is C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 5- or 6-membered saturated or partially unsaturated heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S, bridged bicyclic C5-C 10 Cycloalkyl, C6-C 10 selected from the group consisting of aryl, phenyl fused to a 5- or 6-membered cyclic group containing one heteroatom selected from N, O, and S, and 5-10-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Cy3 has 1 to 3 R 3a may be optionally substituted with; R 3a is H, halogen, OH, CN, oxo, C1-C6 alkyl; C1-C6 alkyl substituted with halogen, OH, CN or C1-C6 alkoxy; C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkylamino, C1-C6 hydroxyalkylamino, (C3-C6 cycloalkyl)carbonylamino, -NRb R c , -NR b COR c , -NR b C(O)OR c , -SO2R b , -C(O)R b , -C(O)OR b , -NR b SO2R c and -CONR b1 R c1 selected from the group consisting of: Cy4 is a saturated or partially unsaturated 4- to 10-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, or S; C6-C 10 selected from the group consisting of aryl and 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S; Cy4 has 1 to 3 R 3b may be optionally substituted with; R 3b H, deuterium, halogen, OH, CN, oxo, NR b R c , C 1~ C6 alkyl, C1-C6 alkyl substituted with deuterium, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R b and R c are each independently H or C1-C6 alkyl; R b1 and R c1 is H or C1-C6 alkyl, and R b1 and R c1 The other is H, C1-C6 alkyl, NR b R c or C1-C6 alkyl substituted with C1-C6 alkoxy] or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof; and an anti-cancer agent as active ingredients, for preventing or treating cancer.

[0054] In the above formula I of the present invention, Z 1 If N, then Z 2 and Z 3 are all CR 1 may be [ka] may be a double bond. 2 and Z 3 are both CHR 1 may be [ka] may be a single bond.

[0055] Alternatively, Z 1 If N, then Z 2 and Z 3 are all CR 1 and [ka] is a double bond, in which case two R 1 are optionally concatenated together to form two R 1 may be taken together with the carbon atom to which it is attached to form a thiophene or pyrrole ring.

[0056] In the above formula I, Z 1 If is CH, then Z 2 is N or CR 1 Z may be 3 is CR 1 may be [ka] may be a double bond.

[0057] In the above formula I of the present invention, [ka] has the following structure: [ka] (In the above structure, two R substituted on the same ring 1 are the same or different from each other) You can choose from:

[0058] In one embodiment, in Formula I: [ka] teeth [ka] may be.

[0059] In one embodiment, in Formula I: [ka] teeth [ka] may be.

[0060] In the above formula I, each R 1 H, halogen, CN, OH, NR b R c , C1-C6 alkoxy, C1-C6 acylamino, C1-C6 alkylsulfonylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C6-C 10 Aryloxy, (C6-C 10 aryl)-(C1-C6 alkyl)oxy and C6-C 10 arylamino, wherein R b and Rc are each independently H or C1-C6 alkyl. For example, each R 1 may independently be H, halogen, CN, OH, or C1-C6 alkoxy. For example, R 1 is an unsubstituted or substituted amino group, e.g., NR b R c , C1-C6 acylamino, C1-C6 alkylsulfonylamino or C6-C 10 It may be arylamino. For example, R 1 may be a hydrocarbon group, such as a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl. For example, R 1 is a ring substituent, such as C3-C6 cycloalkyl, C6-C 10 Aryl, C6-C 10 Aryloxy or (C6-C 10 It may be a (C1-C6 alkyl)oxy group.

[0061] In one embodiment, two R substituted on the same ring 1 When present, one may be H and the other may not be H. In another embodiment, two R substituted on the same ring 1 may both be H.

[0062] For example, R 1 Examples include, but are not limited to, H, F, Br, Cl, I, CN, OH, OCH3, amino, methylamino, dimethylamino, ethylamino, acetylamino, methylsulfonylamino, ethylsulfonylamino, methyl, ethyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, phenoxy, benzyloxy, or phenylamino.

[0063] In the above formula I of the present invention, R' and R'' may each independently be H or C1-C3 alkyl, and R' and R'' may be taken together with the carbon atom to which they are attached to form a C3-C4 cycloalkyl. Optionally, said C1-C3 alkyl and C3-C4 cycloalkyl may be selected from the group consisting of at least one halogen, OH, CN, C1-C3 alkoxy, or NR b R c In this case, R b and R c are each independently H or C1-C6 alkyl.

[0064] For example, R' and R" may each independently be H or C1-C3 alkyl. For example, R' and R" may optionally join together with the carbon atom to which they are attached to form a cyclopropane ring, such that in Formula A: [ka] teeth [ka] may be.

[0065] In one embodiment, R' and R" can be the same or different from each other. When R' and R" are different, the carbon atom to which R' and R" are attached is a chiral center and the compounds of Formula I have stereoisomers, and any such stereoisomers are included within the scope of the present invention.

[0066] For example, when either one of R′ and R″ is H, the compound of formula I [ka] teeth [ka] (R''' is C1-C3 alkyl, such as methyl or ethyl).

[0067] In one embodiment, Formula I of the present invention can be represented by the following formula IA: [ka] (In formula IA, A, Z 1 , Z 2 , Z 3 and B is as defined in Formula I. or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

[0068] In the above formula I of the present invention, A may be Cy1. In this case, Cy1 is C6 to C 10 It may be aryl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S.

[0069] In one embodiment, Cy1 is C6-C 10 It may be aryl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S. In one embodiment, Cy1 may be phenyl, naphthalenyl, thiophenyl, or pyridinyl.

[0070] For example, Cy1 has 1 to 3 R 2a The following ring structures optionally substituted with: [ka] It can have one of:

[0071] In the above formula I of the present invention, when A is Cy1, Cy1 is 1 to 3 R 2a For example, Cy1 may be optionally substituted with 1, 2, or 3 R 2a may be substituted with.

[0072] R 2a H, halogen, OH, CN, oxo, SF5, NR b R c , -Si(C 1~3 Alkyl)3, -SO2R b , -C(O)R b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and [ka] and R 21 H, halogen, OH, NR b R c , C1-C6 alkoxy or C1-C6 acyloxy, and R 22 and R 23 may each independently be H, halogen, or C1-C2 alkyl. In this case, R b and R c may each independently be H or C1-C6 alkyl.

[0073] In one embodiment, each R 2a are H, F, Cl, Br, I, OH, CN, SF5, -Si(CH3)3, CH3SO2-, methyl, ethyl, propyl, isopropyl, CF3, CHF2, CH2F, NH2, CH3NH-, (CH3)2N-, methoxy, ethoxy, OCF3, OCHF2, OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, -CF2CH2F, [ka] They can be independently selected from the group consisting of, but not limited to:

[0074] When A is Cy1, in formula I of the present invention, A has the following structure: [ka] You can choose from:

[0075] For example, in Formula I, A has the following structure: [ka] You can choose from:

[0076] For example, in Formula I, A is [ka] may be.

[0077] In the above formula I of the present invention, A may be Cy1-Y-Cy2. In this case, Y may be O, S, or a direct bond. For example, Y may be O or a direct bond. For example, Y may be a direct bond.

[0078] In Formula I, when A is Cy1-Y-Cy2, Cy1 is C6 to C 10 It may be aryl or a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S. In one embodiment, Cy1 is C6-C 10 It may be aryl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S. In one embodiment, Cy1 is a C6-C 10 It may be aryl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S. For example, Cy1 can be phenyl, naphthalenyl, thiazolyl, thiophenyl, or pyrazolyl.

[0079] In Formula I, when A is Cy1-Y-Cy2, Cy2 is a C6-C cycloalkyl fused to a C3-C6 cycloalkyl. 10 Aryl, C6-C 10 It may be aryl or a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, or S. In one embodiment, Cy2 is C6 to C 10It may be phenyl fused with aryl, C3-C6 cycloalkyl, or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S. In another embodiment, Cy2 is C6-C 10 It may be aryl, phenyl fused with C3-C5 cycloalkyl, or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S. For example, Cy2 can be phenyl, 2,3-dihydroindenyl, bicyclo[4.2.0]octa-1,3,5-trienyl, pyrazolyl, thiophenyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, or pyrrolyl.

[0080] In one embodiment, Cy1 is C6-C 10 aryl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S; Y can be O or a direct bond; Cy2 can be C6-C 10 It may be phenyl fused with aryl, C3-C5 cycloalkyl, or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S.

[0081] For example, in Formula I, when A is Cy1-Y-Cy2, Cy1 can be phenyl and Cy2 can be phenyl, pyrrolyl, pyrazolyl, thiophenyl, pyridinyl, or 2-oxo-1,2-dihydropyridinyl. In this case, Y can be O or a direct bond. In one embodiment, Y can be a direct bond. In one embodiment, Cy1 can be phenyl, Y can be O, and Cy2 can be phenyl or pyridinyl.

[0082] In another embodiment, Cy1 can be thiazolyl, thiophenyl, or pyrazolyl, and Cy2 can be phenyl, 2,3-dihydroindenyl, or bicyclo[4.2.0]octa-1,3,5-trienyl. For example, Cy1 can be thiophenyl and Cy2 can be phenyl.

[0083] In one embodiment, Cy1-Y-Cy2 is R 2a and R 2b The following ring structures optionally substituted with: [ka] It can have one of:

[0084] In formula I, when A is Cy1-Y-Cy2, Cy1 and Cy2 each represent 1 to 3 R 2 In this case, each R 2 is H, halogen, OH, CN, oxo, SF5, -Si(C1-C3 alkyl)3, C1-C6 alkylsulfonyl, C1-C6 alkylcarbonyl, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino; C1-C6 alkyl optionally substituted with halogen, CN, OH, C1-C6 alkoxy, amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino or hydroxy-(C1-C6 alkyl)amino-; C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl and [ka] In this case, R 21 may be H, halogen, OH, C1-C6 alkoxy, C1-C6 acyloxy, amino, C1-C6 alkylamino, or di(C1-C6 alkyl)amino, and R 22 and R 23 may each independently be H, halogen, or C1-C2 alkyl.

[0085] In formula I, when A is Cy1-Y-Cy2, Cy1 is 1 to 3 R 2a In this case, R 2a H, halogen, OH, CN, oxo, SF5, NR b R c , -Si(C1~3 Alkyl)3, -SO2R b , -C(O)R b , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and [ka] The R 21 H, halogen, OH, NR b R c , C1-C6 alkoxy or C1-C6 acyloxy, and R 22 and R 23 may each independently be H, halogen, or C1-C2 alkyl. In one embodiment, Cy1 is selected from one R 2a and R 2a may be H, halogen, OH, CN, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy. For example, R 2a Examples of the group include H, halogen, OH, and CN. For example, R 2a may be H or halogen. For example, R 2a may be H.

[0086] In formula I, when A is Cy1-Y-Cy2, Cy2 is 1 to 3 R 2b For example, Cy2 may be optionally substituted with 1 to 3 R 2b may be optionally substituted with

[0087] In this case, R 2b H, halogen, OH, CN, oxo, NR b R c ;C1-C6 alkyl;Halogen, CN, OH, NR b R cor C1-C6 alkyl substituted with C1-C6 alkoxy; C1-C6 alkyl optionally interrupted with 1 to 3 oxygen atoms and / or nitrogen atoms; and C1-C6 alkyl substituted with hydroxy-(C1-C6 alkyl)amino-.

[0088] For example, each R 2b may independently be, but are not limited to, H, F, Cl, Br, I, OH, CN, oxo, amino, CHNH—, (CH)N—, (CH)NCH—, methyl, ethyl, cyanomethyl, hydroxymethyl, aminomethyl, CHNHCH—, CHNHCH—, or HOCHNHCH—. For example, R 2b may be H, halogen, C1-C6 alkyl; or C1-C6 alkyl substituted with amino, C1-C6 alkylamino, or di(C1-C6 alkyl)amino.

[0089] In formula I of the present invention, when A is Cy1-Y-Cy2, A has the following structure: [ka] You can choose from:

[0090] For example, in Formula I, A has the following structure: [ka] You can choose from:

[0091] In the above formula I of the present invention, B is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, or NR b R c In this case, R b and R c are each H or C1-C6 alkyl. For example, B can be H, CH3, [ka] may be.

[0092] In the above formula I of the present invention, B is —(CH) o -Cy3, in which case o can be 0 or 1.

[0093] In the above formula I of the present invention, B is -(CH2) o - When Cy3 is C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 5- or 6-membered saturated or partially unsaturated heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S, bridged bicyclic C 5~10 Cycloalkyl, C6-C 10 It may be selected from the group consisting of aryl, phenyl fused to a 5- or 6-membered cyclic group containing one heteroatom selected from N, O, and S, and 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S.

[0094] In one embodiment, Cy3 is C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 6-membered saturated or partially unsaturated heterocycloalkyl containing one N, O, or S, bridged bicyclic C 5~8 Cycloalkyl, C6-C 10 It may be selected from the group consisting of aryl, phenyl fused to a 5-membered heterocycloalkyl containing one N, O or S, 5- or 6-membered heteroaryl containing one or two heteroatoms selected from N or S, and 9- or 10-membered bicyclic heteroaryl containing one to three N.

[0095] For example, Cy3 can be C3-C6 cycloalkyl, C3-C6 cycloalkenyl, tetrahydropyranyl, dihydropyranyl, thianyl, 1,1-dioxothianyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, C 6~10It may be, but is not limited to, aryl, thiophenyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, dihydroisobenzofuranyl, indolyl, indazolyl or benzotriazolyl.

[0096] The Cy3 has the following ring structure: [ka] Cy3 can be any one of R 3a may be optionally substituted with

[0097] The Cy3 has 1 to 3 R 3a and R 3a is H, halogen, OH, CN, oxo, C1-C6 alkyl; C1-C6 alkyl substituted with halogen, OH, CN or C1-C6 alkoxy; C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkylamino, C1-C6 hydroxyalkylamino, (C3-C6 cycloalkyl)carbonylamino, -NR b R c , -NR b COR c , -NR b C(O)OR c , -SO2R b , -C(O)R b , -C(O)OR b , -NR b SO2R c and -CONR b1 R c1 In this case, R b and R c may each independently be H or C1-C6 alkyl. b1 and R c1 may be H or C1-C6 alkyl, and R b1 and R c1 The other is H, C1-C6 alkyl, NR b R cIt may be C1-C6 alkyl substituted with or C1-C6 alkoxy.

[0098] For example, R 3a Examples of the alkyl group include, but are not limited to, H, F, Cl, Br, I, OH, CN, oxo, methyl, ethyl, amino, CHNH—, (CH)NH—, 1,1,1-trifluoropropan-2-ylamino, CHCONH—, (CHCO)(CH)N—, CHOCONH—, cyclopropylcarbonylamino, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, methoxy, ethoxy, isopropoxy, methoxymethyl, 2-methoxyethyl, OCHF, OCF, CHSO—, CHCO—, CHSONH—, —COOH, —COOC(CH), —CONH, —CONHCH, —CONHCH, —CON(CH), —CONHCHOCH, or —CONHCHN(CH).

[0099] In the formula I of the present invention, B is -(CH2) o -Cy3, B has the structure [ka] TIFF2026506002000044.tif57149 You can choose from:

[0100] For example, B is [ka] For example, B can be selected from, but is not limited to, [ka] It may be, but is not limited to these.

[0101] In the above formula I of the present invention, B is —(CH)o -Cy3-W-Cy4, where o can be 0 or 1. For example, o can be 0. Additionally, W can be NH, C(O), or a direct bond.

[0102] B is -(CH2) o -Cy3-W-Cy4, Cy3 is C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 5- or 6-membered saturated or partially unsaturated heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S, bridged bicyclic C 5~10 Cycloalkyl, C6-C 10 It may be selected from the group consisting of aryl, phenyl fused to a 5- or 6-membered cyclic group containing one heteroatom selected from N, O, and S, and 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S.

[0103] In one embodiment, Cy3 is C6-C 10 It may be aryl or a 5 or 6 membered heteroaryl containing 1 or 2 heteroatoms selected from N or S.

[0104] B is -(CH2) o -Cy3-W-Cy4, Cy4 is a saturated or partially unsaturated 4- to 10-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, or S, C6-C 10 It may be selected from the group consisting of aryl and 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0105] In one embodiment, Cy4 is a saturated or partially unsaturated 4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, or S, C6-C 10 It may be selected from the group consisting of aryl and 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from N, O and S.

[0106] In one embodiment, B is —(CH)o -Cy3-W-Cy4, where Cy3 can be phenyl or pyridinyl. Additionally, Cy4 can be oxetanyl, tetrahydrofuranyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, morpholinyl, imidazolidinyl, 2-oxoimidazolidinyl, piperazinyl, 2-oxopiperazinyl, hexahydropyrimidinyl, 2-oxohexahydropyrimidinyl, phenyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, or 2-oxopyridinyl. For example, Cy3 can be phenyl, and Cy4 can be pyrazolyl, imidazolyl, triazolyl, or tetrazolyl. For example, Cy3 can be phenyl, and Cy4 can be triazolyl. For example, Cy3 can be pyridinyl and Cy4 can be triazolyl.

[0107] In one embodiment, W can be NH, C(O), or a direct bond. For example, W can be a direct bond.

[0108] In one embodiment, Cy3 is C6-C 10 Cy4 may be a saturated or partially unsaturated 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, or S, and W may be NH or C(O).

[0109] The Cy3-W-Cy4 has the following ring structure: [ka] and the rings corresponding to Cy3 and Cy4 are each R 3a and R 3b may be optionally substituted with

[0110] In one embodiment, Cy3 and Cy4 each independently represent 1 to 3 R 3 may be optionally substituted with

[0111] B is -(CH2) o -Cy3-W-Cy4, the R substituted independently on Cy3 and Cy4 3 is H, deuterium, halogen, OH, CN, oxo, C1-C6 alkyl, C1-C6 alkyl substituted with deuterium, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkylamino, (C3-C6 cycloalkyl)carbonylamino, -NR b R c , -NR b COR c , -NR b C(O)OR c , -SO2R b , -C(O)R b , -C(O)OR b , -NR b SO2R c or -CONR b1 R c1 In this case, R b and R c may each independently be H or C1-C6 alkyl. b1 and R c1 One of them may be H or C1-C6 alkyl, and the other may be H, C1-C6 alkyl; or C1-C6 alkyl substituted with amino, C1-C6 alkylamino, di(C1-C6 alkyl)amino, or C1-C6 alkoxy.

[0112] In one embodiment, Cy3 is 1 to 3 R 3a R 3a is H, halogen, OH, CN, oxo, C1-C6 alkyl; C1-C6 alkyl substituted with halogen, OH, CN or C1-C6 alkoxy; C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 haloalkylamino, C1-C6 hydroxyalkylamino, (C3-C6 cycloalkyl)carbonylamino, -NR b R c, -NR b COR c , -NR b C(O)OR c , -SO2R b , -C(O)R b , -C(O)OR b , -NR b SO2R c and -CONR b1 R c1 In this case, R b and R c may each independently be H or C1-C6 alkyl; R b1 and R c1 may be H or C1-C6 alkyl, and R b1 and R c1 The other is H, C1-C6 alkyl, NR b R c It may be C1-C6 alkyl substituted with or C1-C6 alkoxy.

[0113] In one embodiment, Cy3 has one or two R 3a In this case, R 3a may be H, halogen, OH, CN, oxo, amino, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 haloalkoxy. For example, R 3a Examples of the alkyl group include, but are not limited to, H, halogen, OH, or CN. For example, R 3a may be, but is not limited to, H or F. For example, R 3a may be H.

[0114] The Cy4 has 1 to 3 R 3b In this case, R 3b H, deuterium, halogen, OH, CN, oxo, NR b R c, C1-C6 alkyl, C1-C6 alkyl substituted with deuterium, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkoxy. In this case, R b and R c is H or C1-C6 alkyl. For example, R 3b Examples of the alkyl group include, but are not limited to, H, deuterium, halogen, OH, CN, oxo, C1-C6 alkyl, C1-C6 alkyl substituted with deuterium, and C1-C6 haloalkyl. 3b may be H or C1-C6 alkyl. For example, R 3b Examples of R include, but are not limited to, H, F, oxo, methyl, ethyl, CHF2, and CD3. 3b may be H or methyl.

[0115] In one embodiment, Cy3 has one or two R 3a and R 3a may be H, halogen, OH, or CN; Cy4 may be 1 to 3 R 3b and R 3b may be H, deuterium, halogen, OH, CN, oxo, C1-C6 alkyl, C1-C6 alkyl substituted with deuterium, or C1-C6 haloalkyl.

[0116] B is -(CH2) o -Cy3-W-Cy, in Formula I, B has the following structure: [ka] You can choose from:

[0117] For example, B has the following structure: [ka] You can choose from:

[0118] For example, B is [ka] It may be, but is not limited to these.

[0119] In one embodiment, Formula I of the present invention can be represented by formulas I-1, I-2, I-3, I-4, I-5, I-6 and I-7: [ka] (In formulas I-1, I-2, I-3, I-4, I-5, I-6 and I-7, A, R', R'', R 1 and B are as defined in Formula I, and each R 1 may be the same or different). It can be represented by any one of:

[0120] In some embodiments, the compound of Formula I is the following compound: [ka] TIFF2026506002000053.tif209149 JPEG2026506002000054.jpg186149 TIFF2026506002000055.tif214149 TIFF2026506002000056.tif195149 TIFF2026506002000057.tif202149 TIFF2026506002000058.tif195149 TIFF2026506002000059.tif202149 TIFF2026506002000060.tif200149 TIFF2026506002000061.tif187149 TIFF2026506002000062.tif222149 TIFF2026506002000063.tif212149 JPEG2026506002000064.jpg194149 TIFF2026506002000065.tif194149 TIFF2026506002000066.tif192149 TIFF2026506002000067.tif211149 TIFF2026506002000068.tif212149 TIFF2026506002000069.tif209149 TIFF2026506002000070.tif190149 TIFF2026506002000071.tif213149 TIFF2026506002000072.tif216149 TIFF2026506002000073.tif200149 It may also be a compound selected from the group consisting of:

[0121] definition All technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art, and unless otherwise indicated, conventional measurements, manufacturing methods, conventional components or substances are used in accordance with conventional techniques, e.g., pharmacology, pharmaceutical manufacturing chemistry, mass spectrometry, NMR, HPLC, biochemistry, etc.

[0122] The individual features and elements of each embodiment described and illustrated herein may be combined with the features and elements of any other embodiment without departing from the scope or spirit of the disclosure.

[0123] Unless otherwise stated, in this specification and the appended claims, "or" and "and" mean "and / or." The terms "include" and "included" are open-ended and mean that a compound, composition, or method may include additional features or components in addition to the recited features or components.

[0124] In this specification, a numerical range indicated using the term "to" refers to a range that includes the numerical values ​​before and after the term "to" as the lower and upper limits, respectively.

[0125] As used herein, the term "optional" or "optionally" is intended to mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, the term "optionally substituted" is intended to include both being unsubstituted or substituted with a specified substituent.

[0126] compound The term "alkyl" as used herein refers to a fully saturated bridged or unbridged (or straight-chain or linear) hydrocarbon. The alkyl may be a substituted or unsubstituted alkyl group. The alkyl may be optionally interrupted by at least one oxygen atom or nitrogen atom, and an alkyl group interrupted by an oxygen atom or nitrogen atom refers to an alkyl group in which the oxygen atom or nitrogen atom is inserted between carbon atoms in the alkyl chain. For example, alkyls interrupted by an oxygen atom or nitrogen atom include alkoxyalkyl, alkylaminoalkyl, etc., and examples thereof include those in which the oxygen atom or nitrogen atom is located at the terminal of a substituent, such as a hydroxyalkyl or aminoalkyl. C1-C6 alkyl refers to C1-C6, C1-C 5、 It may be a C1-C4, C1-C3 or C1-C2 alkyl group. Non-limiting examples of alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, isoamyl or n-hexyl.

[0127] The term "alkenyl" as used herein refers to a straight-chain or branched-chain hydrocarbon group having 2 to 6 carbon atoms, 2 to 5 carbon atoms, or 2 to 4 carbon atoms and having one or more double bonds at any position. Examples of alkenyl include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, and hexadienyl.

[0128] The term "alkynyl" as used herein refers to a hydrocarbon group containing at least one triple bond, and includes straight-chain or branched-chain alkynyl groups having 2 to 6 carbon atoms, 2 to 5 carbon atoms, or 2 to 4 carbon atoms. For example, alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0129] Unless otherwise stated, the term "alkoxy," as used herein, refers to a substituent in which a substituted or unsubstituted straight or branched chain alkyl moiety is linked to another chemical structure by an oxygen. Alkoxy includes, but is not limited to, all its possible isomers, such as methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.

[0130] The term "cycloalkyl" as used herein refers to a saturated hydrocarbon ring having the specified number of carbon atoms as ring members (i.e., C3-C8 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms as ring members). Cycloalkyl can be a C3-C6 monocyclic or a C5-C6 20 For example, the monocyclic cycloalkyl may be C3-C6, C3-C5, or C3-C4 cycloalkyl. The monocyclic cycloalkyl may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The bicyclic, tricyclic, or tetracyclic cycloalkyl may be C5-C6. 18 Cycloalkyl, C5-C15 Cycloalkyl, C5-C 11 Cycloalkyl, C5-C 10 Polycyclic cycloalkyls may have two or more cycloalkyls bridged, fused, or spiro-linked, and in tricyclic or tetracyclic cycloalkyls, each cycloalkyl ring may be linked in two or more of bridged, fused, and spiro-linked forms. For example, polycyclic bridged, fused, or spirocycloalkyls include bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, adamantyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.1]octanyl, bicyclo[3.3.0]octanyl, bicyclo[4.2.0]octanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.4]octanyl, octahydro-1H-indenyl, decahydronaphthalenyl, and the like. As used herein, cycloalkyl can optionally include fused with a heteroaryl or heterocycloalkyl (e.g., cyclohexyl fused with pyrazole, piperazine, or tetrahydropyran), where heteroaryl or heterocycloalkyl is as defined below.

[0131] The term "cycloalkenyl" as used herein refers to a non-aromatic unsaturated monocyclic or polycyclic hydrocarbon ring having at least one carbon-carbon double bond and containing a specified number of carbon atoms. For example, monocyclic cycloalkenyl can include, but is not limited to, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, cyclohexa-1,3-dien-1-yl, etc. The above-mentioned points regarding the number of carbon atoms and bonding form of bicyclic, tricyclic, or tetracyclic cycloalkyl equally apply to bicyclic, tricyclic, or tetracyclic cycloalkenyl. For example, bicyclic, tricyclic, or tetracyclic cycloalkenyl can include those in which the carbon-carbon double bond is introduced at any position of the bicyclic, tricyclic, or tetracyclic cycloalkyl exemplified above. As used herein, cycloalkenyl can optionally include fused to a heteroaryl or heterocycloalkyl (e.g., cyclohexenyl fused to pyrazole, piperazine, or tetrahydropyran), where heteroaryl or heterocycloalkyl are defined below.

[0132] The term "aryl" as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon group. Aryl has alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms, and can also include two or more rings simply bonded together (pendant) or fused together. Aryl can be, for example, C6-C 10 It may be aryl or C6-C9 aryl, and examples of aryl include, but are not limited to, phenyl, naphthalenyl (naphthyl), toluyl, or all possible isomers thereof. In the present specification, aryl may be fused with cycloalkyl. For example, C 6~10 An aryl may be fused to a 3- to 8-membered cycloalkyl. In this case, phenyl and cyclobutyl may be fused to form bicyclo[4.2.0]octa-1,3,5-trienyl, and phenyl and cyclopentyl may be fused to form 2,3-dihydroindenyl. In addition, as used herein, an aryl may be optionally fused to a heterocycloalkyl. For example, C6~10 An aryl may be fused with a 5-10 membered heterocycloalkyl, for example, phenyl and tetrahydrofuranyl may be fused to form dihydrobenzofuranyl or dihydroisobenzofuranyl.

[0133] As used herein, the term "heteroaryl" refers to a heterocyclic aromatic group containing at least one heteroatom selected from B, N, O, S, P(=O), Si, and P as a ring-forming atom. Heteroaryl can include two or more rings that are simply bonded (pendant) or fused together. Heteroaryl can contain 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom selected from N, O, and S. Heteroaryl can contain 5 to 10 or 5 to 6 ring atoms. Examples of monocyclic heteroaryl include, but are not limited to, thiophenyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and similar groups. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, indolizinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, purinyl, phthalazinyl, pteridinyl, furopyridinyl, oxochromenyl, dioxoisoindolinyl, imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, and similar groups. As used herein, heteroaryls optionally include those fused to a cycloalkyl group (e.g., pyrazolyl fused to cyclohexyl). Additionally, heteroaryl refers to a group in which the aromaticity of the ring does not affect the ring carbons by oxo, sulfanilidene (=S), imino (=NH) or =N(C1~6 It may also be a functional group that is maintained by replacing it with an alkyl group, etc. For example, heteroaryl can include pyridinonyl (pyridonyl), pyridazinonyl, pyrimidinonyl (pyrimidonyl), pyrazinonyl, etc. When heteroaryl contains N, B, or P in the ring, the N, B, or P of the heteroaryl can be linked to another moiety.

[0134] Unless otherwise specified, the term "heterocycloalkyl," as used herein, refers to a monocyclic or polycyclic, saturated or partially unsaturated ring system containing at least one heteroatom selected from B, N, O, S, P(═O), Si, and P and having the specified number of ring elements (i.e., a 3- to 7-membered heterocycloalkyl refers to a heterocycloalkyl group having 3, 4, 5, 6, or 7 ring elements, including the heteroatom). Polycyclic heterocycloalkyls can also include two or more heterocycloalkyl rings that are simply linked together (pendant), or bridged, fused, or spiro-linked. A heterocycloalkyl can contain 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom selected from N, O, and S. Additionally, a heterocycloalkyl can contain 5 to 10, 4 to 7, 5, or 6 ring atoms.For example, heterocycloalkyl groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, dihydrofuranyl, tetrahydrofuranyl (oxanyl), dihydrothiophenyl, tetrahydrothiophenyl, sulfonyl, thianyl, dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isothioazolinyl, isothioazolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isothioazolinyl, isothioazolinyl, ... Soxazolidinyl, triazolinyl, triazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, tetrahydro-2H-thiopyranyl, dihydrothiopyranyl, dioxanyl, tetrahydrotriazinyl, hexahydrotriazinyl, morpholinyl, thiomorpholinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, piperazinyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydro pyrimidinyl, dihydropyridazinyl, tetrahydropyridazinyl, tetrahydrooxazinyl, hexahydroazepinyl, perhydroazepinyl, perhydrooxepinyl, indolinyl, isoindolinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, chromanyl, isochromanyl, 3-oxabicyclo[2.1.1]hexanyl, 2-oxabicyclo[2.1.1]hexanyl, 2-azabicyclo[2

[0013] Heterocycloalkyls include, but are not limited to, 3-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]heptanyl, 7-azabicyclo[4.1.0]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, tropanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and N-oxides, sulfones, or sulfoxides thereof. As used herein, heterocycloalkyl optionally includes those fused with a cycloalkyl group (e.g., piperidinyl fused with cyclohexyl).If the heterocycloalkyl contains an N, B, or P in the ring, the N, B, or P of the heterocycloalkyl may be linked to another moiety.

[0135] Used herein to indicate chemical bonds between ring atoms [ka] indicates that two atoms are joined by a single or double bond, and each atom can have as many H or substituents as its valence allows. For example, [ka] When used to link these two ring carbon atoms, it represents -CH=CH or -CH2-CH2-, where each H may be optionally substituted with a suitable substituent.

[0136] As used herein, the term "halogen" refers to an atom in Group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, iodine, etc., and can be used interchangeably with the term "halo," which refers to a monovalent functional group composed of a halogen.

[0137] As used herein, the term "cyano" refers to the functional group --CN, which has a triple bond between the carbon and nitrogen atoms.

[0138] As used herein, the term "hydroxy" refers to an --OH functional group (a hydroxyl group).

[0139] As used herein, the term "oxy" refers to the -O- divalent functional group.

[0140] As used herein, the term "oxo" refers to a substituent having the structure =0 in which a double bond exists between the atom to which the substituent is attached and the oxygen atom.

[0141] As used herein, the term "carbonyl" refers to the -C(=O)- divalent functional group.

[0142] As used herein, the term "acyl" refers to a functional group in which the carbon atom at position 1 of an alkyl is substituted with oxo, and includes "formyl" and "alkylcarbonyl." For example, C 1~6 Acyl is C 1~6 The carbon atom at position 1 of the alkyl is substituted with oxo, and C 1~6 Examples of acyl include formyl (HC(O)-), acetyl (CH3C(O)-), propionyl (CH3CH2C(O)-), butanoyl (CH3CH2CH2C(O)-), pentanoyl (CH3CH2CH2CH2CO-), and hexanoyl (CH3CH2CH2CH2CH2C(O)-).

[0143] As used herein, the term "acyloxy" refers to a functional group in which acyl is attached to one end of an oxy, and includes "formyloxy" and "alkylcarbonyloxy". For example, C 1~3 Examples of acyloxy include formyloxy, acetyloxy (acetoxy), and propionyloxy.

[0144] As used herein, the term "carboxy" refers to --COOH.

[0145] As used herein, the term "sulfonyl" refers to a divalent functional group of -S(O)-. For example, C 1~6 Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

[0146] As used herein, the term "amino" refers to -NH2.

[0147] As used herein, the term "alkylamino" refers to a functional group in which one hydrogen of an amino is replaced with an alkyl. For example, C 1~6 Alkylamino is -NH(C1-C6 alkyl), C 1~6Examples of alkylamino include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino.

[0148] The term "dialkylamino" as used herein refers to a functional group in which two hydrogen atoms of an amino group are each replaced with an alkyl group. In this case, the substituted alkyl groups may be the same or different. For example, di(C 1~6 alkyl)amino is -N(C1-C6 alkyl)2, and di(C 1~6 Examples of alkylamino include, but are not limited to, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, methylpropylamino, and ethylpropylamino.

[0149] The term "acylamino" as used herein refers to a functional group in which the carbon atom at position 1 of the alkyl of alkylamino is substituted with oxo, and includes "formylamino" and "alkylcarbonylamino".

[0150] As used herein, the term "carbamoyl" refers to -CONH2.

[0151] As used herein, the term "alkylcarbamoyl" refers to a functional group in which one hydrogen of a carbamoyl is replaced with an alkyl. For example, C 1~6 Alkylcarbamoyl is -CONH(C 1~6 alkyl), and C 1~6 Examples of alkylcarbamoyl include, but are not limited to, -CONHCH3, -CONHCH2CH3, -CONHCH2CH2CH3, -CONHCH2CH2CH2CH3 and the like.

[0152] As used herein, the term "dialkylcarbamoyl" refers to a functional group in which two hydrogens of a carbamoyl are each replaced with an alkyl. For example, C 1~6 Alkylcarbamoyl is -CON(C 1~6 alkyl)2, and C 1~6Examples of alkylcarbamoyl include, but are not limited to, -CON(CH3)2, -CON(CH2CH3)2, -CON(CH3)(CH2CH3), and the like.

[0153] As used herein, the term "substituted" refers to a group in which one or more hydrogen atoms have been replaced with one or more non-hydrogen groups, provided that valency requirements are met and the substitution results in a chemically stable compound. Unless otherwise specified herein as "unsubstituted," all substituents should be interpreted as being capable of being unsubstituted or substituted.

[0154] As used herein, "optionally substituted" moieties referred to herein without being limited to particular substituents can include moieties that are unsubstituted or substituted with any substituent. For example, "optionally substituted" moieties can include the following substituents: (i) halogen, OH, CN, oxo, NH2, NH(C1-C6 alkyl) or N(C1-C6 alkyl)2; (ii) C1-C3 alkyl optionally substituted with at least one substituent selected from the group consisting of halogen, OH, CN, oxo, NH2, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2; (iii) C1-C3 alkoxy optionally substituted with at least one substituent selected from the group consisting of halogen, OH, CN, oxo, NH2, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2; or (iv) C3-C6 cycloalkyl optionally substituted with at least one substituent selected from the group consisting of halogen, OH, CN, oxo, NH2, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2 It can refer to a moiety substituted with

[0155] As used herein, when a combination of substituents is referred to as a single group, such as arylalkyl, cycloalkylalkyl, etc., the last-mentioned group generally contains the atom attached to the end of the molecule.

[0156] In this specification, [ka] , " * " or "-" is used to indicate the point at which a substituent is attached to the remainder of the compound. For example, if - is shown at the end of a substituent, it means that the end is attached to the remainder of the compound. In addition, when two or more substituents are connected by "-", it means that the substituent immediately before the "-" is attached to a substitutable atom of the substituent immediately after the "-".

[0157] As used herein, the term "solvate" can refer to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Thus, a preferred solvent can be a volatile, non-toxic, and / or suitable solvent for administration to humans.

[0158] The term "stereoisomer" as used herein may refer to compounds of the present invention or salts thereof that have the same chemical or molecular formula but are optically or sterically different, and may specifically be diastereomers, enantiomers or geometric isomers.

[0159] In some embodiments, the compounds of the present invention may be in the form of a racemate containing one or more asymmetric centers, a single enantiomer, a mixture of enantiomers, a single diastereomer, a mixture of diastereomers, etc. In one embodiment, due to restricted rotation or the nature of an asymmetric center, the compounds of the present invention may be in the form of an enantiomer or diastereomer.

[0160] When two or more asymmetric centers are present in the compounds of the present invention, several diastereomers and enantiomers of the chemical structures disclosed herein may exist, and it is intended that pure isomers, separate isomers, partially pure isomers, racemic mixtures, etc., all fall within the scope of the present invention.

[0161] The purification of isomers and the separation of isomeric mixtures can be achieved by standard techniques known in the art: for example, diastereomeric mixtures can be separated into their individual diastereomers by chromatographic methods or crystallization, and racemates can be separated into their individual enantiomers by resolution on chiral phases or by chromatographic methods.

[0162] The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, for example, salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like.

[0163] Pharmaceutically acceptable salts of the compounds can be prepared by dissolving the compound of Formula I in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, and the like, adding an excess of an organic acid or an aqueous acidic solution of an inorganic acid, followed by precipitation or crystallization, followed by evaporation of the solvent or excess acid from the mixture, followed by drying to obtain additional salt, or by suction filtration of the precipitated salt.

[0164] General method for preparing compounds The compounds according to the invention can be prepared by chemical modifications well known to those skilled in the art of organic / pharmaceutical chemistry according to the methods representatively shown below.

[0165] The following general reaction schemes are general examples of representative preparation methods for compounds of Formula I. Those skilled in the art can easily prepare compounds of Formula I by appropriately selecting starting materials, reaction temperatures, reaction conditions, catalysts, solvents, treatment methods, etc. suitable for the desired compound based on the preparation methods specifically disclosed in the Examples herein. Hereinafter, in Reaction Schemes 1 to 9, the expression of each substituent in Formula I is the same as that of the substituent at the corresponding position in Formula I, unless otherwise specified. In addition, in Reaction Schemes 1 to 9, the same variables have the same definitions, and repeated explanation of definitions may be omitted.

[0166] In one embodiment, compounds of formula I can be prepared according to the following reaction scheme 1: [ka] (In Reaction Scheme 1, na and nb each independently represent the R 2 and R 3 is an appropriate integer that satisfies the number of The compound can be prepared by reacting intermediate a and intermediate b according to the method described above.

[0167] For example, compounds of formula I can be prepared by coupling intermediate a with intermediate b via an amide coupling reaction using HATU. 2 When is a NO2 group, compounds of formula I having an NH2 substituent on ring B can be prepared by reduction to an NH2 group under reduction reaction conditions.

[0168] Those skilled in the art can substitute various reagents for the reaction reagents used in Reaction Scheme 1 for amide coupling reactions based on general knowledge in the relevant field, and can select appropriate reaction conditions, such as appropriate reaction time and reaction temperature, accordingly. In one embodiment, intermediates a and b can be reacted in HATU, TEA, and DMF at about 20°C to about room temperature for about 2 to about 3 hours. Alternatively, intermediates a and b can be reacted in HATU, DIEA, and DMF at about 10°C to about 30°C for about 2 to about 15 hours. Alternatively, intermediates a and b can be reacted in EDCI, HOBT, DMAP, and DCM at about 10°C to about 20°C for about 10 to about 15 hours. Alternatively, intermediates a and b can be reacted in TEA, HOBT, EDCI, and DCM at about 20°C to about 30°C for about 2 to about 5 hours. Alternatively, intermediates a and b can be reacted in DIEA, HOBT, EDCI and DMF at about 15° C. to about 25° C. for about 2 hours to about 15 hours.

[0169] In one embodiment, the compound of Formula I can be reacted with the compound of Formula I according to the following Reaction Scheme 1A: [ka] (In Reaction Scheme 1A, R' is alkyl.) It can be prepared according to the reaction:

[0170] For example, according to Reaction Scheme 1A, compounds of Formula I in which the ring nitrogen atom is unsubstituted can be prepared by protecting the ring nitrogen atom of intermediate a with an SEM, reacting with intermediate b, and then removing the SEM.

[0171] In one embodiment, the compound of Formula I can be reacted with the compound of Formula I according to the following Reaction Scheme 1B: [ka] (In Reaction Scheme 1B, R Bis alkyl optionally substituted with, for example, halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl or cycloalkyl) It can be prepared according to the reaction:

[0172] For example, R B is a compound prepared according to Reaction Scheme 1A. B It can be introduced to the nitrogen atom by reacting with a halide of the formula:

[0173] In one embodiment, the compound of Formula I is represented by the following Reaction Scheme 1C [ka] (In Reaction Scheme 1C, A 1 and A 2 are Cy in Formula I, respectively. 1 and Cy 2 (This is the structure corresponding to It can be prepared according to the method of

[0174] For example, according to Reaction Scheme 1C, compounds of Formula I can be prepared by coupling a starting material in which ring A1 is halogenated with bis(pinacolato)diborane in the presence of a suitable catalyst (e.g., Pd(dppf)Cl) to synthesize a pinacolborane compound, which can then be coupled with a halide of ring A2.

[0175] In one embodiment, compounds of Formula I are disclosed below in Reaction Scheme 1D. [ka] It can be prepared according to the method of

[0176] For example, according to Reaction Scheme 1D, compounds of Formula I can be prepared by coupling a starting material in which ring A1 is halogenated with a pinacolborane or boronic acid derivative of ring A2 in the presence of a suitable catalyst (e.g., Pd(dppf)Cl).

[0177] In one embodiment, compounds of Formula I may be prepared according to the following Reaction Scheme 1E: [ka] (In Reaction Scheme 1E, B1 and B2 are each a Cy of Formula I. 3 and Cy 4 (This is the structure corresponding to It can be prepared according to the method of

[0178] For example, according to Reaction Scheme 1E, compounds of Formula I can be prepared by coupling a starting material in which ring B1 is halogenated with bis(pinacolato)diborane in the presence of a suitable catalyst (e.g., Pd(dppf)Cl) to synthesize a pinacolborane compound, followed by coupling with a halogenated derivative of ring B2.

[0179] In one embodiment, compounds of Formula I are disclosed in the following Reaction Scheme 1F: [ka] It can be prepared according to the method of

[0180] For example, according to Reaction Scheme 1F, compounds of Formula I can be prepared by coupling a starting material in which ring B1 is halogenated with pinacolborane or a boronic acid compound in ring B2 in the presence of a suitable catalyst (e.g., Pd(dppf)Cl).

[0181] In one embodiment, R of Formula I 1 The group can be introduced after coupling intermediate b with intermediate a. For example, see Reaction Scheme 2 below. [ka] (In Reaction Scheme 2, R is H or alkyl.) As exemplified in R 1 is CN, the compounds of formula I in which CN is substituted can be prepared by coupling an appropriate halogenated intermediate a to which ring B is attached with intermediate b in a suitable solvent (e.g., DCM, toluene) if necessary in the presence of a suitable catalyst (e.g., AlMe), followed by CuCN in a suitable solvent (e.g., N-methyl-2-pyrrolidone).

[0182] In one embodiment, R 1 The intermediate a, in which the following is substituted, can be prepared by the following reaction scheme 2A: [ka] (In Reaction Scheme 2A, R is H or alkyl.) It can be prepared according to the method of

[0183] For example, according to Reaction Scheme 2A, R 1 The intermediate a into which ring B is bonded can be reacted with an appropriate halogenated intermediate a by R 1 can be prepared by reacting the compound with a boronic acid compound of the formula:

[0184] In another embodiment, R 1 Intermediate a, in which is alkyl, can be prepared by the following reaction scheme 2B [ka] (In Reaction Scheme 2B, R 1 is alkyl) It can be prepared according to the method of

[0185] For example, if the alkyl group is R 1Intermediate a introduced as the above can be prepared by reacting an appropriate halogenated intermediate a having ring B attached thereto with a dialkyl zinc in an appropriate solvent (e.g., THF, dioxane, etc.) in the presence of an appropriate catalyst (e.g., Pd(PPh3)4, Pd(dppf)Cl2, etc.) (Negishi reaction).

[0186] In one embodiment, intermediate a can be prepared according to the following reaction scheme 3: [ka] It can be prepared according to the method of

[0187] For example, intermediate a can be prepared by dissolving the appropriate starting material in a solvent (e.g., DCM), adding an appropriate amount of base (e.g., pyridine) and Cu(OAc)2, and then reacting with a boronic acid or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (pinacolborane) derivative of ring B, and hydrolyzing the ester group by adding a suitable base (e.g., LiOH).

[0188] In another embodiment, intermediate a can be prepared according to the following reaction scheme 4: [ka] (In Reaction Scheme 4, X a is halogen, methylsulfonyloxy or trifluoromethylsulfonyloxy) It can be prepared according to the method of

[0189] For example, intermediate a can be prepared by dissolving the appropriate starting material in a solvent (e.g., DMF), adding an appropriate amount of base (e.g., KCO), and then reacting with a halide, methylsulfonate, or trifluoromethylsulfonate derivative of ring B, followed by hydrolysis of the ester group by addition of a suitable base (e.g., LiOH).

[0190] In another embodiment, intermediate a can be prepared according to the following reaction scheme 5: [ka] (In Reaction Scheme 5, X is a halogen.) It can be prepared according to the method of

[0191] For example, intermediate a can be prepared by dissolving the appropriate starting material in a solvent (e.g., DMF), adding appropriate amounts of DMEDA, K3PO4 and CuI, and then reacting with a halide compound of ring B and hydrolyzing the ester group by adding a suitable base (e.g., LiOH).

[0192] In another embodiment, intermediate a can be prepared according to the following reaction scheme 6: [ka] (In Reaction Scheme 6, R i and R ii are each alkyl) It can be prepared according to the method of

[0193] For example, intermediate a can be prepared by treating a mixture of aminated Ring B compound with water and HCl with NaNO, adding NaOAc and 3-oxopentanedioate in a suitable solvent (e.g., EtOH, water) to form a hydrazone compound, then stirring in a suitable solvent (e.g., 1,2-dichlorobenzene) to form a hydroxy-substituted dihydropyridazinone ring, then adding TfO in a suitable solvent (e.g., DCM) to introduce a trifluoromethylsulfonyloxy group, and then adding R 1 can be prepared by reacting the compound with a boronic acid compound of the formula:

[0194] In one embodiment, intermediate a can be prepared according to the following reaction scheme 6A: [ka] It can be prepared according to the method of

[0195] For example, intermediate a can be prepared by reacting a hydrazinated Ring B compound with 2-oxopentanedioate in the presence of MeOH and HCl to form a hydrazone compound, which is then stirred in NaOMe and MeOH to form the tetrahydropyridazinone ring.

[0196] In one embodiment, intermediate a can be prepared according to the following reaction scheme 6B: [ka] It can be prepared according to the method of

[0197] For example, according to Reaction Scheme 6B, the amino group is 1 Intermediate a introduced as can be prepared by sequentially reacting a hydroxy-substituted dihydropyridazinone ester compound with POCl3 and NaN3 to convert the hydroxy group to a chloro group and then to an azide group, followed by reduction of the azide group under Pd / C catalysis.

[0198] In one embodiment, intermediate a can be prepared according to the following reaction scheme 6C: [ka] It can be prepared according to the method of

[0199] For example, a compound having a trimethylsilylethynyl group can be synthesized by reacting intermediate a prepared according to Reaction Scheme 6B with NIS to introduce an iodo group, followed by coupling with ethynyl(trimethyl)silane. Subsequently, intermediate a having a pyrrolodihydropyridazinone core can be prepared via a cyclization reaction under NaH and NMP conditions.

[0200] In one embodiment, intermediate a can be prepared according to the following reaction scheme 6D: [ka] It can be prepared according to the method of

[0201] For example, according to Reaction Scheme 6D, a 3-oxopentanedioate compound can be reacted with 1,4-dithiane-2,5-diol in the presence of LiBr to form a thiophene diester compound. Intermediate a having a thienodihydropyridazinone core can be prepared by reacting the thiophene diester compound with SeO in anisole solvent to further introduce an oxo group into the thiophene diester compound, followed by cyclization with hydrazine, followed by reaction with a boronic acid derivative of Ring B.

[0202] In one embodiment, intermediate a can be prepared according to the following reaction scheme 6E: [ka] (In Reaction Scheme 6E, R i ~R iii is alkyl) It can be prepared according to the method of

[0203] For example, according to Reaction Scheme 6E, intermediate a having a thienodihydropyridazinone nucleus can be prepared by reacting a brominated thiophene ester compound with oxalate in the presence of n-BuLi to synthesize a thiophene oxodiester compound, which can then be reacted with a hydrazine-substituted Ring B compound.

[0204] In another embodiment, R 1 Intermediate a, in which is alkyl, can be prepared by the following reaction scheme 7. [ka] It can be prepared according to the method of

[0205] Intermediate a can be prepared by reacting the compound prepared by the method of Reaction Scheme 6, into which a trifluoromethylsulfonyloxy group has been introduced, with dialkylzinc in an appropriate solvent (e.g., THF, dioxane, etc.) in the presence of an appropriate catalyst (e.g., Pd(PPh3)4, Pd(dppf)Cl2, etc.) (Negishi reaction) to introduce an alkyl group into the dihydropyridazinone ring, and then hydrolyzing the ester group by adding an appropriate base (e.g., LiOH).

[0206] In one embodiment, intermediate a can be prepared according to the following reaction scheme 7A: [ka] It can be prepared according to the method of

[0207] According to Reaction Scheme 7A, a compound having a trifluoromethylsulfonyloxy group introduced therein can be reacted with DPPP and EtSiH in a suitable solvent (e.g., DMF) in the presence of a suitable catalyst (e.g., Pd(OAc)), to remove the trifluoromethylsulfonyloxy group.

[0208] In one embodiment, intermediate a can be prepared according to the following reaction scheme 8: [ka] It can be prepared according to the method of

[0209] For example, according to Reaction Scheme 8, intermediate a having a pyridinone nucleus can be prepared by reacting a coumaric acid compound with an amine compound of Ring B in the presence of pyridine.

[0210] In one embodiment, intermediate b can be prepared according to the following reaction scheme 9: [ka] It can be prepared according to the method of

[0211] For example, a halogenated Ring A compound can be reacted with 1-vinyloxybutane or tributyl(1-ethoxyvinyl)stannane under Heck reaction conditions, followed by treatment with acid to give an acetylated Ring A compound. The reaction can be carried out in the presence of Pd(PP3)4 or Pd(PP3)2Cl2, and solvents such as TEA, butanol, or dioxane can be used. The acetylated Ring A compound can then be reacted with (R)-oriented tert-butylsulfinamide in the presence of a titanium alkoxide, and the imine bond can be reduced to an amine bond, followed by treatment with acid to give intermediate b.

[0212] In one embodiment, when R2 is an alkylsilane group, intermediate b can be prepared according to the following reaction scheme 10: [ka] (In Reaction Scheme 10, R i , R ii and R iii are each an alkyl group, and R i , R ii and R iii two of which may optionally be linked together to form a cycloalkyl It can be prepared according to the method of

[0213] For example, a halogenated ring A compound can be reacted with an appropriate alkylsilane halide compound in the presence of n-BuLi to introduce an alkylsilane group onto ring A.

[0214] anticancer drugs The anticancer agent of the present invention can be selected from the group consisting of chemical anticancer agents, targeted anticancer agents, anticancer viruses, antibody therapeutic agents, cell therapeutic agents, immune checkpoint inhibitors, and combinations thereof.

[0215] The term "chemo-anticancer agent" as used herein is also referred to as an antitumor agent (anti-malignant tumor drug) or a cytotoxic agent. This term is a general term for drugs that exhibit anti-cancer activity primarily by acting directly on DNA, blocking the DNA replication, transcription, and translation processes, or interfering with the synthesis of nucleic acid precursors in metabolic pathways, thereby inhibiting cell division. Antitumor agents act not only on tumor cells but also on normal cells, exhibiting cytotoxicity. Chemo-anticancer agents can be used for maintenance therapy. In addition, the term "maintenance therapy" as used herein refers to treating cancer with drugs after initial anti-cancer therapy, and refers to a treatment method performed to prevent or delay cancer recurrence.

[0216] Specifically, the anticancer chemotherapeutic agent may be any one selected from the group consisting of alkylating agents, microtubule inhibitors, antimetabolites, and topoisomerase inhibitors. The alkylating agent may be any one selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, thiotepa, altretamine, procarbazine, busulfan, streptozotocin, carmustine, lomustine, dacarbazine, cisplatin, carboplatin, and oxaliplatin. The microtubule inhibitor may be any one selected from the group consisting of docetaxel, paclitaxel, velban, Oncovin, and navelbine. The antimetabolite may be any one selected from the group consisting of fluorouracil, capecitabine, cytarabine, gemcitabine, fludarabine, methotrexate, pemetrexed, 6-thioguanine, and mercaptopurine. The topoisomerase inhibitor may be any one selected from the group consisting of Hycamtin, Camptostar, Bepcid, Breoxane, Adriamycin, SN-38, Doxorubicin, and Cervidine.

[0217] As used herein, the term "targeted anticancer drug" refers to a therapeutic agent that specifically kills cancer cells by targeting specific proteins or specific genetic alterations that frequently appear only in cancer cells and blocking signals involved in the growth and development of cancer. These targeted anticancer drugs are classified into monoclonal antibodies that react on the outside of cells and small molecule substances that act on the inside of cells. Monoclonal antibodies are anticancer drugs that block cancer cell-inducing signals transmitted to the outside of cells and act on initiating signals related to proliferation, cell death, etc., while small molecule substances act on complex signal transduction that occurs inside cells.

[0218] Specifically, the targeted proteins include mTOR, PI3K, EGFR, VEGFR, CD20, CD38, RNAK-L, BTK, BCR-ABL, PDGFR / FGFR family, MEK, KRAS, ERK1 / 2, HER2 / Neu, ubiquitin, JAK, ALK, PARP, TGFβR, proteasome, Bcl-2, c-Met, VR1, VR2, VR3, c-KIT, AXL, RET, BRAF, pan-RAF, SHP2, SRC, LCK, DNMT, CDK4 / 6, CDK9, BET, MDM2, IGF1 / 2 or IGF1-R, ROS1, NTRK1, PIK, DHFR, pan Aurora, Aurora A, WEE1, HSP90, A3AR, EZH2, ARID1A, Chk1, ATR, HDAC1 / 3, Akt, PLK1, sumoylation-related proteins, STING, and the like.

[0219] Targeted anticancer drugs include rapamycin, sirolimus, temsirolimus, everolimus, ridaforolimus, INK-128, alpelisib, cetuximab, trastuzumab, pertuzumab, gefitinib, erlotinib, osimertinib, lazertinib, panitumumab, axitinib, lenvatinib, bevacizumab, ramucirumab, aflibercept, rituximab, obinutuzumab, daratumumab, denosumab, ibrutinib, dasatinib, nilotinib, imatinib, bosutinib, galunisertib, bactosertib, futibatinib, nintedanib, sunitinib, Sorafenib, cabozantinib, regorafenib, masitinib, semaxanib, tivozanib, vandetanib, pazopanib, dabrafenib, sotorasib, adagrasib, JDQ443, MRTX1133, urisertinib, afanitib, lapatinib, neratinib, lenalidomide, ixazomib, ruxolitinib, restortinib, pacritinib, trametinib, cobimetinib, selumetinib, binimetinib, alectinib, lorlatinib, crizotinib, venetoclax, bemcentinib, gilteritinib, selpasetinib, pralsetinib, enco Rafenib, vemurafenib, belbalafenib, RMC-4630, batoprotafib, WH-4-023, olaparib, talazoparib, niraparib, rucaparib, azacitidine, decitabine, guadecitabine, abemaciclib, ribociclib, palbociclib, CDN, SB11285, linetelquib, repotrectinib, tepotinib, allizomadrine, JQ1, NVP-ADW742, duvelisib, irbinitinib, danusertib, MK-1775, AMG-900, BIIB021, reversine, MLN-7243, ABT-737, MK-5 108, GSK-343, 2-D08, SCH-900776, entinostat, carfilzomib, apitolisib, ipatasertib, boracetim, AT-7519, methotrexate, wortmannin, ERAS-007, PYR-41, MLN4924, RO-5503781, MK-8242, SAR-405838, CGM097, DS3032b, lactacystin, disulfiram, epigallocatechin 3-gallate, marizomib, oprozomib, delanzomib, epoxomicin, MG132, β-hydroxyβ-methylbutyrate, bortezomib,Navitoclax, naporafenib, PF-07284892, TNO155, hesperadin, LY3295668, tozasertib, azenosertib, ZNL-02-096, RP-6306, GSK-1520489A, BIIB028, MPC-3100, PU-H71, Debio093, SNX-5422, AUY922, KF-26777, MRS-545, CAY104 98, DZNep, EPZ005687, EI1, GSK126, UNC1999, tazemetostat, sinefungin, GSK-343, davidin, CID9549553, SRA737, V158411, PF-477736, AZD7762, prexasertib, beruzosertib, galtisertib, selarasertib, panobinostat, mocetinostat, trichostatin A, CB UD-1001, abexinostat, VQD-002, perifosine, miltefosine, MK-2206, AZD5363, rigosertib, I-BET151, I-BET762, OTX-015, TEN-010, CPI-203, CPI-0610, Orinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1, MS645, figitumumab, mechanomycin It may be any one selected from the group consisting of cermin, rhIGF-1, BI885578, buparlisib, copanlisib, dactolisib, idelalisib, parsaclisib, paxalisib, taselisib, zandelisib, inavolisib, AZD4573, atuveciclib, VIP152, A-1592668, JSH-150, SLS009, roscovitine, and DMXAA.

[0220] As used herein, the term "mTOR (mammalian target of rapamycin)," also known as the mechanistic target of rapamycin or FRAP1 (FK506-binding protein 12-rapamycin-related protein 1), is a protein belonging to the PIKK (phosphatidylinositol 3-kinase-related kinase) family. mTOR, encoded by the FRAP1 gene in humans, is a serine / threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. mTOR inhibitors can inhibit tumor survival by inhibiting autophagy, adipogenesis, proliferation, protein synthesis, and the like. mTOR inhibitors may be, for example, rapamycin, sirolimus, temsirolimus, everolimus, ridaforolimus, or INK-128 (sapanisertib, MLN0128, TAK-228).

[0221] As used herein, the term "PI3K (phosphoinositide 3-kinase)," also known as phosphatidylinositol 3-kinase, is an enzyme involved in cellular functions, such as cell growth, proliferation, differentiation, motility, survival, and intracellular signal regulation, and is also associated with cancer. PI3K includes subunits such as p110-α / β / γ / δ (PI3Kα / β / γ / δ). PI3K-targeting anticancer drugs include alpelisib, wortmannin, LY294002, idelalisib, copanlisib, duvelisib, apitolisib (GDC-0980, RG7422, GNE390), and the like.

[0222] As used herein, the term "epidermal growth factor receptor (EGFR)" refers to a cell membrane receptor that regulates cell growth, division, survival, and cell death. EGFR expression is elevated in tumor tissues in various cancers. Tumor tissues with elevated EGFR expression are known to have increased invasion, metastasis, and resistance to anticancer drugs. In one embodiment, the substance that inhibits EGFR as an EGFR inhibitor may be cetuximab, trastuzumab, pertuzumab, gefitinib, erlotinib, osimertinib, lazertinib, or panitumumab.

[0223] As used herein, the term "vascular endothelial growth factor receptor (VEGFR)" refers to a cell membrane receptor for vascular endothelial growth factor, which induces angiogenesis, and a VEGFR inhibitor inhibits angiogenesis, thereby inhibiting tumor growth and metastasis. In one embodiment, the VEGF inhibitor or VEGFR inhibitor may be axitinib, lenvatinib, bevacizumab, ramucirumab, or aflibercept.

[0224] As used herein, the term "CD20 (B-lymphocyte antigen CD20)" refers to a protein expressed on the surface of B cells and is used as a target protein for the treatment of B-cell lymphoma. The inhibitor targeting CD20 may be rituximab or obinutuzumab.

[0225] As used herein, the term "CD38 (cluster of differentiation 38)" refers to a protein that acts as a signal transduction receptor in immune cells and regulates cell proliferation and cell death, and an inhibitor that targets this protein may be daratumumab.

[0226] As used herein, the term "RANK-L (receptor activator of nuclear factor kappa-B ligand)" refers to the RANK receptor expressed on the surface of osteoclasts, and when activated by binding to this ligand, it acts to cause bone destruction. RANK-L inhibitors are primarily used for cancer patients suffering from bone metastasis or osteoporosis, and may specifically be denosumab.

[0227] As used herein, the term "BTK (Bruton's tyrosine kinase)" refers to an enzyme involved in B-cell proliferation, and its overexpression can lead to hematological cancers. In one embodiment, the BTK-targeting inhibitor may be ibrutinib.

[0228] As used herein, the term "BCR-ABL" refers to a fusion protein that is highly expressed in patients with chronic myeloid leukemia and is known to induce abnormal proliferation of blood cells. Specifically, the inhibitor of this protein may be dasatinib, nilotinib, imatinib, or bosutinib.

[0229] As used herein, the term "transforming growth factor beta receptor (TGFβR)" refers to a cell membrane receptor for a transforming growth factor (TGFβR) that regulates the growth, migration, differentiation, and cell death of epithelial and hematopoietic cells. Inhibitors that target TGFβR may include, but are not limited to, galunisertib or bactosertib.

[0230] As used herein, the term "PDGFR (platelet-derived growth factor receptor)" refers to a cell membrane receptor for PDGF, which is frequently expressed in cancer cells and is known to be involved in angiogenesis, which regulates cancer growth, metastasis, and drug resistance. FGFR (fibroblast growth factor receptor) is a receptor for fibroblast growth factor (FGF) and regulates various biological processes, including cell growth, differentiation, and migration. Mutations in the FGFR gene are frequent, and these mutations are commonly observed in breast cancer, uterine cancer, ovarian cancer, cervical cancer, and other cancers. Inhibitors targeting PDGFR or FGFR may be futibatinib, nintedanib, sunitinib, imatinib, sorafenib, cabozantinib, lenvatinib, regorafenib, masitinib, semaxanib, tivozanib, vandetanib, axitinib, or pazopanib.

[0231] As used herein, the term "MEK (mitogen-activated protein kinase kinase)" refers to a dual-specificity kinase enzyme that phosphorylates MAPK (mitogen-activated protein kinase), also known as MAP2K, MEK, or MAPKK. Inhibition of MEK blocks cell proliferation and induces cell death. The MEK-targeting anticancer drug may be cobimetinib, selumetinib, trametinib, or binimetinib.

[0232] As used herein, the term "KRAS (Kirsten rat sarcoma virus)" refers to a gene that produces a protein called K-Ras, which is part of the RAS / MAPK pathway and is an oncogene that signals for cell growth, division, proliferation, and differentiation. KRAS-targeted anticancer drugs may be sotorasib, adagrasib, JDQ443, or MRTX1133.

[0233] As used herein, the term "ERK1 / 2 (extracellular signal-regulated kinase 1 / 2)" refers to protein kinases, which are widely expressed intracellular signaling molecules involved in functions including regulating meiosis, mitosis, and postmitotic functions in cells. Disruption of the ERK pathway is commonly observed in cancer. ERK1 / 2-targeting anticancer drugs may be linetelquib, urisertinib (BVD-523), or ERAS-007.

[0234] As used herein, the term "HER-2 / neu (human epidermal growth factor receptor 2)" regulates cell proliferation by activating PI3K / AKT. This receptor is known to be overexpressed in metastatic breast cancer and ovarian cancer, inducing resistance to anticancer drugs. The Her2 / neu-targeted anticancer drug may be trastuzumab, afantilib, lapatinib, irbinitinib (tucatinib), or neratinib.

[0235] As used herein, the term "ubiquitin" refers to the ubiquitin-proteasome system (UPS), which maintains cellular homeostasis by binding to other proteins and inducing their degradation by the proteasome, a proteolytic enzyme. Abnormal expression or activity of the UPS has been observed in various tumors, and UPS inhibitors exhibit anti-cancer activity. For example, inhibitors targeting the ubiquitin E1 enzyme may include MLN-7243 (TAK-243), PYR-41, MLN4924, etc., and MDM2 E3 ubiquitin ligase inhibitors may include RO-5503781 (idasanutlin), MK-8242, SAR-405838, CGM097, DS3032b, etc.

[0236] As used herein, "proteasome inhibitor" can treat cancer by blocking the action of proteasome, an intracellular complex that degrades proteins.Proteasome inhibition prevents the degradation of proapoptotic factors, such as p53 protein, thereby activating programmed cell death in tumor cells that depend on the inhibition of proapoptotic pathways.Proteasome inhibitors may include lactacystin, disulfiram, epigallocatechin 3-gallate, marizomib (salinosporamide A), oprozomib (ONX-0912), delanzomib (CEP-18770), epoxomicin, MG132, β-hydroxyβ-methylbutyrate, bortezomib, carfilzomib, ixazomib, etc.

[0237] As used herein, the term "JAK (Janus kinase)" refers to an upstream protein of STAT, a transcription factor that regulates cell proliferation, cell survival, cell migration, and immune response. JAK inhibitors are known to reduce cell proliferation and induce cell death through inhibition of STAT activity. JAKs include JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2). Inhibitors targeting JAK may be ruxolitinib, restortinib, or pacritinib.

[0238] As used herein, the term "ALK (anaplastic lymphoma kinase)" refers to a signal transduction molecule that promotes cell proliferation, cell migration, and angiogenesis, and inhibits cell death, and is overactivated in various cancer tissues. ALK-targeting inhibitors may be alectinib, lorlatinib, or crizotinib.

[0239] As used herein, the term "BCL-2" refers to a protein that inhibits cell death and is overexpressed or overactivated in various cancer tissues. Examples of inhibitors that target BCL-2 include venetoclax, ABT-737, and navitoclax (ABT-263).

[0240] As used herein, the term "C-MET" refers to a receptor for hepatocyte growth factor (HGF) that activates signal transduction related to cell growth, formation, motility, survival, angiogenesis, etc. The C-MET-targeted anticancer drug may be crizotinib, tepotinib, or cabozantinib.

[0241] As used herein, the term "VR (vanilloid receptor)" is also known as TRPV (transient receptor potential vanilloid) and exists in the forms of VR1, VR2, VR3, VR4, VR5, and VR6. VRs are known to regulate cancer cell proliferation, cell death, migration, invasion, and angiogenesis at each stage of cancer progression.

[0242] As used herein, the term "c-KIT," also known as CD117, induces signal transduction that activates cell survival, proliferation, and differentiation. c-KIT is a proto-oncogene, and overexpression or mutation of this gene is associated with the development of cancer. In one embodiment, the c-KIT-targeted anticancer drug may be imatinib, dasatinib, or regorafenib.

[0243] As used herein, the term "AXL (tyrosine-protein kinase receptor UFO)" refers to a tyrosine kinase receptor present on the cell surface that mediates signal transduction involved in cell proliferation and survival. AXL is known to be involved in resistance to anticancer drugs during anticancer treatment. In one embodiment, the AXL-targeted anticancer drug may be bemcentinib or gilteritinib.

[0244] As used herein, the term "RET (rearranged during transfection)" refers to a receptor that mediates signals involved in cell proliferation, cell death, and survival, and mutations in RET are known to be involved in the development of cancer. RET-targeting inhibitors may be, but are not limited to, serpasetinib or pralsetinib.

[0245] As used herein, the term "BRAF" refers to a MAPK signaling molecule involved in cell proliferation, cell cycle regulation, cell survival, angiogenesis, cell migration, etc., and genetic mutations of BRAF have been observed in cancer cells. Inhibitors targeting BRAF may be dabrafenib, encorafenib (LGX818), or vemurafenib.

[0246] As used herein, the term "pan-RAF" encompasses RAF family members, such as BRAF, ARAF, and CRAF. Inhibitors targeting pan-RAF may be naporafenib, belbalafenib, or sorafenib.

[0247] As used herein, the term "SHP2 (Src homology region 2 domain-containing phosphatase 2)," also known as tyrosine-protein phosphatase non-receptor type 11 (PTPN11) or protein tyrosine phosphatase 1D / 2C (PTP-1D / 2C), is known to be a signaling molecule that regulates various cellular processes, including cell growth, differentiation, the mitotic cycle, and oncogenic transformation. Activating SHP2 mutations have been found in neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, colorectal cancer, and other cancers. Examples of inhibitors targeting SHP2 include PF-07284892, RMC-4630 (SHP2-IN-7), and batoprotafib (TNO155).

[0248] As used herein, the term "SRC (proto-oncogene tyrosine protein kinase)" refers to a non-receptor tyrosine kinase protein, also known as c-Src, which regulates embryonic development and cell growth, and whose elevated activity levels are known to be associated with cancer progression. An SRC inhibitor may be, for example, dasatinib or bosutinib.

[0249] As used herein, the term "LCK (lymphocyte-specific protein tyrosine kinase)" refers to a member of the SFK (Src kinase family) that activates T cell receptor signaling. Mutations and dysfunction of LCK inhibit T cell activation, and overexpression of LCK is known to be associated with cancer, asthma, type 1 diabetes, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease (Crohn's disease and ulcerative colitis), and the like. An inhibitor targeting LCK may be, for example, WH-4-023.

[0250] As used herein, the term "PARP (poly [ADP-ribose] polymerase)" refers to a protein that is activated by recognizing damaged DNA in the nucleus and then activates proteins involved in DNA repair. PARP-targeting inhibitors inhibit the proliferation of cancer cells by inhibiting DNA repair in cancer cells. In one embodiment, the PARP-targeting inhibitor may be olaparib, talazoparib, niraparib, or rucaparib.

[0251] As used herein, the term "DNA methyltransferase (DNMT)" refers to an enzyme that attaches methyl groups to histone proteins wrapped around DNA, inhibiting gene expression through this process. DNMT-targeting inhibitors exhibit anticancer activity by inhibiting hypermethylation of tumor suppressor genes and inducing their normal expression. In one embodiment, the DNMT-targeting inhibitor may be azacitidine, decitabine, or guadecitabine.

[0252] As used herein, the term "CDK (cyclin-dependent kinase) 4 / 6" refers to proteins that promote cell growth by regulating the cell cycle and are overactivated during the development and progression of various malignant tumors. Inhibitors targeting CDK4 / 6 exhibit anticancer activity by inhibiting the cell cycle of cancer cells, inhibiting cell proliferation, and inducing cell death. The inhibitor targeting CDK4 / 6 may be abemaciclib (LY2835219), ribociclib, or palbociclib.

[0253] As used herein, the term "Aurora kinase" refers to a serine / threonine kinase essential for cell proliferation and a phosphotransferase enzyme that helps dividing cells distribute genetic material to daughter cells. Aurora kinases play a key role in cell division by controlling chromatid segregation, and defects in segregation can lead to tumorigenesis. Aurora A (Aurora2) functions during mitotic prophase and is involved in the accurate duplication and separation of centrosomes (microtubule-organizing centers in eukaryotic cells). Aurora B (Aurora1) is responsible for linking the mitotic spindle to kinetochores. Aurora C (AURKC) acts in embryonic cells. Inhibitors targeting Aurora A include MK-5108, hesperadin, and LY3295668. Pan-Aurora inhibitors include danusertib, AMG-900, reversine, and tozasertib (VX-680).

[0254] As used herein, the term "WEE1" refers to a 96-kDa nuclear kinase belonging to the Ser / Thr protein kinase family, also known as mitotic inhibitor protein kinase Wee1. Mitogens (MPFs) regulate apoptosis induced by DNA damage, and negative regulation of MPF by WEE1 leads to abnormal mitosis and resistance to apoptosis induced by DNA damage. Inhibitors targeting WEE1 can reduce the sensitivity of cancer cells to DNA damage-induced apoptosis by regulating WEE1. Examples of inhibitors targeting WEE1 include MK-1775 (adavosertib), azenosertib (ZN-C3), and ZNL-02-096.

[0255] As used herein, the term "PKMYT1 (protein kinase, membrane-associated tyrosine / threonine 1)" refers to a member of the Wee1 protein kinase family, a regulator of CDK1 phosphorylation, and a potential therapeutic target for the treatment of certain types of DNA damage-responsive cancers via CCNE1 amplification-induced synthetic lethality. PKMYT1-targeting inhibitors include RP-6306 and GSK-1520489A.

[0256] The term "HSP90 (heat shock protein 90)" as used herein refers to a chaperone protein that assists in the proper folding of other proteins, stabilizes proteins from heat stress, and assists in proteolysis. HSP90 can stabilize several proteins required for tumor growth. HSP90 inhibitors include BIIB021, BIIB028, MPC-3100, PU-H71, Debio093, SNX-5422, and AUY922.

[0257] As used herein, the term "A3AR (adenosine A3 receptor; ADORA3)" refers to a G protein-coupled receptor that couples to Gi / Gq and is involved in various intracellular signaling pathways and physiological functions. It is overexpressed in pathological human cells and can mediate cell proliferation and cell death. Therapeutic agents that target A3AR include reversine, KF-26777, MRS-545, and CAY10498.

[0258] As used herein, the term "EZH2 (enhancer of zeste homolog 2)" refers to the histone lysine N-methyltransferase enzyme encoded by the EZH2 gene. EZH2 is involved in histone methylation and ultimately transcriptional repression. EZH2 is an attractive target for anti-cancer treatment because it helps cancer cells divide and proliferate, and is found in higher concentrations than normal cells in a wide range of cancers, including breast cancer, prostate cancer, bladder cancer, uterine cancer, kidney cancer, melanoma, and lymphoma. Inhibitors that target EZH2 include DZNep, EPZ005687, EI1, GSK126, UNC1999, tazemetostat, and sinefungin.

[0259] As used herein, the term "ARID1A (AT-rich interaction domain-containing protein 1A)" refers to a member of the SWI / SNF family of proteins. It possesses helicase and ATPase activity and modifies the chromatin structure surrounding specific genes, thereby regulating their transcription. The ARID domain is a DNA-binding domain capable of specifically binding to AT-rich DNA sequences known to be recognized by the SWI / SNF complex in the beta-globin locus, and the C-terminus of the protein can stimulate glucocorticoid receptor-dependent transcriptional activation. Mutations in this gene are commonly found in gastric cancer, ovarian clear cell carcinoma, and pancreatic cancer. Examples of inhibitors targeting EZH2 / ARID1A include GSK-343.

[0260] As used herein, the term "SUMOylation" refers to a post-translational modification in which small ubiquitin-like modifier (SUMO) polypeptides are covalently attached to lysine residues of target proteins. The enzymatic pathway of SUMOylation is very similar to that of ubiquitination and involves activating enzymes, conjugation enzymes, ligases, and deconjugating enzymes. Abnormal regulation of the SUMOylation pathway has been observed in cancer and neurological diseases, with SUMO enzymes being upregulated in many cancers and SUMO levels directly correlated with prognosis and disease progression. Examples of SUMOylation inhibitors include Davidin, CID9549553, and 2-D08.

[0261] As used herein, the term "CHK1 (checkpoint kinase 1; CHEK1)" refers to a serine / threonine-specific protein kinase that modulates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of CHK1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair, and apoptosis, thereby preventing damaged cells from progressing through the cell cycle. CHK1 is overexpressed in many tumors, including breast cancer, colon cancer, liver cancer, gastric cancer, and nasopharyngeal cancer. The positive correlation between CHK1 expression and tumor grade and disease recurrence suggests that CHK1 may promote tumor growth. Examples of inhibitors targeting CHK1 include SCH-900776, SRA737, V158411, PF-477736, AZD7762, and LY2880070 (prexasertib).

[0262] As used herein, the term "ATR (ataxia telangiectasia mutated (ATM) and RAD3-related kinase)" refers to a protein kinase involved in cellular responses to certain forms of DNA damage (e.g., double-strand breaks and replication stress). Normal cells repair damaged DNA using the ATM / ATR signaling system, which regulates the cellular response to DNA double-strand breaks and replication stress, known as the DNA damage response (DDR). On the other hand, many cancer cells exhibit high dependency on DNA repair proteins, including ATR, due to defects in ATM in the DNA repair process. Inhibitors targeting ATR may be berzosertib (VX-970), galtisertib (VX-803), or selalasertib (AZD6738).

[0263] As used herein, the term "HDAC (histone deacetylase)" refers to an enzyme that removes acetyl groups from the ε-N-acetyllysine amino acid of histones and non-histone proteins, allowing histones to more tightly wrap around DNA and regulate DNA expression through acetylation and deacetylation. HDACs include subgroups, such as class I, HDAC1, HDAC2, and HDAC3, and class IIA, such as HDAC4, HDAC5, and HDAC7. HDAC inhibitors have shown anticancer effects in studies of pancreatic cancer, esophageal squamous cell carcinoma (ESCC), multiple myeloma, prostate cancer, gastric cancer, leukemia, breast cancer, liver cancer, ovarian cancer, nasal cancer, Hodgkin's lymphoma, and neuroblastoma. Examples of inhibitors that target HDAC include panobinostat (LBH589), entinostat, mocetinostat, trichostatin A, CBUD-1001, and abexinostat (PCI-24781, CRA-024781).

[0264] As used herein, the term "AKT (protein kinase B: PKB)" refers to a series of serine / threonine-specific protein kinases that play key roles in several cellular processes, such as glucose metabolism, apoptosis, cell proliferation, and transcription, and are associated with tumor cell survival, proliferation, and invasiveness. AKT is commonly observed in tumor cells, and these cells depend on AKT for survival. Examples of inhibitors that target AKT include VQD-002, perifosine, miltefosine, MK-2206, AZD5363, and ipatasertib.

[0265] As used herein, the term "PLK1 (Polo-like kinase 1)," also known as serine / threonine-protein kinase 1 or serine / threonine protein kinase 13 (STPK13), is a 66-kDa enzyme composed of 603 amino acids. Most colorectal and lung cancers are caused by K-RAS mutations and are known to be PLK1-dependent. When PLK1 expression is suppressed in cell culture by RNA interference, K-RAS cells can be selectively killed without harming normal cells. Examples of inhibitors that target PLK1 include boracetib and rigosertib.

[0266] As used herein, the term "BET (bromodomain and extraterminal domain protein)" refers to a bromodomain protein of approximately 110 amino acids that recognizes acetylated lysine residues, including BRD2, BRD3, BRD4, and BRDT. BET transduces signals transmitted by acetylated lysine residues and converts these signals into various normal or abnormal phenotypes. Bromodomains translate dysregulated cellular acetylomes into disease phenotypes, and BET is a target in cancer and multiple sclerosis. Inhibitors that target BET include JQ1, I-BET151 (GSK1210151A), I-BET762 (GSK525762), OTX-015, TEN-010, CPI-203, CPI-0610, Orinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1, and MS645.

[0267] As used herein, the term "IGF (insulin-like growth factor)" refers to proteins with high sequence similarity to insulin, which are involved in communication between cells and with the physiological environment, and include IGF1 / 2, IGF-1R, IGF-2R, etc. IGF-1 has been shown to stimulate the growth of prostate and breast cancer cells, and IGFs have been implicated in diseases such as cancer and diabetes. Inhibitors targeting IGF1 / 2 or IGF-1R include NVP-ADW742, figitumumab, mecasermin, rhIGF-1, BI885578, etc.

[0268] As used herein, the term "PIK (phosphatidylinositol kinase)" refers to phosphatidylinositol 3-kinase (PI3K) and phosphatidylinositol 4-kinase (PI4K). PI3K is involved in cell signaling by phosphorylating phosphoinositides at the 3-hydroxyl group of the inositol ring, while PI4K acts on phosphatidylinositol (PI) to produce the second messenger inositol-1,4,5-trisphosphate, abnormalities of which are associated with cancer. Examples of inhibitors targeting PIK include duvelisib, buparlisib, copanlisib, dactolisib, idelalisib, parsaclisib, paxalisib, taselisib, zandelisib, and inavolisib.

[0269] As used herein, the term "CDK9 (cyclin-dependent kinase 9)" refers to a cyclin-dependent kinase associated with P-TEFb and a cell cycle regulator. CDK9 is involved in several protein-protein interaction networks, which are often involved in transcriptional dysregulation in cancer. Examples of inhibitors targeting CDK9 include AZD4573, atuveciclib, VIP152, A-1592668, JSH-150, SLS009, AT-7519, and roscovitine.

[0270] As used herein, the term "DHFR (dihydrofolate reductase)" refers to an enzyme that reduces dihydrofolate to tetrahydrofolate using NADPH as an electron donor. It is a component of the multiprotein complex TAK / P-TEFb, an elongation factor for RNA polymerase II transcription and function by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. DHFR regulates intracellular levels of tetrahydrofolate, and its inhibition can limit cell growth and proliferation, hallmarks of cancer and bacterial infections. Examples of inhibitors that target DHFR include methotrexate, pralatrexate, pemetrexed, raltitrexed, trimetrexate, nolatrexed, piritrexim, and talotrexin.

[0271] As used herein, the term "STING (stimulator of interferon genes)" refers to an in vivo sensor that recognizes DNA fragments from cancer cells and activates immune cells such as dendritic cells in the body by stimulating interferon genes. STING agonists exhibit immunostimulatory and cancer angiogenesis inhibitory effects. For example, STING agonists may be CDN, SB11285, DMXAA, etc.

[0272] The compound of formula I of the present invention can be used in combination with other target inhibitors described above to enhance the effect of the target inhibitor, thereby significantly inhibiting the expression and activity of the target protein or gene. Specifically, the compound of formula I not only has anti-cancer effect itself, but can also improve the anti-cancer effect of the target inhibitor. Therefore, when the compound of formula I is used together with the target inhibitor, these compounds can exhibit anti-cancer effect superior to the sum of the anti-cancer effects when used alone.

[0273] The term "anticancer viral therapeutic agent" as used herein refers to a therapeutic agent that eliminates cancer by inserting a specific gene that targets cancer cells into a virus that has the ability to replicate and infect. The anticancer viral therapeutic agent may be talimogene laherparepvec.

[0274] The term "antibody therapeutic agent" as used herein refers to a therapeutic agent that exhibits anti-cancer activity using an antibody that recognizes a specific protein on cancer cells as an antigen. The antibody therapeutic agent may be cetuximab, trastuzumab, rituximab, ibritumomab, tositumomab, brentuximab, ofatumumab, obinutuzumab, necitumumab, bevacizumab, ramucirumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, or the like.

[0275] The term "immune cell therapy agent" as used herein refers to a therapeutic agent that exhibits anti-cancer effects by activating immune responses in the body using immune cells, such as dendritic cells, natural killer cells, and T cells. Immune cell therapy agents are used by extracting and enhancing immune cells in the body, or by genetically modifying them and then injecting them back into the body. Representative immune cell therapy agents include T cell receptor-modified T cells (TCR-T), chimeric antigen receptor-modified T cells (CAR-T), and the like. Specifically, the immune cell therapy agent may be, but is not limited to, tisagenlecleucel or axicabtageneciloreucel.

[0276] The term "immune checkpoint inhibitor" as used herein refers to a substance that inhibits the activity of immune checkpoint proteins, which inhibit the differentiation, proliferation, and activity of immune cells. This substance is known to eliminate cancer cells by preventing them from evading the immune system. The immune checkpoint inhibitor may be any one selected from the group consisting of anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-B7-H4 antibody, anti-HVEM antibody, anti-TIM3 antibody, anti-GAL9 antibody, anti-LAG3 antibody, anti-VISTA antibody, anti-KIR antibody, anti-BTLA antibody, and anti-TIGIT antibody. In one embodiment, the immune checkpoint inhibitor includes, but is not limited to, ipilimumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

[0277] As used herein, the term "antibody-drug conjugate (ADC)" refers to a therapeutic agent that exhibits potent anticancer activity through targeted delivery by chemically linking an antibody to a cytotoxic drug. Examples of ADCs include gemtuzumab-ozogamicin, brentuximab-vedotin, trastuzumab-emtansine, inotuzumab-ozogamicin, and eribulin mesylate.

[0278] The anticancer agent may include one or more anticancer agents. Specifically, a compound, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof may be used together with two anticancer agents. For example, the two anticancer agents may be a chemical anticancer agent and a targeted anticancer agent; a chemical anticancer agent and an anticancer virus; a targeted anticancer agent and an antibody therapeutic agent; a chemical anticancer agent and a cell therapy agent; and a chemical anticancer agent and an immune checkpoint inhibitor. In addition, the two anticancer agents may be a targeted anticancer agent and an anticancer virus; a targeted anticancer agent and an antibody therapeutic agent; a targeted anticancer agent and a cell therapy agent; or a targeted anticancer agent and an immune checkpoint inhibitor. In addition, the two anticancer agents may be an anticancer virus and an antibody therapeutic agent; an anticancer virus and a cell therapy agent; and an anticancer virus and an immune checkpoint inhibitor. In addition, the two anticancer agents may be an antibody therapeutic agent and a cell therapy agent; and an antibody therapeutic agent and an immune checkpoint inhibitor.

[0279] The compound, its solvate, stereoisomer, or pharmaceutically acceptable salt may be used together with three anti-cancer drugs. In addition to the two anti-cancer drugs, one different anti-cancer drug may also be included and used.

[0280] The compound, its solvate, stereoisomer, or pharmaceutically acceptable salt may be used together with four anti-cancer drugs. In addition to the three anti-cancer drugs, one different anti-cancer drug may also be included and used.

[0281] The compound, its solvates, stereoisomers, or pharmaceutically acceptable salts may be used together with five anti-cancer drugs. In addition to the four anti-cancer drugs, one different anti-cancer drug may also be included and used.

[0282] The compound, its solvates, stereoisomers or pharmaceutically acceptable salts can be used together with six anti-cancer drugs.

[0283] The compounds, solvates, stereoisomers or pharmaceutically acceptable salts thereof can be used in combination with anti-cancer vaccines.

[0284] The term "anti-cancer vaccine" as used herein refers to an active immunotherapy that involves administering tumor-specific antigens (TSAs) carried by cancer cells to cancer patients to activate the immune system and enhance immune function in vivo, thereby eliminating cancer cells. Anti-cancer vaccines include DNA vaccines, peptide vaccines, and cellular vaccines, depending on the type of antigen and the method of antigen delivery. Cellular vaccines and DNA vaccines, which are developed by introducing antigens, are representative vaccines currently in development.

[0285] The compound, its solvate, stereoisomer, or pharmaceutically acceptable salt can be used in combination with an anti-cancer agent and an anti-cancer vaccine, wherein the compound and the anti-cancer agent are the same as those described above.

[0286] Pharmaceutical Uses, Pharmaceutical Compositions, and Methods of Administration The compounds of Formula 1 or Formula I, or stereoisomers, solvates or pharmaceutically acceptable salts thereof, can be used to prevent or treat SOS1-mediated diseases. The compounds of Formula I, stereoisomers, solvates and pharmaceutically acceptable salts are as described above.

[0287] As used herein, the term "prevent" or "prevention" refers to preventing a disease, for example, preventing a disease, condition, or disorder in a subject who may have a predisposition to the disease, condition, or disorder, but who has not yet experienced or exhibited symptoms or symptoms of the disease.

[0288] The term "treat" or "treatment" as used herein refers to inhibiting a disease, e.g., inhibiting a disease, condition or disorder in a subject experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder, i.e., preventing further occurrence of the pathology and / or symptoms, or ameliorating a disease, e.g., ameliorating a disease, condition or disorder in a subject experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder, i.e., reversing the pathology and / or symptoms, e.g., reducing the severity of the disease.

[0289] SOS1-mediated diseases can include diseases that can be prevented or treated by inhibiting the interaction between SOS1 and RAS family proteins or between SOS1 and RAC1. SOS1-mediated diseases can include diseases associated with abnormal activity of SOS1 and / or RAS family proteins. The SOS1-mediated disease can be, for example, cancer. The cancer can be, for example, pancreatic cancer, lung cancer, colorectal cancer, biliary tract cancer, multiple myeloma, melanoma, uterine cancer, cervical cancer, endometrial cancer, thyroid cancer, chronic lymphocytic leukemia, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, or sarcoma. In one embodiment, the cancer can be pancreatic cancer, lung cancer (e.g., non-small cell lung cancer), biliary tract cancer, or colorectal cancer.

[0290] The cancer may be, for example, a cancer dependent on the RAS family and MAPK signaling pathway. Examples of cancer include cancers with protein or gene mutations, gene amplification, and / or overexpression (e.g., mutations, amplification, and / or overexpression of RAF and MEK) in the RAS family and MAPK signaling pathway, such as KRAS, NRAS, HRAS, receptor tyrosine kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A / B, FGFR1 / 2 / 3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3, AXL), GAP (e.g., NF1), and SOS1. In addition, the cancer may be a RAC1-dependent cancer.

[0291] The SOS1-mediated disease may be, for example, a disease associated with dysregulation of the RAS family protein pathway, i.e., a RASopathy, such as neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines (NSML, also known as Leopard syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome, CFC syndrome (cardio-facio-cutaneous syndrome), Regius syndrome (also known as NF1-like syndrome), or hereditary gingival fibromatosis.

[0292] According to one embodiment, the compounds of formula I can be used to treat diseases associated with abnormal activity of SOS1 or RAS family proteins or dysregulation of RAS family protein pathways by inhibiting the interaction between SOS1 and RAS family proteins or between SOS1 and RAC1.

[0293] When used to treat cancer, the compounds of the present invention may be used alone or in combination with other anti-cancer therapies, such as radiation therapy, taxane derivatives (e.g., paclitaxel, docetaxel), platinum compounds (e.g., cisplatin, carboplatin), antimetabolites (e.g., 5-FU, gemcitabine, cytarabine, 6-thioguanine), CDK4 / 6 inhibitors (e.g., abemaciclib, palbociclib), immunotherapeutics (e.g., anti-CTLA4 antibodies, anti-PD1 antibodies), angiogenesis inhibitors (e.g., , bevacizumab, nintedanib, regorafenib), topoisomerase inhibitors (e.g., irinotecan, SN-38, doxorubicin), ERK inhibitors (e.g., ulisertinib, linetelquib), MDM2 inhibitors (e.g., alizomadrine), PARP inhibitors (e.g., niraparib), MCL-1 inhibitors, mTOR inhibitors (e.g., rapamycin, temsirolimus, INK-128 (sapanisertib, everolimus), BET inhibitors (e.g., JQ1), C DK9 inhibitors (e.g., AT-7519), IGF1 / 2 or IGF1-R inhibitors (e.g., NVP-ADW742), PIK inhibitors (e.g., duvelisib), EGFR inhibitors (e.g., apatinib, osimertinib, cetuximab, lazertinib, gefitinib, neratinib), ErbB2 (HER2) inhibitors (e.g., trastuzumab, irbinitinib, neratinib), ALK inhibitors (e.g., crizotinib, alectinib), MEK inhibitors (e.g., thrombinib, lametinib, cobimetinib), BCR-ABL inhibitors (e.g., imatinib, nilotinib, dasatinib), FGFR1, FGFR2 or FGFR3 inhibitors (e.g., nintedanib), ROS1 inhibitors (e.g., crizotinib, entrectinib, repotrectinib), c-MET inhibitors (e.g., tepotinib), AXL inhibitors (e.g., bemcentinib), NTRK1 inhibitors (e.g., repotrectinib), RET inhibitors (e.g., pralsetinib), KRAS G12C inhibitors (e.g., sotorasib, adagrasib, trametinib, JDQ443), KRASG12D inhibitors (e.g., MRTX1133), SHP2 inhibitors (e.g., TNO155), mutBRAF inhibitors (e.g., dabrafenib), PI3K inhibitors (e.g., alpelisib, apitolisib), Aurora A inhibitors (e.g., MK-5108), panAurora inhibitors (e.g., danusertib, AMG-900, reversine), BTK inhibitors (e.g., ibrutinib), Wee1 inhibitors (e.g., MK-1775), DHFR inhibitors (e.g., methotrexate), HSP90 inhibitors (e.g., BIIB021), A3AR antagonists (e.g., reversine), ubiquitin E1 enzyme inhibitors (e.g., MLN-7243), Bcl-2 inhibitors (e.g., ABT-737), EZH2 inhibitors (e.g., GSK-343), ARID1A inhibitors (e.g., For example, it may be administered in combination with an inhibitor such as GSK-343, a sumoylation inhibitor (e.g., 2-D08), a Chk1 inhibitor (e.g., SCH-900776), an HDAC inhibitor (e.g., entinostat), a JAK1 / 2 inhibitor (e.g., ruxolitinib), a proteasome inhibitor (e.g., carfilzomib), an Akt inhibitor (e.g., ipatasertib), a GR inhibitor (e.g., prednisolone), a PLK1 inhibitor (e.g., boracetomib), or a pan-RAF inhibitor (e.g., sorafenib).

[0294] The compound of formula I of the present invention can be used together with other anti-cancer therapies described above to enhance the effect of the anti-cancer therapy, thereby significantly inhibiting the expression and activity of target proteins or genes. Specifically, the compound of formula I not only has its own anti-cancer effect, but can also improve the anti-cancer effect of target inhibitors. Therefore, when the compound of formula I is used together with the above-mentioned anti-cancer therapies, these compounds can exhibit anti-cancer effects that are superior to the sum of the anti-cancer effects when used alone.

[0295] In one embodiment, the pharmaceutical composition may comprise a conventional pharmaceutically acceptable carrier, excipient, or additive. The pharmaceutical composition may be formulated according to conventional methods and prepared into various oral dosage forms, such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or parenteral dosage forms, such as intramuscular, intravenous, or subcutaneous dosage forms. The pharmaceutical composition may be a single composition or separate compositions. The pharmaceutical composition comprises a compound, stereoisomer, solvate, or pharmaceutically acceptable salt according to one aspect as the active ingredient of the pharmaceutical composition.

[0296] When the pharmaceutical composition is prepared in the form of an oral preparation, examples of the additives or carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. When the pharmaceutical composition of the present invention is prepared in the form of an injection, examples of the additives or carriers include water, saline, aqueous glucose solution, aqueous sugar analogue solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifier, etc.

[0297] The dosage of the pharmaceutical composition is an amount effective for the treatment or prevention of a subject or patient, and can be administered orally or parenterally as desired. The pharmaceutical composition can be administered orally in an amount of 0.01 to 1000 mg, more specifically 0.1 to 300 mg, of the active ingredient per kg of body weight per day, or parenterally in an amount of 0.01 to 100 mg, more specifically 0.1 to 50 mg, of the active ingredient per kg of body weight per day, in one or several divided doses. The dosage to be administered to a particular subject or patient should be determined taking into account several relevant factors, such as body weight, age, sex, the patient's health condition, diet, administration time, administration method, and disease severity, and it should be understood that the dosage can be increased or decreased as appropriate by a specialist. The dosages listed above are not intended to limit the scope of the present invention in any way. A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the necessary effective amount of the pharmaceutical composition. For example, dosages of the compounds of the invention employed in pharmaceutical compositions by a physician or veterinarian may be started at levels lower than those required to achieve the desired therapeutic effect and may be gradually increased until the desired effect is achieved.

[0298] In one embodiment, pharmaceutical compositions include within their scope pharmaceutical compositions comprising as an active ingredient a therapeutically effective amount of at least one of the compounds of one embodiment, alone or in combination with a pharmaceutical carrier. The term "therapeutically effective amount" or "effective amount" refers to an amount sufficient to effect a beneficial or desired clinical result, for example, an amount sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of a disease.

[0299] Optionally, a compound according to one embodiment can be administered alone, in combination with a compound according to another embodiment, or in combination with one or more other therapeutic agents, such as anti-cancer agents or other pharmaceutically active substances, simultaneously, separately or sequentially. Examples of anti-cancer agents that can be administered in combination are described above.

[0300] In another aspect, there is provided a method for preventing or treating an SOS1-mediated disease, comprising administering to a subject a compound of formula I, a solvate, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0301] Among the terms or elements referred to in the description of the method, the same terms or elements as those already mentioned are the same as those described above.

[0302] Administration may be oral or parenteral. The pharmaceutical composition may be administered orally in a single or multiple divided doses, typically in an amount of 0.01 to 1000 mg, more specifically 0.1 to 300 mg, of the active ingredient per kg of body weight per day, or parenterally in an amount of 0.01 to 100 mg, more specifically 0.1 to 50 mg, of the active ingredient per kg of body weight per day. The dose to be administered to a specific subject or patient should be determined taking into account several relevant factors, such as body weight, age, sex, the patient's health condition, diet, administration time, administration method, and disease severity, and the dose may be increased or decreased as appropriate by a specialist.

[0303] The term "subject" as used herein refers to a subject in need of treatment for a disease, and more specifically refers to mammals, such as humans or non-human primates, mice, dogs, cats, horses, and cows.

[0304] In another aspect, there is provided a pharmaceutical use of a compound of formula I, a solvate, stereoisomer or pharmaceutically acceptable salt thereof for the prevention or treatment of an SOS1-mediated disease; or a use of a compound of formula I, a solvate, stereoisomer or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of an SOS1-mediated disease.

[0305] Among the terms or elements referred to in the description of the method or use, the same terms or elements as those already mentioned are the same as those described above.

[0306] [Effects of the invention] The compound of formula I, its solvate, stereoisomer or pharmaceutically acceptable salt has effective inhibitory activity against SOS1, particularly inhibiting the interaction between SOS1 and RAS family proteins or between SOS1 and RAC1.In addition, when combined with other anticancer drugs, the compound exhibits synergistic effects for inhibiting the growth of cancer cells in lung cancer, pancreatic cancer, gastric cancer and colorectal cancer.Therefore, pharmaceutical compositions for treating cancer, comprising the novel compound and anticancer drug as active ingredients, can be useful for preventing or treating cancer. [Brief explanation of the drawings]

[0307] [Figure 1] 1 is a graph showing the results obtained by assessing cell viability following administration of INK-128 alone or in combination with the compound of Example 295 to lung cancer cells NCI-H358. [Figure 2] 1 is a graph showing the results obtained by assessing cell viability following administration of sotorasib alone or in combination with the compound of Example 295 to lung cancer cells NCI-H358. [Figure 3] 1 is a graph showing results obtained by assessing cell viability following administration of example compounds and sotorasib, alone or in combination, to lung cancer cells NCI-H358. [Figure 4] 1 is a graph showing results obtained by assessing cell viability following administration of example compounds and sotorasib, alone or in combination, to pancreatic cancer cells MIA PaCa-2. [Figure 5] 1 is a graph showing results obtained by assessing cell viability following administration of example compounds and adagrasib, alone or in combination, to lung cancer cells NCI-H358. [Figure 6] 1 is a graph showing results obtained by assessing cell viability following administration of example compounds and adagrasib alone or in combination to pancreatic cancer cells MIA PaCa-2. [Figure 7]1 is a graph showing results obtained by assessing cell viability following administration of an example compound and trametinib, alone or in combination, to lung cancer cells NCI-H358. [Figure 8] 1 is a graph showing results obtained by assessing cell viability following administration of an example compound and trametinib, alone or in combination, to lung cancer cells NCI-H358. [Figure 9] 1 is a graph showing the results obtained by assessing cell viability following administration of an example compound and trametinib, either alone or in combination, to gastric cancer cells SNU-1. [Figure 10] 1 is a graph showing the results obtained by assessing cell viability following administration of an example compound and trametinib, either alone or in combination, to gastric cancer cells SNU-1. [Figure 11] 1 is a graph showing results obtained by assessing cell viability following administration of example compounds and trametinib, alone or in combination, to SW480 colorectal cancer cells. [Figure 12] 1 is a graph showing results obtained by assessing cell viability following administration of example compounds and trametinib, alone or in combination, to SW480 colorectal cancer cells. [Figure 13] 1 is a graph showing results obtained by assessing cell viability following administration of an example compound and osimertinib, either alone or in combination, to lung cancer cells H1975. [Figure 14] 1 is a graph showing results obtained by assessing cell viability following administration of an example compound and osimertinib, alone or in combination, to lung cancer cells HCC827. [Figure 15] 1 is a graph showing results obtained by assessing cell viability following administration of an example compound and lazertinib, either alone or in combination, to lung cancer cells H1975. [Figure 16] 1 is a graph showing results obtained by assessing cell viability following administration of an example compound and lazertinib, either alone or in combination, to HCC827 lung cancer cells. [Figure 17]1 is a graph showing results obtained by assessing cell viability following administration of an example compound and alpelisib, alone or in combination, to PIK3CA mutant breast cancer cells MCF7. [Figure 18] 1 is a graph showing the results obtained by evaluating cell viability following administration of an example compound and JDQ443, alone or in combination, to lung cancer cells H358, which have the KRAS G12C variant. [Figure 19] 1 is a graph showing the results obtained by assessing cell viability following administration of example compounds and TNO155, alone or in combination, to lung cancer cells H358, which have the KRAS G12C variant. [Figure 20] 1 is a graph showing the results obtained by assessing cell viability following administration of an example compound and cisplatin, alone or in combination, to lung cancer cells H358, which have the KRAS G12C variant. [Figure 21] 1 is a graph showing the results obtained by evaluating cell viability following administration of an example compound and linetelquib, either alone or in combination, to lung cancer cells H358 harboring the KRAS G12C variant. [Figure 22] 1 is a graph showing the results obtained by evaluating cell viability following administration of an example compound and urisertinib, alone or in combination, to lung cancer cells H358, which have the KRAS G12C variant. [Figure 23] 1 is a graph showing the results obtained by assessing cell viability following administration of an example compound and pralsetinib, alone or in combination, to lung cancer cells H358, which have the KRAS G12C variant. [Figure 24] 1 is a graph showing the results obtained by evaluating cell viability following administration of an example compound and repotrectinib, alone or in combination, to lung cancer cells H358, which have the KRAS G12C variant. [Figure 25] 1 is a graph showing the results obtained by assessing cell viability following administration of an example compound and tepotinib, alone or in combination, to c-Met-overexpressing gastric cancer cells SNU-5. [Figure 26] 1 is a graph showing the results obtained by evaluating cell viability following administration of an example compound and bemcentinib, alone or in combination, to lung cancer PC-9 cells with high AXL expression. [Figure 27] 1 is a graph showing results obtained by assessing cell viability following administration of an example compound and arlizomadrine, alone or in combination, to lung cancer cells A549 harboring the KRAS G12S variant. [Figure 28] 1 is a graph showing the results obtained by assessing cell viability following administration of an example compound and everolimus, alone or in combination, to LoVo colorectal cancer cells harboring the KRAS G13D variant. [Figure 29] 1 is a graph showing the results obtained by evaluating cell viability following administration of an example compound and MRTX1133, either alone or in combination, to pancreatic cancer cells AsPC-1, which have the KRAS G12D variant. [Figure 30a] 1 is a graph showing results obtained by using SynergyScreen to evaluate the synergistic effect of combined administration of example compounds to lung cancer cells H358. [Figure 30b] 1 is a graph showing results obtained by using SynergyScreen to evaluate the synergistic effect of combined administration of example compounds to lung cancer cells H358. [Figure 30c] 1 is a graph showing results obtained by using SynergyScreen to evaluate the synergistic effect of combined administration of example compounds to lung cancer cells H358. [Figure 31a] 1 is a graph showing results obtained by using SynergyScreen to evaluate the synergistic effect of combined administration of example compounds to lung cancer cells H358. [Figure 31b] 1 is a graph showing results obtained by using SynergyScreen to evaluate the synergistic effect of combined administration of example compounds to lung cancer cells H358. [Figure 31c]1 is a graph showing results obtained by using SynergyScreen to evaluate the synergistic effect of combined administration of example compounds to lung cancer cells H358.

[0308] [Detailed Description for Carrying Out the Invention] Hereinafter, the present invention will be described in more detail by the following examples, but the following examples are merely illustrative of the present invention and the scope of the present invention is not limited thereby.

[0309] [Preparation Example] Preparation Example 1: 6-oxo-1-phenyl-pyridazine-3-carboxylic acid Step 1: Synthesis of methyl-6-oxo-1-phenyl-pyridazine-3-carboxylate [ka] A mixture of phenylboronic acid (380 mg, 3.1 mmol), methyl-6-oxo-1H-pyridazine-3-carboxylate (504 mg), Cu(OAc) (113 mg, 623 μmol), and pyridine (1.6 g, 19.8 mmol) in DCM (10 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 20 °C for 16 h. The reaction mixture was poured into distilled water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (21% EtOAc in petroleum ether) to give methyl-6-oxo-1-phenyl-pyridazine-3-carboxylate (450 mg, 62.7% yield) as a yellow solid. 1 LC / MS (ESI) m / z =231.0 [M+H] + .

[0310] Step 2: Synthesis of 6-oxo-1-phenyl-pyridazine-3-carboxylic acid [ka] To a solution of methyl-6-oxo-1-phenyl-pyridazine-3-carboxylate (450 mg, 2.0 mmol) in ACN (5 mL) and HO (1 mL) was added 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (544 mg, 3.9 mmol), followed by stirring at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was added with water (20 mL), acidified (pH = 2.0) with 1 N aqueous HCl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give Intermediate A (410 mg, crude, 95% yield) as a yellow solid. 1 LC / MS (ESI) m / z = 217.0 [M+H] + . Preparation Example 2: (1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethanamine

[0311] Step 1: Synthesis of 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone [ka] 1-Vinyloxybutane (74.2 g, 741 mmol) and TEA (11.2 g, 111 mmol) were added dropwise to a mixture of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (20.0 g, 74.1 mmol) and Pd(PPh) (4.3 g, 3.7 mmol) in n-BuOH (200 mL). The mixture was degassed and purged with N three times and then stirred at 135 °C under a N atmosphere for 18 h. 4 N HCl (120 mL) and THF (100 mL) were added to the mixture, which was stirred at 20 °C for 2.5 h. The reaction mixture was poured into water (600 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (3% EtOAc in PE) to give 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone (20.45 g, 47.37% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 8.94 (d, J = 1.6 Hz, 1H), 8.69 (s,1H), 8.53 (s, 1H), 2.75 (s, 3H).

[0312] Step 2: Synthesis of (R)-2-methyl-N-[1-[3-nitro-5-(trifluoromethyl)phenyl]ethylidene]propane-2-sulfinamide [ka] To a solution of 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone (20.5 g, 87.7 mmol) in THF (200 mL) was added Ti(OEt) (50.0 g, 219 mmol) and (R)-2-methylpropane-2-sulfinamide (13.8 g, 114 mmol), followed by stirring at 80 °C for 14 h under N. The mixture was quenched with ice water (300 mL) at 20 °C, and the precipitate was dissolved in EtOAc (500 mL) and filtered off. The organic layer was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (15–20% EtOAc in PE) to give (R)-2-methyl-N-[1-[3-nitro-5-(trifluoromethyl)phenyl]ethylidene]propane-2-sulfinamide (20.4 g, 69.0% yield) as a yellow oil.1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 2.85 (s, 3H), 1.25 (s,9H); LC / MS (ESI) m / z=337.0 [M+H] + .

[0313] Step 3: Synthesis of (R)-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]propane-2-sulfinamide [ka] To a solution of (R)-2-methyl-N-[1-[3-nitro-5-(trifluoromethyl)phenyl]ethylidene]propane-2-sulfinamide (20.4 g, 60.5 mmol) in THF (200 mL) and HO (4 mL) was added NaBH (1.6 g, 42.4 mmol), followed by stirring at −78° C. under N for 3 h. The reaction mixture was quenched with saturated aqueous NH Cl (150 mL) at 20° C., diluted with EtOAc (100 mL), and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The two diastereomers in a 95:5 ratio were purified by silica gel column chromatography (20% EtOAc in petroleum ether) to give the major product, (R)-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]propane-2-sulfinamide (14.3 g, 69.9% yield, >99% ee) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 6.07 (d, J = 8.8 Hz, 1H),4.73-4.63 (m, 1H), 1.45 (d, J = 7.2 Hz, 3H), 1.13 (s, 9H); LC / MS (ESI) m / z =339.0 [M+H] + .

[0314] Step 4: Synthesis of (1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethanamine [ka] To a solution of (R)-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]propane-2-sulfinamide (14.3 g, 42.3 mmol) in dioxane (50 mL) was added 4 N HCl / dioxane (50 mL) at 0° C., followed by stirring for 3 hours at 0° C. The mixture was concentrated under reduced pressure to give a residue, which was triturated with MTBE (200 mL) at 20° C. for 20 minutes, and the mixture was filtered to give Intermediate B (8.4 g, 73.4% yield, HCl salt) as an off-white solid. 1 LC / MS (ESI) m / z = 235.1 [M+H] + .

[0315] Preparation Example 3: 3-[(1R)-1-aminoethyl]-5-(trifluoromethyl)aniline [ka] To a solution of intermediate B (3.00 g, 11.09 mmol, HCl salt) in MeOH (30 mL), Pd / C (600 mg, 10% purity) was added, followed by stirring under H (40 Psi) at 20° C. for 5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate C (2.5 g, 93.72% yield, HCl salt) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (brs, 3H), 6.97 (s, 1H), 6.84 (brd, J = 5.2 Hz, 2H), 5.75 (s,2H), 4.44-4.24 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H); LC / MS (ESI) m / z = 205.0 [M+H] + . Preparation Example 4: 2-[3-[(1R)-1-aminoethyl]phenyl]-2,2-difluoroethanol

[0316] Step 1: Synthesis of ethyl 2-(3-acetylphenyl)-2,2-difluoro-acetate [ka] To a solution of 1-(3-iodophenyl)ethanone (5.0 g, 20.32 mmol) in DMSO (50 mL), Cu (3.87 g, 60.96 mmol) and ethyl 2-bromo-2,2-difluoroacetate (12.37 g, 60.96 mmol) were added, followed by stirring at 80 °C under N for 12 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (8% EtOAc in petroleum ether) to give ethyl 2-(3-acetylphenyl)-2,2-difluoroacetate (2.93 g, 52.38% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 8.19 (s, 1H), 8.09 (d, J = 8.0 Hz,1H), 7.81 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 4.31 (q, J = 7.2 Hz,2H), 2.64 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 243.0 [M+H] + .

[0317] Step 2: Synthesis of ethyl 2-[3-[(Z)-N-[(R)-tert-butylsulfinyl]-C-methyl-carbimidoyl]phenyl]-2,2-difluoro-acetate [ka] To a solution of ethyl 2-(3-acetylphenyl)-2,2-difluoroacetate (2.93 g, 12.10 mmol) in THF (30 mL) was added Ti(OEt) (6.90 g, 30.24 mmol) and (R)-2-methylpropane-2-sulfinamide (1.91 g, 15.73 mmol), followed by stirring for 12 h at 80° C. The mixture was quenched with ice water (80 mL) at 20° C., and the precipitate was dissolved in EtOAc (200 mL) and filtered off. The organic layer was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (12% EtOAc in petroleum ether) to give ethyl 2-[3-[(Z)-N-[(R)-tert-butylsulfinyl]-C-methyl-carbimidoyl]phenyl]-2,2-difluoro-acetate (3.0 g, 63.90% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 8.10 (s, 1H), 8.02 (d, J = 8.0 Hz,1H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 4.32 (q, J = 7.2 Hz,2H), 2.80 (s, 3H), 1.34 (s, 12H); LC / MS (ESI) m / z = 346.0 [M+H] + .

[0318] Step 3: Synthesis of (R)-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide [ka] To a solution of ethyl 2-[3-[(Z)-N-[(R)-tert-butylsulfinyl]-C-methyl-carbimidoyl]phenyl]-2,2-difluoroacetate (1 g, 2.90 mmol) in THF (10 mL) was added NaBH (240.97 mg, 6.37 mmol) at −78° C., followed by stirring at 0° C. for 2 hours. The reaction mixture was quenched with saturated aqueous NH Cl (40 mL) at 20° C., diluted with EtOAc (30 mL), and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The diastereomers formed in an approximately 3:1 ratio were initially purified using silica gel column chromatography (22% EtOAc in petroleum ether) to give the product. The product was subjected to preparative HPLC (Xtimate C18 150 × 40 mm × 10 μm; mobile phase: [water (NH3HO)-ACN]; B%: 25%-55%, 10 min) to isolate the major product. CH3CN was then removed under reduced pressure, and the remaining solvent was removed by lyophilization to give (R)-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (613 mg, 46.17% yield, 99.90% purity, 94.9% ee) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.48-7.40 (m, 3H), 4.59-4.50 (m, 1H), 3.95 (t, J =13.6 Hz, 2H), 3.52 (d, J = 5.2 Hz, 1H), 1.75 (s, 1H), 1.55 (d, J = 6.8 Hz, 3H),1.23 (s, 9H); LC / MS (ESI) m / z = 306.3 [M+H] + .

[0319] Step 4: Synthesis of 2-[3-[(1R)-1-aminoethyl]phenyl]-2,2-difluoro-ethanol [ka] To a solution of (R)-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (613 mg, 2.01 mmol) in dioxane (5 mL) was added 4N HCl / dioxane (5 mL), followed by stirring at 0° C. for 2 hours. The mixture was concentrated under reduced pressure to give Intermediate D (400 mg, crude) as a pale yellow oil. LC / MS (ESI) m / z=202.0 [M+H] + .

[0320] Preparation Example 5: 2-[3-[(1R)-1-aminoethyl]-2-fluoro-phenyl]-2,2-difluoro-ethanol Step 1: Synthesis of 1-(2-fluoro-3-iodo-phenyl)ethanol [ka] To a solution of 2-fluoro-3-iodo-benzaldehyde (4.0 g, 16.00 mmol) in THF (40 mL) was added dropwise MeMgBr (3 M, 8.00 mL) at −78° C., followed by stirring for 3 hours. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The product was purified by silica gel column chromatography (7% EtOAc in petroleum ether) to obtain 1-(2-fluoro-3-iodo-phenyl)ethanol (4.45 g, 83.63% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.72-7.64 (m, 1H), 7.55-7.45 (m, 1H), 6.93 (t, J = 7.6 Hz, 1H), 5.20 (q, J = 6.4 Hz, 1H), 1.52 (d, J = 6.4 Hz, 3H).

[0321] Step 2: Synthesis of 1-(2-fluoro-3-iodo-phenyl)ethanone [ka] To a solution of 1-(2-fluoro-3-iodo-phenyl)ethanol (4.45 g, 16.73 mmol) in MeCN (50 mL) was added TPAP (587.80 mg, 1.67 mmol) and NMO (2.94 g, 25.09 mmol), followed by stirring for 2 h at 20° C. The mixture was filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (0% EtOAc in petroleum ether) to give 1-(2-fluoro-3-iodo-phenyl)ethanone (3.8 g, 12.95 mmol, 77.44% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.97-7.88 (m, 1H), 7.85-7.78 (dm, 1H), 7.00 (t, J = 7.6 Hz, 1H), 2.65 (d, J = 5.2 Hz, 3H).

[0322] Step 3: Synthesis of ethyl 2-(3-acetyl-2-fluoro-phenyl)-2,2-difluoro-acetate [ka] To a solution of 1-(2-fluoro-3-iodo-phenyl)ethanone (3.0 g, 11.36 mmol) and ethyl 2-bromo-2,2-difluoro-acetate (6.92 g, 34.09 mmol, 4.38 mL) in DMSO (30 mL) was added Cu (2.17 g, 34.09 mmol), followed by stirring at 80 °C for 12 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (5% EtOAc in petroleum ether) to give ethyl 2-(3-acetyl-2-fluoro-phenyl)-2,2-difluoro-acetate (1.8 g, 56.05% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ 8.08-8.00 (m, 1H), 7.87-7.81 (m, 1H),7.36 (t, J = 7.6 Hz, 1H), 4.42-4.37 (m, 2H), 2.66 (d, J = 5.2 Hz, 3H), 1.35 (t,J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 261.0 [M+H] + .

[0323] Step 4: Synthesis of ethyl 2-[3-[[(R)-tert-butylsulfinyl]-C-methyl-carbimidoyl]-2-fluoro-phenyl]-2,2-difluoro-acetate [ka] To a solution of ethyl 2-(3-acetyl-2-fluoro-phenyl)-2,2-difluoro-acetate (1.8 g, 6.92 mmol) and (R)-2-methylpropane-2-sulfinamide (1.26 g, 10.38 mmol) in THF (20 mL) was added Ti(OEt) (4.73 g, 20.75 mmol), followed by stirring at 80 °C for 16 h. The reaction mixture was poured into water (30 mL) and EtOAc (30 mL), filtered, and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (6% EtOAc in petroleum ether) to give ethyl 2-[3-[[(R)-tert-butylsulfinyl]-C-methyl-carbimidoyl]-2-fluoro-phenyl]-2,2-difluoro-acetate (1.9 g, 74.09% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.86-7.72 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H), 4.44-4.30 (m, 2H), 2.77 (s, 3H), 1.32 (s, 9H); LC / MS (ESI) m / z = 364.0 [M+H] + .

[0324] Step 5: Synthesis of (R)-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluoro-phenyl]ethyl]-2-methyl-propane-2-sulfinamide [ka] To a solution of ethyl 2-[3-[[(R)-tert-butylsulfinyl]-C-methyl-carbimidoyl]-2-fluoro-phenyl]-2,2-difluoro-acetate (900 mg, 2.48 mmol) in THF (10 mL) and HO (0.2 mL) was added NaBH (210 mg, 5.55 mmol) at −78° C. The mixture was slowly warmed to 10° C. and then stirred at 10° C. for 2 h. The reaction mixture was poured into ice-water (30 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The product was first purified using silica gel column chromatography (50% EtOAc in petroleum ether), and then the two diastereomers (in a ca. 3:1 ratio) were separated and purified using preparative HPLC (Xtimate C18 150 × 40 mm × 10 μm; mobile phase: [water (NH3HO)-ACN]; B%: 25%–55%, 10 min). CH3CN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give the major product, (R)-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluoro-phenyl]ethyl]-2-methyl-propane-2-sulfinamide (440 mg, 50.90% yield, 92.65% purity, >99% ee) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (t, J = 6.8 Hz, 1H), 7.48-7.39 (m, 1H), 7.35-7.25 (m, 1H),5.87 (d, J = 7.6 Hz, 1H), 5.70 (t, J = 6.4 Hz, 1H), 4.68 (quintet, J = 7.2 Hz, 1H), 3.90 (dt, J = 6.4, 14.4 Hz, 2H), 1.40 (d, J = 6.8Hz, 3H), 1.10 (s, 9H); LC / MS (ESI) m / z = 324.3 [M+H] + .

[0325] Step 6: Synthesis of 2-[3-[(1R)-1-aminoethyl]-2-fluoro-phenyl]-2,2-difluoro-ethanol [ka] To a solution of (R)-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)-2-fluoro-phenyl]ethyl]-2-methyl-propane-2-sulfinamide (440 mg, 1.36 mmol) in dioxane (4 mL) was added 4N HCl / dioxane (2 mL) at 0° C., followed by stirring at 0° C. for 1 hour. The mixture was concentrated under reduced pressure to give Intermediate E (347 mg, 100% yield, HCl salt) as a yellow oil. LC / MS (ESI) m / z = 220.0 [M+H] + .

[0326] Preparation Example 6: Methyl-5-bromo-6-oxo-1-phenyl-pyridazine-3-carboxylate Step 1: Synthesis of methyl-5-bromo-6-oxo-1H-pyridazine-3-carboxylate [ka] To a solution of methyl-6-oxo-1H-pyridazine-3-carboxylate (3.0 g, 19.46 mmol) in AcOH (60 mL) was added KOAc (6.69 g, 68.13 mmol) and Br (6.84 g, 42.82 mmol, 2.21 mL), followed by stirring at 90 °C for 12 h. The mixture was quenched by the addition of aqueous NaHSO (500 mL, 3 mol / L) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give methyl-5-bromo-6-oxo-1H-pyridazine-3-carboxylate (3.0 g, 54.24% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 13.94 (brs, 1H), 8.26 (s, 1H), 3.85 (s, 3H); LC / MS (ESI) m / z =232.9 [M+H] + .

[0327] Step 2: Synthesis of methyl-5-bromo-6-oxo-1-phenyl-pyridazine-3-carboxylate [ka] To a solution of methyl-5-bromo-6-oxo-1H-pyridazine-3-carboxylate (3.00 g, 12.87 mmol) and phenylboronic acid (2.35 g, 19.31 mmol) in DCM (40 mL) was added pyridine (6.62 g, 83.68 mmol) and Cu(OAc) (1.17 g, 6.44 mmol), followed by stirring at 30 °C for 24 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (15% EtOAc in petroleum ether) to give intermediate F (2.5 g, 57.43% yield) as a pale yellow solid. LC / MS (ESI) m / z = 309.0 [M+H] + .

[0328] Preparation Example 7: Methyl-1-(2-nitrophenyl)-6-oxopyridazine-3-carboxylate [ka] A mixture of methyl-6-oxo-1H-pyridazine-3-carboxylate (1 g, 6.49 mmol), 1-fluoro-2-nitro-benzene (1.10 g, 7.79 mmol), and KCO (1.35 g, 9.73 mmol) in DMF (10 mL) was degassed and purged with N three times, then stirred at 80 °C under N atmosphere for 12 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (40% EtOAc in petroleum ether) to give intermediate G (1.2 g, 57.34% yield) as a white solid. LC / MS (ESI) m / z = 275.9 [M+H] + .

[0329] Furthermore, the following intermediates G-1 to G-4 were prepared in the same manner as for intermediate G. [ka] Preparation Example 8: Methyl-6-oxo-1-phenyl-4-(trifluoromethylsulfonyloxy)pyridazine-3-carboxylate Step 1: Synthesis of dimethyl 3-oxo-2-(phenylhydrazono)pentanedioate [ka] A mixture of HCl (10.20 g, 100.71 mmol, 10 mL, 36% purity), distilled water (20 mL), and aniline (1.86 g, 19.98 mmol, 1.82 mL) was treated with a solution of NaNO (1.38 g, 19.98 mmol) in distilled water (15 mL) at 5 °C. The solution was poured into a mixture of dimethyl 3-oxopentanedioate (3.48 g, 19.98 mmol, 2.88 mL) in EtOH (12 mL) and NaOAc (12 g, 146.28 mmol) in distilled water (40 mL), and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give dimethyl 3-oxo-2-(phenylhydrazono)pentanedioate (5.5 g, 89.02% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ 11.99 (s, 1H), 7.49-7.40 (m, 4H), 7.19-7.10 (m, 1H), 3.89 (s, 2H),3.85 (s, 3H), 3.62 (s, 3H).

[0330] Step 2: Synthesis of methyl-4-hydroxy-6-oxo-1-phenylpyridazine-3-carboxylate [ka] A solution of dimethyl 3-oxo-2-(phenylhydrazono)pentanedioate (5.30 g, 19.05 mmol) in 1,2-dichlorobenzene (50 mL) was stirred for 3 hours at 175° C. The mixture was purified by silica gel column chromatography (35% EtOAc in petroleum ether) to give methyl-4-hydroxy-6-oxo-1-phenyl-pyridazine-3-carboxylate (2.6 g, 52.67% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 13.10-10.54 (m, 1H), 7.58-7.42 (m, 5H), 6.21 (s, 1H), 3.88-3.78 (m,3H).

[0331] Step 3: Synthesis of methyl-6-oxo-1-phenyl-4-(trifluoromethylsulfonyloxy)pyridazine-3-carboxylate [ka] To a solution of methyl-4-hydroxy-6-oxo-1-phenyl-pyridazine-3-carboxylate (200 mg, 812.29 μmol) in DCM (4 mL) was added trifluoromethanesulfonic anhydride (TfO, 297.93 mg, 1.06 mmol, 174.23 μL) in DCM (10 mL) dropwise at −70° C., and the mixture was stirred at 20° C. for 1 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (12% EtOAc in petroleum ether) to give Intermediate H (220 mg, 71.60% yield) as a yellow solid. LC / MS (ESI) m / z = 379.0 [M+H] + ).

[0332] Preparation Example 9: (1R)-1-(3-ethoxyphenyl)ethanamine Step 1: Synthesis of 1-(3-ethoxyphenyl)ethanone [ka] To a mixture of 1-(3-hydroxyphenyl)ethanone (5.00 g, 36.7 mmol) and iodoethane (10.5 g, 67.2 mmol) in acetone (50 mL) was added KCO (10.2 g, 73.5 mmol), followed by stirring at 25 °C under N for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (6% EtOAc in petroleum ether) to give 1-(3-ethoxyphenyl)ethanone (5.65 g, 93.69% yield) as a white oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.52 (td, J = 1.2, 7.6 Hz, 1H), 7.49-7.45 (m, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.05-7.13 (m, 1H), 4.08 (q, J = 6.8 Hz, 2H), 2.60-2.58 (m, 3H), 1.43 (t, J = 6.8 Hz, 3H).

[0333] Step 2: Synthesis of (R)-N-[1-(3-ethoxyphenyl)ethylidene]-2-methyl-propane-2-sulfinamide [ka] To a solution of 1-(3-ethoxyphenyl)ethanone (1.50 g, 9.14 mmol) and (R)-2-methylpropane-2-sulfinamide (1.66 g, 13.7 mmol) in THF (20 mL) was added Ti(OEt) (6.25 g, 27.4 mmol), followed by stirring at 80 °C for 12 h. The reaction mixture was poured into water (50 mL), and a large amount of white solid was obtained. The mixture was filtered. The filter cake was washed with EtOAc, and the filtrates were combined, separated, and the organic layer was dried over NaSO and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0–18% EtOAc in petroleum ether) to give (R)-N-[1-(3-ethoxyphenyl)ethylidene]-2-methyl-propane-2-sulfinamide (2.20 g, 90.07% yield) as a yellow oil. 1H NMR (400MHz, chloroform-d) δ = 7.50-7.36 (m, 2H), 7.32 (t, J = 8.4Hz, 1H), 7.02 (dd, J = 1.6, 8.0 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 2.75 (s,3H), 1.43 (t, J = 7.2 Hz, 3H), 1.32 (s, 9H); LC / MS (ESI) m / z = 268.1 [M+H] + .

[0334] Step 3: Synthesis of (R)-N-[(1R)-1-(3-ethoxyphenyl)ethyl]-2-methyl-propane-2-sulfinamide [ka] To a solution of (R)-N-[1-(3-ethoxyphenyl)ethylidene]-2-methyl-propane-2-sulfinamide (900 mg, 3.37 mmol) in THF (10 mL) and HO (0.2 mL) at −78° C., NaBH (285 mg, 7.53 mmol) was added dropwise, and the mixture was then stirred at −78° C. for 10 minutes and warmed to 0° C. The resulting mixture was stirred at 0° C. for an additional 2 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give a residue as a mixture of diastereomers. The residue was purified by silica gel column chromatography (0–17% EtOAc in petroleum ether) to give the major product, (R)—N-[(1R)-1-(3-ethoxyphenyl)ethyl]-2-methyl-propane-2-sulfinamide (716 mg, 78.96% yield) as a colorless oil. 1 H NMR (400MHz, chloroform-d) δ 7.29 (s, 1H), 7.28-7.30 (m, 1H), 6.92-6.97 (m, 2H), 6.84 (dd, J = 8.4, 2.0 Hz, 1H), 4.51-4.58 (m, 1H), 4.04-4.09 (m, 2H), 3.45 (brs, 1H), 1.29-1.79 (m, 15H); LC / MS (ESI) m / z = 270.1 [M+H] + .

[0335] Step 4: Synthesis of (1R)-1-(3-ethoxyphenyl)ethanamine [ka] A solution of (R)-N-[(1R)-1-(3-ethoxyphenyl)ethyl]-2-methyl-propane-2-sulfinamide (60.0 mg, 223 μmol) in 4N HCl / dioxane (1 mL) was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give Intermediate I (53 mg, crude, HCl salt) as a colorless oil. LC / MS (ESI) m / z = 166.1 [M+H] + .

[0336] Preparation Example 10: (1R)-1-(3-trimethylsilylphenyl)ethanamine [ka] To a solution of (1R)-1-(3-bromophenyl)ethanamine (100 mg, 499.81 μmol) in THF (2 mL) was added n-BuLi (2.5 M, 899.66 μL) dropwise at −78° C. The mixture was stirred for 1 h, and then trimethylsilyl chloride (135.75 mg, 1.25 mmol, 158.59 μL) was added at −78° C. The resulting mixture was stirred at 20° C. for 17 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (25% EtOAc in petroleum ether) to give Intermediate J (22 mg, 22.76% yield) as a pale yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.49 (s, 1H), 7.44-7.40 (m, 1H), 7.38-7.32 (m, 2H), 4.14 (dd, J = 3.6, 6.8 Hz, 1H), 1.42 (d, J = 6.8 Hz, 3H), 0.28 (s, 9H).

[0337] Preparation Example 11: Methyl-5-oxo-4-phenyl-pyrazine-2-carboxylate [ka] Intermediate K was prepared in a manner similar to Step 1 of Preparative Example 1, except that methyl-6-oxo-1H-pyrazine-3-carboxylate was used instead of methyl-6-oxo-1H-pyridazine-3-carboxylate. LC / MS (ESI) m / z = 231.0 [M+H] + . Additionally, the following intermediates K-1 to K-22 were prepared in a similar manner to that of intermediate K. [ka] TIFF2026506002000132.tif161149

[0338] Preparation Example 12: (1R)-1-[(3-pentafluoro-λ 6 -sulfanyl)phenyl]ethanamine [ka] The starting materials and reagents used in Step 1 of Preparation Example 2 were 1-bromo-3-pentafluoro-λ 6 Intermediate L was prepared in a similar manner to steps 1-4 of Preparative Example 2, except that 1-sulfanylbenzene, tributyl(1-ethoxyvinyl)stannane, Pd(PPh)Cl, and dioxane were used. LC / MS (ESI) m / z = 247.1 [M+H] + .

[0339] Preparation Example 13: (R)-3-(1-aminoethyl)-2-fluorobenzonitrile [ka] Intermediate M was prepared in the same manner as in Preparation Example 12. MS (ESI) m / z = 164.1 [M+H] + .

[0340] Preparation Example 14: (R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethanamine Step 1: Synthesis of 1-bromo-2-methyl-5-nitro-3-(trifluoromethyl)benzene [ka] To a mixture of 1-bromo-2-methyl-3-(trifluoromethyl)benzene (10 g, 41.84 mmol) in HSO (80 mL) was slowly added HNO (54.480 g, 864.59 mmol, 38.91 mL) at 0 °C, followed by stirring at 20 °C for 2 h under a N atmosphere. The reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (0% EtOAc in PE) to give 1-bromo-2-methyl-5-nitro-3-(trifluoromethyl)benzene (6 g, 50.49% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ = 8.69 (d, J = 2.4 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 2.58 (d, J =1.2 Hz, 3H).

[0341] Steps 2-5: Synthesis of (R)-1-(2-methyl-5-nitro-3-(trifluoromethyl)phenyl)ethanamine [ka] Intermediate N was prepared in a manner similar to Preparative Example 12 by using 1-bromo-2-methyl-5-nitro-3-(trifluoromethyl)benzene as the starting material. MS (ESI) m / z = 248.08 [M+H] + .

[0342] Preparation Example 15: 1-[3-(dimethylcarbamoyl)-4-methoxy-phenyl]-6-oxo-pyridazine-3-carboxylic acid Step 1: Synthesis of 5-bromo-2-methoxy-N,N-dimethyl-benzamide [ka] To a solution of 5-bromo-2-methoxybenzoic acid (1 g, 4.33 mmol) in DMF (15 mL) was added DIEA (2.24 g, 17.31 mmol, 3.02 mL) and HATU (2.47 g, 6.49 mmol). The mixture was stirred at 25 °C for 0.5 hours. N-methylmethanamine hydrochloride (1.06 g, 12.98 mmol) was added thereto, and the resulting mixture was stirred at 60 °C for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (35% EtOAc in PE) to give 5-bromo-2-methoxy-N,N-dimethyl-benzamide (930 mg, 83.25% yield) as a yellow oil. MS (ESI) m / z = 258.0 [M+H] + .

[0343] Step 2: Synthesis of 1-[3-(dimethylcarbamoyl)-4-methoxy-phenyl]-6-oxo-pyridazine-3-carboxylic acid [ka] A mixture of methyl-6-oxo-1H-pyridazine-3-carboxylate (89.57 mg, 581.14 μmol), 5-bromo-2-methoxy-N,N-dimethylbenzamide (100 mg, 387.43 μmol), CuI (73.79 mg, 387.43 μmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (110.22 mg, 774.86 μmol), and KCO (160.64 mg, 1.16 mmol) in DMF (3 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 6 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were discarded. The aqueous layer was adjusted to pH 3-4 with 1N HCl aqueous solution and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give intermediate O (50 mg, 40.67% yield) as a yellow oil. MS (ESI) m / z = 318.1 [M+H] + .

[0344] Preparation Example 16: (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol Step 1: Synthesis of ethyl 2-[3-(1,1-dimethoxyethyl)-2-fluoro-phenyl]-2,2-difluoro-acetate [ka] To a solution of ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate (7.1 g, 27.29 mmol) obtained in Step 3 of Preparative Example 5 in MeOH (100 mL) was added trimethoxymethane (8.69 g, 81.86 mmol, 8.97 mL) and NBS (291.39 mg, 1.64 mmol). The mixture was stirred at 50° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (10% EtOAc in PE) to give ethyl 2-[3-(1,1-dimethoxyethyl)-2-fluorophenyl]-2,2-difluoroacetate (6.42 g, 76.82% yield) as a colorless oil.1 H NMR (400 MHz, DMSO-d6) δ = 7.80 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 6.8 Hz, 1H), 7.40 (t, J =7.6 Hz, 1H), 4.39 - 4.31 (m, 2H), 3.08 (s, 6H), 1.53 (s, 3H), 1.20 (t, J = 7.2Hz, 3H).

[0345] Step 2: Synthesis of 1-[3-(1,1-dimethoxyethyl)-2-fluorophenyl]-1,1-difluoro-2-methyl-propan-2-ol [ka] A mixture of ethyl 2-[3-(1,1-dimethoxyethyl)-2-fluoro-phenyl]-2,2-difluoro-acetate (6.42 g, 20.96 mmol) and MeMgBr (1 M, 62.88 mL) in THF (65 mL) was degassed and purged with N three times at 0 °C, and then the mixture was stirred under N atmosphere at 0 °C for 4 h. The reaction mixture was quenched at 20 °C by the addition of saturated aqueous NH Cl (100 mL), diluted with EtOAc (100 mL), and extracted with EtOAc (100 mL × 3). The mixture was dried over anhydrous Na SO and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (10% EtOAc in PE) to give 1-[3-(1,1-dimethoxyethyl)-2-fluorophenyl]-1,1-difluoro-2-methyl-propan-2-ol (4.5 g, 73.45% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ = 7.70 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 6.8 Hz, 1H), 7.26 (t, J =7.6 Hz, 1H), 5.33 (s, 1H), 3.11 - 3.07 (m, 6H), 1.54 (s, 3H), 1.20 (s, 6H).

[0346] Step 3: Synthesis of 1-[3-(1,1-dimethoxyethyl)-2-fluorophenyl]-1,1-difluoro-2-methyl-propan-2-ol [ka] A solution of 1-[3-(1,1-dimethoxyethyl)-2-fluoro-phenyl]-1,1-difluoro-2-methyl-propan-2-ol (4.5 g, 15.40 mmol) and TsOH (5.30 g, 30.79 mmol) in HO (4.5 mL) and EtOH (45 mL) was prepared. The reaction mixture was stirred under N at 15 °C for 2 hours. The solution was concentrated under reduced pressure, and the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product, 1-[3-(1,1-difluoro-2-hydroxy-2-methyl-propyl)-2-fluoro-phenyl]ethanone (3.7 g, 97.61% yield), as a yellow oil was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 7.94 - 7.87 (m, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.42 - 7.38 (m,1H), 5.42 (s, 1H), 2.60 - 2.57 (m, 3H), 1.22 (s, 6H).

[0347] Steps 4-6: Synthesis of (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol [ka] Intermediate P was prepared in a manner similar to steps 4-6 of Preparative Example 5. LC / MS (ESI) m / z = 247.1 [M+H] + .

[0348] Preparation Example 17: Methyl-1-(2-methylthiazol-5-yl)-6-oxopyridazine-3-carboxylate [ka] A mixture of methyl-6-oxo-1H-pyridazine-3-carboxylate (150 mg, 973.25 μmol), 5-bromo-2-methyl-thiazole (207.94 mg, 1.17 mmol), CuI (18.54 mg, 97.32 μmol), CsF (443.52 mg, 2.92 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (27.69 mg, 194.60 μmol) in MeCN (3 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 85 °C under a N2 atmosphere for 12 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (45% EtOAc in PE) to give intermediate Q (70 mg, 16.89% yield) as an off-white solid. MS (ESI) m / z = 252.1 [M+H] +

[0349] The following intermediates Q-1, Q-2 and Q-3 were prepared in a similar manner. [ka]

[0350] Preparation Example 18: Methyl-1-(1,3-dihydroisobenzofuran-5-yl)-6-oxo-pyridazine-3-carboxylate [ka] A mixture of methyl-6-oxo-1H-pyridazine-3-carboxylate (150.99 mg, 979.65 μmol), 5-bromo-1,3-dihydroisobenzofuran (194.99 mg, 979.65 μmol, 1.0 equiv.), KCO (406.18 mg, 2.94 mmol), CuI (186.58 mg, 979.65 μmol), and (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (278.70 mg, 1.96 mmol) in dioxane (3 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 100 °C for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (32% EtOAc in PE) to give Intermediate R (60 mg, 14.32% yield) as a white solid. MS (ESI) m / z = 273.1 [M+H] + .

[0351] Preparation Example 19: Methyl-1-(5-chloro-1-methyl-pyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate [ka] Methyl-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate, intermediate K-22 (300 mg, 1.28 mmol), SelectF (680.66 mg, 1.92 mmol), and ZrCl (59.70 mg, 256.18 μmol, 21.32 μL) were added to MeCN (6 mL). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (35% EtOAc in PE) to give intermediate S (123 mg, 35.74% yield) as a yellow oil. MS (ESI) m / z = 269.1 [M+H] + .

[0352] Preparation Example 20: Methyl-4-anilino-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate [ka] To a mixture of iodobenzene (155.01 mg, 759.81 μmol, 84.70 μL) and methyl-4-amino-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate (100 mg, 379.90 μmol) in toluene (5 mL), Xantphos (21.98 mg, 37.99 μmol), t-BuONa (54.77 mg, 569.86 μmol), and Pd(dba) (34.79 mg, 37.99 μmol) were added, and the reaction mixture was stirred at 100° C. under N for 5 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (61% EtOAc in PE) to give intermediate T (28 mg, 15.91% yield) as a yellow solid. MS (ESI) m / z = 340.0 [M+1+H] + .

[0353] Preparation Example 21: 1-[3-(4-methyl-1,2,4-triazol-3-yl)phenyl]-6-oxo-pyridine-3-carboxylate [ka] A mixture of intermediate K-1 (200 mg, 620.82 μmol), 4-methyl-1,2,4-triazole (67.06 mg, 807.07 μmol), Pd(OAc) (13.94 mg, 62.08 μmol), tricyclohexylphosphonium tetrafluoroborate (45.72 mg, 124.16 μmol), 2,2-dimethylpropanoic acid (126.81 mg, 1.24 mmol, 142.64 μL), and KCO (171.61 mg, 1.24 mmol) in toluene (2 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 120 °C for 144 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (8% MeOH in DCM) to give intermediate U (180 mg, 21.38% yield, 23.912%) as a colorless oil. MS (ESI) m / z = 324.9 [M+H] + .

[0354] The following intermediates U-1, U-2, U-3, U-4 and U-5 were also prepared in an analogous manner. [ka]

[0355] Preparation Example 21A: 1-[4-methyl-3-(3-methyltriazol-4-yl)phenyl]-6-oxo-pyridazine-3-carboxylic acid [ka] A mixture of methyl-1-(3-bromo-4-methyl-phenyl)-6-oxo-pyridazine-3-carboxylate (100 mg, 309.46 μmol), 1-methyltriazole (51.43 mg, 618.92 μmol), K2CO3 (85.54 mg, 618.92 μmol), Pd(OAc)2 (6.95 mg, 30.95 μmol), and XPhos (29.51 mg, 61.89 μmol) in DMF (4 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C under a N2 atmosphere for 12 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL). The combined organic layers were discarded. The aqueous layer was adjusted to pH 2-3 with 1 N aqueous HCl and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give intermediate U-5 (80 mg, 29.26% yield) as a yellow oil. LCMS (ESI) m / z = 321.1 [M+H] + ).

[0356] Preparation Example 22: Ethyl-1-[3-(1-methyltetrazol-5-yl)phenyl]-6-oxo-pyridine-3-carboxylate [ka] A mixture of intermediate K-1 (104.55 mg, 324.54 μmol), 1-methyltetrazole (54.57 mg, 649.08 μmol), KOAc (63.70 mg, 649.08 μmol), and Pd(PPh)Cl (22.78 mg, 32.45 μmol) in NMP (3 mL) was degassed and purged with N three times, and then the mixture was stirred at 120 °C under a N atmosphere for 12 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (48% EtOAc in PE) to give intermediate V (154 mg, 68.66% yield) as a yellow oil. MS (ESI) m / z = 326.0 [M+H]+ .

[0357] Preparation Example 23: (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine [ka] Intermediate W was prepared in a manner similar to steps 2-4 of Preparative Example 2.

[0358] Preparation Example 24: 1-(2-chloro-3-fluorophenyl)ethanamine [ka] Intermediate X was prepared in a manner similar to steps 2-4 of Preparative Example 2.

[0359] Preparation Example 25: (R)-1-(1H-pyrazol-3-yl)ethan-1-amine [ka] Intermediate Y was prepared in the same manner as in Steps 2 to 4 of Preparation Example 2. LC / MS m / z = 112.7 [M+H] + .

[0360] Preparation Example 26: (R)-1-(5-bromothiophen-2-yl)ethanamine [ka] Intermediate Z was prepared in a manner similar to steps 2-4 of Preparative Example 2 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.06 (d, J = 4.0 Hz, 1H), 6.89 (dd, J = 0.8, 4.0 Hz, 1H), 5.90(d, J = 7.2 Hz, 1H), 4.57 (t, V = 6.8 Hz, 1H), 1.47 (d, J = 6.8 Hz, 3H), 1.12(s, 9H); MS (ESI) m / z = 311.8 [M-16+H] + .

[0361] Preparation Example 27: (R)-1-(5-bromothiazol-2-yl)ethanamine Step 1: Synthesis of (NZ,S)-N-[1-(5-bromothiazol-2-yl)ethylidene]-2-methyl-propane-2-sulfinamide [ka] To a solution of 1-(5-bromothiazol-2-yl)ethanone (500 mg, 2.43 mmol) in THF (8 mL) was added Ti(OEt) (8.31 g, 36.5 mmol) and (S)-2-methylpropane-2-sulfinamide (1.18 g, 9.72 mmol), followed by stirring at 95 °C under N for 16 h. The mixture was diluted with EtOAc (20 mL), quenched with water (30 mL), and extracted with EtOAc (10 mL × 2). The mixture was dried over anhydrous NaSO and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (20% EtOAc in PE) to give (NZ,S)—N-[1-(5-bromothiazol-2-yl)ethylidene]-2-methyl-propane-2-sulfinamide (700 mg, 93.0% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 2.81 (s, 3H), 1.32 (s, 9H); LC / MS (EI) m / z = 310.9[M+H] + .

[0362] Step 2: Synthesis of (S)-N-[(1R)-1-(5-bromothiazol-2-yl)ethyl]-2-methylpropane-2-sulfinamide [ka] To a solution of (NZ,S)—N-[1-(2-bromothiazol-5-yl)ethylidene]-2-methyl-propane-2-sulfinamide (620 mg, 2.00 mmol) in THF (5 mL) was added L-selectride (1 M, 4.01 mL), followed by stirring at −70° C. under N for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) at 20° C. and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (25% EtOAc in PE) to give the major product, (S)—N-[(1R)-1-(5-bromothiazol-2-yl)ethyl]-2-methylpropane-2-sulfinamide (610 mg, 95% yield) as a yellow oil. 1 LC / MS (EI) m / z = 311.0 [M+H] + .

[0363] Step 3: Synthesis of (R)-1-(5-bromothiazol-2-yl)ethyl]ethanamine [ka] To a solution of (S)—N-[(1R)-1-(5-bromothiazol-2-yl)ethyl]-2-methylpropane-2-sulfinamide (200 mg, 643 μmol) in MeOH (2 mL) was added 4 N HCl / dioxane solution (2.00 mL) at 0° C., followed by stirring for 1 hour at 20° C. The mixture was concentrated under reduced pressure to give the HCl salt of intermediate AA as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 3H), 7.98 (s, 1H), 4.88-4.75 (m, 1H), 1.59 (d, J = 6.8 Hz,3H)

[0364] Preparation Example 27A: (R)-1-(2-bromothiazol-5-yl)ethanamine [ka] Intermediate AA-1 was prepared in a manner similar to that of Preparative Example 27. 1 H NMR (400 MHz, DMSO-d6) δ = 8.52(s, 3H), 7.79 (s, 1H), 4.86 - 4.76 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H).

[0365] Preparation Example 28: Methyl-1-[3-(dimethylcarbamoyl)-2-fluoro-phenyl]-4-hydroxy-6-oxo-pyridazine-3-carboxylate Step 1: Synthesis of 2-fluoro-N,N-dimethyl-3-nitrobenzamide [ka] A mixture of 2-fluoro-3-nitro-benzoic acid (2.9 g, 15.67 mmol), N-methylmethanamine hydrochloride (5.55 g, 47.00 mmol, HCl), DIEA (8.10 g, 62.67 mmol, 10.92 mL), and HATU (8.94 g, 23.50 mmol) in DMF (30 mL) was degassed and purged with N three times, and then the mixture was stirred at 60 °C under N atmosphere for 3.5 h. The reaction mixture was poured into water (250 mL) and extracted with EtOAc (100 mL × 3). The combined organic layer was washed with brine (50 mL × 4), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by flash silica gel chromatography (12% EtOAc in PE) to give 2-fluoro-N,N-dimethyl-3-nitrobenzamide (4.3 g, 68.56% yield) as a yellow solid. MS (ESI) m / z = 213.1 [M+H] + .

[0366] Step 2: Synthesis of 3-amino-2-fluoro-N,N-dimethyl-benzamide [ka] A mixture of 2-fluoro-N,N-dimethyl-3-nitro-benzamide (4.3 g, 20.27 mmol), Fe (11.32 g, 202.66 mmol), and NH4Cl (10.84 g, 202.66 mmol) in EtOH (40 mL) and HO (8 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C under a N2 atmosphere for 1.5 h. The mixture was filtered, and the filtrate was poured into water (50 mL) and extracted with EtOAc (50 mL × 4). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 3-amino-2-fluoro-N,N-dimethyl-benzamide (crude, 2.81 g, 71.75% yield). MS (ESI) m / z = 183.1 [M+H] + .

[0367] Steps 3 and 4: Synthesis of methyl-1-[3-(dimethylcarbamoyl)-2-fluoro-phenyl]-4-hydroxy-6-oxo-pyridazine-3-carboxylate [ka] Intermediate AB was prepared in a manner similar to steps 1 and 2 of Preparative Example 8, except that in step 1 of Preparative Example 8, 3-amino-2-fluoro-N,N-dimethyl-benzamide was used instead of aniline. 1 H NMR (400MHz, DMSO-d6) δ= 12.46 - 12.04 (m, 1H), 7.65 - 7.61 (m, 1H), 7.53 (ddd, J = 1.6,6.0, 7.6 Hz, 1H), 7.45 - 7.40 (m, 1H), 6.23 (s, 1H), 3.83 (s, 3H), 3.01 (s,3H), 2.86 (s, 3H); MS (ESI) m / z = 336.1 [M+H] + .

[0368] Preparation Example 29: Methyl-1-[3-(dimethylcarbamoyl)-2-fluoro-phenyl]-6-oxo-pyridazine-3-carboxylate Step 1: Synthesis of methyl-1-[3-(dimethylcarbamoyl)-2-fluoro-phenyl]-6-oxo-4-(trifluoromethylsulfonyloxy)pyridazine-3-carboxylate [ka] In a similar manner to Step 3 of Preparation Example 8, methyl-1-[3-(dimethylcarbamoyl)-2-fluoro-phenyl]-6-oxo-4-(trifluoromethylsulfonyloxy)pyridazine-3-carboxylate (554 mg, 73.37% yield) was obtained as a yellow oil. MS (ESI) m / z = 468.0 [M+H] + .

[0369] Step 2: Synthesis of methyl-1-[3-(dimethylcarbamoyl)-2-fluoro-phenyl]-6-oxo-pyridazine-3-carboxylate [ka] A mixture of methyl-1-[3-(dimethylcarbamoyl)-2-fluorophenyl]-6-oxo-4-(trifluoromethylsulfonyloxy)pyridazine-3-carboxylate (554 mg, 1.19 mmol), Pd(OAc) (39.92 mg, 177.81 μmol), DPPP (146.67 mg, 355.62 μmol), and EtSiH (179.19 mg, 1.54 mmol, 246.14 μL) in DMF (5 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under a N atmosphere for 1 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (46% EtOAc in PE) to give intermediate AC (215 mg, 50.51% yield) as a yellow oil. MS (ESI) m / z = 320.0 [M+H] + .

[0370] Preparation Example 30: 5-(1-methylpyrazol-4-yl)-4-oxo-1H-pyro[2,3-d]pyridazine-7-carboxylic acid Steps 1 and 2: Synthesis of 4-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridazine-3-carboxylate [ka] Methyl-4-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)-6-oxo-1,6-dihydropyridazine-3-carboxylate was prepared in a manner similar to steps 1 and 2 of Preparative Example 8, except that 1-methyl-1H-pyrazol-4-amine was used instead of aniline in step 1 of Preparative Example 8. MS (ESI) m / z = 250.1 [M+H] + .

[0371] Step 3: Synthesis of methyl-4-chloro-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate [ka] A mixture of methyl-4-hydroxy-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate (4.3 g, 17.19 mmol) in POCl (50 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under a N atmosphere for 8 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. Methyl-4-chloro-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate (crude, 4.1 g, 82.21% yield) was used in the next step as a yellow solid without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 8.36 (s, 1H), 7.86 (s, 1H), 7.51 (s, 1H), 3.91 (s, 3H), 3.89 (s,3H); MS (ESI) m / z = 268.9 [M+H] + .

[0372] Step 4: Synthesis of methyl-4-azido-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate [ka] To a solution of methyl-4-chloro-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate (4.1 g, 15.26 mmol) in DMF (45 mL) was added NaN (1.4 g, 21.54 mmol). The mixture was stirred at 20 °C for 5 h. The reaction mixture was adjusted to pH > 9 with aqueous NaCO and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. Ice-cold water (aqueous layer:water = 1:50) was added to the aqueous layer, and the pH was adjusted to 11 with aqueous NaOH. Saturated aqueous NaClO (50 mL) was then added dropwise to the aqueous layer, and the mixture was stirred at 20 °C for 12 h. Methyl-4-azido-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate (crude, 4.2 g, 99.71% yield) was used in the next step without further purification as a yellow solid. MS (ESI) m / z = 275.9 [M+H] + .

[0373] Step 5: Synthesis of methyl-4-amino-1-(1-methylpyrazol-4-yl)-6-oxopyridazine-3-carboxylate [ka] A mixture of methyl-4-azido-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate (4.2 g, 15.26 mmol) and Pd / C (1 g, 15.26 mmol, 10% purity) in MeOH (30 mL) and AcOH (30 mL) was degassed and purged with H three times, and then the mixture was stirred under an H atmosphere at 60° C. for 6 h. The mixture was filtered and concentrated under reduced pressure to give methyl-4-amino-1-(1-methylpyrazol-4-yl)-6-oxopyridazine-3-carboxylate (4 g, 68.17% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ= 8.23 ​​(s, 1H), 7.76 (s, 1H), 7.02 (br s, 2H), 5.85 (s, 1H), 3.87(s, 6H); MS (ESI) m / z = 249.9 [M+H] + .

[0374] Step 6: Synthesis of methyl-4-amino-5-iodo-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate [ka] A mixture of methyl-4-amino-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate (4 g, 16.05 mmol), NIS (3.79 g, 16.85 mmol) in DMF (40 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 20 °C for 3 hours. The mixture was filtered to give a residue. The residue was triturated with DCM (50 mL) at 20 °C for 30 minutes. The mixture was filtered to give methyl-4-amino-5-iodo-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate (2.4 g, 38.07% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.23 ​​(br s, 1H), 7.78 (br s, 1H), 7.08 (br s, 2H), 3.88 (br s,6H); MS (ESI) m / z = 375.8 [M+H] + .

[0375] Step 7: Synthesis of methyl-4-amino-1-(1-methylpyrazol-4-yl)-6-oxo-5-(2-trimethylsilylethynyl)pyridazine-3-carboxylate [ka] A mixture of methyl-4-amino-5-iodo-1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate (900 mg, 2.40 mmol), ethynyl(trimethyl)silane (589.12 mg, 6.00 mmol), CuI (45.69 mg, 239.92 μmol), TEA (728.32 mg, 7.20 mmol, 1.00 mL), and Pd(PPh)Cl (168.40 mg, 239.92 μmol) in THF (5 mL) was degassed and purged with N three times, and then the mixture was stirred at 70 °C under a N atmosphere for 2 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (30% EtOAc in PE) to give methyl-4-amino-1-(1-methylpyrazol-4-yl)-6-oxo-5-(2-trimethylsilylethynyl)pyridazine-3-carboxylate (700 mg, 74.25% yield) as a yellow solid. MS (ESI) m / z = 346.1 [M+H] + .

[0376] Step 8: Synthesis of 5-(1-methylpyrazol-4-yl)-4-oxo-1H-pyrrolo[2,3-d]pyridazine-7-carboxylic acid [ka] To a solution of methyl-4-amino-1-(1-methylpyrazol-4-yl)-6-oxo-5-(2-trimethylsilylethynyl)pyridazine-3-carboxylate (200 mg, 578.99 μmol) in NMP (2 mL) was added NaH (27.79 mg, 694.79 μmol) at 0°C. The mixture was stirred at 100°C under a N2 atmosphere for 0.5 h. The reaction was slowly quenched with EtOH until hydrogen evolution ceased. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The organic layer was discarded. The aqueous layer was adjusted to pH 3-4 with 1N aqueous HCl. The aqueous layer was purified by reverse-phase HPLC (10% MeOH in HO) to give intermediate AD (110 mg, 65.52% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 11.83 (br s, 1H), 8.27 (br s, 1H), 7.89 (s, 1H), 7.40 (br s, 1H),6.68 (br s,1H), 4.03 (q, J = 7.2 Hz, 1H), 3.88 (s, 3H); MS (ESI) m / z = 260.0[M+H] + . Additionally, the following intermediate AD-1 was prepared in a similar manner as for intermediate AD. [ka]

[0377] Preparation Example 31: Methyl-4-oxo-5-phenyl-1H-pyrrolo[2,3-d]pyridazine-7-carboxylate Steps 1-5: Synthesis of methyl-4-amino-6-oxo-1-phenyl-5-(2-trimethylsilylethynyl)pyridazine-3-carboxylate [ka] Methyl-4-amino-6-oxo-1-phenyl-5-(2-trimethylsilylethynyl)pyridazine-3-carboxylate was prepared in a manner similar to steps 3 to 7 of preparative example 30, using methyl-4-hydroxy-6-oxo-1-phenyl-pyridazine-3-carboxylate obtained in step 2 of preparative example 8 as the starting material.

[0378] Step 6: Synthesis of methyl-4-oxo-5-phenyl-1H-pyrrolo[2,3-d]pyridazine-7-carboxylate [ka] A mixture of methyl-4-amino-6-oxo-1-phenyl-5-(2-trimethylsilylethynyl)pyridazine-3-carboxylate (90 mg, 263.59 μmol) and CuI (25.10 mg, 131.80 μmol) in DMF (2 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under a N atmosphere for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (30% EtOAc in PE) to give Intermediate AE (20 mg, 25.99% yield) as a yellow solid. MS (ESI) m / z = 270.1 [M+H] +

[0379] Preparation Example 32: Methyl-5-(2-fluorophenyl)-4-oxo-1H-pyrrolo[2,3-d]pyridazine-7-carboxylate [ka] Intermediate AF (1.23 g, 58.08% yield) was prepared as a yellow solid in a similar manner to Preparative Example 30 using 2-fluoroaniline as the starting material. 1 H NMR (400MHz, chloroform-d) δ = 10.09 (s, 1H), 7.39-7.51 (m, 2H), 7.33 (t, J = 2.8 Hz, 1H), 7.26-7.30 (m, 1H), 7.20-7.25 (m, 1H), 6.99 (t, J = 2.8 Hz, 1H), 4.02 (s, 3H); MS (ESI) m / z = 165.1 [M+H] + .

[0380] Preparation Example 33: Ethyl-4-oxo-5-phenyl-thieno[2,3-d]pyridazine-7-carboxylate Step 1: Synthesis of ethyl 2-(2-ethoxy-2-oxo-ethyl)thiophene-3-carboxylate [ka] To a solution of 1,4-dithiane-2,5-diol (5.0 g, 32.84 mmol) and diethyl 3-oxopentanedioate (19.92 g, 98.53 mmol) in dioxane (50 mL) was added LiBr (855.75 mg, 9.85 mmol). The mixture was stirred at 105 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (10% EtOAc in PE) to give ethyl 2-(2-ethoxy-2-oxo-ethyl)thiophene-3-carboxylate (4.74 g, 59.56% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.45 (d, J = 5.6 Hz, 1H), 7.14 (d, J = 5.6 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 4.22-4.16 (m, 4H), 1.35 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H).

[0381] Step 2: Synthesis of ethyl 2-(2-ethoxy-2-oxoacetyl)thiophene-3-carboxylate [ka] To a solution of ethyl 2-(2-ethoxy-2-oxo-ethyl)thiophene-3-carboxylate (2.0 g, 8.25 mmol) in anisole (50 mL) was added SeO (2.29 g, 20.64 mmol). The mixture was stirred at 125 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (10% EtOAc in PE) to give the crude product. The product was purified by silica gel column chromatography (10% EtOAc in PE) to give ethyl 2-(2-ethoxy-2-oxoacetyl)thiophene-3-carboxylate (840 mg, 39.71% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ = 7.64 (d, J = 5.2 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 4.41-4.35 (m, 2H), 4.35-4.29 (m, 2H), 1.38 (td, J = 7.2, 14.0 Hz, 6H).

[0382] Step 3: Synthesis of ethyl-4-oxo-5H-thieno[2,3-d]pyridazine-7-carboxylate [ka] To a solution of ethyl 2-(2-ethoxy-2-oxo-acetyl)thiophene-3-carboxylate (640 mg, 2.50 mmol) in EtOH (7 mL) was added NHNH·HO (160 mg, 3.13 mmol). The mixture was stirred at 20 °C for 0.25 h. The reaction mixture was filtered to obtain a filter cake. The product was purified by silica gel column chromatography (10% EtOAc in DCM) to give ethyl-4-oxo-5H-thieno[2,3-d]pyridazine-7-carboxylate (180 mg, 32.14% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 13.95-12.84 (m, 1H), 8.16 (d, J=5.4 Hz, 1H), 7.66 (d, J=5.2 Hz,1H), 4.40 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H); MS (ESI) m / z = 225.0 [M+H] + .

[0383] Step 4: Synthesis of ethyl-4-oxo-5-phenyl-thieno[2,3-d]pyridazine-7-carboxylate [ka] To a solution of ethyl 4-oxo-5H-thieno[2,3-d]pyridazine-7-carboxylate (180 mg, 802.73 μmol) and phenylboronic acid (146.81 mg, 1.20 mmol) in DCM (4 mL) was added pyridine (380.97 mg, 4.82 mmol) and Cu(OAc) (29.16 mg, 160.55 μmol). The mixture was stirred under air at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (100% EtOAc in PE) to give intermediate AG (84 mg, 34.84% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 8.24 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 5.2 Hz, 1H), 7.62-7.53 (m,4H), 7.53-7.47 (m, 1H), 7.42-7.36 (m, 1H), 7.18-7.12 (m, 1H), 4.42 (q, J = 7.2Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); MS (ESI) m / z = 300.9 [M+H] + . Additionally, the following intermediate AG-1 was prepared in a similar manner as for intermediate AG. [ka]

[0384] Preparation Example 34: Ethyl-6-(2-fluorophenyl)-7-oxo-thieno[2,3-d]pyridazine-4-carboxylate Step 1: Synthesis of methyl 3-(2-ethoxy-2-oxo-acetyl)thiophene-2-carboxylate [ka] To a mixture of methyl 3-bromothiophene-2-carboxylate (5 g, 22.62 mmol) in THF (100 mL) was added n-BuLi (2.5 M, 9.95 mL) at −78 °C under a N atmosphere. After 10 min, methyl 3-bromothiophene-2-carboxylate (5 g, 22.62 mmol) and diethyl oxalate (9.92 g, 67.85 mmol) in THF (100 mL) were added to the mixture at −20 °C. After 10 min, the cooling bath was removed, and the reaction mixture was warmed to 15 °C. The mixture was diluted with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE / EtOAc=10 / 1) to give methyl 3-(2-ethoxy-2-oxo-acetyl)thiophene-2-carboxylate (1.1 g) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 8.17 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 5.2 Hz, 1H), 4.25 (s, 2H),3.80 (s, 3H), 1.28 (s, 3H).

[0385] Step 2: Synthesis of ethyl-6-(2-fluorophenyl)-7-oxo-thieno[2,3-d]pyridazine-4-carboxylate [ka] A mixture of methyl 3-(2-ethoxy-2-oxoacetyl)thiophene-2-carboxylate (600 mg), (2-fluorophenyl)hydrazine (374.88 mg, 2.97 mmol), and Na2CO3 (525.03 mg, 4.95 mmol) in EtOH (15 mL) was degassed and purged with N2 three times, and then the mixture was stirred under N2 atmosphere at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 33%–63%, 10 min). The desired fraction was concentrated under reduced pressure, and the remaining solvent was removed by lyophilization to give intermediate AH (54 mg, 13.47% yield over two steps) as a yellow solid. MS (ESI) m / z = 319.1 [M+H] + .

[0386] Preparation Example 35: 1-(Difluoromethyl)-5-iodo-pyrazole [ka] To a mixture of 5-iodo-1H-pyrazole (1.21 g, 6.24 mmol) and KOH (4.20 g, 74.90 mmol) in MeCN (10 mL) / HO (10 mL) was added 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (5 g, 18.73 mmol) at −70° C. The mixture was then stirred at 20° C. under N for 2 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (3% EtOAc in PE) to give intermediate AI (0.54 g, 34.71% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.76 (d, J =2.6 Hz, 1 H) 6.79 (d, J = 1.6 Hz, 1 H) 7.64 (s, 1H) 7.70 (s, 1 H) 7.79 (s, 1 H) 7.80 (m, 1 H) 7.85 (s, 1 H) 7.94 (s, 1 H) 7.99(s, 1 H) 8.15 (d, J =2.6 Hz, 1 H); MS (ESI) m / z = 244.9 [M+1+H] + .

[0387] Preparation Example 36: (R)-1-(3-(difluoromethyl)-5-nitrophenyl)ethanamine Step 1: Synthesis of 1-bromo-3-(difluoromethyl)-5-nitro-benzene [ka] A mixture of 3-bromo-5-nitro-benzaldehyde (13.7 g, 59.56 mmol) and DAST (48.00 g, 297.81 mmol, 39.35 mL) in DCM (140 mL) was degassed and purged with N three times and stirred at 0–20°C for 18 h. The mixture was then stirred under N2 atmosphere at 0–20°C for 18 h. The resulting solution was poured onto ice and extracted with dichloromethane (300 mL). The reaction mixture was then extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (8% EtOAc in PE) to give 1-bromo-3-(difluoromethyl)-5-nitro-benzene (14.27 g, 56.62 mmol, 95.07% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ = 8.57 (s, 1H), 8.40 (s, 1H), 8.29 (s, 1H), 7.34 - 7.05 (m, 1H)

[0388] Steps 2-5: Synthesis of (R)-1-(3-(difluoromethyl)-5-nitrophenyl)ethanamine [ka] Intermediate AJ was prepared in the same manner as in Preparation Example 13 using 1-bromo-3-(difluoromethyl)-5-nitro-benzene. MS (ESI) m / z = 216.1 [M+H] + .

[0389] Preparation Example 37: Methyl-1-(2-fluorophenyl)-4-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxylate [ka] Intermediate AK was prepared in a manner similar to steps 1 and 2 of Preparative Example 8, except that 2-fluoroaniline was used instead of aniline. MS (ESI) m / z = 264.1 [M+H] + .

[0390] Preparation Example 38: Methyl-1-(2-fluoro-4-methoxyphenyl)-6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-1,6-dihydropyridazine-3-carboxylate [ka] Intermediate AL was prepared in the same manner as in Preparation Example 8 using 2-fluoro-4-methoxyaniline. MS (ESI) m / z = 426.0 [M+H] + .

[0391] Preparation Example 39: Methyl-4-amino-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate [ka] Intermediate AM was prepared in a manner similar to steps 3 to 5 of Preparative Example 30. MS (ESI) m / z = 246.1 [M+H] +

[0392] Preparation Example 40: Methyl-5-amino-6-oxo-1-phenyl-pyridazine-3-carboxylate Step 1: Synthesis of methyl-5-(tert-butoxycarbonylamino)-6-oxo-1-phenyl-pyridazine-3-carboxylate [ka] A mixture of Intermediate F (200.00 mg, 647.01 μmol), tert-butyl carbamate (151.59 mg, 1.29 mmol), Pd(OAc) (7.26 mg, 32.35 μmol), Xantphos (56.16 mg, 97.05 μmol), and CsCO (421.62 mg, 1.29 mmol) in dioxane (3 mL) was degassed and purged with N three times, and then the mixture was stirred at 80 °C under a N atmosphere for 4 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (9% EtOAc in PE) to give methyl-5-(tert-butoxycarbonylamino)-6-oxo-1-phenyl-pyridazine-3-carboxylate (120 mg, 44.49% yield) as a yellow oil. MS (ESI) m / z = 346.0 [M+H] + .

[0393] Step 2: Synthesis of methyl-5-amino-6-oxo-1-phenyl-pyridazine-3-carboxylate [ka] A mixture of methyl-5-(tert-butoxycarbonylamino)-6-oxo-1-phenyl-pyridazine-3-carboxylate (120.00 mg, 347.47 μmol) in HCl / dioxane (3 mL) was stirred under air at 50° C. for 2 hours. The mixture was concentrated under reduced pressure to give the crude product. Intermediate AN (crude, 110 mg, 95.06% yield, HCl) was used in the next step without further purification as a yellow solid. MS (ESI) m / z = 246.0 [M+H] + .

[0394] Preparation Example 41: Methyl-5-methyl-6-oxo-1-phenylpyridazine-3-carboxylate [ka] A mixture of intermediate F (200 mg, 647.01 μmol), dimethylzinc (30.88 mg, 323.51 μmol), and Pd(dppf)Cl (94.68 mg, 129.40 μmol) in dioxane (3 mL) was degassed and purged with N three times, and then the mixture was stirred at 80 °C under a N atmosphere for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (10% EtOAc in PE) to give intermediate AO (55 mg, 32.89% yield) as a brown solid. MS (ESI) m / z = 245.0 [M+H] + .

[0395] Preparation Example 42: Methyl-4-[tert-butoxycarbonyl(methyl)amino]-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate Step 1: Synthesis of methyl-4-(tert-butoxycarbonylamino)-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate [ka] A mixture of intermediate AM (300 mg, 1.14 mmol), DMAP (69.62 mg, 569.86 μmol), TEA (172.99 mg, 1.71 mmol), and BocO (298.49 mg, 1.37 mmol) in THF (2 mL) was stirred at 60 °C for 14 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give methyl-4-(tert-butoxycarbonylamino)-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate (558 mg, crude) as a yellow oil. MS (ESI) m / z = 364.1 [M+H] +

[0396] Step 2: Synthesis of methyl-4-[tert-butoxycarbonyl(methyl)amino]-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate [ka] To a mixture of methyl-4-(tert-butoxycarbonylamino)-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate (558 mg, crude) in THF (10 mL) was added NaH (184.27 mg, 4.61 mmol, 60% purity) under N2 atmosphere at 0 °C for 0.5 h. Then, MeI (1.09 g, 7.68 mmol) was added, and the mixture was stirred at 60 °C under N2 atmosphere for 16 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE / EtOAc = 5 / 1) to give intermediate AP (220 mg, 51.14% yield for two steps) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.55-7.62 (m, 2H), 7.36-7.48 (m, 2H), 7.12 (s, 1H), 3.78 (s, 3H),3.26 (s, 3H), 1.40 (s, 9H); MS (ESI) m / z = 378.2 [M+H] + .

[0397] Preparation Example 43: 1-(2,3-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid Step 1: Synthesis of methyl-1-(2,3-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate [ka] A mixture of methyl 2-oxo-2H-pyran-5-carboxylate (100 mg, 0.65 mmol) and 2,3-difluoroaniline (84 mg, 0.65 mmol) in pyridine (2 mL) was stirred at 80 °C overnight. DW was added to the mixture, and the mixture was extracted with EtOAc. The organic layer was washed with water and 1N HCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product. Methyl-1-(2,3-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (51 mg, crude) was obtained as a yellow solid and used in the next step without further purification. LC / MS (ESI) m / z = 266.1 [M+H] + .

[0398] Step 2: Synthesis of 1-(2,3-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid [ka] To a solution of methyl-1-(2,3-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (90 mg, 0.34 mmol) in THF (4 mL) and HO (2 mL) was added LiOH·HO (35.6 mg, 0.84 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The aqueous layer was adjusted to pH 3-4 with 1N aqueous HCl and then extracted with EtOAc (10 mL × 2). The organic layer was washed with water (20 mL) and brine (20 mL), dried over MgSO, filtered, and concentrated under reduced pressure to give intermediate AQ (43.9 mg, 51.5% yield) as a white solid. LC / MS (ESI) m / z = 266.1 [M+H] + .

[0399] Intermediates AQ-1, AQ-2, AQ-3 and AQ-4 were also prepared in a similar manner as for intermediate AQ. [ka]

[0400] Preparation Example 44: 1-(1-acetylpiperidin-4-yl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid Step 1: Synthesis of methyl-1-(1-acetyl-4-piperidyl)-6-oxo-pyridazine-3-carboxylate [ka] The Boc protecting group of intermediate G-3 was deprotected. Subsequently, a mixture of methyl-6-oxo-1-(4-piperidyl)pyridazine-3-carboxylate (100 mg, 421.49 μmol), AcO (60.00 mg, 587.73 μmol), and TEA (127.95 mg, 1.26 mmol) in DCM (6 mL) was degassed and purged with N three times, then stirred at 25 °C under a N atmosphere for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (97% EtOAc in PE) to give methyl-1-(1-acetyl-4-piperidyl)-6-oxo-pyridazine-3-carboxylate (184.9 mg, 63.16% yield) as a white solid. MS (ESI) m / z = 280.0 [M+H] +

[0401] Step 2: Synthesis of 1-(1-acetylpiperidin-4-yl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid [ka] Intermediate AR was prepared in a manner similar to Step 2 of Preparative Example 43.

[0402] Preparation Example 45: 1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid Step 1: Synthesis of dimethyl (2Z)-2-(phenylhydrazono)pentanedioate [ka] A mixture of dimethyl 2-oxopentanedioate (200 mg, 1.15 mmol), phenylhydrazine (124.36 mg, 1.15 mmol, 113.06 μL), and HCl (23.29 mg, 230.00 μmol, 22.84 μL) in MeOH (2 mL) was degassed and purged with N three times, and then the mixture was stirred under a N atmosphere at 20 °C for 16 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (12% EtOAc in PE) to give dimethyl (2Z)-2-(phenylhydrazono)pentanedioate (400 mg, 64.88% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 8.36 (s, 1H), 7.86 (s, 1H), 7.51 (s, 1H), 3.91 (s, 3H), 3.89 (s,3H); MS (ESI) m / z = 265.0 [M+H] + .

[0403] Step 2: Synthesis of 6-oxo-1-phenyl-4,5-dihydropyridazine-3-carboxylic acid [ka] A mixture of dimethyl (2Z)-2-(phenylhydrazono)pentanedioate (270 mg, 1.02 mmol) and NaOMe (66.23 mg, 1.23 mmol) in MeOH (1 mL) was degassed and purged with N three times, and then the mixture was stirred at 50 °C under a N atmosphere for 3 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The aqueous layer was adjusted to pH = 3-4 with 1N aqueous HCl and then extracted with EtOAc (30 mL × 3). The organic layer was washed with water (30 mL) and brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. Intermediate AS (100 mg, 13.80% yield) was obtained as a yellow oil and used in the next step without further purification. MS (ESI) m / z = 218.9 [M+H] + .

[0404] Preparation Example 46: Methyl-6-oxo-1-[3-(5-trimethylsilylisoxazol-3-yl)phenyl]pyridazine-3-carboxylate Step 1: Synthesis of methyl-1-(3-formylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate [ka] Methyl-1-(3-formylphenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate was prepared in a manner similar to that of Preparation Example 11. MS (ESI) m / z = 258.1 [M+H] + .

[0405] Step 2: Synthesis of methyl-1-[3-(hydroxyiminomethyl)phenyl]-6-oxo-pyridazine-3-carboxylate [ka] To a solution of NaHCO3 (39.04 mg, 464.70 μmol, 18.07 μL) in HO (5 mL) was added NH2OH·HCl (32.29 mg, 464.70 μmol). The resulting solution was then added to a suspension of methyl-1-(3-formylphenyl)-6-oxo-pyridazine-3-carboxylate (100 mg, 387.25 μmol) in EtOH (5 mL) with vigorous stirring at 15 °C for 15 h. The product was filtered. The filtrate was then poured into water (20 mL) and extracted with EtOAc (20 mL × 4). The combined organic layers were washed with brine (520 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give methyl-1-[3-(hydroxyiminomethyl)phenyl]-6-oxo-pyridazine-3-carboxylate (crude, 100 mg, 317.70 μmol, 82.04% yield). MS (ESI) m / z = 273.9 [M+H] + .

[0406] Step 3: Synthesis of methyl-6-oxo-1-[3-(5-trimethylsilylisoxazol-3-yl)phenyl]pyridazine-3-carboxylate [ka] To a solution of ethynyl(trimethyl)silane (107.84 mg, 1.10 mmol, 152.10 μL) and NaClO (0.6 mL, 5% purity) in THF (1 mL) was added a solution of methyl-1-[3-(hydroxyiminomethyl)phenyl]-6-oxo-pyridazine-3-carboxylate (100 mg, 365.97 μmol) obtained in THF (1 mL) at 0 °C, and the mixture was stirred for 3 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (18% EtOAc in PE) to give intermediate AT (35 mg, 76.38 μmol, 20.87% yield) as a white solid. MS (ESI) m / z = 370.1 [M+H] + .

[0407] Preparative Example 47: 2-[(1S)-1-aminomethyl]-6-(trifluoromethyl)pyridin-4-amine and 2-[(1R)-1-aminomethyl]-6-(trifluoromethyl)pyridin-4-amine Step 1: Synthesis of 1-[4-amino-6-(trifluoromethyl)-2-pyridyl]ethanone [ka] 1-Tributyl(1-ethoxyvinyl)stannane (2.23 g, 2.09 mmol) and Pd(dppf)Cl (93.1 mg, 127 μmol) were added to a mixture of 2-chloro-6-(trifluoromethyl)pyridin-4-amine (500 mg, 2.54 mmol) in dioxane (5 mL). The mixture was degassed and purged with N three times and stirred at 100 °C under a N atmosphere for 16 h. 1N HCl solution (3 mL) was added to the mixture, which was then stirred at 25 °C for 30 min. The mixture was quenched with saturated aqueous CsF (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (20% EtOAc in PE) to give 1-[4-amino-6-(trifluoromethyl)-2-pyridyl]ethanone (420 mg, 80.0% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.37 (d, J = 2.4 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 4.56 (s, 2H), 2.70 (s, 3H).

[0408] Steps 2-4: Synthesis of (R)-N-[(1S)-1-[4-amino-6-(trifluoromethyl)-2-pyridyl]ethyl]-2-methyl-propane)-2-sulfinamide and (R)-N-[(1R)-1-[4-amino-6-(trifluoromethyl)-2-pyridyl]ethyl]-2-methyl-propane)-2-sulfinamide [ka] Intermediates AU-1 and AU-2 were prepared in a manner similar to steps 2-4 of Preparative Example 2. 1H NMR (400 MHz, DMSO-d6) δ = 8.28 (d, J = 1.2 Hz, 3H), 6.91 (d, J = 1.6 Hz, 1H), 6.71 (d, J =1.6 Hz, 1H), 4.38 - 4.27 (m, 1H), 1.44 (d, J = 6.8Hz, 3H). 1 H NMR(400 MHz, DMSO-d6) δ = 8.28 (d, J = 1.2 Hz,3H), 6.91 (d, J = 1.6 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 4.38 - 4.27 (m, 1H),1.44 (d, J = 6.8 Hz, 3H).

[0409] Preparation Example I: 1-(5-bromothiophen-3-yl)-N-methylmethanamine [ka] To a solution of 5-bromothiophene-3-carbaldehyde (0.3 mL, 2.75 mmol) in MeOH (5 mL) was added methylamine hydrochloride (223 mg, 3.30 mmol). The reaction mixture was stirred at room temperature for 15 minutes and cooled to 0°C. Sodium borohydride (104 mg, 2.75 mmol) was added to the mixture. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with water and concentrated under reduced pressure. The residue was extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash chromatography (0-5% MeOH in DCM) to give intermediate CA (58.7 mg, 10.4% yield) as a brown liquid. 1H NMR (500 MHz, MeOD) δ 8.26 (d, J = 2.6 Hz, 1H), 8.08 (dd, J = 9.7, 2.6 Hz, 1H), 7.62 (d,J = 1.9 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.54 - 7.47 (m, 2H), 7.46 - 7.42 (m, 2H),7.41 - 7.31 (m, 4H), 6.66 (d, J = 9.7 Hz, 1H), 5.20 (q, J = 7.1 Hz, 1H), 4.05(s, 2H), 2.63 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H); LC / MS m / z = 206 [M+H] + .

[0410] Preparation Example II: N-(5-amino-2-fluoro-phenyl)acetamide Step 1: Synthesis of N-(2-fluoro-5-nitro-phenyl)acetamide [ka] A mixture of 2-fluoro-5-nitro-aniline (2.0 g, 12.8 mmol) in AcOH (4 mL) was stirred at 70° C. for 10 minutes. AcO (2.62 g, 25.6 mmol) was added to the mixture and stirred at 70° C. for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give N-(2-fluoro-5-nitro-phenyl)acetamide (2.27 g, 89% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.18 (s, 1H), 9.00 (dd, J = 2.8, 6.8 Hz, 1H), 8.05 - 8.00 (m, 1H),7.56 (dd, J = 9.2, 10.4 Hz, 1H), 2.16 (s, 3H).

[0411] Step 2: Synthesis of N-(5-amino-2-fluoro-phenyl)acetamide [ka] To a mixture of N-(2-fluoro-5-nitro-phenyl)acetamide (2.27 g, 11.4 mmol), Fe (3.20 g, 57.2 mmol), and NH4Cl (6.13 g, 114.5 mmol) in THF (8 mL) was added HO (4 mL) and MeOH (32 mL). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with MeOH (100 mL) and filtered through Celite. The filtrate was concentrated in vacuo to give intermediate CB (1.75 g, 90% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.84 (t, J = 9.6 Hz, 1H),6.32 - 6.18 (m, 1H), 4.96 (s, 2H), 2.04 (s, 3H).

[0412] Preparation Example III: 1-Acetylpiperidin-4-yl methanesulfonate [ka] To a solution of 1-(4-hydroxypiperidin-1-yl)ethan-1-one (200 mg, 1.39 mmol) in DCM (3 mL) was added triethylamine (0.29 mL, 2.09 mmol). Methanesulfonyl chloride (0.11 mL, 1.39 mmol) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. DW was added to the mixture and extracted with MC. The combined organic layers were dried over MgSO4, filtered, and concentrated to give intermediate CC (240 mg, 78% yield). LC / MS m / z = 222.1 [M+H] + .

[0413] Preparation Example IV: 1-Methyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate [ka] To a solution of 1-methylpiperidin-4-one (0.92 g, 8.13 mmol) in THF (10 mL) was added LDA (1.0 M in THF / hexane, 8.13 mL) at -78 °C. The mixture was warmed to room temperature and stirred for 30 minutes. Once the solution was cooled to -78 °C, 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (4.36 g, 12.2 mmol) was added in one portion. The solution was warmed to room temperature and stirred for 3 hours. The reaction mixture was poured into water and extracted with ether. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography (0-20% EtOAc in hexane) to give intermediate CD (1.22 g, 61.3%). LC / MS m / z = 246 [M+H] + .

[0414] Preparation Example V: N-(3-bromophenyl)cyclopropanecarboxamide [ka] To a solution of cyclopropanecarboxylic acid (253 μL, 3.20 mmol) in DCM (5 mL) was added HATU (1.66 g, 4.36 mmol), DIEA (1.01 mL, 5.81 mmol), and 3-bromoaniline (0.5 g, 2.91 mmol). The mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration and washed with DCM. The product was purified by flash chromatography (25-50% EtOAc in hexanes) to give intermediate CE (0.98 g, 140%). LC / MS m / z = 240 [M+H] + .

[0415] Preparation Example VI: 3-Tetrahydrofuran-2-ylaniline Step 1: Synthesis of 5-(3-nitrophenyl)-2,3-dihydrofuran [ka] A mixture of 1-bromo-3-nitro-benzene (2.0 g, 9.90 mmol), 2,3-dihydrofuran (3.47 g, 49.5 mmol), Pd(OAc) (222 mg, 990 μmol), PPh (519 mg, 1.98 mmol), and KCO (13.6 g, 99.0 mmol) in DMF (20 mL) was stirred at 110 °C for 16 h. The reaction mixture was filtered, and water (50 mL) was added to the filtrate. The mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with saturated NaCl solution (2 × 30 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give 5-(3-nitrophenyl)-2,3-dihydrofuran (1.1 g, 58% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 8.21 - 8.11 (m, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.57 - 7.48 (m,1H), 6.12 (d, J = 5.6 Hz, 1H), 5.90 (d, J = 5.6 Hz, 2H), 5.02 - 4.89 (m, 1H),4.87 - 4.78 (m, 1H).

[0416] Step 2: Synthesis of 3-tetrahydrofuran-2-ylaniline [ka] To a solution of 5-(3-nitrophenyl)-2,3-dihydrofuran (0.9 g, 4.71 mmol) in IPA (10 mL) was added Pd / C (90 mg, 5% purity) under a N atmosphere. The reaction mixture was stirred at 20° C. under 15 psi of H for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give intermediate CF (0.7 g, 91% yield) as a yellow gum. 1H NMR (400 MHz, CDCl3) δ = 7.12 (d, J = 7.6 Hz, 1H), 6.75 - 6.65 (m, 2H), 6.60 - 6.55 (m,1H), 4.82 (t, J = 7.2 Hz, 1H), 4.13 - 4.04 (m, 1H), 3.96-3.88 (m,1H), 2.36 -2.22 (m, 1H), 2.03 - 1.93 (m, 2H), 1.84-1.79 (m, 1H).

[0417] Preparation Example VII: 2-Fluoro-3,4-dimethoxy-aniline Step 1: Synthesis of 3-fluoro-1,2-dimethoxy-4-nitro-benzene [ka] To 1-fluoro-2,3-dimethoxy-benzene (300 mg, 1.92 mmol) was added HNO (5.6 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 15 minutes and at 20 °C for another 15 minutes. The reaction mixture was poured into ice, and the resulting solid was filtered, washed with water, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE: EtOAc = 10:1) to give 3-fluoro-1,2-dimethoxy-4-nitro-benzene (120 mg, 31% yield). 1 H NMR (400 MHz, DMSO-d6) δ = 7.97 (dd, J = 8.4, 9.6 Hz, 1H), 7.11 (dd, J = 1.6, 9.6 Hz, 1H),3.96 (s, 3H), 3.85 (s, 3H).

[0418] Step 2: Synthesis of 2-fluoro-3,4-dimethoxy-aniline [ka] To a solution of 3-fluoro-1,2-dimethoxy-4-nitro-benzene (120 mg, 597 μmol) in EtOH (5 mL) was added Pt-V / C (16 mg) under a N atmosphere. The suspension was degassed and purged with H three times. The mixture was then stirred at 20 °C under H (15 Psi) for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate CG (100 mg, crude) as a brown liquid. 1 H NMR (400 MHz, DMSO-d6) δ = 6.59 (dd, J = 2.0, 8.8 Hz, 1H), 6.47 - 6.38 (m, 1H), 4.70 (s,2H), 3.75 (s, 3H), 3.68(s, 3H).

[0419] Preparation Example VIII: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.2.0]octa-1,3,5-triene-3-carbaldehyde Step 1: Synthesis of 4-bromobicyclo[4.2.0]octa-1,3,5-triene-3-carbaldehyde [ka] To a solution of dichloro(methoxy)methane (251.21 mg, 2.19 mmol) and TiCl4 (497.40 mg, 2.62 mmol) in DCM (6 mL) was added 3-bromobicyclo[4.2.0]octa-1,3,5-triene (200 mg, 1.09 mmol) in DCM (2 mL) dropwise at 0 °C. The reaction mixture was stirred at 20 °C under N2 for 16 h. To the mixture was added cold 5% aqueous HCl (20 mL) at 0 °C and stirred for 15 min. The mixture was extracted with CHCl2 (20 × 3 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (1% EtOH in PE) to give 4-bromobicyclo[4.2.0]octa-1,3,5-triene-3-carbaldehyde (180 mg, 33.77% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.23 (s, 1H), 7.53 (d, J = 7.6 Hz, 2H), 3.26 - 3.21 (m, 2H),3.18 - 3.13 (m, 2H); MS (ESI) m / z = 212.8 [M+1+H] + .

[0420] Step 2: Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[4.2.0]octa-1,3,5-triene-3-carbaldehyde [ka] To a mixture of 4-bromobicyclo[4.2.0]octa-1,3,5-triene-3-carbaldehyde (50 mg, 236.91 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (120.32 mg, 473.81 μmol) in dioxane (2 mL) was added AcOK (69.75 mg, 710.72 μmol) and Pd(dppf)Cl (17.33 mg, 23.69 μmol). The mixture was stirred at 90 °C for 2 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (2% EtOAc in PE) to give intermediate CH (52 mg, yield 67.44%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 10.26 (s, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.40 (s, 1H), 3.22 (s,4H), 1.33 (s, 12H); MS (ESI) m / z = 259.0 [M+2+H] + .

[0421] Preparative Example IX: 5-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazole Step 1: Synthesis of 1-azido-3-bromobenzene [ka] A solution of 3-bromoaniline (2 g, 11.63 mmol, 1.27 mL) in MeCN (20 mL) was cooled to 0 °C in an ice bath, and t-BuONO (1.44 g, 13.95 mmol, 1.66 mL) was added thereto, followed by the slow addition of TMSN (1.61 g, 13.95 mmol, 1.83 mL) with stirring. The resulting solution was stirred at 15 °C for 2 h, after which TLC (EtOAc:petroleum ether = 0:1) showed the reaction was complete. Without workup, the product was concentrated under reduced pressure and purified by silica gel chromatography (0% EtOAc in petroleum ether) to give 1-azido-3-bromobenzene (1.56 g, 67.4% yield) as a yellow oil. 1 LC / MS (ESI) m / z = 318.3 [M+H] +

[0422] Step 2: Synthesis of 1-(3-bromophenyl)-5-methyl-triazole [ka] To a solution of 1-azido-3-bromobenzene (800 mg, 4.04 mmol) in MeCN (10 mL) was added tetramethylguanidine (1.40 g, 12.12 mmol) and 1-dimethoxyphosphorylpropan-2-one (671.09 mg, 4.04 mmol, 554.62 μL). The mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (15% EtOAc in PE) to give 1-(3-bromophenyl)-5-methyl-triazole (350 mg, 1.32 mmol, 32.73% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.89 (t, J = 2.0 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.71 (d, J = 0.8Hz, 1H), 7.67 - 7.63 (m, 1H), 7.60 - 7.55 (m, 1H), 2.34 (d, J = 0.4 Hz, 3H); MS(ESI) m / z = 238.0 [M+H] + .

[0423] Step 3: Synthesis of 5-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazole [ka] Intermediate CI was prepared in a manner similar to Step 2 of Preparative Example VIII. MS (ESI) m / z = 285.2 [M+H] + .

[0424] Preparative Example X: 1-(trideuteromethyl)triazole [ka] To a solution of 1H-triazole (1.99 g, 28.74 mmol) in THF (25 mL) was added KCO (7.95 g, 57.49 mmol) and trideuterated (iodo)methane (5 g, 2.15 mL, 34.49 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give Intermediate CJ (crude, 800 mg, 32.32% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 8 8.06 (s, 1H), 7.70 (s, 1H).

[0425] Preparative Example XI: Tributyl-(3-methyltriazol-4-yl)stannane (T-3) [ka] A solution of 1-methyltriazole (3 g, 36.10 mmol) in THF (30 mL) was cooled to −78 °C, and then n-BuLi (2.5 M, 16.17 mL) was slowly added, and the reaction mixture was stirred at −78 °C for 2 h. Subsequently, tributyl(chloro)stannane (16.94 g, 52.04 mmol, 14 mL) was slowly added, and the reaction mixture was stirred at −78 °C under a nitrogen atmosphere. The reaction mixture was quenched by the slow addition of water at 0 °C and extracted with EtOAc (70 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over NaSO, and concentrated under reduced pressure to give the crude product, Intermediate CK (17.35 g, 34.97 mmol, 96.85% yield, 75% purity), as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (br s, 1H), 4.06 - 4.00 (m, 3H), 1.50 - 1.44 (m, 4H), 1.28 (brd, J = 7.2 Hz, 8H), 1.19 - 1.12 (m, 6H), 0.87 - 0.82 (m, 9H).

[0426] Preparative Example XII: Tributyl-[3-(trideuteriomethyl)triazol-4-yl]stannane (T-9) [ka] A solution of 1-(trideuteriomethyl)triazole (1 g, 11.61 mmol) in THF (20 mL) was cooled to −78 °C, and then n-BuLi (2.5 M, 5.20 mL) was slowly added, and the reaction mixture was stirred at −78 °C for 1 h. Subsequently, tributyl(chloro)stannane (5.22 g, 16.03 mmol, 4.31 mL) was slowly added, and the reaction mixture was stirred at −78 °C for 1 h under a nitrogen atmosphere. The reaction mixture was quenched by the slow dropwise addition of aqueous NH₄Cl (20 mL) at 0 °C and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na₂SO₄, and concentrated under reduced pressure to give the crude intermediate CL (4 g, 10.66 mmol) as a yellow oil. This yellow oil was used in the next reaction without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (s, 1H), 1.49 (m, 4H), 1.35 - 1.21 (m, 8H), 1.19 - 1.09 (m,6H), 0.88 - 0.83 (m, 9H).

[0427] Preparation Example BA: 1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylic acid [ka] Step 1: Synthesis of 3-bromo-5-(3-methyltriazol-4-yl)pyridine A solution of 3,5-dibromopyridine (10.92 g, 46.10 mmol), tributyl-(3-methyltriazol-4-yl)stannane (22.3 g, 59.92 mmol), and Pd(PPh)Cl (3.24 g, 4.61 mmol) in toluene (200 mL) was purged with nitrogen three times, and the mixture was then stirred at 90 °C under a nitrogen atmosphere for 16 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (80% EA in petroleum ether) to give 3-bromo-5-(3-methyltriazol-4-yl)pyridine (4.4 g, 39.93% yield) as a yellow solid. 1 LC / MS (ESI) m / z = 153.0 [M+H] + .

[0428] Step 2: Synthesis of [5-(3-methyltriazol-4-yl)-3-pyridyl]boronic acid A solution of 3-bromo-5-(3-methyltriazol-4-yl)pyridine (6.76 g, 28.28 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxoborrolan-2-yl)-1,3,2-dioxaborolane (14.36 g, 56.55 mmol), Pd(dppf)Cl (2.31 g, 2.83 mmol), and KOAc (5.55 g, 56.55 mmol) in dioxane (120 mL) was purged with nitrogen three times, and the mixture was stirred under a nitrogen atmosphere at 100° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (3% MeOH in DCM) to give [5-(3-methyltriazol-4-yl)-3-pyridyl]boronic acid (6.76 g, 78.52% yield, 67% purity) as a dark brown solid. LCMS (ESI) m / z = 205.1 [M+H] + .

[0429] Step 3: Synthesis of methyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylate A solution of methyl-6-oxo-1H-pyridazine-3-carboxylate (3.78 g, 24.51 mmol), [5-(3-methyltriazol-4-yl)-3-pyridyl]boronic acid (5 g, 24.51 mmol), Cu(OAc) (4.45 g, 24.51 mmol), TEA (4.96 g, 49.02 mmol, 6.82 mL), and pyridine (3.88 g, 49.02 mmol, 3.96 mL) in MeCN (100 mL) was purged with oxygen three times, and the mixture was stirred under an oxygen atmosphere at 90 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (3% MeOH in DCM) to give methyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylate (1.83 g, 5.27 mmol, 21.51% yield, 89.98% purity) as a dark brown solid. LCMS (ESI) m / z = 312.9 [M+H] + .

[0430] Step 4: Synthesis of 1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylic acid To a solution of methyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylate (1.0 g, 3.20 mmol) in THF (4 mL) and HO (2 mL) was added NaOH (256.16 mg, 6.40 mmol). The mixture was purged with nitrogen three times and then stirred under a nitrogen atmosphere at 25 °C for 16 h. The mixture was adjusted to pH 2-3 with 1N aqueous HCl, and intermediate BA (725 mg, 74.01% yield, 97.5% purity) was obtained by solid filtration as a yellow solid. LCMS (ESI) m / z = 299.0 [M+H] + .

[0431] Preparation Example BB: (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine [ka] Step 1: Synthesis of 1-bromo-3-(difluoromethyl)-2-fluoro-benzene To a solution of 3-bromo-2-fluoro-benzaldehyde (9 g, 44.33 mmol) in DCM (150 mL) was added DAST (diethylaminosulfur trifluoride; 14.29 g, 88.67 mmol, 11.71 mL), and the mixture was stirred at 25 °C for 1 h. After the addition of saturated aqueous NaHCO (50 mL), the combined organic layer was extracted with DCM (50 mL × 3). This was washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The organic layer was dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (100% petroleum ether) to give 1-bromo-3-(difluoromethyl)-2-fluoro-benzene (3.9 g, 39.1% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.98 - 7.79 (m, 1H), 7.72 - 7.57 (m, 1H), 7.37 (s, 1H), 7.31 (br t,J = 7.8 Hz, 1H), 7.24 (s, 1H), 7.10 (s, 1H).

[0432] Step 2: Synthesis of 1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanone A mixture of 1-bromo-3-(difluoromethyl)-2-fluorobenzene (17 g, 75.55 mmol), tributyl(1-ethoxyvinyl)stannane (28.65 g, 79.33 mmol, 26.80 mL), and Pd(PPh)Cl (2.65 g, 3.78 mmol) in dioxane (300 mL) was degassed and purged with N three times, and then the mixture was stirred at 100 °C under a N atmosphere for 16 h. The mixture was quenched with 4 N HCl (30 mL) and then stirred at 20 °C for 1 h. The mixture was poured into water (200 mL) and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine (100 mL × 3), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (2% EtOAc in petroleum ether) to give 1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanone (10 g, 70.35% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.03-7.93 (m, 1H), 7.93-7.82 (m, 1H), 7.49-7.14 (m, 2H), 2.63-2.58(m, 3H).

[0433] Step 3: Synthesis of (NZ,R)-N-[1-[3-(difluoromethyl)-2-fluoro-phenyl]ethylidene]-2-methyl-propane-2-sulfinamide A mixture of 1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanone (10 g, 53.15 mmol), 2-methylpropane-2-sulfinamide (6.44 g, 53.15 mmol), and Ti(OEt) (36.37 g, 159.45 mmol, 33.07 mL) in THF (80 mL) was degassed and purged with N three times, and then the mixture was stirred at 80 °C under a N atmosphere for 16 h. The mixture was poured into water (100 mL) and filtered, and the filtrate was extracted with EtOAc (100 mL × 3). The organic layer was washed with brine (50 mL × 3), dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (35% EtOAc in petroleum ether) to give (NZ,R)-N-[1-[3-(difluoromethyl)-2-fluoro-phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (13.0 g, 81.65% yield, 97.25% purity) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.90-7.81 (m, 1H), 7.81-7.73 (m, 1H), 7.47-7.40 (m, 1H), 7.29-7.10(m, 1H), 2.71 (br s, 3H), 1.22 (s, 9H); MS (ESI) m / z = 292.1 [M+H] + .

[0434] Step 4: Synthesis of (R)-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-propane-2-sulfinamide A solution of (NZ,R)-N-[1-[3-(difluoromethyl)-2-fluoro-phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (13 g, 44.62 mmol) in THF (200 mL) and HO (5 mL) was cooled to −70 °C, and NaBH (1.35 g, 35.70 mmol) was added in three batches, followed by stirring at −70 °C for 2 h under a N atmosphere. The mixture was quenched with aqueous NH Cl (200 mL) at 20 °C, diluted with EtOAc (150 mL), and then extracted with EtOAc (150 mL × 3). The organic layer was dried over anhydrous Na SO and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (30% EtOAc in petroleum ether) to give (R)-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-propane-2-sulfinamide (4.4 g, 33.61% yield, 100% purity, 98.34% ee) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 6.8 Hz, 1H), 7.37-7.33 (m,1H), 7.33-7.06 (m, 1H), 5.88 (d, J = 8.0 Hz, 1H), 5.75 (s, 1H), 4.69 (quintet, J = 7.0 Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H), 1.10 (s, 9H); LC / MS(ESI) m / z = 294.1 [M+H] + .

[0435] Step 5: Synthesis of (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine A mixture of (R)-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-2-methyl-propane-2-sulfinamide (2.00 g, 6.82 mmol) in 4N HCl / dioxane (15 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give intermediate BB (1.5 g, 94.02% yield, 96.43% purity, HCl salt) as a white solid. LC / MS (ESI) m / z = 190.1 [M+H] + .

[0436] Preparation Example BC: 5-Methyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylic acid [ka] Step 1: Synthesis of methyl-5-methyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylate A solution of methyl-5-methyl-6-oxo-1H-pyridazine-3-carboxylate (200 mg, 1.19 mmol), [5-(3-methyltriazol-4-yl)-3-pyridyl]boronic acid (242.63 mg, 1.19 mmol), Cu(OAc) (216.03 mg, 1.19 mmol), TEA (240.71 mg, 2.38 mmol, 331.11 μL), and pyridine (188.17 mg, 2.38 mmol, 192.01 μL) in MeCN (5 mL) was purged with nitrogen three times and then stirred at 90 °C under a nitrogen atmosphere for 16 h. After the addition of water (30 mL), the reaction mixture was extracted with EtOAc (30 mL × 3). The organic layer was washed with brine (50 mL), dried over NaSO, and then concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (1% MeOH in DCM) to give methyl-5-methyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylate (305 mg, 69.15% yield, 88% purity) as a yellow solid. LC / MS (ESI) m / z = 327.1 [M+H] + .

[0437] Step 2: Synthesis of 5-methyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylic acid LiOH·HO (117.67 mg, 2.80 mmol) and HO (2 mL) were added to a solution of methyl-5-methyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylate (305 mg, 934.70 μmol) in THF (4 mL), which was then stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent and then diluted with water (10 mL). The reaction mixture was adjusted to pH 3-4 with 1N aqueous HCl and then extracted with EtOAc (20 mL × 3). The organic layer was washed with brine (30 mL), dried over NaSO, and then concentrated under reduced pressure to give intermediate BC (63 mg, 20.29% yield, 94% purity) as a white solid. LC / MS (ESI) m / z = 313.1 [M+H] + .

[0438] Preparation Example BD: 1-[5-(2-methylpyrazol-3-yl)-3-pyridyl]-6-oxo-pyridazine-3-carboxylic acid [ka] A solution of intermediate K-7 (500 mg, 1.61 mmol), (2-methylpyrazol-3-yl)boronic acid (406.06 mg, 3.22 mmol), K2CO3 (557.09 mg, 4.03 mmol), and Pd(PPh3)4 (186.32 mg, 161.24 μmol) in dioxane (5 mL) and HO (0.5 mL) was purged with nitrogen three times and then stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to remove the solvent and then diluted with water (10 mL). The reaction mixture was adjusted to pH 3–4 by the addition of 1 N aqueous HCl and then extracted with EtOAc (20 mL × 3). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, intermediate BD (835 mg, crude) as a brown solid. LC / MS (ESI) m / z = 298.1 [M+H] + .

[0439] Preparative Example BE: 1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridine-3-carboxylic acid (4-4) [ka] Step 1: Synthesis of ethyl-1-(5-bromo-3-pyridyl)-6-oxo-pyridine-3-carboxylate A solution of ethyl 6-oxo-1H-pyridine-3-carboxylate (535.17 mg, 3.20 mmol), 3-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1 g, 3.52 mmol), Cu(OAc) (290.75 mg, 1.60 mmol), 4AMS (500 mg, 3.20 mmol), and boric acid (395.92 mg, 6.40 mmol) in MeCN (15 mL) was purged with oxygen three times and then stirred under an oxygen atmosphere at 90 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (30% EtOAc in petroleum ether) to give ethyl-1-(5-bromo-3-pyridyl)-6-oxo-pyridine-3-carboxylate (87 mg, 7.65% yield, 90.95% purity) as a white solid. LCMS (ESI) m / z = 322.9 [M + H] + .

[0440] Step 2: Synthesis of ethyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridine-3-carboxylate A solution of ethyl 1-(5-bromo-3-pyridyl)-6-oxo-pyridine-3-carboxylate (87 mg, 269.23 μmol), tributyl-(3-methyltriazol-4-yl)stannane (250.48 mg, 673.08 μmol), and Pd(dppf)Cl (19.70 mg, 26.92 μmol) in toluene (2 mL) was purged with nitrogen three times and then stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (2% MeOH in DCM) to give ethyl 1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridine-3-carboxylate (30 mg, 32.07% yield, 93.62% purity) as a white solid. LCMS (ESI) m / z = 326.1 [M + H] + .

[0441] Step 3: Synthesis of 1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridine-3-carboxylic acid To a solution of ethyl-1-[5-(3-methyltriazol-4-yl)-3-pyridyl]-6-oxo-pyridine-3-carboxylate (30 mg, 92.22 μmol) in THF (1 mL) and HO (0.5 mL) was added NaOH (7.38 mg, 184.43 μmol). After three nitrogen purges, the mixture was stirred at 25°C under a nitrogen atmosphere for 1 hour. The mixture was adjusted to pH 5-6 with 1N aqueous HCl, and the organic layer was then concentrated under reduced pressure to give intermediate BE (25 mg, crude product) as a yellow oil. LCMS (ESI) m / z = 298.0 [M + H] + .

[0442] Preparation Example BF: (R)-1-(2-fluoro-3-(1,1,2-trifluoroethyl)phenyl)ethan-1-amine (A-5) [ka] Step 1: Synthesis of (R)-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)carbamate To a solution of 2-{3-[(1R)-1-aminoethyl]-2-fluorophenyl}-2,2-difluoromethane-1-ol hydrochloride (Intermediate E; 500 mg, 1.96 mmol) in DCM (3.99 mL) was added di-tert-butyl dicarbonate (854 mg, 3.91 mmol) and DIPEA (0.68 mL, 3.91 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 h. DCM was added and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex: EtOAc = 20:1 to 10:1) to afford (R)-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)carbamate (456 mg, 73% yield) as a colorless oil. LC / MS (ESI) m / z = 264.04 [M+H] + .

[0443] Step 2: Synthesis of tert-butyl (R)-(1-(2-fluoro-3-(1,1,2-trifluoroethyl)phenyl)ethyl)carbamate To a solution of (R)-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)carbamate (221 mg, 0.692 mmol) in DCM (6.92 mL) was added DAST (0.37 mL, 2.77 mmol) at 0 °C under a N atmosphere. The mixture was then warmed to room temperature and stirred overnight. The mixture was quenched with saturated aqueous NaHCO and extracted with DCM. The organic layer was extracted with saturated aqueous NHCl and washed with brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. This was purified by silica gel column chromatography (hexane: EtOAc = 20:1 to 10:1) to give tert-butyl (R)-(1-(2-fluoro-3-(1,1,2-trifluoroethyl)phenyl)ethyl)carbamate (26 mg, 12% yield) as a colorless oil. LC / MS (ESI) m / z = 265.99 [M+H] + .

[0444] Step 3: Synthesis of (R)-1-(2-fluoro-3-(1,1,2-trifluoroethyl)phenyl)ethan-1-amine TFA (0.15 mL) was added dropwise to a solution of tert-butyl (R)-(1-(2-fluoro-3-(1,1,2-trifluoroethyl)phenyl)ethyl)carbamate (56 mg, 0.174 mmol) in DCM (0.7 mL), and the mixture was then stirred at 0 °C for 1 h. The mixture was warmed to room temperature and quenched with saturated aqueous NaHCO3. The organic solvent was removed by filtration under reduced pressure, and the aqueous layer was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give intermediate BF (34.5 mg, 89% yield) as a yellow oil. LC / MS (ESI) m / z = 222.06 [M+H] + .

[0445] Preparative Example BG: 3-methyl-5'-(1-methyl-1H-1,2,3-triazol-5-yl)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid (4-5) [ka] Step 1: Synthesis of ethyl-5'-bromo-3-methyl-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate To a solution of ethyl 5-methyl-6-oxo-1,6-dihydronicotinate (500 mg, 2.76 mmol) in MeCN (21.2 mL) was added 5-bromo-3-pyridineboronic acid pinacol ester (1.18 mg, 4.14 mmol), Cu(OAc) (501 mg, 2.76 mmol), and pyridine (0.89 mL, 11 mmol), and the mixture was stirred at 90 °C for 16 h. After the addition of water, the reaction mixture was extracted with EtOAc. The combined organic layers were washed with copper(II) sulfate pentahydrate, dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (50% EtOAc in hexanes) to give ethyl 5'-bromo-3-methyl-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate (460 mg, 49% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.06 (d, J= 2.4 Hz, 1H), 8.01 (t, J = 2.0 Hz, 1H), 7.84 (d, J = LC / MS (ESI) m / z = 336.95,338.95 [M+H] + .

[0446] Step 2: Synthesis of ethyl-3-methyl-5'-(1-methyl-1H-1,2,3-triazol-5-yl)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate A solution of ethyl 5'-bromo-3-methyl-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate (300 mg, 0.890 mmol), tributyl(1-methyl-1H-1,2,3-triazol-5-yl)stannane (Intermediate CK; 993 mg, 2.67 mmol), TEA (124 μL, 0.890 mmol), and Pd(PPh)Cl (62.6 mg, 0.089 mmol) in toluene (8.9 mL) was purged with nitrogen three times and then stirred at 100 °C under a nitrogen atmosphere for 17 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 5), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (17% EtOAc in hexanes) to give ethyl-3-methyl-5′-(1-methyl-1H-1,2,3-triazol-5-yl)-2-oxo-2H-[1,3′-bipyridine]-5-carboxylate (81 mg, 27% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.16 (d, J =2.0 Hz, 1H), 7.97 (t, J = 2.2 Hz, 1H), 7.87-7.86 (m, LC / MS (ESI) m / z =340.07 [M+H] + . Step 3: Synthesis of 3-methyl-5'-(1-methyl-1H-1,2,3-triazol-5-yl)-2-oxo-2H-[1,3'-bipyridine]-5-carboxylic acid To a solution of 5'-bromo-3-methyl-2-oxo-2H-[1,3'-bipyridine]-5-carboxylate (81 mg, 0.239 mmol) in THF (2.39 mL) was added LiOH·HO (30 mg, 0.716 mmol) and HO (1.19 mL), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water and adjusted to pH = 1 with 1N aqueous HCl, and intermediate BG (73 mg, 98% yield) was obtained as a white solid by solid filtration. LC / MS (ESI) m / z = 312.04 [M+H] + .

[0447] Preparation Example BH: 6-oxo-1-[5-[3-(trideuteriomethyl)triazol-4-yl]-3-pyridyl]pyridazine-3-carboxylic acid (4-2) [ka] Step 1: Synthesis of methyl-6-oxo-1-[5-[3-(trideuteriomethyl)triazol-4-yl]-3-pyridyl]pyridazine-3-carboxylate A solution of 1-(5-bromo-3-pyridyl)-6-oxo-pyridazine-3-carboxylate (1 g, 3.22 mmol), tributyl-[3-(trideuteriomethyl)triazol-4-yl]stannane (Intermediate CL; 3.63 g, 9.67 mmol), and Pd(PPh)Cl (226.34 mg, 322.47 μmol) in toluene (10 mL) was purged with nitrogen three times and stirred at 100 °C under a nitrogen atmosphere for 16 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (5% MeOH in DCM) to give methyl-6-oxo-1-[5-[3-(trideuteriomethyl)triazol-4-yl]-3-pyridyl]pyridazine-3-carboxylate (420 mg, 30.57% yield, 74% purity) as a yellow solid. LCMS (ESI) m / z = 316.1 [M + H] + .

[0448] Step 2: Synthesis of 6-oxo-1-[5-[3-(trideuteriomethyl)triazol-4-yl]-3-pyridyl]pyridazine-3-carboxylic acid To a solution of methyl-6-oxo-1-[5-[3-(trideuteriomethyl)triazol-4-yl]-3-pyridyl]pyridazine-3-carboxylate (420 mg, 1.33 mmol) in THF (8 mL) and HO (2 mL) was added NaOH (79.92 mg, 2.00 mmol). After purging with nitrogen three times, the mixture was stirred under a nitrogen atmosphere at 25 °C for 2 h. The mixture was adjusted to pH 6-7 with 1N aqueous HCl and then concentrated under reduced pressure to give intermediate BH (420 mg, 65.93% yield, 63% purity) as a yellow solid. LCMS (ESI) m / z = 302.1 [M + H] + . [Example]

[0449] Example 1: N-[(1R)-1-(3-chlorophenyl)ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] To a solution of intermediate A (60 mg, 278 μmol) in DMF (1.5 mL), HATU (158 mg, 416 μmol) and TEA (84.3 mg, 833 μmol) were added, and the mixture was stirred at 20 °C for 15 min. (1R)-1-(3-chlorophenyl)ethanamine (51.8 mg, 333 μmol) was added, and the mixture was stirred at 20 °C for approximately 2 h under N2. The reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine (10 mL × 3), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 45% to 75%, 8 min). The CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give the compound of Example 1 (46.1 mg, 47.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 10.0 Hz, 1H), 7.70-7.64 (m,2H), 7.57-7.52 (m, 2H), 7.50-7.44 (m, 2H), 7.35 (d, J = 5.2 Hz, 2H), 7.31-7.26(m, 1H), 7.14 (d, J = 10.0 Hz, 1H), 5.17-5.08 (m, 1H), 1.47 (d, J = 7.2 Hz,3H); LC / MS (ESI) m / z = 354.3 [M+H] + .

[0450] Example 2: N-[(1R)-1-(3-bromophenyl)ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] To a solution of Intermediate A (1.00 g, 4.63 mmol) in DMF (10 mL) were added HATU (2.64 g, 6.94 mmol) and TEA (1.40 g, 13.88 mmol). The mixture was stirred at 20 °C for 15 minutes. (1R)-1-(3-bromophenyl)ethanamine (1.11 g, 5.55 mmol) was added to the mixture, which was then stirred at 20 °C for about 3 hours under a N atmosphere. The reaction mixture was poured into water (25 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product (1.00 g). 50 mg of the crude product was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 50% to 80%, 8 min). CH3CN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give Example 2 (9.9 mg, 10.76% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.71-7.64 (m,2H), 7.60 (s, 1H), 7.56 (t, J = 7.2 Hz, 2H), 7.51-7.45 (m, 1H), 7.45-7.37 (m,2H), 7.34-7.23 (m, 1H), 7.14 (d, J = 9.6 Hz, 1H), 5.12 (quintet, J = 7.2 , 14.8 Hz 1H), 1.47 (d, J = 6.8 Hz, 3H); LC / MS (ESI) m / z =400.3 [M+H] + .

[0451] Examples 3 to 10 The compounds shown in the table below were prepared in a similar manner to Example 2 by replacing (1R)-1-(3-bromophenyl)ethanamine with the appropriate amine compound. [Table 1] TIFF2026506002000235.tif166149

[0452] Example 11: N-[(1R)-1-(3-methylsulfonylphenyl)ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] A mixture of the compound of Example 2 (50 mg, 125.55 μmol), CHSONa (15.38 mg, 150.66 μmol), CuI (2.39 mg, 12.55 μmol), L-proline (2.89 mg, 25.11 μmol), and NaOH (1.00 mg, 25.11 μmol) in DMSO (1.5 mL) was degassed and purged with N three times, and then the mixture was stirred at 95 °C under a N atmosphere for 16 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 35% to 65%, 8 min). The ACN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give the compound of Example 11 (14.5 mg, 29.06% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 8.3 Hz, 1H), 7.96 (s, 1H), 7.89 (d, J = 9.6 Hz, 1H),7.80 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70-7.64 (m, 2H),7.64-7.58 (m, 1H), 7.58-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.14 (d, J = 9.6 Hz,1H), 5.24 (quintet, J = 7.3 Hz, 1H), 3.20 (s, 3H), 1.51 (d,J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 398.3 [M+H] + .

[0453] Example 12: N-[(1R)-1-(4-methylsulfonylphenyl)ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] Example 12 was prepared as a white solid in a manner similar to that of Example 11, except that N-[(1R)-1-(4-bromophenyl)ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide was used instead of Example 2. 1 H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 6.8 Hz, 1H), 7.87 (d, J = 5.6 Hz, 3H), 7.66 (s, 4H),7.55 (s, 2H), 7.14 (d, J = 8.8 Hz, 1H), 5.20 (s, 1H), 3.19-3.16 (m, 3H), 1.50(d, J = 5.2 Hz, 3H); LC / MS (ESI) m / z = 398.3 [M+H] + .

[0454] Example 13: 6-oxo-N-[(1R)-1-(3-phenoxyphenyl)ethyl]-1-phenyl-pyridazine-3-carboxamide [ka] A mixture of the compound of Example 2 (100 mg, 251.10 μmol), phenol (35.45 mg, 376.65 μmol), CuI (9.56 mg, 50.22 μmol), CsCO (245.44 mg, 753.29 μmol), and L-proline (5.78 mg, 50.22 μmol) in DMSO (2 mL) was stirred for 2 hours at 130° C. under N atmosphere and microwave irradiation. The reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Gemini NX C18 5 μm × 10 × 150 mm; mobile phase: [ACN / EtOH (0.1% NH3H2O)]; B%: 25% to 75%, 30 min), the ACN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give Example 13 (2.2 mg, 2.12% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.88-8.79 (m, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.93-7.85 (m, 1H),7.92-7.84 (m, 1H), 7.68-7.62 (m, 2H), 7.57-7.51 (m, 2H), 7.48 (d, J = 7.2 Hz,1H), 7.39-7.31 (m, 3H), 7.18-7.08 (m, 4H), 7.01-6.95 (m, J = 8.0 Hz, 2H),6.86-6.80 (m, 1H), 5.13 (quintet, J = 7.6 Hz, 1H), 1.47 (d,J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 412.3 [M+H] + .

[0455] Example 14: N-[(1R)-1-(3-cyclopropylphenyl)ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] A mixture of the compound of Example 2 (50 mg, 125.55 μmol), cyclopropylboronic acid (14.02 mg, 163.21 μmol), KPO (93.27 mg, 439.42 μmol), Pd(OAc) (2.82 mg, 12.55 μmol), and P(Cy) (7.04 mg, 25.11 μmol) in toluene (1 mL) and HO (0.1 mL) was degassed and purged with N three times, and then the mixture was stirred at 100° C. under a N atmosphere for 12 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 48% to 78%, 15 min), the ACN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give the compound of Example 14 (15.8 mg, 35.01% yield) as a white solid. 1 H NMR (400MHz, 400MHz, DMSO-d6)δ 8.79 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H),7.71-7.64 (m, 2H), 7.60-7.50 (m, 2H), 7.50-7.44 (m, 1H), 7.21-7.08 (m, 4H),6.90 (d, J = 7.6 Hz, 1H), 5.09 (quintet, J = 7.6 Hz, 1H),1.96-1.80 (m, 1H), 1.45 (d, J = 7.2 Hz, 3H), 0.99-0.84 (m, 2H), 0.69-0.57 (m,2H); LC / MS (ESI) m / z = 360.3 [M+H] + .

[0456] Example 15: 6-oxo-1-phenyl-N-[(1R)-1-[3-(trifluoromethyl)phenyl]ethyl]pyridazine-3-carboxamide [ka] To a solution of intermediate A (40 mg, 185 μmol) in DMF (1.5 mL), HATU (106 mg, 278 μmol) and TEA (56.2 mg, 555 μmol) were added, followed by stirring at 20 °C for 15 min. (1R)-1-[3-(trifluoromethyl)phenyl]ethanamine (42.0 mg, 222 μmol) was then added to the mixture, which was stirred at 20 °C for 2 h under N. The reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 50% to 80%, 8 min). The ACN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give Example 15 (34.4 mg, 48.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.76 (s, 1H),7.72-7.65 (m, 3H), 7.61-7.52 (m, 4H), 7.50-7.45 (m, 1H), 7.14 (d, J = 9.6 Hz,1H), 5.17-5.26 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 388.3 [M+H] + .

[0457] Example 16: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide Step 1: Synthesis of N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] To a solution of Intermediate A (65 mg, 300 μmol) in DMF (1.5 mL) was added HATU (171 mg, 451 μmol) and TEA (91.3 mg, 902 μmol), followed by stirring at 20° C. for 15 min. Intermediate B (84.5 mg, 361 μmol) was then added to the mixture, which was stirred at 20° C. for 2 h under N. The reaction mixture was poured into water (15 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (25% EtOAc in petroleum ether) to give N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide (99 mg, 76.2% yield) as a yellow oil. LC / MS (ESI) m / z = 433.0 [M+H] + .

[0458] Step 2: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] To a solution of N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide (99 mg, 229 μmol) in EtOH (2 mL) and HO (0.2 mL) was added Fe (63.9 mg, 1.1 mmol) and NHCl (98 mg, 1.8 mmol), followed by stirring at 85 °C for 3 h. The reaction mixture was adjusted to pH 8–9 with aqueous NaHCO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 50%–80%, 8 min). The ACN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give Example 16 (24.5 mg, 26.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 10.0 Hz, 1H), 7.70-7.63 (m,2H), 7.57-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.14 (d, J = 9.6 Hz, 1H), 6.82 (s,1H), 6.78 (s, 1H), 6.70 (s, 1H), 5.54 (s, 2H), 4.98-5.07 (m, 1H), 1.44 (d, J =7.2 Hz, 3H); LC / MS (ESI) m / z = 403.3 [M+H] + .

[0459] Example 17: N-[(1R)-1-(3-chlorophenyl)ethyl]-6-oxo-1-tetrahydropyran-4-yl-pyridazine-3-carboxamide Step 1: Synthesis of methyl-6-oxo-1-tetrahydropyran-4-yl-pyridazine-3-carboxylate [ka] To a solution of methyl-6-oxo-1H-pyridazine-3-carboxylate (300 mg, 1.95 mmol) in DMF (5 mL) was added KCO (538.0 mg, 3.89 mmol) and 4-bromotetrahydropyran (481.8 mg, 2.92 mmol), followed by stirring at 100 °C for 16 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (28% EtOAc in petroleum ether) to give methyl-6-oxo-1-tetrahydropyran-4-yl-pyridazine-3-carboxylate (266.0 mg, 57.36% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.87-7.82 (m, 1H), 7.05-7.00 (m, 1H), 5.12-4.95 (m, 1H), 3.95-3.99(m, 2H), 3.89-3.85 (m, 3H), 3.53-3.43 (m, 2H), 1.97-1.83 (m, 2H), 1.73-1.77 (m,2H); LC / MS (ESI) m / z = 239.0 [M+H] + .

[0460] Step 2: Synthesis of 6-oxo-1-tetrahydropyran-4-yl-pyridazine-3-carboxylic acid [ka] To a solution of methyl-6-oxo-1-tetrahydropyran-4-yl-pyridazine-3-carboxylate (100 mg, 419.8 μmol) in THF (2 mL) and HO (1 mL) was added LiOH·HO (70.46 mg, 1.68 mmol), followed by stirring at 15 °C for 12 h. The reaction mixture was acidified with 1N aqueous HCl (pH = 3-4) and then extracted with EtOAc. The organic layer was washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure to give 6-oxo-1-tetrahydropyran-4-yl-pyridazine-3-carboxylic acid (88 mg, crude) as a white solid. LC / MS (ESI) m / z = 225.1 [M+H] + .

[0461] Step 3: Synthesis of N-[(1R)-1-(3-chlorophenyl)ethyl]-6-oxo-1-tetrahydropyran-4-yl-pyridazine-3-carboxamide [ka] To a solution of 6-oxo-1-tetrahydropyran-4-yl-pyridazine-3-carboxylic acid (88 mg, 392.5 μmol) in DMF (1.5 mL), (1R)-1-(3-chlorophenyl)ethanamine (73.30 mg, 471.0 μmol), HATU (194.0 mg, 510.2 μmol), and DIEA (152.2 mg, 1.18 mmol) were added, followed by stirring at 15 °C for 12 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 40% to 70%, 8 min). The ACN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give the compound of Example 17 (38.5 mg, 27.11% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.49 (s, 1H),7.42-7.34 (m, 2H), 7.34-7.27 (m, 1H), 7.01 (d, J = 9.6 Hz, 1H), 5.17 (quintet, J = 7.2 Hz, 1H), 5.10-4.99 (m, 1H), 3.99-4.03 (m, 2H), 3.56-3.47(m, 2H), 2.30-2.18 (m, 2H), 1.74-1.66 (m, 2H), 1.53 (d, J = 7.2 Hz, 3H); LC / MS(ESI) m / z = 362.3 [M+H] + .

[0462] Example 18: 1-(1-acetyl-4-piperidyl)-N-[(1R)-1-(3-chlorophenyl)ethyl]-6-oxo-pyridazine-3-carboxamide Steps 1-3: Synthesis of tert-butyl 4-[3-[[(1R)-1-(3-chlorophenyl)ethyl]carbamoyl]-6-oxo-pyridazin-1-yl]piperidine-1-carboxylate [ka] tert-Butyl 4-[3-[[(1R)-1-(3-chlorophenyl)ethyl]carbamoyl]-6-oxo-pyridazin-1-yl]piperidine-1-carboxylate was obtained as a yellow oil in the same manner as in Steps 1 to 3 of Example 17, except that in Step 1, tert-butyl 4-bromopiperidine-1-carboxylate was used instead of 4-bromotetrahydropyran. 1 H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 9.6 Hz, 1H), 7.34 (s,1H), 7.31-7.27 (m, 2H), 7.25-7.22 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.98 (d. J =7.2 Hz, 3H), 1.48 (s, 9H).

[0463] Step 4: Synthesis of N-[(1R)-1-(3-chlorophenyl)ethyl]-6-oxo-1-(4-piperidyl)pyridazine-3-carboxamide [ka] To a solution of tert-butyl 4-[3-[[(1R)-1-(3-chlorophenyl)ethyl]carbamoyl]-6-oxo-pyridazin-1-yl]piperidine-1-carboxylate (417 mg, 904.65 μmol) in dioxane (3 mL), HCl / dioxane (4 M, 3 mL) was added, followed by stirring at 10° C. for 12 hours. The mixture was concentrated under reduced pressure to give N-[(1R)-1-(3-chlorophenyl)ethyl]-6-oxo-1-(4-piperidyl)pyridazine-3-carboxamide (350 mg, 100% yield, HCl salt) as a yellow solid. LC / MS (ESI) m / z = 261.0 [M+H] + .

[0464] Step 5: Synthesis of 1-(1-acetyl-4-piperidyl)-N-[(1R)-1-(3-chlorophenyl)ethyl]-6-oxo-pyridazine-3-carboxamide [ka] To a solution of N-[(1R)-1-(3-chlorophenyl)ethyl]-6-oxo-1-(4-piperidyl)pyridazine-3-carboxamide (50 mg, 125.85 μmol, HCl salt) in DCM (1 mL) was added TEA (38.20 mg, 377.55 μmol) and (2,5-dioxopyrrolidin-1-yl)acetate (20 mg, 127.29 μmol), and the mixture was stirred at 15° C. for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 30% to 90%, 8 min). The ACN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give Example 18 (19.2 mg, 37.87% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (br d, J = 8.8 Hz, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.47 (br d,J = 4.4 Hz, 1H), 7.40-7.33 (m, 2H), 7.30 (td, J=2.8, 5.6 Hz, 1H), 7.01 (d, J =9.6 Hz, 1H), 5.20-5.10 (m, 1H), 5.05-4.95 (m, 1H), 4.58 (d, J = 13.6 Hz, 1H),3.99 (d, J = 11.6 Hz, 1H), 3.22 (s, 1H), 2.75-2.67 (m, 1H), 2.04 (s, 3H),2.04-1.92 (m, 2H), 1.89-1.76 (m, 2H), 1.52 (d, J = 7.2 Hz, 3H); LC / MS (ESI) m / z= 403.3 [M+H] + .

[0465] Example 19: (R)—N-(1-(3-chlorophenyl)ethyl)-1-(1-(methylsulfonyl)piperidin-4-yl)-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 19 was obtained in the same manner as in Example 18, except that in Step 5, methanesulfonyl chloride was used instead of (2,5-dioxopyrrolidin-1-yl)acetate. 1 H NMR (400MHz, DMSO-d6) δ 8.84 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.47 (s, 1H),7.41-7.34 (m, 2H), 7.34-7.27 (m, 1H), 7.01 (d, J = 9.6 Hz, 1H), 5.16 (quintet, J = 7.2 Hz, 1H), 4.98-4.87 (m, 1H), 3.72 (d, J = 12.0 Hz, 2H),3.01-2.93 (m, 2H), 2.92 (s, 3H), 2.25 (q, J = 12.0 Hz, 2H), 1.89 (d, J = 11.2Hz, 2H), 1.53 (d, J = 7.2 Hz, 3H). LC / MS (ESI) m / z = 403.3 [M+H] + .

[0466] Example 20: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-(2-pyridyl)pyridazine-3-carboxamide Step 1: Synthesis of methyl-6-oxo-1-(2-pyridyl)pyridazine-3-carboxylate [ka] A mixture of methyl-6-oxo-1H-pyridazine-3-carboxylate (200 mg, 1.30 mmol), 2-bromopyridine (410.05 mg, 2.60 mmol), DMEDA (68.63 mg, 778.60 μmol), CuI (123.57 mg, 648.83 μmol), and KPO (688.62 mg, 3.24 mmol) in DMF (5 mL) was degassed and purged with N three times, and then the mixture was stirred at 110 °C under a N atmosphere for 3 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (59% EtOAc in petroleum ether) to give methyl-6-oxo-1-(2-pyridyl)pyridazine-3-carboxylate (100 mg, 30.66% yield) as a yellow oil. LC / MS (ESI) m / z = 232.0 [M+H] + .

[0467] Step 2: Synthesis of 6-oxo-1-(2-pyridyl)pyridazine-3-carboxylic acid [ka] To a solution of methyl-6-oxo-1-(2-pyridyl)pyridazine-3-carboxylate (100 mg, 432.51 μmol) in THF (2 mL), LiOH·HO (72.60 mg, 1.73 mmol) and HO (1 mL) were added, followed by stirring at 20 °C for 2 h. The mixture was adjusted to pH 3–4 and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 0%–30%, 15 min). The ACN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give 6-oxo-1-(2-pyridyl)pyridazine-3-carboxylic acid (40 mg, 40.45% yield) as a white solid. LC / MS (ESI) m / z = 218.0 [M+H] + .

[0468] Step 3: Synthesis of N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-(2-pyridyl)pyridazine-3-carboxamide [ka] To a solution of 6-oxo-1-(2-pyridyl)pyridazine-3-carboxylic acid (30 mg, 138.13 μmol) and Intermediate B (37.38 mg, 138.13 μmol) in DCM (1 mL) was added TEA (41.93 mg, 414.40 μmol), HOBt (22.40 mg, 165.76 μmol), and EDCI (31.78 mg, 165.76 μmol), followed by stirring at 25° C. for 2 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (80% EtOAc in petroleum ether) to give N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-(2-pyridyl)pyridazine-3-carboxamide (59 mg, 89.34% yield) as a colorless solid. LC / MS (ESI) m / z = 434.0 [M+H] + .

[0469] Step 4: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-(2-pyridyl)pyridazine-3-carboxamide [ka] To a solution of N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-(2-pyridyl)pyridazine-3-carboxamide (59 mg, 136.15 μmol) in saturated aqueous NH4Cl (1 mL) and MeOH (3 mL) was added Fe (60.83 mg, 1.09 mmol), followed by stirring at 60° C. for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was then purified by preparative HPLC (Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 21%–41%, 10 min). The ACN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give Example 20 (7.3 mg, 12.70% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 8.4 Hz, 1H), 8.64 (dd, J = 1.2, 4.8 Hz, 1H), 8.11-8.03(m, 1H), 7.94 (d, J = 10.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.61-7.54 (m,1H), 7.17 (d, J = 10.0 Hz, 1H), 6.79 (d, J = 15.2 Hz, 2H), 6.69 (s, 1H), 5.54(s, 2H), 5.02 (quintet, J = 7.2 Hz, 1H), 1.42 (d, J = 7.2Hz, 3H); LC / MS (ESI) m / z = 404.3 [M+H] + .

[0470] Example 21: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-(4-pyridyl)pyridazine-3-carboxamide Step 1: Synthesis of methyl-6-oxo-1-(4-pyridyl)pyridazine-3-carboxylate [ka] A mixture of methyl-6-oxo-1H-pyridazine-3-carboxylate (300 mg, 1.95 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (478.98 mg, 2.34 mmol), Cu(OAc) (70.71 mg, 389.30 μmol), 4A MS (300 mg), and boric acid (240.72 mg, 3.89 mmol) in ACN (8 mL) was degassed and purged with O three times, and then the mixture was stirred under an O atmosphere at 80 °C for 18 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, methyl-6-oxo-1-(4-pyridyl)pyridazine-3-carboxylate (380 mg, 67.55% yield) as a white solid. LC / MS (ESI) m / z = 232.0 [M+H] + .

[0471] Step 2: Synthesis of 6-oxo-1-(4-pyridyl)pyridazine-3-carboxylic acid [ka] To a solution of methyl-6-oxo-1-(4-pyridyl)pyridazine-3-carboxylate (180 mg, 778.52 μmol) in THF (2 mL) was added LiOH·HO (65.34 mg, 1.56 mmol) and HO (1 mL), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was acidified with 1 N aqueous HCl (pH = 3-4), extracted with EtOAc, and the precipitated material in the aqueous layer was filtered to give 6-oxo-1-(4-pyridyl)pyridazine-3-carboxylic acid (50 mg, 28.09% yield) as a white solid (filter cake). LC / MS (ESI) m / z = 218.0 [M+H] + .

[0472] Step 3: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-(4-pyridyl)pyridazine-3-carboxamide [ka] To a solution of 6-oxo-1-(4-pyridyl)pyridazine-3-carboxylic acid (40 mg, 184.18 μmol) and intermediate C (44.32 mg, 184.18 μmol, HCl salt) in DMF (1 mL) was added TEA (55.91 mg, 552.54 μmol), HOBt (29.86 mg, 221.01 μmol), and EDCI (42.37 mg, 221.01 μmol), followed by stirring for 2 h at 25° C. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC (Phenomenex C18 75 × 30 mm × 3 μm, mobile phase: [water (NHH0 + NHHCO)-ACN]; B%: 21% to 51%, 11 min). The ACN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give Example 21 (11.6 mg, 14.66% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.96 (d, J = 8.4 Hz, 1H), 8.78-8.73 (m, 2H), 7.92-7.87 (m, 3H),7.19 (d, J = 9.6 Hz, 1H), 6.81 (d, J = 14.4 Hz, LC / MS (ESI) m / z = 404.3 [M+H] + .

[0473] Example 22: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-(5-methyl-2-thienyl)-6-oxo-pyridazine-3-carboxamide [ka] The compound of Example 22 was prepared in a manner similar to that of Example 21, except that in Step 1, 4,4,5,5-tetramethyl-2-(5-methyl-2-thienyl)-1,3,2-dioxaborolane was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 9.6 Hz, 1H), 7.84 (d, J =4.0 Hz, 1H), 7.23 (d, J = 9.6 Hz, 1H), 6.88-6.81 LC / MS (ESI) m / z = 423.3 [M+H] + .

[0474] Example 23: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-(2-methoxyphenyl)-6-oxo-pyridazine-3-carboxamide Step 1: Synthesis of methyl-1-(2-methoxyphenyl)-6-oxopyridazine-3-carboxylate [ka] A mixture of methyl-6-oxo-1H-pyridazine-3-carboxylate (200 mg, 1.30 mmol), (2-methoxyphenyl)boronic acid (236.62 mg, 1.56 mmol), Cu(OAc) (47.14 mg, 259.53 μmol), and pyridine (667.19 mg, 8.43 mmol) in DCM (3 mL) was stirred under air at 20 °C for 16 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by flash silica gel chromatography (30% EtOAc in petroleum ether) to give methyl-1-(2-methoxyphenyl)-6-oxopyridazine-3-carboxylate (180 mg, 47.16% yield) as a white oil. LC / MS (ESI) m / z = 261.0 [M+H] + .

[0475] Step 2: Synthesis of 1-(2-methoxyphenyl)-6-oxo-pyridazine-3-carboxylic acid [ka] A mixture of methyl-1-(2-methoxyphenyl)-6-oxo-pyridazine-3-carboxylate (180 mg, 691.66 μmol) and LiOH·HO (87.07 mg, 2.07 mmol) in THF (3 mL) and HO (1.5 mL) was stirred under air at 20 °C for 2 h. The reaction mixture was acidified with 1N aqueous HCl (pH = 3-4) and extracted with EtOAc. The organic layer was washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure to give crude 1-(2-methoxyphenyl)-6-oxo-pyridazine-3-carboxylic acid (160 mg, 81.91% yield) as a yellow solid. LC / MS (ESI) m / z = 247.0 [M+H] + .

[0476] Step 3: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-(2-methoxyphenyl)-6-oxo-pyridazine-3-carboxamide [ka] A mixture of 1-(2-methoxyphenyl)-6-oxo-pyridazine-3-carboxylic acid (50 mg, 203.07 μmol), Intermediate C (45.61 mg, 223.38 μmol), HATU (115.82 mg, 304.61 μmol), and DIPEA (78.74 mg, 609.22 μmol) in DMF (2 mL) was degassed and purged with N three times, then stirred at 20 °C under N atmosphere for 3 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was then purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm, mobile phase: [water (0.225% FA)-ACN]; B%: 38%–68%, 7 min). The ACN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give Example 23 (26.6 mg, 30.28% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 10.0 Hz, 1H), 7.51-7.47 (m,1H), 7.43 (dd, J = 1.6, 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.12-7.08 (m,2H), 6.82 (s, 1H), 6.78 (s, 1H), 6.71 (s, 1H), 6.48-5.10 (m, 2H), 5.02 (t, J =7.6 Hz, 1H), 3.76 (s, 3H), 1.42 (d, J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 433.3[M+H] + .

[0477] Examples 24 to 45 Using starting materials and intermediates corresponding to the structures of the desired compounds, the compounds of Examples 24 to 45 were prepared in a manner similar to that of Example 23. On the other hand, when preparing the compounds of Examples 40 and 41, the coupling reagents used in Step 3 were changed to HOBt and EDCI. [Table 2] TIFF2026506002000262.tif192149 TIFF2026506002000263.tif217149 TIFF2026506002000264.tif223149 TIFF2026506002000265.tif223149 TIFF2026506002000266.tif192149 TIFF2026506002000267.tif210149

[0478] Example 46: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide Step 1: Synthesis of 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone [ka] A mixture of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (50 g, 185.18 mmol), tributyl(1-ethoxyvinyl)stannane (70.2 g, 194.38 mmol, 65.61 mL), Pd(PPh)Cl (13.00 g, 18.52 mmol), and TEA (37.48 g, 370.37 mmol, 51.55 mL) in dioxane (500 mL) was degassed and purged with N three times, and then the mixture was stirred at 80 °C under a N atmosphere for 16 h. The mixture was quenched with 6 N HCl (200 mL) and stirred at 20 °C for 1 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over NaSO, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (5% EtOAc in PE) to give 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone (66 g, 76.43% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 2.76 (s, 3H).

[0479] Step 2: Synthesis of (R)-2-methyl-N-[1-[3-nitro-5-(trifluoromethyl)phenyl]ethylidene]propane-2-sulfinamide [ka] To a solution of 1-[3-nitro-5-(trifluoromethyl)phenyl]ethanone (66 g, 283.09 mmol) in THF (650 mL) was added Ti(OEt) (161.44 g, 707.72 mmol, 146.76 mL) and (R)-2-methylpropane-2-sulfinamide (44.60 g, 368.01 mmol), followed by stirring at 85° C. for 16 h under a N atmosphere. The reaction mixture was poured into water (200 mL) and EtOAc (200 mL), filtered, and the filtrate was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over NaSO, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (12% EtOAc in PE) to give (R,E)-2-methyl-N-[1-[3-nitro-5-(trifluoromethyl)phenyl]ethylidene]propane-2-sulfinamide (77 g, 71.07% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 2.76 (s, 3H); LC / MS (ESI)m / z = 336.9 [M+H] + .

[0480] Step 3: Synthesis of (R)-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]propane-2-sulfinamide [ka] To a solution of (R)-2-methyl-N-[1-[3-nitro-5-(trifluoromethyl)phenyl]ethylidene]propane-2-sulfinamide (38.5 g, 114.47 mmol) in THF (350 mL) and HO (7 mL) was added NaBH (3.27 g, 86.43 mmol) in three portions, and the mixture was stirred at −78 °C under N for 3 h. The reaction mixture was quenched with saturated aqueous NH Cl (150 mL) at 20 °C, poured into water (200 mL), and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (15% EtOAc in PE) to give the major product, (R)-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]propane-2-sulfinamide (30 g, 32.01% yield) as a green solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 6.07 (d, J = 8.8 Hz, 1H),4.73-4.63 (m, 1H), 1.45 (d, J = 7.2 Hz, 3H), 1.13 (s, 9H); LC / MS (ESI) m / z =338.9 [M+H] + .

[0481] Step 4: Synthesis of (1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethanamine [ka] To a solution of (R)-2-methyl-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]propane-2-sulfinamide (30 g, 88.67 mmol) in dioxane (30 mL) was added 4 N HCl / dioxane (60 mL) at 0° C., followed by stirring for 3 hours at 20° C. The mixture was concentrated under reduced pressure to give a residue which was triturated with MTBE (100 mL) at 20° C. for 12 hours and then filtered to give the HCl salt of (1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethanamine (23 g, 91.02% yield) as a white solid. 1 LC / MS (ESI) m / z = 234.9 [M+H] + .

[0482] Step 5: Synthesis of 3-[(1R)-1-aminoethyl]-5-(trifluoromethyl)aniline [ka] To a solution of (1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethanamine (10 g, 42.70 mmol, HCl salt) in MeOH (100 mL) was added Pd / C (2 g, 10% purity), followed by stirring under H atmosphere at 40° C. for 6 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate C (8.5 g, 93.87% yield) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (br s, 3H), 6.97 (s, 1H), 6.84 (s, 2H), 5.75 (s, 2H), 4.30 (q,J = 6.8 Hz, 1H), 1.47 (d, J = 6.8 Hz, 3H); LC / MS (ESI) m / z = 204.9 [M+H] + .

[0483] Step 6: Synthesis of 1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate [ka] A mixture of (2-fluorophenyl)boronic acid (17.70 g, 126.52 mmol), methyl-6-oxo-1H-pyridazine-3-carboxylate (15 g, 97.32 mmol), Cu(OAc) (5.30 g, 29.20 mmol), and pyridine (50.04 g, 632.61 mmol, 51.06 mL) in MeCN (500 mL) was degassed and purged with O three times and stirred under an O atmosphere at 110° C. for 40 h. The reaction mixture was concentrated under reduced pressure, poured into distilled water (500 mL), and extracted with EtOAc. The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (30% EtOAc in petroleum ether) to give 1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate (20 g, 20.35% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 7.97 (d, J = 10.0 Hz, 1H), 7.60 (dd quintet, 2H), 7.46 (t, J = 9.6 Hz, 1H), 7.40 (dt, J = 1.2, 7.6 Hz, 1H),7.21 (d, J = 9.6 Hz, 1H), 3.85 (s, 3H); LC / MS (ESI) m / z = 249.1 [M+H] + .

[0484] Step 7: Synthesis of 1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylic acid [ka] To a solution of 1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxylate (20 g, 80.58 mmol) in THF (180 mL) was added LiOH·HO (10.14 g, 241.73 mmol) and HO (20 mL). The mixture was stirred at 20 °C for 1 h. The mixture was poured into water (200 mL) and extracted with EtOAc (100 mL × 3). After removing the organic layer, the mixture was adjusted to pH 3-4 with 1N aqueous HCl and then extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, and concentrated under reduced pressure to give intermediate DA (18 g, 92.36% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ 13.79 (br s, 1H), 7.95 (d, J = 9.6 Hz, 1H),7.65 - 7.53 (m, 2H), 7.46 (t, J = 9.2 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.18 (d, J= 10.0 Hz, 1H); LC / MS (ESI) m / z = 235.0 [M+H] + .

[0485] Step 8: Synthesis of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] To a solution of Intermediate DA (6.45 g, 27.54 mmol) and Intermediate C (7.29 g, 30.30 mmol, HCl salt) in DMF (65 mL) was added DIEA (10.68 g, 82.63 mmol, 14.39 mL), HOBt (7.44 g, 55.09 mmol), and EDCI (10.56 g, 55.09 mmol). The mixture was degassed and purged with N three times and then stirred under N atmosphere at 20 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (40% EtOAc in PE) to give the major product, Example 46 (7.1 g, 60.75% yield), as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.91 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.67 (dt, J =1.6, 7.6 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.47 - 7.37 (m, 2H), 7.18 (d, J = 9.6Hz, 1H), 6.80 (s, 1H), 6.77 (s, 1H), 6.70 (s, 1H), 5.54 (s, 2H), 5.02 (quintet, J = 7.2 Hz, 1H), 1.42 (d, J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 421.3[M+H] + .

[0486] Example 47: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-(2-hydroxyphenyl)-6-oxo-pyridazine-3-carboxamide [ka] A mixture of Example 23 compound (30 mg, 69.38 μmol) and BBr3 (1 M, 346.91 μL) was stirred under air at 20 °C for 2 hours, poured onto ice-water (5 mL), and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The product was purified by preparative HPLC (Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 18% to 38%, 10 min). The ACN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give Example 47 compound (12.9 mg, 43.87% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (br s, 1H), 8.78 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 9.6 Hz,1H), 7.34-7.27 (m, 2H), 7.09 (d, J = 9.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H),6.93 (t, J = 7.6 Hz, 1H), 6.81 (s, 1H), 6.77 (s, 1H), 6.69 (s, 1H), 5.54 (s,2H), 5.06-4.98 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H); LC / MS (ESI) m / z = 419.3 [M+H] + .

[0487] Example 48: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-5-hydroxy-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 48 was obtained by reacting Intermediate F in the same manner as in Steps 2 and 3 of Example 23. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (brs, 1H), 7.55-7.49 (m, 2H), 7.49-7.38 (m, 3H), 7.18 (brs,1H), 7.01 (brs, 1H), 6.83 (s, 1H), 6.79 (s, 1H), 6.69 (s, 1H), 5.56 (br s, 2H),5.04 (quintet, J = 7.2 Hz, 1H), 1.43 (d, J = 7.2 Hz, 3H);LC / MS (ESI) m / z = 419.3 [M+H] + .

[0488] Example 49: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-4-methyl-6-oxo-1-phenyl-pyridazine-3-carboxamide Step 1: Synthesis of methyl-4-methyl-6-oxo-1-phenyl-pyridazine-3-carboxylate [ka] A mixture of intermediate H (80 mg, 211.48 μmol), dimethylzinc (2 M, 52.87 μL), and Pd(PPh3)4 (48.88 mg, 42.30 μmol) in THF (2 mL) was degassed and purged with N2 three times, then stirred at 70 °C under a N2 atmosphere for 4 h. The reaction mixture was poured into distilled water (10 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The product was purified by flash silica gel chromatography (20% EtOAc in petroleum ether) to give methyl-4-methyl-6-oxo-1-phenyl-pyridazine-3-carboxylate (60 mg, 79.08% yield) as a white solid. LC / MS (ESI) m / z = 245.0 [M+H] + .

[0489] Steps 2 and 3: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-4-methyl-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] The compound of Example 49 was obtained by reacting methyl-4-methyl-6-oxo-1-phenyl-pyridazine-3-carboxylate in the same manner as in Steps 2 and 3 of Example 23, except that the coupling reagents used in Step 3 of Example 23 were changed to HOBt and EDCI. 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (br d, J = 8.0 Hz, 1H), 7.64 (br d, J = 7.6 Hz, 2H), 7.51 (brt, J = 7.6 Hz, 2H), 7.47-7.41 (m, 1H), 6.98 (s, 1H), 6.80 (s, 1H), 6.77 (br s,1H), 6.71 (br s, 1H), 5.58 (br s, 2H), 4.98 (br t, J = 7.2 Hz, 1H), 2.25 (s,3H), 1.40 (br d, J = 6.8 Hz, 3H); LC / MS (ESI) m / z = 417.3 [M+H] + .

[0490] Example 50: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-4-ethynyl-6-oxo-1-phenyl-pyridazine-3-carboxamide Step 1: Synthesis of methyl-6-oxo-1-phenyl-4-(2-trimethylsilylethynyl)pyridazine-3-carboxylate [ka] A mixture of intermediate H (200 mg, 528.71 μmol), ethynyl(trimethyl)silane (129.82 mg, 1.32 mmol, 183.11 μL), CuI (10.07 mg, 52.87 μmol), TEA (160.50 mg, 1.59 mmol, 220.77 μL), and Pd(PPh) (61.10 mg, 52.87 μmol) in THF (2 mL) was degassed and purged with N three times, then stirred under a N atmosphere at 70° C. for 2 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by flash silica gel chromatography (10% EtOAc in petroleum ether) to give methyl-6-oxo-1-phenyl-4-(2-trimethylsilylethynyl)pyridazine-3-carboxylate (50 mg, 17.85% yield) as a white solid. LC / MS (ESI) m / z = 327.0 [M+H] + .

[0491] Steps 2 and 3: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-4-ethynyl-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] The compound of Example 50 was obtained by reacting methyl-6-...

Claims

1. A pharmaceutical composition for preventing or treating cancer, comprising a compound of formula I: 【Chemistry 1】 [In the formula, 【Chemistry 2】 is a single or double bond; Z １ is N or CH; Z １ If N, then Z ２ and Z ３ Both are CHR １ and 【Transformation 3】 is a single bond, or Z ２ and Z ３ All are CR １ and 【Chemistry 4】 is a double bond; Z １ When is CH, Z ２ is N or CR １ and Z ３ is CR １ and 【Transformation 5】 is a double bond; or Z １ If N, then Z ２ and Z ３ All are CR １ and 【Transformation 6】 is a double bond, in which case two R １ are optionally linked together to form two R １ may be taken together with the carbon atom to which it is attached to form a thiophene or pyrrole ring; Each R １ is H, halogen, CN, OH, NR ｂ R ｃ , C １ ~C ６ Alkoxy, C １ ~C ６ Acylamino, C １ ~C ６ Alkylsulfonylamino, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, C ６ ~C １０ Aryl, C ６ ~C １０ Aryloxy, (C ６ ~C １０ aryl)-(C １ ~C ６ alkyl)oxy and C ６ ~C １０ arylamino; R' and R'' are each independently H or C １ ~C ３ alkyl, or R′ and R″ together with the carbon atom to which they are attached form C ３ ~C ４ may form a cycloalkyl, １ ~C ３ Alkyl and C ３ ~C ４ Cycloalkyl is at least one halogen, OH, CN, C １ ~C ３ Alkoxy or NR ｂ R ｃ may be optionally substituted with; A is Cy １ or Cy １ -Y-Cy ２ and Y is O, S or a direct bond; Cy １ is C ６ ~C １０ aryl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S; Cy １ is 1 to 3 R ２ａ may be optionally substituted with; R ２ａ is H, halogen, OH, CN, oxo, SF ５ , N.R. ｂ R ｃ , -Si(C １～３ alkyl) ３ , -SO ２ R ｂ , -C(O)R ｂ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C ３ ~C ６ Cycloalkyl and 【Transformation 7】 selected from the group consisting of: R ２１ is H, halogen, OH, NR ｂ R ｃ , C １ ~C ６ Alkoxy or C １ ~C ６ acyloxy, and R ２２ and R ２３ are each independently H, halogen or C １ ~C ２ is alkyl; Cy ２ is C ６ ~C １０ Aryl, C ３ ~C ６ phenyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O, and S fused to a cycloalkyl; Cy ２ is 1 to 3 R ２ｂ may be optionally substituted with; R ２ｂ is H, halogen, OH, CN, oxo, NR ｂ R ｃ ; C １ ~C ６ Alkyl; halogen, CN, OH, NR ｂ R ｃ or C １ ~C ６ C substituted with alkoxy １ ~C ６ alkyl; C optionally interrupted by 1 to 3 oxygen and / or nitrogen atoms １ ~C ６ alkyl; and hydroxy-(C １ ~C ６ C substituted with alkyl)amino- １ ~C ６ selected from the group consisting of alkyl; B is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl, NR ｂ R ｃ C substituted with １ ~C ６ Alkyl, -(CH ２ ) ｏ -Cy ３ or -(CH ２ ) ｏ -Cy ３ -W-Cy ４ and W is NH, C(O) or a direct bond; o is an integer of 0 or 1; Cy ３ is C ３ ~C ８ Cycloalkyl, C ３ ~C ８ cycloalkenyl, 5- or 6-membered saturated or partially unsaturated heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S, bridged bicyclic C ５～１０ Cycloalkyl, C ６ ~C １０ selected from the group consisting of aryl, phenyl fused to a 5- or 6-membered cyclic group containing one heteroatom selected from N, O, and S, and 5- to 10-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S; Cy ３ is 1 to 3 R ３ａ and optionally substituted with R ３ａ is H, halogen, OH, CN, oxo, C １ ~C ６ Alkyl; halogen, OH, CN or C １ ~C ６ C substituted with alkoxy １ ~C ６ Alkyl; C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Haloalkylamino, C １ ~C ６ Hydroxyalkylamino, (C ３ ~C ６ cycloalkyl)carbonylamino, —NR ｂ R ｃ , -NR ｂ COR ｃ 、 -NR ｂ C(O)OR ｃ 、 -SO ２ R ｂ , -C(O)R ｂ , -C(O)OR ｂ , -NR ｂ SO ２ R ｃ and -CONR ｂ１ R ｃ１ selected from the group consisting of: Cy ４ is a saturated or partially unsaturated 4- to 10-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, C ６ ~C １０ selected from the group consisting of aryl and 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S; Cy ４ is 1 to 3 R ３ｂ and optionally substituted with R ３ｂ is H, deuterium, halogen, OH, CN, oxo, NR ｂ R ｃ , C １ ~C ６ Alkyl, deuterium-substituted C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy or C １ ~C ６ haloalkoxy; R ｂ and R ｃ are each independently H or C １ ~C ６ is alkyl; R ｂ１ and R ｃ１ One of the two is H or C １ ~C ６ alkyl, and R ｂ１ and R ｃ１ The other is H, C １ ~C ６ Alkyl, NR ｂ R ｃ C substituted with １ ~C ６ Alkyl or C １ ~C ６ C substituted with alkoxy １ ~C ６ alkyl] a compound of formula (I), a solvate, stereoisomer or pharmaceutically acceptable salt thereof; and an anticancer agent as active ingredients.

2. In the above formula I, 【Transformation 8】 but 【Chemistry 9】 wherein R １ 2. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein:

3. In the above formula I, 【Chemistry 10】 but 【Chemistry 11】 and R １ The pharmaceutical composition for preventing or treating cancer according to claim 2, wherein:

4. Each R １ is H, F, Br, Cl, I, CN, OH, OCH ３ 4. The pharmaceutical composition according to claim 3 for preventing or treating cancer, characterized in that the amino, methylamino, dimethylamino, ethylamino, acetylamino, methylsulfonylamino, ethylsulfonylamino, methyl, ethyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, phenoxy, benzyloxy or phenylamino is independently selected from the group consisting of:

5. Two R substituted on the same ring １ 5. The pharmaceutical composition for preventing or treating cancer according to claim 4, wherein one of the following is H and the other is not H.

6. Two R substituted on the same ring １ The pharmaceutical composition according to claim 4 for preventing or treating cancer, wherein each of

7. In the above formula I, 【Chemistry 12】 but 【Chemistry 13】 The pharmaceutical composition according to claim 2 for preventing or treating cancer, characterized in that it is

8. R' and R'' are each H or C １ ~C ３ alkyl, and R′ and R″ optionally together with the carbon atom to which they are attached form C ３ ~C ４ The pharmaceutical composition according to claim 1 for preventing or treating cancer, which may form a cycloalkyl.

9. In formula I, 【Chemistry 14】 but 【Chemistry 15】 9. The pharmaceutical composition for preventing or treating cancer according to claim 8, wherein R''' is methyl or ethyl.

10. The compound has the following formula IA: 【Chemistry 16】 (In the formula, A, Z １ , Z ２ , Z ３ and B are as defined in claim 1). The pharmaceutical composition according to claim 9 for preventing or treating cancer, characterized in that the compound is represented by:

11. A is Cy １ The pharmaceutical composition according to claim 1 for preventing or treating cancer, characterized in that it is

12. Cy １ is C ６ ~C １０ 12. The pharmaceutical composition according to claim 11 for preventing or treating cancer, characterized in that it is an aryl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S.

13. A is Cy １ and Cy １ 13. The pharmaceutical composition for preventing or treating cancer according to claim 12, wherein is phenyl, naphthalenyl, thiophenyl or pyridinyl.

14. Cy １ 1 to 3 R ２ａ The following ring structures optionally substituted with: 【Chemistry 17】 12. The pharmaceutical composition according to claim 11 for preventing or treating cancer, characterized in that it comprises any one of:

15. Cy １ 1 to 3 R ２ａ and each R ２ａ are F, Cl, Br, I, OH, CN, and SF ５ , -Si(CH ３ ) ３ , C.H. ３ SO ２ -, methyl, ethyl, propyl, isopropyl, CF ３ , CHF ２ , C.H. ２ F, N.H. ２ , C.H. ３ NH-, (CH ３ ) ２ N-, methoxy, ethoxy, OCF ３ , OCHF ２ , OCH ２ F, cyclopropyl, cyclobutyl, cyclopentyl, -CF ２ CH ２ F. [Chemistry 18] The pharmaceutical composition according to claim 11 for preventing or treating cancer, characterized in that the compound is independently selected from the group consisting of:

16. A is Cy １ -Y-Cy ２ The pharmaceutical composition according to claim 1 for preventing or treating cancer, characterized in that it is

17. Cy １ is C ６ ~C １０ aryl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S; Y is O or a direct bond; Cy ２ is C ６ ~C １０ Aryl, C ３ ~C ５ phenyl fused to a cycloalkyl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N and S; 17. The pharmaceutical composition according to claim 16 for preventing or treating cancer.

18. Cy １ is phenyl, and Cy ２ is phenyl, pyrrolyl, pyrazolyl, thiophenyl, pyridinyl or 2-oxo-1,2-dihydropyridinyl, or Cy １ is thiazolyl, thiophenyl or pyrazolyl, and Cy ２ is phenyl, 2,3-dihydroindenyl, or bicyclo[4.2.0]octa-1,3,5-trienyl 18. The pharmaceutical composition according to claim 17 for preventing or treating cancer.

19. 18. The pharmaceutical composition for preventing or treating cancer according to claim 17, wherein Y is a direct bond.

20. Cy １ -Y-Cy ２ is R ２ａ and R ２ｂ The following ring structures optionally substituted with: 【Chemistry 19】 The pharmaceutical composition according to any one of claims 16 to 19 for preventing or treating cancer, characterized in that it comprises any one of:

21. Cy １ There is one R ２ａ and optionally substituted with R ２ａ H, halogen, OH, CN, amino, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy and C １ ~C ６ haloalkoxy; Cy ２ 1 to 3 R ２ｂ and optionally substituted with R ２ｂ is H, halogen, OH, CN, oxo, NR ｂ R ｃ ; C １ ~C ６ Alkyl; halogen, CN, OH, NR ｂ R ｃ or C １ ~C ６ C substituted with alkoxy １ ~C ６ alkyl; C optionally interrupted by 1 to 3 oxygen and / or nitrogen atoms １ ~C ６ alkyl; and hydroxy-(C １ ~C ６ C substituted with alkyl)amino- １ ~C ６ 17. The pharmaceutical composition according to claim 16 for preventing or treating cancer, characterized in that the compound is selected from the group consisting of alkyl.

22. R ２ａ 22. The pharmaceutical composition according to claim 21 for preventing or treating cancer, wherein is H.

23. R ２ａ is H; Each R ２ｂ H, F, Cl, Br, I, OH, CN, oxo, amino, CH ３ NH-, (CH ３ ) ２ N-, (CH ３ ) ２ NCH ２ -, methyl, ethyl, cyanomethyl, hydroxymethyl, aminomethyl, CH ３ NHCH ２ -, C ２ H ５ NHCH ２ - and HOC ２ H ４ NHCH ２ - independently selected from the group consisting of 22. The pharmaceutical composition according to claim 21 for preventing or treating cancer.

24. In formula I, A is of the following structure: 【Chemistry 20】 【change】 The pharmaceutical composition according to claim 1 for preventing or treating cancer, characterized in that the composition is selected from the group consisting of:

25. B is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxy-C １ ~C ６ Alkyl or NR ｂ R ｃ C substituted with １ ~C ６ The pharmaceutical composition according to claim 1 for preventing or treating cancer, characterized in that it is alkyl.

26. B is -(CH ２ ) ｏ -Cy ３ 2. The pharmaceutical composition according to claim 1 for preventing or treating cancer, wherein:

27. Cy ３ is C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkenyl, 6-membered saturated or partially unsaturated heterocycloalkyl containing one N, O or S, bridged bicyclic C ５～８ Cycloalkyl, C ６ ~C １０ 27. The pharmaceutical composition according to claim 26, for preventing or treating cancer, characterized in that the heteroaryl is selected from the group consisting of aryl, phenyl fused with a 5-membered heterocycloalkyl containing one N, O or S, a 5- or 6-membered heteroaryl containing one or two heteroatoms selected from N or S, and a 9- or 10-membered bicyclic heteroaryl containing one to three N.

28. Cy ３ is C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, tetrahydropyranyl, dihydropyranyl, thianyl, 1,1-dioxothianyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, C ６～１０ 28. A pharmaceutical composition for preventing or treating cancer according to claim 27, characterized in that it is aryl, thiophenyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, dihydroisobenzofuranyl, indolyl, indazolyl or benzotriazolyl.

29. Cy ３ 1 to 3 R ３ａ The following ring structures optionally substituted with 【Chemistry 21】 27. The pharmaceutical composition according to claim 26 for preventing or treating cancer, characterized in that it comprises any one of:

30. R ３ａ is H, F, Cl, Br, I, OH, CN, oxo, methyl, ethyl, amino, CH ３ NH-, (CH ３ ) ２ NH-, 1,1,1-trifluoropropan-2-ylamino, CH ３ CONH-, (CH ３ CO)(CH ３ ) N-, CH ３ OCONH-, cyclopropylcarbonylamino, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, methoxy, ethoxy, isopropoxy, methoxymethyl, 2-methoxyethyl, OCHF ２ , OCF ３ , C.H. ３ SO ２ -, CH ３ CO-, CH ３ SO ２ NH-, -COOH, -COOC(CH ３ ) ３ , -CONH ２ , -CONHCH ３ , -CONHC ２ H ５ , -CON(CH ３ ) ２ , -CONHC ２ H ４ OCH ３ and -CONHC ２ H ４ N (CH ３ ) ２ 27. The pharmaceutical composition according to claim 26 for preventing or treating cancer, characterized in that it is selected from the group consisting of:

31. B is -(CH ２ ) ｏ -Cy ３ -W-Cy ４ 2. The pharmaceutical composition according to claim 1 for preventing or treating cancer, wherein:

32. Cy ３ is C ６ ~C １０ aryl or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N or S; W is NH, C(O) or a direct bond; Cy ４ is a saturated or partially unsaturated 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O or S, C ６ ~C １０ aryl and 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S; 32. The pharmaceutical composition according to claim 31 for preventing or treating cancer.

33. Cy ３ is C ６ ~C １０ aryl, and Cy ４ is a saturated or partially unsaturated 4- to 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, or S, and W is NH or C(O).

34. 33. The pharmaceutical composition for preventing or treating cancer according to claim 32, wherein W is a direct bond.

35. Cy ３ is phenyl or pyridinyl; Cy ４ is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, morpholinyl, imidazolidinyl, 2-oxoimidazolidinyl, piperazinyl, 2-oxopiperazinyl, hexahydropyrimidinyl, 2-oxohexahydropyrimidinyl, phenyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, or 2-oxopyridinyl 33. The pharmaceutical composition according to claim 32 for preventing or treating cancer.

36. Cy ３ -W-Cy ４ is R ３ａ and R ３ｂ The following ring structures optionally substituted with: 【Chemistry 22】 32. The pharmaceutical composition according to claim 31 for preventing or treating cancer, characterized in that it comprises any one of:

37. Cy ３ is one or two R ３ａ and R ３ａ is H, halogen, OH or CN; Cy ４ 1 to 3 R ３ｂ and R ３ｂ H, deuterium, halogen, OH, CN, oxo, C １ ~C ６ Alkyl, deuterium-substituted C １ ~C ６ Alkyl or C １ ~C ６ haloalkyl 32. The pharmaceutical composition according to claim 31 for preventing or treating cancer.

38. R ３ａ is H or F; R ３ｂ is H, F, oxo, methyl, ethyl, CHF ２ and CDs ３ selected from the group consisting of 38. The pharmaceutical composition according to claim 37 for preventing or treating cancer.

39. B has the following structure: H、CH ３ 、 【Chemistry 23】 【change】 【change】 32. The pharmaceutical composition according to claim 31 for preventing or treating cancer, characterized in that it is any one of the following:

40. The compound is: 【Chemistry 24】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 The pharmaceutical composition according to claim 1 for preventing or treating cancer, characterized in that the composition is selected from the group consisting of:

41. 2. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the anticancer agent is any one selected from the group consisting of chemical anticancer agents, targeted anticancer agents, anticancer viruses, antibody therapeutic agents, cell therapeutic agents, and immune checkpoint inhibitors.

42. 42. The pharmaceutical composition for preventing or treating cancer according to claim 41, wherein the anticancer chemical agent is any one selected from the group consisting of alkylating agents, microtubule inhibitors, antimetabolites and topoisomerase inhibitors.

43. 43. The pharmaceutical composition for preventing or treating cancer according to claim 42, wherein the anticancer chemotherapy drug is any one selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, thiotepa, altretamine, procarbazine, busulfan, streptozotocin, carmustine, lomustine, dacarbazine, cisplatin, carboplatin, oxaliplatin, docetaxel, velban, Oncovin, navelbine, fluorouracil, capecitabine, cytarabine, gemcitabine, fludarabine, methotrexate, pemetrexed, 6-thioguanine, mercaptopurine, Hycamtin, Camptostar, Bepcid, paclitaxel, Breoxane, adriamycin, SN-38, doxorubicin, and cerbidine.

44. Targeted anticancer drugs include mTOR, PI3K, EGFR, VEGFR, CD20, CD38, RNAK-L, BTK, Bcr-abl, PDGFR / F GFR family, MEK, KRAS, ERK1 / 2, HER2 / Neu, ubiquitin, JAK, ALK, PARP, TGFβR, proteaso Bcl-2, C-Met, VR1, VR2, VR3, c-kit, AXL, RET, BRAF, pan-RAF, SHP2, SRC, LCK , DNMT, CDK4 / 6, CDK9, BET, MDM2, IGF1 / 2 or IGF1-R, ROS1, NTRK1, PIK, DHFR, pan Aurora, Aurora 42. The pharmaceutical composition of claim 41 for preventing or treating cancer, which targets any one protein selected from the group consisting of A, WEE1, HSP90, A3AR, EZH2, ARID1A, Chk1, ATR, HDAC1 / 3, Akt, PLK1, sumoylation-related protein and STING.

45. Targeted anticancer drugs include rapamycin, sirolimus, temsirolimus, everolimus, ridaforolimus, INK-128, alpelisib, cetuximab, trastuzumab, pertuzumab, gefitinib, erlotinib, osimertinib, lazertinib, panitumumab, axitinib, lenvatinib, bevacizumab, ramucirumab, aflibercept, rituximab, obinutuzumab, daratumumab, denosumab, ibrutinib, dasatinib, nilotinib, imatinib, bosutinib, galunisertib, bactosertib, futibatinib, nintedanib, sunitinib, Sorafenib, cabozantinib, regorafenib, masitinib, semaxanib, tivozanib, vandetanib, pazopanib, dabrafenib, sotorasib, adagrasib, JDQ443, MRTX1133, urisertinib, afanitib, lapatinib, neratinib, lenalidomide, ixazomib, ruxolitinib, restortinib, pacritinib, trametinib, cobimetinib, selumetinib, binimetinib, alectinib, lorlatinib, crizotinib, venetoclax, bemcentinib, gilteritinib, selpasetinib, pralsetinib, enco Rafenib, vemurafenib, belbalafenib, RMC-4630, batoprotafib, WH-4-023, olaparib, talazoparib, niraparib, rucaparib, azacitidine, decitabine, guadecitabine, abemaciclib, ribociclib, palbociclib, CDN, SB11285, linetelquib, repotrectinib, tepotinib, allizomadrine, JQ1, NVP-ADW742, duvelisib, irbinitinib, danusertib, MK-1775, AMG-900, BIIB021, reversine, MLN-7243, ABT-737, MK-5 108, GSK-343, 2-D08, SCH-900776, entinostat, carfilzomib, apitolisib, ipatasertib, boracetim, AT-7519, methotrexate, wortmannin, ERAS-007, PYR-41, MLN4924, RO-5503781, MK-8242, SAR-405838, CGM097, DS3032b, lactacystin, disulfiram, epigallocatechin 3-gallate, marizomib, oprozomib, delanzomib, epoxomicin, MG132, β-hydroxy β-methylbutyrate, bortezomib,Navitoclax, naporafenib, PF-07284892, TNO155, hesperadin, LY3295668, tozasertib, azenosertib, ZNL-02-096, RP-6306, GSK-1520489A, BIIB028, MPC-3100, PU-H71, Debio093, SNX-5422, AUY922, KF-26777, MRS-545, CAY10498, DZNe p, EPZ005687, EI1, GSK126, UNC1999, tazemetostat, sinefungin, GSK-343, davidin, CID9549553, SRA737, V158411, PF-477736, AZD7762, prexasertib, beruzosertib, galtisertib, selarasertib, panobinostat, mocetinostat, trichostatin A, CBUD-1001, avexinos Tat, VQD-002, perifosine, miltefosine, MK-2206, AZD5363, rigosertib, I-BET151, I-BET762, OTX-015, TEN-010, CPI-203, CPI-0610, Orinone, RVX-208, ABBV-744, LY294002, AZD5153, MT-1, MS645, figitumumab, mecasermin, rhIGF-1, BI885578, The pharmaceutical composition according to claim 44, for preventing or treating cancer, wherein the compound is any one selected from the group consisting of buparlisib, copanlisib, dactolisib, idelalisib, parsaclisib, paxalisib, taselisib, zandelisib, inavolisib, AZD4573, atuveciclib, VIP152, A-1592668, JSH-150, SLS009, roscovitine, and DMXAA.

46. 42. The pharmaceutical composition for preventing or treating cancer according to claim 41, wherein the anti-cancer virus is talimogene laherparepvec.

47. 42. The pharmaceutical composition for preventing or treating cancer according to claim 41, wherein the antibody therapeutic agent is any one selected from the group consisting of cetuximab, trastuzumab, pertuzumab, panitumumab, rituximab, daratumumab, denosumab, ibritumomab, tositumomab, brentuximab, ofatumumab, obinutuzumab, necitumumab, bevacizumab, ramucirumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and ipilimumab.

48. The pharmaceutical composition for preventing or treating cancer according to claim 41, wherein the cell therapy agent is any one selected from the group consisting of tisagenlecleucel and axicabtageneciloreucel.

49. The pharmaceutical composition for preventing or treating cancer according to claim 41, wherein the immune checkpoint inhibitor is any one selected from the group consisting of an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, an anti-B7-H4 antibody, an anti-HVEM antibody, an anti-TIM3 antibody, an anti-GAL9 antibody, an anti-LAG3 antibody, an anti-VISTA antibody, an anti-KIR antibody, an anti-BTLA antibody, and an anti-TIGIT antibody.

50. 50. The pharmaceutical composition according to claim 49, for preventing or treating cancer, wherein the immune checkpoint inhibitor is any one selected from the group consisting of ipilimumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

51. 2. The pharmaceutical composition of claim 1, wherein the cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, biliary tract cancer, multiple myeloma, melanoma, uterine cancer, cervical cancer, endometrial cancer, thyroid cancer, chronic lymphocytic leukemia, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

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