SOS1 inhibitors and their uses

Abstract

Provided are novel compounds of formula I and uses of compounds of formula I for the prevention or treatment of diseases associated with SOS1. In one aspect of the present invention, the novel compounds are useful for the prevention or treatment of SOS1-mediated diseases, such as cancer and RASopathy, by inhibiting the interaction between SOS1 and RAS family proteins or between SOS1 and RAC1.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to novel compounds having SOS1 inhibitory activity, solvates, stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them as active ingredients for preventing or treating diseases, and pharmaceutical 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, BI-3406, BI-1701963, 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 compounds of formula I, solvates, stereoisomers or pharmaceutically acceptable salts thereof.

[0014] Another object of the present invention is to provide pharmaceutical compositions comprising compounds of Formula I, solvates, stereoisomers or pharmaceutically acceptable salts thereof.

[0015] Another object of the present invention is to provide a method for preventing or treating SOS1 mediated diseases by administering a compound of formula I, a solvate, stereoisomer or a pharmaceutically acceptable salt thereof.

[0016] [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.

[0017] 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 2are 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 and two R 1 can be 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 Rd and R e are each independently H or optionally substituted C1-C6 alkyl. or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof.

[0018] 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:

[0019] 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.

[0020] 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.

[0021] In the above formula 1, E may be O or S. For example, E may be O.

[0022] In formula 1, X may be O or S. For example, X may be O.

[0023] 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. [ka] may be a single bond or a double bond. 1 , Z 2 and Z 3 At most one of is N or NH.

[0024] 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.

[0025] 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.

[0026] 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 1~3 In 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'' can be H and the other can be methyl, ethyl, difluoromethyl, fluoromethyl, hydroxymethyl, aminomethyl, etc., but is not limited to these.

[0027] 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.

[0028] 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 1 may be H, OH, CH3, -CH=CH2, -C≡CH, CN, or optionally substituted cyclopropyl.

[0029] In one embodiment, R 1may 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.

[0030] 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.

[0031] In some embodiments, R 1 is an optionally substituted 4- to 7-membered heterocycloalkyl, optionally substituted C-C 10 Aryl, optionally substituted C-C 10 Aryloxy, optionally substituted (C6-C 10aryl)-(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.

[0032] 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.

[0033] In A of the above formula 1, Cy1 and Cy2 each independently represent C6 to C 10 C6-C fused with aryl, C3-C8 cycloalkyl 10 It may be aryl or 5- to 10-membered heteroaryl.

[0034] In one embodiment, Cy1 is C6 to C10 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.

[0035] 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.

[0036] 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 10 aryl, 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 10In 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.

[0037] 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.

[0038] 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.

[0039] In the formula 1 of the present invention, when A is Cy1-Y-Cy2, Cy 1 is 1 to 3 R 2a and optionally substituted with Cy 2 is 1 to 3 R 2b R 2a and R 2bis as set forth in Formula I below.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] In the above formula I of the present invention, Z 1If 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.

[0053] 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.

[0054] 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.

[0055] 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:

[0056] In one embodiment, in Formula I: [ka] teeth [ka] may be.

[0057] In one embodiment, in Formula I: [ka] teeth [ka] may be.

[0058] 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 R c are each independently H or C1-C6 alkyl. For example, each R 1may 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.

[0059] 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.

[0060] 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.

[0061] 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 cIn this case, R b and R c are each independently H or C1-C6 alkyl.

[0062] 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.

[0063] 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.

[0064] 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).

[0065] 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 , Z3 and B is as defined in Formula I. or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

[0066] 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.

[0067] 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.

[0068] For example, Cy1 has 1 to 3 R 2a The following ring structures optionally substituted with: [ka] It can have one of:

[0069] 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.

[0070] 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.

[0071] 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, CH3NH2-, (CH3)2N-, methoxy, ethoxy, OCF3, OCHF2, OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, [ka] They can be independently selected from the group consisting of, but not limited to:

[0072] When A is Cy1, in formula I of the present invention, A has the following structure: [ka] You can choose from:

[0073] For example, in Formula I, A has the following structure: [ka] You can choose from:

[0074] For example, in Formula I, A is [ka] may be.

[0075] 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.

[0076] 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 may be phenyl, naphthalenyl, thiazolyl, thiophenyl, or pyrazolyl.

[0077] 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 10 It 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 10It 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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:

[0082] 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.

[0083] 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(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] 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.

[0084] 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

[0085] In this case, 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-.

[0086] For example, each R 2bmay 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.

[0087] In formula I of the present invention, when A is Cy1-Y-Cy2, A has the following structure: [ka] You can choose from:

[0088] For example, in Formula I, A has the following structure: [ka] You can choose from:

[0089] 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.

[0090] In the above formula I of the present invention, B is —(CH) o -Cy3, in which case o can be 0 or 1.

[0091] 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.

[0092] 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.

[0093] 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 6~10 It may be, but is not limited to, aryl, thiophenyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, dihydroisobenzofuranyl, indolyl, indazolyl or benzotriazolyl.

[0094] The Cy3 has the following ring structure: [ka] Cy3 can be any one of R 3a may be optionally substituted with

[0095] 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 c It may be C1-C6 alkyl substituted with or C1-C6 alkoxy.

[0096] For example, R 3aExamples 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).

[0097] In the formula I of the present invention, B is -(CH2) o -Cy3, B has the structure [ka] TIFF2024534804000043.tif36149 You can choose from:

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] In one embodiment, W can be NH, C(O), or a direct bond. For example, W can be a direct bond.

[0106] 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).

[0107] 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

[0108] In one embodiment, Cy3 and Cy4 each independently represent 1 to 3 R 3 may be optionally substituted with

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] B is -(CH2) o -Cy3-W-Cy, in Formula I, B has the following structure: [ka] You can choose from:

[0115] For example, B has the following structure: [ka] You can choose from:

[0116] For example, B is [ka] It may be, but is not limited to these.

[0117] 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:

[0118] In some embodiments, the compound of Formula I is the following compound: [ka] TIFF2024534804000052.tif188149 TIFF2024534804000053.tif185149 TIFF2024534804000054.tif200149 TIFF2024534804000055.tif191149 TIFF2024534804000056.tif180149 TIFF2024534804000057.tif190149 TIFF2024534804000058.tif192149 TIFF2024534804000059.tif198149 TIFF2024534804000060.tif188149 TIFF2024534804000061.tif180149 TIFF2024534804000062.tif201149 TIFF2024534804000063.tif189149 TIFF2024534804000064.tif194149 TIFF2024534804000065.tif177149 TIFF2024534804000066.tif189149 TIFF2024534804000067.tif199149 It may also be a compound selected from the group consisting of: 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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-C 15 Cycloalkyl, C5-C 11 Cycloalkyl, C5-C 10Polycyclic 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] As used herein, the term "cyano" refers to the functional group --CN, which has a triple bond between the carbon and nitrogen atoms.

[0135] As used herein, the term "hydroxy" refers to an --OH functional group (a hydroxyl group).

[0136] As used herein, the term "oxy" refers to the -O- divalent functional group.

[0137] 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.

[0138] As used herein, the term "carbonyl" refers to the -C(=O)- divalent functional group.

[0139] 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)-).

[0140] 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.

[0141] As used herein, the term "carboxy" refers to --COOH.

[0142] 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.

[0143] As used herein, the term "amino" refers to -NH2.

[0144] 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.

[0145] 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.

[0146] 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".

[0147] As used herein, the term "carbamoyl" refers to -CONH2.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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

[0152] 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.

[0153] 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 "-".

[0154] 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 volatile, non-toxic, and / or suitable for administration to humans.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] For example, compounds of formula I can be prepared by coupling intermediate compound a with intermediate compound 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.

[0165] 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.

[0166] 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:

[0167] 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.

[0168] 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:

[0169] 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:

[0170] 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

[0171] 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.

[0172] In one embodiment, compounds of Formula I are disclosed below in Reaction Scheme 1D. [ka] It can be prepared according to the method of

[0173] 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).

[0174] 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

[0175] 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.

[0176] 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

[0177] 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).

[0178] 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).

[0179] 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

[0180] 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:

[0181] 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

[0182] 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.) (Zn-Negishi reaction).

[0183] 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

[0184] 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).

[0185] 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

[0186] 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).

[0187] 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

[0188] 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).

[0189] 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

[0190] 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 The compound can be prepared by reacting the compound with a boronic acid compound of the formula:

[0191] 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

[0192] 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.

[0193] 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

[0194] 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.

[0195] 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

[0196] 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.

[0197] 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

[0198] 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.

[0199] 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

[0200] 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.

[0201] 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

[0202] 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.) (Zn 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).

[0203] 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

[0204] 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.

[0205] 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

[0206] 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.

[0207] 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

[0208] 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.

[0209] 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

[0210] 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.

[0211] Pharmaceutical uses, pharmaceutical compositions and methods of administration In another aspect, there is provided a pharmaceutical composition for preventing or treating an SOS1-mediated disease, comprising a compound, stereoisomer, solvate, or pharmaceutically acceptable salt of Formula I. The compound, stereoisomer, solvate, and pharmaceutically acceptable salt of Formula I are as described above.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] When used in the treatment of 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), CDK4 / 6 inhibitors (e.g., abemaciclib, palbociclib), immunotherapeutics (e.g., anti-CTLA4 antibodies, anti-PD1 antibodies), angiogenesis inhibitors (e.g., bevacizumab), topoisomerase inhibitors (e.g., irinotecan), ERK inhibitors (e.g., uristatinib), MDM2 inhibitors, PARP inhibitors, MCL-1 inhibitors, mTOR inhibitors (e.g., rapamycin), and the like. It may be administered in combination with other agents such as thrombin time-dependent vasopressin (TNF-α), thrombin time-dependent vasopressin (THD ...

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] [Effects of the invention] The compounds of formula I, their solvates, stereoisomers or pharmaceutically acceptable salts have effective inhibitory activity against SOS1, particularly inhibiting the interaction between SOS1 and RAS family proteins or between SOS1 and RAC1, and are therefore useful for the prevention or treatment of SOS1-mediated diseases, particularly diseases associated with abnormal activity of SOS1 and / or RAS family proteins.

[0231] [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.

[0232] [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 anhydrous 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. 1LC / MS (ESI) m / z =231.0 [M+H] + .

[0233] 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 anhydrous 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] + .

[0234] Preparation Example 2: (1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethanamine 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 anhydrous 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).

[0235] 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] + .

[0236] 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 anhydrous 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] + .

[0237] 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] + .

[0238] 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] + .

[0239] Preparation Example 4: 2-[3-[(1R)-1-aminoethyl]phenyl]-2,2-difluoroethanol 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 anhydrous 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] + .

[0240] 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] + .

[0241] 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 anhydrous 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] + .

[0242] 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] + .

[0243] 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).

[0244] 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).

[0245] 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 hours. 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 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] + .

[0246] 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 anhydrous 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] + .

[0247] 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 anhydrous 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] + .

[0248] 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] + .

[0249] 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 anhydrous 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] + .

[0250] 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] + .

[0251] 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 anhydrous 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] + .

[0252] Furthermore, the following intermediates G-1 to G-4 were prepared in the same manner as for intermediate G. [ka]

[0253] 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).

[0254] 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-phenylpyridazine-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).

[0255] 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 anhydrous 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] + ).

[0256] 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).

[0257] 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 and separated. The organic layer was dried over anhydrous 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] + .

[0258] 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 anhydrous 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] + .

[0259] 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] + .

[0260] 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 anhydrous 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).

[0261] 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] + .

[0262] Additionally, the following intermediates K-1 to K-22 were prepared in a similar manner to that of intermediate K. [ka] TIFF2024534804000126.tif156149

[0263] 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] + .

[0264] 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] + .

[0265] 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).

[0266] 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] + .

[0267] 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] + .

[0268] 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] + .

[0269] 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).

[0270] 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).

[0271] 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).

[0272] 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] + .

[0273] 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, 107.65 μL), and (1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (27.69 mg, 194.65 μmol) in MeCN (3 mL) was degassed and purged with N three times, and then the mixture was stirred at 85 °C under N 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 x 2), dried over anhydrous NaSO, 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] +

[0274] The following intermediates Q-1, Q-2 and Q-3 were prepared in a similar manner. [ka]

[0275] 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), 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] + .

[0276] Preparation Example 19: Methyl 1-(5-chloro-1-methyl-pyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate [ka] To a solution of methyl 1-(1-methylpyrazol-4-yl)-6-oxo-pyridazine-3-carboxylate, intermediate K-22 (300 mg, 1.28 mmol) in MeCN (6 mL) was added SelectF (680.66 mg, 1.92 mmol) and ZrCl (59.70 mg, 256.18 μmol, 21.32 μL). 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] + .

[0277] 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] + .

[0278] 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) as a colorless oil. MS (ESI) m / z = 324.9 [M+H] + .

[0279] The following intermediates U-1, U-2, U-3, U-4 and U-5 were also prepared in an analogous manner. [ka]

[0280] 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 × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give intermediate U-5 (80 mg, 29.26% yield) as a yellow oil. MS (ESI) m / z = 321.1 [M+H] + ).

[0281] 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]+ .

[0282] 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.

[0283] 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.

[0284] 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] + .

[0285] 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] + .

[0286] 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] + .

[0287] 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] + .

[0288] 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)

[0289] 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).

[0290] 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] + .

[0291] 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] + .

[0292] 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] + .

[0293] 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] + .

[0294] 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] + .

[0295] 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] + .

[0296] 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] + .

[0297] 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 hours. 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 hours. 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] + .

[0298] 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] + .

[0299] 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] + .

[0300] 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] + .

[0301] 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 no hydrogen evolution occurred. 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]

[0302] 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.

[0303] 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] +

[0304] 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] + .

[0305] 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).

[0306] 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).

[0307] 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] + .

[0308] 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] + .

[0309] Additionally, the following intermediate AG-1 was prepared in a similar manner as for intermediate AG. [ka]

[0310] 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).

[0311] 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] + .

[0312] 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] + .

[0313] 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)

[0314] Steps 2-5: Synthesis of (R)-1-(3-(difluoromethyl)-5-nitrophenyl)ethanamine [ka] Intermediate AJ was prepared in a manner similar to that of Preparation Example 13 using 1-bromo-3-(difluoromethyl)-5-nitro-benzene. MS (ESI) m / z = 216.1 [M+H] + .

[0315] 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] + .

[0316] 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] + .

[0317] 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] +

[0318] 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] + .

[0319] 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] + .

[0320] 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] + .

[0321] 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] +

[0322] 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] + .

[0323] 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] + .

[0324] 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] + . Intermediates AQ-1, AQ-2, AQ-3 and AQ-4 were also prepared in a similar manner as for intermediate AQ. [ka]

[0325] 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, 55.05 μL), and TEA (127.95 mg, 1.26 mmol, 176.00 μL) 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] +

[0326] 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. Preparation Example 45: 1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

[0327] 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] + .

[0328] 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] + .

[0329] 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] + .

[0330] 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] + .

[0331] 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] + .

[0332] 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).

[0333] 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).

[0334] 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] + .

[0335] 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).

[0336] 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).

[0337] 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] + .

[0338] 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] + .

[0339] 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] + .

[0340] 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).

[0341] 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).

[0342] 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).

[0343] 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).

[0344] 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] + .

[0345] 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] + .

[0346] 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 H NMR (400MHz, DMSO-d6) δ 7.40 - 7.34 (m, 2H), 7.34 - 7.30 (m, 1H), 7.13 (td, J = 2.0, 7.2Hz, 1H); LC / MS (ESI) m / z = 318.3 [M+H] +

[0347] 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] + .

[0348] 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] + .

[0349] 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, 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 the crude product (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). [Example]

[0350] 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 anhydrous 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. 1H 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] + .

[0351] 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 (30 mL × 3). The combined organic layer was washed with brine (30 mL), 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 (column: 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. 1H 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] + .

[0352] 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] TIFF2024534804000219.tif152149

[0353] 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 x 30 mm x 3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%, 8 min). CH3CN 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] + .

[0354] 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] + .

[0355] 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 anhydrous 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), CH3CN 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. 1H 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] + .

[0356] 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 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%: 48% to 78%, 15 min), CH3CN 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. 1H 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] + .

[0357] 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 CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give the compound of Example 15 (34.4 mg, 48.0% yield) as a white solid. 1H 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] + .

[0358] 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), HATU (171 mg, 451 μmol) and TEA (91.3 mg, 902 μmol) were added, followed by stirring at 20° C. for 15 minutes. Intermediate B (84.5 mg, 361 μmol) was then added to the mixture, which was stirred at 20° C. for 2 hours 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 anhydrous 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] + .

[0359] 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 anhydrous 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 CH3CN 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. 1 H 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] + .

[0360] 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 anhydrous 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. 1 H 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] + .

[0361] 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]+ .

[0362] 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 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%: 40% to 70%, 8 min). The CH3CN 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] + .

[0363] 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).

[0364] 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] + .

[0365] 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 anhydrous 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). CH3CN 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. 1H 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] + .

[0366] 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. 1H 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] + .

[0367] 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 anhydrous 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] + .

[0368] 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). CH3CN 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] + .

[0369] 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 anhydrous 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] + .

[0370] 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 CH3CN 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] + .

[0371] 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 CHCN (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 anhydrous 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] + .

[0372] 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] + .

[0373] 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 anhydrous 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). CHCN 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] + .

[0374] 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] + .

[0375] 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 anhydrous 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] + .

[0376] 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] + .

[0377] 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 anhydrous 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 CH3CN 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] + .

[0378] 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] JPEG2024534804000246.jpg181149 JPEG2024534804000247.jpg190149 JPEG2024534804000248.jpg197149 JPEG2024534804000249.jpg208149 JPEG2024534804000250.jpg157149 JPEG2024534804000251.jpg176149

[0379] 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 anhydrous NaSO, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel 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).

[0380] 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 anhydrous 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] + .

[0381] 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 anhydrous 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] + .

[0382] 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] + .

[0383] 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] + .

[0384] 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] + .

[0385] 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] + .

[0386] Step 8: (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, 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 anhydrous 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] + .

[0387] 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 (30 mg, 69.38 μmol) and BBr (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 anhydrous NaSO, 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). CH3CN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give Example 47 (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] + .

[0388] 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] + .

[0389] 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 anhydrous 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] + .

[0390] 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] + .

[0391] 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 anhydrous 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] + .

[0392] 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-oxo-1-phenyl-4-(2-trimethylsilylethynyl)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. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.54-7.49 (m,2H), 7.48-7.43 (m, 1H), 7.34 (s, 1H), 6.80 LC / MS(ESI) (m / z) = 427.3 [M+H] + .

[0393] Example 51: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-1-(2-aminophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide Steps 1 and 2: Synthesis of 1-(2-nitrophenyl)-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-pyridazine-3-carboxamide [ka] Intermediate G was reacted in the same manner as in Steps 2 and 3 of Example 23, except that in Step 3, intermediate C was replaced with intermediate B and the coupling reagents were changed to HOBt and EDCI, to give 1-(2-nitrophenyl)-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-pyridazine-3-carboxamide as a crude yellow solid. LC / MS (ESI) m / z = 278.1 [M+H] + .

[0394] Step 3: Synthesis of (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-1-(2-aminophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] A mixture of 1-(2-nitrophenyl)-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-pyridazine-3-carboxamide (100 mg, 209.49 μmol) and Fe (117.00 mg, 2.09 mmol) in saturated aqueous NH4Cl (1 mL) and EtOH (3 mL) was stirred at 60 °C under air for 2 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 anhydrous Na2SO4, 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 (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 23% to 63%, 15 min). The CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give Example 51 (49 mg, 55.84% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 9.6 Hz, 1H), 7.12 (br d, J =1.6 Hz, 1H), 7.11-7.08 (m, 1H), 7.08-7.06 (m, 1H), 6.83-6.77 (m, 3H), 6.69 (s,1H), 6.62 (t, J = 7.2 Hz, 1H), 5.53 (s, 2H), 5.12 (s, 2H), 5.05-4.99 (m, 1H),1.43 (d, J = 7.2 Hz, 3H).LC / MS (ESI) m / z = 418.4 [M+H] + .

[0395] Example 52: (R)-1-(2-acetamidophenyl)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide Step 1: Synthesis of methyl 1-(2-aminophenyl)-6-oxo-pyridazine-3-carboxylate [ka] To a solution of intermediate G (400 mg, 1.45 mmol) in MeOH (6 mL) and saturated aqueous NH4Cl (2 mL) was added Fe (405.83 mg, 7.27 mmol), followed by stirring at 60°C for 12 hours. The mixture was concentrated under reduced pressure, and then EtOH (6 mL) was added to it. The resulting mixture was stirred at 90°C for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure, water (10 mL) was added, and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give methyl 1-(2-aminophenyl)-6-oxo-pyridazine-3-carboxylate (180 mg, 21.21% yield) as a yellow oil. LC / MS (ESI) m / z = 246.0 [M+H] + .

[0396] Step 2: Synthesis of methyl 1-(2-acetamidophenyl)-6-oxopyridazine-3-carboxylate [ka] To a solution of methyl 1-(2-aminophenyl)-6-oxo-pyridazine-3-carboxylate (180 mg, 733.99 μmol) in DCM (3 mL) was added TEA (222.82 mg, 2.20 mmol) and AcO (112.40 mg, 1.10 mmol), followed by stirring at 20 °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 anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (50% EtOAc in petroleum ether) to give methyl 1-(2-acetamidophenyl)-6-oxopyridazine-3-carboxylate (180 mg, 32.44% yield) as a white solid. LC / MS (ESI) m / z = 288.0 [M+H] + .

[0397] Steps 3 and 4: Synthesis of (R)-1-(2-acetamidophenyl)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 52 was obtained by reacting methyl 1-(2-acetamidophenyl)-6-oxopyridazine-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 (400MHz, DMSO-d6) δ 9.29 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 7.97-7.84 (m, 2H),7.50-7.40 (m, 2H), 7.32-7.21 (m, 1H), 7.12 (d, J = 10.0 Hz, 1H), 6.79 (d, J =16.4 Hz, 2H), 6.69 (s, 1H), 5.55 (s, 2H), 5.04 (quintet, J= 7.2 Hz, 1H), 1.91 (s, 3H), 1.42 (d, J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 460.3[M+H] + .

[0398] Example 53: 1-(3-acetamidophenyl)-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]-6-oxo-pyridazine-3-carboxamide Step 1: Synthesis of methyl 1-(3-acetamidophenyl)-6-oxo-pyridazine-3-carboxylate [ka] A mixture of methyl 6-oxo-1H-pyridazine-3-carboxylate (500 mg, 3.24 mmol), (3-acetamidophenyl)boronic acid (754.83 mg, 4.22 mmol), Cu(OAc) (294.62 mg, 1.62 mmol), and pyridine (1.67 g, 21.09 mmol, 1.70 mL) in DCM (5 mL) was stirred at 20 °C for 14 h under air atmosphere. The reaction mixture was poured into water (20 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 silica gel column chromatography (65% EtOAc in petroleum ether) to give methyl 1-(3-acetamidophenyl)-6-oxo-pyridazine-3-carboxylate (400 mg, 35.62% yield) as a pale yellow solid. LC / MS (ESI) m / z = 288.0 [M+H] + .

[0399] Steps 2 and 3: Synthesis of 1-(3-acetamidophenyl)-N-[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]-6-oxo-pyridazine-3-carboxamide [ka] In step 3, except that intermediate C was replaced with intermediate D and the coupling reagents were changed to HOBt and EDCI, methyl 1-(3-acetamidophenyl)-6-oxo-pyridazine-3-carboxylate was reacted in the same manner as in steps 2 and 3 of example 23 to obtain the compound of example 53. 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H),7.85 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.54-7.48 (m, 2H), 7.41 (s, 2H),7.39-7.36 (m, 1H), 7.29 (br d, J = 7.6 Hz, 1H), 7.13 (d, J = 9.6 Hz, 1H), 5.63(br s, 1H), 5.18 (quintet, J = 7.2 Hz, 1H), 3.82 (br t, J =14.4 Hz, 2H), 2.06 (s, 3H), 1.49-1.44 (m, 3H); LC / MS (ESI) m / z = 457.4 [M+H] + .

[0400] Example 54: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-5-cyclopropyl-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamide Step 1: Synthesis of 5-cyclopropyl-6-oxo-1-phenyl-pyridazine-3-carboxylic acid [ka] A mixture of intermediate F (50 mg, 161.75 μmol), cyclopropylboronic acid (18.06 mg, 210.28 μmol), KPO (120.17 mg, 566.13 μmol), Pd(OAc) (3.63 mg, 16.18 μmol), and P(Cy) (9.07 mg, 32.35 μmol) in toluene (1 mL) and HO (0.1 mL) was degassed and purged with N three times, then stirred at 100 °C under a N atmosphere for 12 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc. The combined organic layers were discarded. The aqueous layer was acidified with 1 N aqueous HCl (pH = 3-4) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give 5-cyclopropyl-6-oxo-1-phenyl-pyridazine-3-carboxylic acid (41 mg, 84.67% yield) as a yellow solid. LC / MS (ESI) m / z = 257.1 [M+H] + .

[0401] Step 2: Synthesis of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-5-cyclopropyl-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 54 was obtained by reacting 5-cyclopropyl-6-oxo-1-phenyl-pyridazine-3-carboxylic acid in the same manner as in Step 3 of Example 23. 1 H NMR (400MHz, DMSO-d6) δ8.78 (d, J = 8.4 Hz, 1H), 7.69-7.58 (m, 2H), 7.57-7.49 (m, 2H),7.49-7.43 (m, 1H), 7.34 (s, 1H), 6.79 (d, J = 16.4 Hz, 2H), 6.69 (s, 1H), 5.53(s, 2H), 5.01 (quintet, J = 7.2 Hz, 1H), 2.26-2.13 (m, 1H),1.43 (d, J = 7.2 Hz, 3H), 1.13-1.05 (m, 2H), 0.97-0.88 (m, 2H). LC / MS(ESI) m / z = 443.3 [M+H] + .

[0402] Example 55: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-4-cyclopropyl-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 55 was obtained in the same manner as in Example 54, except that in Step 1 of Example 54, intermediate F was replaced with intermediate H, and the coupling reagents used in Step 2 were changed to HOBt and EDCI. 1 H NMR (400MHz, DMSO-d6) δ 9.13 (d, J = 8.0 Hz, 1H), 7.66-7.58 (m, 2H), 7.53-7.47 (m, 2H),7.45-7.40 (m, 1H), 6.79 (d, J = 14.4 Hz, 2H), 6.71 (s, 1H), 6.60 (s, 1H), 5.56(s, 2H), 4.99 (quintet, J =7.2 Hz, 1H), 2.05-1.95 (m, 1H),1.40 (d, J = 7.2 Hz, 3H), 1.03-0.81 (m, 4H); LC / MS (m / z) = 443.3 [M+H] + .

[0403] Example 56: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-5-cyano-6-oxo-1-phenyl-pyridazine-3-carboxamide Step 1: Synthesis of 5-bromo-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] To a stirred solution of Intermediate B (400 mg, 1.71 mmol) in DCM (2 mL) and toluene (2 mL), AlMe (2.67 mL, 4.27 mmol, 1.6 M solution in toluene) was added dropwise, and the mixture was stirred at 20 °C under a N atmosphere for 15 min. Intermediate F (528 mg, 1.71 mmol) was then added to it, and the reaction mixture was stirred at 40 °C under a N atmosphere for another 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 anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The product was purified by silica gel column chromatography (0–20% EtOAc in petroleum ether) to give 5-bromo-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide (253 mg, 28.97% yield) as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ 8.39 (s, 3H), 7.93 (s, 1H), 7.59-7.54(m, 4H), 7.53-7.50 (m, 1H), 7.35 (d, J = 7.2 Hz, 1H), 5.38-5.30 (m, 1H), 1.65(d, J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 511.1 [M+H] + .

[0404] Step 2: Synthesis of 5-cyano-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] To a solution of 5-bromo-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide (163 mg, 318.83 μmol) in NMP (2 mL) was added CuCN (142.78 mg, 1.59 mmol, 348.24 μL), and the mixture was stirred in a microwave under N at 180° C. for 1 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc, and 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 silica gel column chromatography (15% EtOAc in petroleum ether) to give 5-cyano-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide (140 mg, 81.99% yield) as a yellow oil. LC / MS (ESI) m / z = 456.1 [M+H] + .

[0405] Step 3: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-5-cyano-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] To a solution of 5-cyano-N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide (140 mg, 306.10 μmol) in MeOH (3 mL) and NH₄Cl (1 mL) was added Fe (170.94 mg, 3.06 mmol), followed by stirring at 55°C for 2 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex C18 75 × 30 mm × 3 μm, mobile phase: [water (NH₃H₂O + NH₄HCO₃)-ACN]; B%: 31% to 71%, 14 min). Most of the CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give Example 56 (9.6 mg, 7.27% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 8.0 Hz, 1H), 8.58 (s, 1H), 7.68 (d, J = 7.2 Hz, 2H),7.59-7.49 (m, 3H), 6.82 (s, 1H), 6.78 (s, LC / MS(ESI) m / z = 428.3 [M+H] + .

[0406] Example 57: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] A mixture of Intermediate A (70 mg, 323.79 μmol), Intermediate D (91.21 mg, 453.30 μmol), EDCI (124.14 mg, 647.57 μmol), HOBt (87.50 mg, 647.57 μmol), and DIEA (104.62 mg, 809.46 μmol, 140.99 μL) in DMF (2 mL) was degassed and purged with N three times, then stirred under a N atmosphere at 20° 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 a residue. The residue was purified by preparative HPLC (Phenomenex C18 75 × 30 mm × 3 μm, mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 22% to 52%, 10 min). CH3CN was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give Example 57 (28.0 mg, 15.32% yield) as a white solid. 1H NMR(400 MHz, DMSO-d6) δ 8.92(d, J = 8.4 Hz, 1H), 7.89(d, J = 9.8 Hz, 1H), 7.70-7.64(m, 2H),7.57-7.50(m, 4H), 7.50-7.46(m, 1H), 7.45-7.37(m, 2H), 7.14(d, J = 9.8 Hz, 1H),5.60(t, J = 6.4 Hz, 1H), 5.19(quintet, J = 7.2 Hz, 1H),3.83(dt, J = 6.4, 14.4 Hz, 2H), 1.49(d, J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 400.3 [M+H] + .

[0407] Example 58: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]-1-(3-methylsulfonylphenyl)-6-oxo-pyridazine-3-carboxamide Step 1: Synthesis of methyl 1-(3-methylsulfonylphenyl)-6-oxo-pyridazine-3-carboxylate [ka] A mixture of methyl 6-oxo-1H-pyridazine-3-carboxylate (150 mg, 973.25 μmol), (3-methylsulfonylphenyl)boronic acid (214.14 mg, 1.07 mmol), Cu(OAc) (35.35 mg, 194.65 μmol), and pyridine (500.39 mg, 6.33 mmol) in DCM (3 mL) was degassed and purged with N three times, then stirred under a N atmosphere 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 (60% EtOAc in petroleum ether) to give methyl 1-(3-methylsulfonylphenyl)-6-oxo-pyridazine-3-carboxylate (300 mg, 41.67% yield) as a white solid. LC / MS (ESI) m / z = 308.9 [M+H] + .

[0408] Step 2: Synthesis of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)phenyl]ethyl]-1-(3-methylsulfonylphenyl)-6-oxo-pyridazine-3-carboxamide [ka] The compound of Example 58 was obtained in the same manner as in Example 57, except that intermediate A was replaced with 1-(3-methylsulfonylphenyl)-6-oxo-pyridazine-3-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ9.03 (d, J = 8.4 Hz, 1H), 8.31 (t, J = 2.0 Hz, 1H), 8.12 -8.01 (m, 2H), 7.92 (d, J = 9.6 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.57-7.52 (m,2H), 7.45 (t, J = 7.2 Hz, 1H), 7.41-7.38 (m, 1H), 7.20 (d, J = 9.6 Hz, 1H),5.63 (br s, 1H), 5.21 (quintet, J = 7.2 Hz, 1H), 3.84 (t, J= 14.4 Hz, 2H), 3.41-3.31 (s, 3H), 1.51 (d, J = 7.2 Hz, 3H); LC / MS (ESI) m / z =478.3 [M+H] + .

[0409] Example 59: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxy-ethyl)-2-fluoro-phenyl]ethyl]-6-oxo-1-phenyl-pyridazine-3-carboxamide [ka] The compound of Example 59 was obtained in the same manner as in Example 57, except that Intermediate D was replaced with Intermediate E. 1H NMR (400MHz, DMSO-d6) δ 8.97 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.72-7.60 (m,3H), 7.56 (t, J = 7.6 Hz, 2H), 7.51-7.39 (m, 2H), 7.32-7.25 (m, 1H), 7.14 (d, J= 9.6 Hz, 1H), 5.72 (t, J = 6.4 Hz, 1H), 5.40 (quintet, J =7.2 Hz, 1H), 3.91 (dt, J = 6.4, 14.4 Hz, 2H), 1.47 (d, J = 7.2 Hz, 3H); LC / MS(ESI) m / z = 418.3 [M+H] + .

[0410] Example 60: (R)—N-(1-(3-ethoxyphenyl)ethyl)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 60 was obtained in the same manner as in Example 57, except that Intermediate D was replaced with Intermediate I. 1 H NMR (400MHz, DMSO-d6) δ 8.80 (brd, J = 8.4 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.67 (d, J =7.6 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.50-7.43 (m, 1H), 7.20 (t, J = 7.6 Hz,1H), 7.14 (d, J = 9.6 Hz, 1H), 6.98-6.88 (m, 2H), 6.77 (d, J = 8.0 Hz, 1H),5.10 (quintet, J =7 .2 Hz, 1H), 3.97 (q, J = 6.8 Hz, 2H),1.45 (d, J = 6.8 Hz, 3H), 1.29 (t, J = 6.8 Hz, 3H); LC / MS (ESI) m / z = 364.3[M+H] + .

[0411] Example 61: 6-oxo-1-phenyl-N-[(1R)-1-(3-trimethylsilylphenyl)ethyl]pyridazine-3-carboxamide [ka] To a solution of intermediate A (24.60 mg, 113.78 μmol) in DMF (2 mL), HATU (64.89 mg, 170.67 μmol) and TEA (34.54 mg, 341.33 μmol, 47.51 μL) were added, and the mixture was stirred at 20 °C for 15 min. Intermediate J (22 mg, 113.78 μmol) was added, followed by stirring at 20 °C for 2.75 h under N. The reaction mixture was poured into water (20 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 (C18-6 100 × 30 mm × 5 μm, mobile phase: [water (FA)-ACN]; B%: 62%-92%, 15 min). Most of the CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give Example 61 (11.4 mg, 23.65% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 8.4Hz, 1H), 7.88 (d, J = 9.6Hz, 1H), 7.70-7.64 (m,2H), 7.56-7.50 (m, 3H), 7.49-7.44 (m, 1H), 7.40-7.35 (m, 2H), 7.32-7.27 (m,1H), 7.14 (d, J = 9.6Hz, 1H), 5.14 (quintet, J = 7.2Hz,1H), 1.47 (d, J = 7.2Hz, 3H), 0.22 (s, 9H); LC / MS (ESI) m / z = 392.4 [M+H] + .

[0412] Example 62: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-phenyl-pyridine-3-carboxamide [ka] The compound of Example 62 was obtained in the same manner as in Example 23, except that in Step 1 of Example 23, ethyl 6-oxo-1H-pyridine-3-carboxylate and phenylboronic acid were used as starting materials, and the coupling reagents used in Step 3 were changed to HOBt and EDCI. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 7.6 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.95 (dd, J =2.6, 9.6 Hz, 1H), 7.59-7.53 (m, 2H), 7.53-7.46 LC / MS (ESI) m / z = 402.3 [M+H] + .

[0413] Example 63: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-5-oxo-4-phenyl-pyrazine-2-carboxamide Step 1: Synthesis of N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-5-oxo-4-phenyl-pyrazine-2-carboxamide [ka] N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-5-oxo-4-phenyl-pyrazine-2-carboxamide was obtained in a similar manner to Step 1 of Example 56, replacing Intermediate F with Intermediate K. LC / MS (ESI) m / z = 433.0 [M+H] + .

[0414] Step 2: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-5-oxo-4-phenyl-pyrazine-2-carboxamide [ka] The compound of Example 63 was obtained by reacting N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-5-oxo-4-phenyl-pyrazine-2-carboxamide in a manner similar to that of Step 3 of Example 56. 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.58-7.50 (m,5H), 6.87 (s, 1H), 6.80 (s, 1H), 6.70 (s, 1H), 5.55 (s, 2H), 5.08-5.00 (m, 1H),1.47 (d, J = 7.2 Hz, 3H); LC / MS (ESI) m / z = 403.3 [M+H] + .

[0415] Example 64: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-carboxamide Step 1: Synthesis of 1-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid [ka] To a solution of intermediate K-9 (57.6 mg, 0.30 mmol) in EtOH (1.3 mL) was added NaOH (2N, 297 μL). The mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature and extracted with EtOAc. The aqueous layer was adjusted to pH = 2-3 with 2N aqueous HCl and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give 1-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (65.7 mg, crude). LC / MS (m / z) = 181.1 [M + H] + .

[0416] Step 2: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] A mixture of 1-cyclopropyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (65.7 mg, 0.36 mmol), Intermediate C (82 mg, 0.40 mmol), HATU (208 mg, 0.55 mmol), and DIEA (191 μL, 1.09 mmol) in DMF (2 mL) was degassed and purged with N three times, then stirred at room temperature under a N atmosphere for 3 hours. The reaction mixture was poured into water 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 residue was purified by preparative HPLC. The solvent was removed under reduced pressure to give Example 64 (20.3 mg, 15.2% yield). 1 H NMR (400 MHz, MeOD) δ 7.90 (d, J = 9.6 Hz, 1H), 7.06 - 6.98 (m, 2H), 6.96 (s, 1H), 6.88(s, 1H), 5.17 - 5.10 (m, 1H), 4.05 (tt, J = 7.6, LC / MS (m / z) = 367.1 [M + H] + .

[0417] Example 65 and Example 66 The compounds shown in the following table were prepared in a similar manner to Example 64 by using starting materials that correspond to the structure of the desired compound based on Preparation Example 11. [Table 3]

[0418] Example 67: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-(1-methanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-oxo-1,6-dihydropyridazine-3-carboxamide Step 1: Synthesis of methyl 1-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-6-oxo-1,6-dihydropyridazine-3-carboxylate [ka] To a solution of intermediate K-10 (48.5 mg, 0.21 mmol) in DCM (200 μL) was added TEA (86 μL, 0.62 mmol). The mixture was cooled to 0-5 °C, and then methanesulfonyl chloride (19.15 μL, 0.25 mmol) was added dropwise slowly while maintaining the reaction temperature below 20 °C. After the addition, the mixture was stirred at room temperature for 16 h. The reaction was quenched by the slow addition of H2O, and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed sequentially with saturated NH4Cl, saturated NaHCO3, saturated NH4Cl, and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The residue was purified by preparative HPLC. The solvent was removed under reduced pressure to give methyl 1-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (7.8 mg, 12.1% yield). LC / MS (m / z) = 314.1 [M + H] + .

[0419] Steps 2 and 3: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-(1-methanesulfonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 67 (2.6 mg, yield 31.4%) was obtained in the same manner as in Example 64. 1H NMR (400 MHz, DMSO) δ 8.84 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.05 (d, J =9.8 Hz, 1H), 6.83 (s, 1H), 6.79 (s, 1H), 6.70 (d, J = 7.2 Hz, 3H), 6.28 (s,2H), 5.04 (s, 1H), 3.94 (s, 2H), 3.42 (d, J = 5.4 Hz, 1H), 2.99 (s, 3H), 2.67(s, 2H), 1.47 (d, J = 6.9 Hz, 3H); LC / MS m / z = 486.2 [M+H] + .

[0420] Example 68: 1-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] Example 68 (5.3 mg, 15% yield) was obtained in the same manner as in Example 67, except that in Step 1 of Example 67, methanesulfonyl chloride was replaced with acetic anhydride. 1 H NMR (400 MHz, MeOD) δ 7.94 (dd, J = 9.7, 1.3 Hz, 1H), 7.06 (dd, J = 9.7, 1.3 Hz, 1H),6.90 (d, J = 9.7 Hz, 2H), 6.81 (s, 1H), 6.18 (s, 1H), 5.13 (q, J = 7.1 Hz, 1H),4.31 - 4.25 (m, 2H), 3.90 - 3.77 (m, 2H), 2.67 (s, 1H), 2.59 (s, 1H), 2.18 (d,J = 7.6 Hz, 3H), 1.54 (d, J = 7.1 Hz, 3H); LC / MS m / z = 450.2 [M+H] + .

[0421] Example 69: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-(1-methanesulfonyl-1,2,5,6-tetrahydropyridin-3-yl)-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] The intermediate K-11 used as the starting material was acidified, and then the compound of Example 69 (3.5 mg, yield 11.5%) was obtained in the same manner as in Example 67. 1 H NMR (400 MHz, MeOD) δ 7.94 (d, J = 9.7 Hz, 1H), 7.26 (s, 1H), 7.18 (s, 1H), 7.11 - 7.03(m, 2H), 6.30 (dq, J = 4.2, 2.0 Hz, 1H), 5.18 (q, J = 6.9 Hz, 1H), 4.14 (d, J =2.2 Hz, 1H), 3.53 (t, J = 5.8 Hz, 2H), 3.00 (s, 3H), 2.53 (dq, J = 5.9, 3.2 Hz,2H), 1.57 (d, J = 7.1 Hz, 3H); LC / MS m / z = 486.2 [M+H] + .

[0422] Example 70: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-{bicyclo[1.1.1]pentan-1-yl}-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 70 (2.9 mg, yield 90%) was obtained in the same manner as in Example 64. 1H NMR (400 MHz, MeOD) δ 7.61 (s, 1H), 7.29 (s, 1H), 7.20 (s, 1H), 7.12 (s, 1H), 5.16 (q, J= 7.0 Hz, 1H), 2.58 (s, 1H), 2.19 (s, 6H), 1.56 (d, J = 7.1 Hz, 3H); LC / MS m / z= 393.2 [M+H] + .

[0423] Example 71: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-[3-(hydroxymethyl)phenyl]-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] The compound of Example 71 (38.1 mg, yield 87%) was obtained in the same manner as in Example 64. 1 H NMR (400 MHz, DMSO) δ 8.59 (d, J = 7.7 Hz, 1H), 8.35 (d, J = 2.6 Hz, 1H), 7.96 (dd, J =9.6, 2.7 Hz, 1H), 7.55 - 7.30 (m, 5H), 6.77 (s, LC / MS m / z = 432.2 [M+H] + .

[0424] Example 72 and Example 73 The compounds shown in the following table were prepared in a similar manner to Example 71 by using the appropriate starting materials, each corresponding to the structure of the desired compound based on Preparative Example 7. [Table 4]

[0425] Example 74: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1'-methanesulfonyl-6-oxo-2',3'-dihydro-1'H,6H,6'H-[1,4'-bipyridine]-3-carboxamide [ka] Intermediate K-13 was acidified, and then the compound of Example 74 (7.2 mg, yield 7.3%) was obtained in the same manner as in Example 67. 1 H NMR (400 MHz, MeOD) δ 8.18 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 9.6, 2.6 Hz, 1H), 6.88 (q,J = 1.7 Hz, 2H), 6.80 (d, J = 2.0 Hz, 1H), 6.54 (d, J = 9.6 Hz, 1H), 6.04 -5.97 (m, 1H), 5.10 (q, J = 7.0 Hz, 1H), 4.01 (q, J = 2.9 Hz, 2H), 3.61 - 3.53(m, 2H), 2.95 (s, 3H), 2.61 (dq, J = 6.1, 3.1Hz, 2H), 1.51 (d, J = 7.1 Hz,3H); LC / MS m / z = 485.2 [M+H] + .

[0426] Example 75: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-[3-(morpholine-4-carbonyl)phenyl]-6-oxo-1,6-dihydropyridine-3-carboxamide Step 1: Synthesis of (R)-3-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-oxopyridin-1(2H)-yl)benzoic acid [ka] To a solution of the compound of Example 72 (10.2 mg, 0.020 mmol) in DCM (1 mL) was added TFA (7.83 μL, 0.10 mmol). The mixture was stirred at room temperature. The mixture was concentrated under reduced pressure to give (R)-3-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-oxopyridin-1(2H)-yl)benzoic acid (crude, 10 mg, 0.022 mmol), which was used in the next step without further purification. LC / MS m / z = 446.2 [M+H] + .

[0427] Step 2: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-[3-(morpholine-4-carbonyl)phenyl]-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] A mixture of (R)-3-(5-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2-oxopyridin-1(2H)-yl)benzoic acid (10 mg, 0.022 mmol), morpholine (2.15 mg, 0.025 mmol), HATU (12.81 mg, 0.034 mmol), and DIEA (8.6 μL, 0.067 mmol) in DMF (0.1 mL) was degassed and purged with N three times, then stirred at room temperature under a N atmosphere for 3 hours. The reaction mixture was poured into water 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 residue was purified by preparative HPLC. The solvent was removed under reduced pressure to give Example 75 (0.9 mg, 7.8% yield). 1H NMR (400 MHz, MeOD) δ 8.31 (d, J = 2.7 Hz, 1H), 8.05 (dd, J = 9.6, 2.6 Hz, 1H), 7.71 -7.63 (m, 1H), 7.58 (d, J = 7.4 Hz, 3H), 7.11 (s, 1H), 7.06 (s, 1H), 6.99 (s,1H), 6.66 (d, J = 9.6 Hz, 1H), 5.14 (q, J = 7.1 Hz, 1H), 3.76 (s, 5H), 3.65 (s,3H), 3.52 (s, 2H), 1.52 (d, J = 7.1 Hz, 3H); LC / MS m / z = 515.2 [M+H] + .

[0428] Example 76: N-(1-(3-chlorophenyl)cyclopropyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide Step 1: Synthesis of 1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid [ka] To a solution of intermediate K-14 (91.3 mg, 0.37 mmol) in THF (1 mL) was added LiOH·HO (30.9 mg, 0.74 mmol) and HO (0.5 mL). The mixture was stirred at 25 °C for 3 h. The reaction mixture was adjusted to pH = 3-4 with 1 N aqueous HCl and extracted with EtOAc. The aqueous layer was filtered to give 1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (79.9 mg, 0.37 mmol, 93% yield) as a yellow solid. LC / MS (m / z) = 235.1 [M+H] + .

[0429] Step 2: Synthesis of N-(1-(3-chlorophenyl)cyclopropyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] To a solution of 1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (25 mg, 0.11 mmol) and 1-(3-chlorophenyl)cyclopropan-1-amine (15.9 μL, 0.12 mmol) in DMF (1 mL) was added EDCI (21.7 mg, 0.14 mmol), HOBt (18.9 mg, 0.14 mmol), and DIEA (55.8 μL, 0.32 mmol). The mixture was degassed and purged with N three times and then stirred at 25 °C under a N atmosphere for 1 h. The reaction mixture was partitioned between H O and EtOAc. The organic layer was separated, washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give Example 76 (9.4 mg, 22.9% yield). LC / MS m / z = 384.1 [M+H] + .

[0430] Example 77: N-[(1R)-1-(3-chlorophenyl)propyl]-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 77 (17.5 mg, yield 38.6%) was obtained in the same manner as in Example 76, except that (R)-1-(3-chlorophenyl)propan-1-amine was used instead of 1-(3-chlorophenyl)cyclopropan-1-amine. LC / MS m / z = 386.1 [M+H] + .

[0431] Example 78: N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl]-1-[3-(1-methyl-1H-pyrazol-5-yl)phenyl]-6-oxo-1,6-dihydropyridine-3-carboxamide Steps 1 and 2: Synthesis of (R)-1-(3-bromophenyl)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] The procedure was similar to that of Example 64, except that the coupling reagents used in Step 2 were changed to HOBt and EDCI, and (R)-1-(3-bromophenyl)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (20.2 mg, yield 55.3%) was obtained. LC / MS m / z = 495 [M+H] + .

[0432] Step 3: Synthesis of N-[(1R)-1-[3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl]ethyl]-1-[3-(1-methyl-1H-pyrazol-5-yl)phenyl]-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)-1-(3-bromophenyl)-N-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (13.4 mg, 0.027 mmol) in 1,4-dioxane (0.5 mL) and water (0.1 mL) was added (1-methyl-1H-pyrazol-5-yl)boronic acid (3.75 mg, 0.030 mmol), potassium carbonate (14.96 mg, 0.11 mmol), and Pd(dppf)Cl·DCM (2.21 mg, 2.71 μmol). The mixture was heated at 150 °C in a microwave oven for 10 min. The mixture was cooled to room temperature, water was added, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product. The residue was purified by preparative HPLC. The solvent was removed under reduced pressure to give Example 78 (3.7 mg, 27.5% yield). 1H NMR (400 MHz, MeOD) δ 8.35 (d, J = 2.6 Hz, 1H), 8.05 (dd, J = 9.6, 2.6 Hz, 1H), 7.73 -7.61 (m, 3H), 7.54 (dt, J = 9.1, 1.9 Hz, 2H), 7.32 (s, 1H), 7.24 (s, 1H), 7.16(s, 1H), 6.67 (dd, J = 9.6, 0.7 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 5.16 (q, J =7.1 Hz, 1H), 3.92 (s, 3H), 1.54 (d, J = 7.1 Hz, 3H); LC / MS m / z = 482.2 [M+H] + .

[0433] Example 79: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-[3-(methylamino)phenyl]-6-oxo-1,6-dihydropyridine-3-carboxamide Step 1: Synthesis of ethyl 1-[3-[tert-butoxycarbonyl(methyl)amino]phenyl]-6-oxo-pyridine-3-carboxylate [ka] A mixture of intermediate K-1 (300 mg, 931 μmol), tert-butyl N-methylcarbamate (146 mg, 1.12 mmol), Pd(dba) (85.2 mg, 93.1 μmol), Xantphos (53.8 mg, 93.1 μmol), and CsCO (758 mg, 2.33 mmol) in dioxane (6 mL) was stirred at 100 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, PE:EA = 2:1 to 5:1) to give ethyl 1-[3-[tert-butoxycarbonyl(methyl)amino]phenyl]-6-oxo-pyridine-3-carboxylate (200 mg, 57% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 8.21 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 2.4, 9.6 Hz, 1H), 7.54 -7.41 (m, 3H), 7.26 (br d, J = 7.2 Hz, 1H), 6.56 (d, J = 9.6 Hz, 1H), 4.25 (q, J= 7.2 Hz, 2H), 3.23 (s, 3H), 1.42 (s, 9H), 1.26 (t, J = 7.2 Hz, 3H).

[0434] Steps 2 and 3: Synthesis of tert-butyl N-[3-[5-[[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-pyridyl]phenyl]-N-methyl-carbamate [ka] tert-Butyl N-[3-[5-[[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-pyridyl]phenyl]-N-methyl-carbamate (150 mg, yield 76%) was obtained in a similar manner to that of Example 76. 1 H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 7.2 Hz, 1H), 8.52 (s, 1H), 8.36 (d, J = 2.4 Hz, 2H),8.22 (s, 1H), 7.97 - 7.88 (m, 1H), 7.54 - 7.48 (m, 1H), 7.46 - 7.41 (m, 2H),7.28 (d, J = 7.6 Hz, 1H), 6.54 (d, J = 9.6 Hz, 1H), 5.31 (t, J = 6.8 Hz, 1H),3.32 (s, 3H), 1.49 (d, J = 7.2 Hz, 3H), 1.42 (s, 9H).

[0435] Step 4: Synthesis of tert-butyl N-[3-[5-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-pyridyl]phenyl]-N-methyl-carbamate [ka] A mixture of tert-butyl N-methyl-N-[3-[5-[[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-pyridyl]phenyl]carbamate (100 mg, 178 μmol) and Pt-V / C (100 mg, 5% purity) in THF (1 mL) was stirred under H (15 psi) at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl N-[3-[5-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-pyridyl]phenyl]-N-methyl-carbamate (90 mg, 95% yield) as a colorless solid. MS (EI) m / z: 553.2 [M+Na] + .

[0436] Step 5: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-[3-(methylamino)phenyl]-6-oxo-pyridine-3-carboxamide [ka] To a mixture of tert-butyl N-[3-[5-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-pyridyl]phenyl]-N-methylcarbamate (50 mg, 94.2 μmol) in TFA (0.3 mL) was added DCM (1 mL) at 0° C., followed by stirring at 0° C. for 1 h. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: [water (FA)-ACN]; B%: 24% to 54%, 10 min) to give Example 79 (13.9 mg, 33% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.58 (d, J = 7.6 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.94 (dd, J =2.4, 9.6 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.77 (s, 2H), 6.70 (s, 1H), 6.65(dd, J = 1.6, 8.4 Hz, 1H), 6.57 - 6.48 (m, 3H), 6.16 - 5.37 (m, 2H), 5.01 (t, J= 7.2 Hz, 1H), 2.70 (s, 3H), 1.40 (d, J = 7.2 Hz, 3H). MS (EI) m / z: 431.1 [M+H] + .

[0437] Example 80: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-(3-methanesulfonamidophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] The compound of Example 80 (16.94 mg, yield 35%) was obtained as a white solid in the same manner as in Steps 1 to 4 of Example 79, except that methanesulfonamide was used instead of tert-butyl N-methylcarbamate in Step 1. 1H NMR (400 MHz, DMSO-d6) δ = 10.16 - 9.90 (m, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.35 (d, J = 2.4Hz, 1H), 7.97 (dd, J = 2.8, 9.6 Hz, 1H), 7.58 - 7.45 (m, 1H), 7.30 (d, J = 8.0Hz, 1H), 7.24 (t, J = 2.0 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 6.76 (s, 2H), 6.69(s, 1H), 6.53 (d, J = 9.6 Hz, 1H), 5.54 (s, 2H), 5.01 (t, J = 7.2 Hz, 1H), 3.07(s, 3H), 1.40 (d, J = 7.2 Hz, 3H); MS (EI) m / z: 495.1 [M+H] + .

[0438] Examples 81 to 88 Prepare the compounds shown in the table below in a manner similar to Steps 1-4 of Example 79, replacing tert-butyl N-methylcarbamate in Step 1 of Example 79 with a secondary amine. [Table 5] JPEG2024534804000312.jpg188149 JPEG2024534804000313.jpg117149

[0439] Example 89: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-[3-(3-methyl-2-oxo-imidazolidin-1-yl)phenyl]-6-oxo-pyridine-3-carboxamide Step 1: Synthesis of ethyl 1-[3-(3-methyl-2-oxo-imidazolidin-1-yl)phenyl]-6-oxo-pyridine-3-carboxylate [ka] To a mixture of ethyl 6-oxo-1-[3-(2-oxoimidazolidin-1-yl)phenyl]pyridine-3-carboxylate (200 mg, 611 μmol), synthesized in a similar manner to Step 1 of Example 79, in DMF (4 mL) was added NaH (36.6 mg, 916 μmol, purity 60%) at 0° C., and the mixture was stirred at 0° C. for 15 minutes. Then, MeI (130 mg, 916 μmol) was added to the mixture, and the mixture was stirred at 25° C. for 16 hours. The mixture was quenched with ice water (10 mL) and extracted with EA (3×10 mL). The combined organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse-phase HPLC (0.1% FA condition) to give ethyl 1-[3-(3-methyl-2-oxo-imidazolidin-1-yl)phenyl]-6-oxo-pyridine-3-carboxylate (150 mg, 71% yield) as a yellow solid. MS (EI) m / z: 342.1 [M+H] + .

[0440] Steps 2-4: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-[3-(3-methyl-2-oxo-imidazolidin-1-yl)phenyl]-6-oxo-pyridine-3-carboxamide [ka] The compound of Example 89 (5.97 mg, yield 41%) was obtained in the same manner as in Steps 2 to 4 of Example 79, except that the reagent for the reduction reaction in Step 4 was changed. 1H NMR (400 MHz, DMSO-d6) δ = 8.59 (d, J = 7.6 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.96 (dd, J =2.8, 9.6 Hz, 1H), 7.70 (t, J = 2.0 Hz, 1H), 7.63 (dd, J = 1.6, 8.4 Hz, 1H),7.48 (t, J = 8.0 Hz, 1H), 7.07 (dd, J = 1.2, 7.6 Hz, 1H), 6.76 (s, 2H), 6.69(s, 1H), 6.53 (d, J = 9.6 Hz, 1H), 5.54 (d, J = 7.2 Hz, 1H), 5.07 - 4.94 (m,1H), 3.86 - 3.75 (m, 2H), 3.46 (t, J = 8.0 Hz, 2H), 2.77 (s, 3H), 1.39 (d, J =7.2 Hz, 3H); MS (EI) m / z: 500.2 [M+H] + .

[0441] Example 90 and Example 91: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-{3-[((2S)-1,1,1-trifluoropropan-2-yl)amino]phenyl}-1,6-dihydropyridine-3-carboxamide and N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-{3-[((2R)-1,1,1-trifluoropropan-2-yl)amino]phenyl}-1,6-dihydropyridine-3-carboxamide Step 1: Synthesis of ethyl 6-oxo-1-[3-[(1,1,1-trifluoropropan-2-yl)amino]phenyl]dihydropyridine-3-carboxylate [ka] A mixture of 1,1,1-trifluoropropan-2-amine (510 mg, 3.41 mmol, HCl), intermediate EA (1.0 g, 3.10 mmol), RuPhos Pd G2 (241 mg, 310 μmol), and Cs2CO3 (5.06 g, 15.5 mmol) in dioxane (5 mL) was stirred at 100 °C for 16 h. Water (20 mL) was added to the mixture, and it was extracted with EA (3 × 15 mL). The combined organic layers were dried over Na2SO4. The residue was purified by reverse-phase HPLC (0.1% FA condition) to give ethyl 6-oxo-1-[3-[(1,1,1-trifluoropropan-2-yl)amino]phenyl]dihydropyridine-3-carboxylate (800 mg, 72% yield) as a yellow oil. MS (EI) m / z: 355.2 [M+H] + .

[0442] Steps 2 and 3: Synthesis of N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-[(1,1,1-trifluoropropan-2-yl)amino]phenyl]dihydropyridine-3-carboxamide [ka] N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-[(1,1,1-trifluoropropan-2-yl)amino]phenyl]dihydropyridine-3-carboxamide (140 mg, 55% yield) was obtained in a similar manner to that in Example 76. MS (EI) m / z: 543.4 [M+H] + .

[0443] Step 4: Separation of N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-[[(2S)-1,1,1-trifluoropropan-2-yl]amino]phenyl]dihydropyridine-3-carboxamide and N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-[[(2R)-1,1,1-trifluoropropan-2-yl]amino]phenyl]dihydropyridine-3-carboxamide [ka] N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-[(1,1,1-trifluoropropan-2-yl)amino]phenyl]dihydropyridine-3-carboxamide (140 mg) was purified by preparative HPLC (column: DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); mobile phase: [0.1% NH H O IPA]; B%: 25% to 25%, 2.65 min) to give one of the diastereomers, N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-[[(2S)-1,1,1-trifluoropropan-2-yl]amino]phenyl]dihydropyridine-3-carboxamide (30 mg) as a yellow solid.

[0444] N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-[(1,1,1-trifluoropropan-2-yl)amino]phenyl]dihydropyridine-3-carboxamide (140 mg) was purified by preparative HPLC (column: DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 μm); mobile phase: [0.1% NH H O IPA]; B%: 25% to 25%, 2.65 min) to give the other diastereomer, N-[(1R)-1-[3-nitro-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-[[(2R)-1,1,1-trifluoropropan-2-yl]amino]phenyl]dihydropyridine-3-carboxamide (30 mg) as a yellow solid.

[0445] Step 5: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-{3-[((2S)-1,1,1-trifluoropropan-2-yl)amino]phenyl}-1,6-dihydropyridine-3-carboxamide and N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1-{3-[((2R)-1,1,1-trifluoropropan-2-yl)amino]phenyl}-1,6-dihydropyridine-3-carboxamide [ka] The two diastereomers were reacted in the same manner as in Step 4 of Example 89 to give the compound of Example 90 (5.64 mg, yield 23%) and the compound of Example 91 (5.47 mg, yield 23%). 1H NMR(400 MHz, DMSO-d6) δ = 8.63 - 8.51 (m, 1H),8.35 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.32 - 7.18 (m, 1H), 6.87 - 6.83 (m,1H), 6.77 (s, 3H), 6.70 (s, 1H), 6.67 - 6.61 (m, 1H), 6.55 - 6.46 (m, 1H), 6.37- 6.27 (m, 1H), 5.55 (d, J = 7.6 Hz, 1H), 5.08 - 4.94 (m, 1H), 4.50 - 4.35 (m,1H), 1.39 (d, J = 6.8 Hz, 3H), 1.31 (d, J = 6.4 Hz, 3H); MS (EI) m / z: 513.2[M+H] + . 1 H NMR(400 MHz, DMSO-d6) δ = 8.63 - 8.50 (m, 1H),8.34 (d, J = 0.8 Hz, 1H), 7.98 - 7.89 (m, 1H), 7.30 - 7.21 (m, 1H), 6.84 (d, J =7.2 Hz, 1H), 6.79 - 6.73 (m, 3H), 6.69 (s, 1H), 6.64 (d, J = 7.2 Hz, 1H), 6.50(d, J = 9.6 Hz, 1H), 6.32 (d, J = 8.8 Hz, 1H), 5.54 (d, J = 6.4 Hz, 2H), 5.00(t, J = 6.4 Hz, MS (EI) m / z: 513.2 [M+H] + .

[0446] Example 92: Methyl N-[3-[5-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-pyridyl]phenyl]carbamate Step 1: Synthesis of ethyl 1-[3-(tert-butoxycarbonylamino)phenyl]-6-oxo-pyridine-3-carboxylate [ka] Ethyl 1-[3-(tert-butoxycarbonylamino)phenyl]-6-oxo-pyridine-3-carboxylate (200 mg, 35% yield) was obtained using tert-butyl N-carbamate in a manner similar to Step 1 of Example 79 as a yellow solid. MS (EI) m / z: 359.0 [M+H] + .

[0447] Step 2: Synthesis of ethyl 1-(3-aminophenyl)-6-oxo-pyridine-3-carboxylate [ka] To a mixture of ethyl 1-[3-(tert-butoxycarbonylamino)phenyl]-6-oxo-pyridine-3-carboxylate (800 mg, 1.34 mmol) in DCM (20 mL) was added TFA (600 μL) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The mixture was concentrated in vacuo. The residue was purified by reverse-phase HPLC (0.1% FA condition) to give ethyl 1-(3-aminophenyl)-6-oxo-pyridine-3-carboxylate (320 mg, 92% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ =8.15 (s, 1H), 7.87 - 7.83 (m, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.66- 6.58 (m, 1H), 6.54 - 6.49 (m, 3H), 5.42 - 5.38 (m, 2H), 4.27 - 4.21 (m, 2H),1.26 (t, J = 7.2 Hz, 3H).

[0448] Step 3: Synthesis of ethyl 1-[3-(methoxycarbonylamino)phenyl]-6-oxo-pyridine-3-carboxylate [ka] To a solution of ethyl 1-(3-aminophenyl)-6-oxo-pyridine-3-carboxylate (240 mg, 929 μmol) and TEA (470 mg, 4.65 mmol) in DCM (5 mL) was added methyl carbonochloridate (0.53 g, 5.61 mmol) at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 3 h. The reaction mixture was added to water (30 mL), then adjusted to pH 9 with Na2CO3 and extracted with DCM (3 × 50 mL). The combined organic layers were concentrated in vacuo. The residue was purified by reverse-phase HPLC (0.1% FA condition) to afford ethyl 1-[3-(methoxycarbonylamino)phenyl]-6-oxo-pyridine-3-carboxylate (130 mg, 44% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.92 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 7.96 - 8.80 (m, 1H), 7.61- 7.50 (m, 2H), 7.48 - 7.39 (m, 1H), 7.16 - 7.68 (m, 1H), 6.55 (d, J = 9.6 Hz,1H), 4.28 - 4.20 (m, 2H), 3.68 (s, 3H),1.26 (t, J = 7.2 Hz, 3H).

[0449] Steps 4-6: Synthesis of methyl N-[3-[5-[[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]carbamoyl]-2-oxo-1-pyridyl]phenyl]carbamate [ka] The compound of Example 92 (23.0 mg, yield 39%) was obtained as a white solid in the same manner as in Steps 2 to 4 of Example 89. 1H NMR (400 MHz, DMSO-d6) δ = 9.92 (s, 1H), 8.59 (d, J = 7.6 Hz, 1H), 8.39 - 8.31 (m, 1H), 8.03- 7.89 (m, 1H), 7.59 - 7.44 (m, 3H), 7.15 - 7.04 (m, 1H), 6.80 - 6.75 (m, 2H),6.69 (s, 1H), 5.59 - 5.51 (m, 2H), 5.11 - 4.92 (m, 1H), 3.71 - 3.65 (m, 3H),1.39 (d, J = 7.6 Hz, 3H); MS (EI) m / z: 475.1 [M+H] + .

[0450] Example 93: N-[(1R)-1-(3-amino-5-trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-(2-oxo-1H-imidazol-3-yl)phenyl]pyridine-3-carboxamide Step 1: Synthesis of ethyl 1-[3-(2,2-diethoxyethylcarbonylamino)phenyl]-6-oxo-pyridine-3-carboxyl(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate [ka] To a mixture of ethyl 1-(3-aminophenyl)-6-oxo-pyridine-3-carboxylate (50 mg, 193 μmol) from Step 2 of Example 92 and TEA (58.7 mg, 580 μmol) in THF (2 mL) was added triphosgene (11.4 mg, 38.7 μmol) at 0° C. for 30 minutes, followed by the addition of 2,2-diethoxyethanamine (30.9 mg, 232 μmol) and TEA (58.7 mg, 580 μmol). The reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was quenched with 1N aqueous KCO solution (5 mL), adjusted to pH 9, and extracted with EtOAc (10 mL×2). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give ethyl 1-[3-(2,2-diethoxyethylcarbonylamino)phenyl]-6-oxo-pyridine-3-carboxyl(2-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (80 mg, crude) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ = 8.88 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.80 - 7.96 (m, 1H), 7.59(s, 1H), 7.39 - 7.35 (m, 2H), 6.90 - 7.04 (m, 1H), 6.55 (d, J = 9.6 Hz, 1H),6.20 - 7.24 (m, 1H), 4.40 - 4.58 (m, 1H), 4.26 - 4.22 (m, 2H), 3.65 - 3.59 (m,2H), 3.40 - 3.58 (m, 2H), 3.10 - 3.26 (m, 2H), 1.29 - 1.24 (m, 3H), 1.15 - 1.11(m, 6H).

[0451] Step 2: Synthesis of ethyl 6-oxo-1-[3-(2-oxo-1H-imidazol-3-yl)phenyl]pyridine-3-carboxylate

Chem.

[0452] Steps 3 and 4: Synthesis of N-[(1R)-1-(3-amino-5-trifluoromethyl)phenyl]ethyl]-6-oxo-1-[3-(2-oxo-1H-imidazol-3-yl)phenyl]pyridine-3-carboxamide [ka] The compound of Example 93 (4.99 mg, yield 28%) was obtained as a white solid in the same manner as in Example 76. 1H NMR (400 MHz, CDCl3) δ = 8.35 (d, J = 2.2Hz, 1H), 8.00 - 8.10 (m, 1H), 7.86 - 7.73 (m, 2H), 7.60 - 7.68 (m, 1H), 7.30 -7.46 (m, 1H), 6.99 - 6.86 (m, 3H), 6.80 (s, 1H), 6.65 (d, J = 9.7 Hz, 1H), 6.58(d, J = 2.8 Hz, 1H), 5.00 - 5.20 (m, 1H), 1.40 - 1.60(m, 3H). MS (EI) m / z:[M+H]+ 484.1.

[0453] Example 94: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-(2,3-difluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] A solution of Intermediate C (22 mg, 0.10 mmol), Intermediate AQ (30 mg, 0.12 mmol), HOBt (32.9 mg, 0.21 mmol), EDCI (32.1 mg, 0.16 mmol), and DIPEA (42 μL, 0.24 mmol) in DMF (1 mL) was prepared. The reaction mixture was stirred at room temperature for 2 h. Water and saturated NaHCO3 solution were added to the mixture, and it was extracted with EA. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure, and the crude residue was purified by prep / LC to give Example 94 (24.7 mg, 47.3% yield). 1 H NMR (400 MHz, DMSO) δ 8.58 (d, J = 7.7 Hz, 1H), 8.38 (d, J = 2.6 Hz, 1H), 8.01 (dd, J =9.7, 2.6 Hz, 1H), 7.66 (q, J = 7.9 Hz, 1H), 7.53 - 7.38 (m, 2H), 6.77 (s, 2H),6.71 (s, 1H), 6.59 (d, J = 9.7 Hz, 1H), 5.01 (t, J = 7.2 Hz, 1H), 1.40 (d, J =7.1 Hz, 3H); LC / MS (ESI) m / z = 438.1 [M+H] + .

[0454] Examples 95 to 99 The compounds shown in the following table were prepared in a similar manner to Example 94 by using starting materials that correspond to the structure of the desired compound based on Preparation Example 43, or by replacing Intermediate C with Intermediate E. [Table 6] JPEG2024534804000329.jpg129149

[0455] Example 100: 1-(2-fluorophenyl)-N-[(1R)-1-{2'-[(methylamino)methyl]-[1,1'-biphenyl]-3-yl}ethyl]-6-oxo-1,6-dihydropyridine-3-carboxamide

[0456] Step 1: Synthesis of (R)-N-(1-(3-bromophenyl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] (R)—N-(1-(3-bromophenyl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (1.01 g, 55.3% yield) was obtained in a similar manner to Step 2 of Example 76. LC / MS m / z = 415.1 [M+H] + .

[0457] Step 2: Synthesis of 1-(2-fluorophenyl)-N-[(1R)-1-{2'-[(methylamino)methyl]-[1,1'-biphenyl]-3-yl}ethyl]-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)-N-(1-(3-bromophenyl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (50 mg, 0.12 mmol) in 1,4-dioxane (2.5 mL) and distilled water (0.5 mL) was added (2-((methylamino)methyl)phenyl)boronic acid (23.8 mg, 0.14 mmol), Pd(PPh3)4 (13.9 mg, 0.012 mmol), and K2CO3 (49.6 mg, 0.36 mmol). The reaction mixture was heated in a microwave at 150 °C for 10 minutes. The mixture was cooled, water was added, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 100 (27.8 mg, 50.7% yield). 1H NMR (500 MHz, MeOD) δ 8.27 (d, J = 2.6 Hz, 1H), 8.07 (dd, J = 9.6, 2.6 Hz, 1H), 7.57 (dd,J = 6.1, 2.9 Hz, 2H), 7.50 (dd, J = 5.9, 3.6 Hz, 4H), 7.47 (d, J = 6.6 Hz, 2H),7.40 - 7.32 (m, 5H), 7.23 (dt, J = 6.8, 2.0 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H),5.16 (q, J = 7.1 Hz, 1H), 4.18 (s, 2H), 3.98 (s, 1H), 2.53 (s, 3H), 1.57 (d, J= 7.1 Hz, 3H); LC / MS m / z = 456.2 [M+H] + .

[0458] Examples 101 to 107 The compounds shown in the table below were prepared in a similar manner to Example 100 by using the appropriate boronic acid derivative in Step 2. [Table 7] JPEG2024534804000333.jpg199149 JPEG2024534804000334.jpg60149

[0459] Example 108: 1-(2-fluorophenyl)-N-[(1R)-1-[2'-(methylamino)-[1,1'-biphenyl]-3-yl]ethyl]-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)—N-(1-(3-bromophenyl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (50 mg, 0.12 mmol) obtained from Step 1 of Example 100 in 1,4-dioxane (2.5 mL) and distilled water (0.5 mL) was added (3-((tert-butoxycarbonyl)(methyl)amino)phenyl)boronic acid (35.2 mg, 0.14 mmol), Pd(PPh) (13.9 mg, 0.012 mmol), and KCO (49.7 mg, 0.36 mmol). The reaction mixture was heated in a microwave at 150° C. for 10 minutes. The mixture was cooled, water was added, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was dissolved in DCM, and 4N HCl in dioxane (85 μL) was added thereto. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated and basified with saturated NaHCO3 solution. The aqueous layer was extracted with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The mixture was purified by preparative HPLC to give the compound of Example 108 (9.6 mg, yield 18.1%). 1 H NMR (500 MHz, MeOD) δ 8.25 (d, J = 2.6 Hz, 1H), 8.08 (dd, J = 9.6, 2.6 Hz, 1H), 7.56 (d,J = 6.4 Hz, 2H), 7.52 - 7.47 (m, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.37 (dd, J =8.5, 6.5 Hz, 3H), 7.32 (d, J = 7.9 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.86 (d,J = 7.6 Hz, 1H), 6.82 (t, J = 2.1 Hz, 1H), 6.65 (d, J = 9.6 LC / MS m / z = 442.2 [M+H] + .

[0460] Example 109: 1-(2-fluorophenyl)-N-[(1R)-1-(3-{4-[(methylamino)methyl]thiophen-2-yl}phenyl)ethyl]-6-oxo-1,6-dihydropyridine-3-carboxamide Step 1: Synthesis of (R)-1-(2-fluorophenyl)-6-oxo-N-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)—N-(1-(3-bromophenyl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (100 mg, 0.24 mmol) from Step 1 of Example 100 in 1,4-dioxane (3 mL) was added bis(pinacolato)diborane (70.9 mg, 0.72 mmol), Pd(dppf)Cl·DCM (19.7 mg, 0.024 mmol), and KOAc (70.6 mg, 0.72 mmol). The reaction mixture was heated in a microwave at 150° C. for 10 minutes. The mixture was cooled and extracted with EtOAc. The organic layer was dried over anhydrous NaSO and concentrated in vacuo to give the crude product. The product was purified by flash chromatography (0-5% MeOH in DCM) to give (R)-1-(2-fluorophenyl)-6-oxo-N-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,6-dihydropyridine-3-carboxamide (113.4 mg, 102% yield) as a brown liquid. LC / MS m / z = 463.3 [M+H] + .

[0461] Step 2: Synthesis of 1-(2-fluorophenyl)-N-[(1R)-1-(3-{4-[(methylamino)methyl]thiophen-2-yl}phenyl)ethyl]-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] The compound of Example 109 (2.3 mg, yield 3.0%) was obtained in a similar manner to Step 2 of Example 100. 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 = 462.2 [M+H] + .

[0462] Example 110: 1-(2-fluorophenyl)-N-[(1R)-(1-(3-(3-[(methylamino)methyl]thiophen-2-yl)phenyl)ethyl)]-6-oxo-1,6-dihydropyridine-3-carboxamide Step 1: Synthesis of (R)-1-(2-fluorophenyl)-N-(1-(3-(3-formylthiophen-2-yl)phenyl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] (R)-1-(2-fluorophenyl)-N-(1-(3-(3-formylthiophen-2-yl)phenyl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (295.9 mg, 92% yield) was obtained in the same manner as in Step 2 of Example 100, by using (3-formylthiophen-2-yl)boronic acid. LC / MS (m / z) = 447.1 [M+H] + .

[0463] Step 2: Synthesis of 1-(2-fluorophenyl)-N-[(1R)-(1-(3-(3-[(methylamino)methyl]thiophen-2-yl)phenyl)ethyl)]-6-oxo-1,6-dihydropyridine 3-carboxamide [ka] To a solution of (R)-1-(2-fluorophenyl)-N-(1-(3-(3-formylthiophen-2-yl)phenyl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (176.2 mg, 0.39 mmol) in EtOH (4 mL) was added methylamine hydrochloride (40.0 mg, 0.59 mmol). The reaction mixture was stirred at room temperature for 15 minutes and cooled to 0° C. Sodium triacetoxyborohydride (167 mg, 0.79 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 NaSO and concentrated under reduced pressure. The residue was purified by preparative HPLC and pTLC to give Example 110 (26 mg, 14.27% yield). 1 H NMR (500 MHz, MeOD) δ 8.26 (d, J = 2.6 Hz, 1H), 8.08 (dt, J = 9.7, 1.8 Hz, 1H), 7.56 (t,J = 6.6 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.44 (s, 1H), 7.43 - 7.38 (m, 4H),7.38 (s, 1H), 7.36 (s, 1H), 7.35 - 7.30 (m, 2H), 7.18 (d, J = 5.3 Hz, 1H), 6.65(d, J = 9.6 Hz, 1H), 5.21 (q, J = 7.1 Hz, 1H), 3.81 (s, 2H), 2.34 (s, 3H), 1.57(d, J = 7.1 Hz, 3H); LC / MS m / z = 462.2 [M+H] + .

[0464] Example 111: 1-(2-fluorophenyl)-N-[(1R)-1-(3-(2-[(methylamino)methyl]thiophen-3-yl)phenyl)ethyl]-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] Example 111 (33 mg, 13.0% yield) was obtained in a similar manner to Example 110 by using (2-formylthiophen-3-yl)boronic acid in Step 1. 1 H NMR (500 MHz, MeOD) δ 8.25 (d, J = 2.6 Hz, 1H), 8.07 (dd, J = 9.7, 2.6 Hz, 1H), 7.56(ddd, J = 7.7, 5.1, 1.8 Hz, 1H), 7.52 - 7.44 (m, 1H), 7.43 - 7.30 (m, 6H), 7.26(d, J = 7.7 Hz, 1H), 7.05 (d, J = 5.1 Hz, 1H), 6.65 (d, J = 9.7 Hz, 1H), 5.20(q, J = 7.0 Hz, 1H), 3.93 (s, 2H), 2.32 (s, 2H), 1.56 (d, J = 7.0 Hz, 3H);LC / MS m / z = 462.2 [M+H] + .

[0465] Example 112: (R)-1-(2-fluorophenyl)-N-(1-(1-(2-((methylamino)methyl)phenyl)-1H-pyrazol-3-yl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide Step 1: Synthesis of (R)—N-(1-(1H-pyrazol-3-yl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] (R)—N-(1-(1H-pyrazol-3-yl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (20.1 mg, 17.0% yield) was obtained in a similar manner to Step 2 of Example 76. LC / MS m / z = 327.7 [M+H] + .

[0466] Step 2: Synthesis of (R)-1-(2-fluorophenyl)-N-(1-(1-(2-((methylamino)methyl)phenyl)-1H-pyrazol-3-yl)ethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide [ka] To a solution of (R)—N-(1-(1H-pyrazol-3-yl)ethyl)-1-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide (20.1 mg, 0.062 mmol) in anhydrous THF (0.2 mL) was added 2-((methylamino)methyl)phenylboronic acid (12.2 mg, 0.074 mmol), Cu(OAc) (22.4 mg, 0.12 mmol), pyridine (39.7 μL, 0.49 mmol), and TEA (42.9 μL, 0.31 mmol). The reaction mixture was heated in a microwave at 140° C. for 10 minutes. The mixture was cooled to room temperature and filtered through Celite, rinsing with MeOH. The filtrate was concentrated, and the concentrate was purified by preparative HPLC to give Example 112 (1.9 mg, 6.9% yield). 1 H NMR (500 MHz, MeOD) δ 8.25 (d, J = 2.6 Hz, 1H), 8.10 (d, J = 2.6 Hz, 1H), 8.07 (dd, J =9.6, 2.6 Hz, 1H), 7.63 (ddd, J = 15.1, 7.5, 1.5 Hz, 2H), 7.62 - 7.52 (m, 2H),7.49 (qd, J = 7.5, 1.6 Hz, 2H), 7.37 (q, J = 8.6 Hz, 2H), 6.65 (d, J = 9.6 Hz,1H), 6.60 (d, J = 2.5 Hz, 1H), 5.40 - 5.31 (m, 1H), 4.13 (d, J = 3.6 Hz, 2H),2.87 (s, 3H), 1.65 (d, J = 7.2 Hz, 3H); LC / MS m / z = 446.2 [M+H] + .

[0467] Example 113: 1-(3-acetamido-4-fluoro-phenyl)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-pyridine-3-carboxamide Step 1: Synthesis of 1-(3-acetamido-4-fluoro-phenyl)-6-oxo-pyridine-3-carboxylic acid [ka] A mixture of intermediate AQ-2 (250 mg, 1.01 mmol) in AcOH (2 mL) was stirred at 70° C. for 10 minutes. AcO (514 mg, 5.04 mmol) was added to the mixture, and the mixture was stirred at 70° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give 1-(3-acetamido-4-fluoro-phenyl)-6-oxo-pyridine-3-carboxylic acid (180 mg, 61% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 2.4, 6.8Hz, 1H), 7.86 (dd, J = 2.4, 9.6 Hz, 1H), 7.38 (dd, J = 8.8, 10.4 Hz, 1H), 7.28- 7.16 (m, 1H), 6.54 (d, J = 9.6 Hz, 1H), 2.12 (s, 3H).

[0468] Steps 2 and 3: Synthesis of 1-(3-acetamido-4-fluoro-phenyl)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-pyridine-3-carboxamide [ka] Example 113 (20.3 mg, 53% yield) was obtained as a white solid in a similar manner to Steps 3 and 4 of Example 89. 1 H NMR (400 MHz, DMSO-d6) δ = 9.98 (s, 1H), 8.61 - 8.55 (m, 1H), 8.36 - 8.32 (m, 1H), 8.04 (d,J = 4.8 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.48 - 7.38 (m, 1H), 7.28 - 7.22 (m, 1H),6.88 - 6.82 (m, 1H), 6.76 (s, 1H), 6.68 (s, 1H), 6.56 - 6.52 (m, 1H), 5.58 -5.52 (m, 1H), 5.06 - 4.96 (m, 1H), 2.14 - 2.09 (m, 3H), 1.42 (d, J = 7.2 Hz,3H); MS (EI) m / z: 477.1 [M+H] + .

[0469] Example 114: 1-(3-acetamido-2-fluoro-phenyl)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-pyridine-3-carboxamide Step 1: Synthesis of methyl 1-(3-bromo-2-fluoro-phenyl)-6-oxo-pyridine-3-carboxylate [ka] Methyl 1-(3-bromo-2-fluoro-phenyl)-6-oxo-pyridine-3-carboxylate (1.89 g, 22% yield) was obtained in a similar manner to Preparative Example 43, Step 1 as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.44 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 2.4, 9.6 Hz, 1H), 7.89 -7.81 (m, 1H), 7.66 - 7.60 (m, 1H), 7.34 (dd, J = 1.2, 8.0 Hz, 1H), 6.60 (d, J =9.6 Hz, 1H), 3.78 (s, 3H).

[0470] Step 2: Synthesis of methyl 1-(3-acetamido-2-fluoro-phenyl)-6-oxo-pyridine-3-carboxylate [ka] A solution of methyl 1-(3-bromo-2-fluorophenyl)-6-oxo-pyridine-3-carboxylate (500 mg, 1.53 mmol), acetamide (226 mg, 3.83 mmol), Pd(dba) (140 mg, 153 μmol), Xantphos (88.7 mg, 153 μmol), and CsCO (1.25 g, 3.83 mmol) in dioxane (10 mL) was stirred at 100 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 to 2 / 1) to give methyl 1-(3-acetamido-2-fluoro-phenyl)-6-oxo-pyridine-3-carboxylate (380 mg, 81% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.94 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.98 - 7.86 (m, 2H), 7.32- 7.28 (m, 2H), 6.64 - 6.58 (m, 1H), 3.78 (s, 3H), 2.11 (s, 3H).

[0471] Steps 3-5: Synthesis of 1-(3-acetamido-2-fluoro-phenyl)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-pyridine-3-carboxamide [ka] The compound of Example 114 (15.4 mg, yield 47%) was obtained as a white solid in the same manner as in Steps 2 to 4 of Example 89. 1 H NMR (400 MHz, DMSO-d6) δ = 9.97 (s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H),8.08 - 7.96 (m, 2H), 7.34 (d, J = 5.6 Hz, 2H), 6.76 (s, 2H), 6.71 (s, 1H), 6.58(d, J = 9.6 Hz, 1H), 5.60 - 5.52 (m, 2H), 5.01 (t, J = 7.2 Hz, 1H), 2.12 (s,3H), 1.40 (d, J = 7.2 Hz, 3H); MS (EI) m / z: 477.1 [M+H] + .

[0472] Example 115: N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-1-cyclopentyl-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] The compound of Example 115 (9 mg, yield 51.6%) was obtained in the same manner as in Example 64. 1H NMR (400 MHz, DMSO) δ 8.52 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 9.7 Hz, 1H), 6.98 (d, J =9.7 Hz, 1H), 6.88 (s, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 5.24 (p, J = 7.7 Hz,1H), 5.09 - 5.00 (m, 1H), 1.97 (d, J = 8.9 Hz, 5H), 1.83 (t, J = 6.2 Hz, 2H),1.64 (d, J = 6.9 Hz, 2H), 1.49 (d, J = 7.0 Hz, 3H); LC / MS m / z = 395.2 [M+H] + .

[0473] Examples 116 and 117 The compounds shown in the following table were prepared in a similar manner to Example 115 by preparing the appropriate starting materials, each corresponding to the structure of the desired compound based on Preparative Example 7. [Table 8]

[0474] Example 118: 1-(1-acetylpiperidin-4-yl)-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-6-oxo-1,6-dihydropyridazine-3-carboxamide [ka] In a manner similar to Preparation Example 7 and Step 2 of Example 115, the compound of Example 118 (10 mg, 15% yield) was obtained. 1H NMR (400 MHz, DMSO) δ 8.77 (d, J = 8.5 Hz, 1H), 7.81 (dd, J = 9.7, 1.9 Hz, 1H), 7.02 (d,J = 9.7 Hz, 1H), 6.87 - 6.76 (m, 2H), 6.70 (d, J = 8.9 Hz, 2H), 5.56 (d, J =9.7 Hz, 2H), 5.11 - 5.01 (m, 1H), 4.98 (d, J = 12.5 Hz, 1H), 4.58 (d, J = 13.3Hz, 1H), 3.97 (s, 1H), 3.30 - 3.14 (m, 2H), 2.74 - 2.65 (m, 1H), 2.04 (d, J =3.9 Hz, 3H), 1.87 - 1.75 (m, 2H), 1.49 (d, J = 7.1 Hz, 3H); LC / MS m / z = 425.2[M+H] + .

[0475] Example 119 and Example 120 The compounds shown in the following table were prepared in a similar manner to Example 118 by replacing intermediate CC with the appropriate methanesulfonate compound, each corresponding to the structure of the desired compound. [Table 9]

[0476] Example 121 and Example 122: N-[(1R)-1-[5-amino-2-chloro-3-(trifluoromethyl)phenyl]ethyl]-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxamide and N-[(1S)-1-[5-amino-2-chloro-3-(trifluoromethyl)phenyl]ethyl]-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxamide

[0477] Step 1: Synthesis of 1-bromo-2-chloro-5-nitro-3-(trifluoromethyl)benzene [ka] To a solution of 1-bromo-2-chloro-3-(trifluoromethyl)benzene (8.3 g, 31.99 mmol) in HSO (15 mL) was added HNO (10.270 g, 159.72 mmol, 7.34 mL, 98% purity) at 0 °C for 40 min, followed by stirring at 20 °C for 4 h. The reaction mixture was poured onto ice water (30 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (1% EtOAc in PE) to give 1-bromo-2-chloro-5-nitro-3-(trifluoromethyl)benzene (9.3 g, 95.49% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ 8.50 (d, J = 2.8 Hz, 1 H) 8.90 (d, J = 2.8 Hz, 1 H).

[0478] Step 2: Synthesis of 1-(2-chloro-5-nitro-3-(trifluoromethyl)phenyl)ethan-1-one [ka] To a mixture of 1-bromo-2-chloro-5-nitro-3-(trifluorophenyl)benzene (3 g, 9.85 mmol), tributyl(1-ethoxyvinyl)stannane (3.340 g, 9.25 mmol, 3.12 mL) in dioxane (40 mL), TEA (1.99 g, 19.71 mmol, 2.74 mL) and Pd(PPh3)2Cl2 (691.64 mg, 985.39 μmol) were added and stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was cooled to 0 °C, treated with 4 M HCl, and stirred for 3 h. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The mixture was dried over Na2SO4, filtered, and the filtrate was concentrated. The aqueous layer was adjusted to pH 9 with aqueous NaOH, and sodium hypochlorite (100 mL) was slowly added and stirred. The product was purified by silica gel column chromatography (5% EtOAc in PE) to give 1-[2-chloro-5-nitro-3-(trifluoromethyl)phenyl]ethanone (1.47 g, 55.75% yield) as a yellow solid.1 H NMR (400MHz, DMSO-d6) δ 2.68 (m, 3 H) 8.59 (d, J = 2.8 Hz, 1 H) 8.81 (d, J = 2.8 Hz, 1 H).

[0479] Step 3: Synthesis of (R,Z)-N-(1-(2-chloro-5-nitro-3-(trifluoromethyl)phenyl)ethylidene)-2-methylpropane-2-sulfinamide [ka] To a solution of 1-[2-chloro-5-nitro-3-(trifluoromethyl)phenyl]ethanone (1.47 g, 5.49 mmol) and (R)-2-methylpropane-2-sulfinamide (665.82 mg, 5.49 mmol) in THF (35 mL) was added Ti(OEt) (3.76 g, 16.48 mmol, 3.42 mL). The reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 16 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 NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (6% EtOAc in PE) to give (NZ,R)-N-[1-[2-chloro-5-nitro-3-(trifluoromethyl)phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (1.66 g, 81.50% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 1.20 (br d, J = 17.2 Hz, 9 H) 2.50 (s, 2 H) 2.69 (s, 1 H) 8.53 (m,1 H) 8.67 (br s, 1 H).

[0480] Step 4: (R)-N-[(1R)-1-[2-chloro-5-nitro-3-(trifluoro)phenyl]ethyl]-2-methyl-propane-2-sulfinamide and (R)-N-[(1S)-1-[2-chloro-5-nitro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide [ka] To a solution of (NZ,R)-N-[1-[2-chloro-5-nitro-3-(trifluoro)phenyl]ethylidene]-2-methyl-propane-2-sulfinamide (480 mg, 1.29 mmol) in THF (12 mL) and HO (0.5 mL) was added NaBH (0.210 g, 5.55 mmol), followed by stirring at −70° C. for 4 h under a N atmosphere. The mixture was quenched with aqueous ammonium chloride at room temperature, diluted with EtOAc (50 mL), and extracted with EtOAc (50 mL × 3). The organic layer was dried over NaSO and filtered under reduced pressure to give the crude product. The product was purified by silica column chromatography (28% EtOAc in PE) to give (R)-N-[(1R)-1-[2-chloro-5-nitro-3-(trifluoro)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (70 mg, 14.50% yield, 100% ee) and (R)-N-[(1S)-1-[2-chloro-5-nitro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (100 mg, 20.72% yield, 98.76% ee) as yellow solids.

[0481] (R)_ 1 HNMR (400 MHz, DMSO-d6) δ ppm 1.12 (s, 9 H)1.44 (d, J = 6.8 Hz, 3 H) 4.95 (m, 1 H) 6.34 (d, J = 8.8 Hz, 1 H) 8.45 (d, J =2.8 Hz, 1 H) 8.84 (d, J = 2.8 Hz, 1 H); MS (ESI) m / z = 372.9 [M+H] + .LC / MS t R = 0.571 min in 5-95AB_1 min. (RP-18, 5um, 3.0*25mm), MS (ESI) m / z = 372.9 [M+H] + ;SFC (EB5303-244-P1S1): t R = IC_3_IPA_DEA_40_0.503 min in 25ML, ee = 100%. (S)_ 1HNMR (400 MHz, DMSO-d6) δ ppm 1.14 (s, 9 H)1.53 (d, J = 6.8 Hz, 3 H) 4.97 (quintet, J = 6.8 Hz, 1 H)5.92 (d, J = 6.4 Hz, 1 H) 8.44 (d, J = 2.8 Hz, 1 H) 8.73 (d, J = 2.8 Hz, 1 H);LC / MS (EB5303-244-P1A2): t R = 0.576 min in 5-95AB_1 min. (RP-18, 5um, 3.0*25mm), MS (ESI) m / z = 372.9 [M+H] + ;SFC (EB5303-244-P1S2): t R = IC_3_IPA_DEA_40_0.421 min at 25ML, ee = 98.76%.

[0482] Step 5: (1R)-1-[2-chloro-5-nitro-3-(trifluoromethyl)phenyl]ethanamine hydrochloride and (1S)-1-[2-chloro-5-nitro-3-(trifluoromethyl)phenyl]ethanamine [ka] (R)-N-[(1R)-1-[2-chloro-5-nitro-3-(trifluoromethyl)phenyl]ethyl]-2-methyl-propane-2-sulfinamide (70 mg, 187.77 μmol) was added to 4N HCl / dioxane (3 mL) and stirred at 0° C. for 1 hour. The mixture was filtered under reduced pressure to give intermediate AV-1 (50 mg, 87.28%, HCl salt) as a yellow solid. LC / MS (ESI) m / z = 268.9 [M+H] + . Intermediate AV-2 (89 mg, 210.19 μmol, 78.36% yield, HCl salt) was obtained as a yellow solid in the same manner as above. LC / MS (ESI) m / z = 269.0 [M+H] + .

[0483] Step 6-1: Synthesis of N-[(1R)-1-[2-chloro-5-nitro-3-(trifluoromethyl)phenyl]ethyl]-1-(2-fluorophenyl)-6-oxo-pyridazine-3-carboxamide [ka] ...

Claims

1. The following formula I: 【Chemical 1】 [wherein, [Chemical 2] is a single bond or a double bond; Z １ is N or CH; Z １ When Z is N, ２ and Z ３ are both CHR １ and [Chemical Formula 3] is a single bond or Z ２ and Z ３ are both CR １ and 【Chemical Formula 4】 is a double bond; Z １ When Z is CH, ２ Z is N or CR １ and when Z ３ is CR, １ Z is CR 【Chemical Formula 5】 is a double bond; or Z １ When Z is N, ２ both Z ３ and Z １ are both CR [Chemical Formula 6] is a double bond, in which case two Rs １ are optionally linked to each other to form a thiophene or pyrrole ring together with the carbon atom to which two Rs １ are attached; Each R １ is independently selected from the group consisting of 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 cycloalkyl, and the C １ -C ３ alkyl and C ３ -C ４ cycloalkyl may be optionally substituted with at least one halogen, OH, CN, C １ -C ３ alkoxy or NR ｂ R ｃ and may be optionally substituted; A is Cy １ or Cy １ -Y-Cy ２ and; Y is O, S or a direct bond; Cy １ is C ６ to C １０ aryl or a 5- or 6-membered heteroaryl containing one or two heteroatoms selected from N, O, and S; Cy １ may be optionally replaced by 1 to 3 R ２ａ ; R ２ａ is H, halogen, OH, CN, oxo, SF ５ , NR 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 【Chemical Formula 7】 is 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 alkyl; Cy ２ is C ６ to C １０ aryl, C ３ to C ６ phenyl fused with cycloalkyl or a 5- or 6-membered heteroaryl containing one or two heteroatoms selected from N, O, and S; Cy ２ may be optionally replaced by 1 to 3 R ２ｂ ; 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 alkyl substituted with alkoxy; C １ ~C ６ alkyl; C １ ~C ６ alkyl optionally interrupted by 1 to 3 oxygen atoms and / or nitrogen atoms; and C １ ~C ６ alkyl substituted with hydroxy-(C １ ~C ６ alkyl)amino-; selected from the group consisting of; 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 substituted C １ ~C ６ alkyl, -(CH ２ ) ｏ -Cy ３ or -(CH ２ ) ｏ -Cy ３ -W-Cy ４ wherein; W is NH, C(O) or a direct bond; o is an integer of 0 or 1; Cy ３ is C ３ to C ８ cycloalkyl, C ３ to C ８ cycloalkenyl, N, O and S, a 5- or 6-membered saturated or partially unsaturated heterocycloalkyl containing 1 or 2 heteroatoms selected therefrom, a bridged bicyclic C ５～１０ cycloalkyl, C ６ to C １０ aryl, N, O and S, phenyl condensed with a 5- or 6-membered cyclic group containing 1 heteroatom selected therefrom, and 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, and is selected from the group consisting of; Cy ３ may be optionally replaced by 1 to 3 R ３ａ ; R ３ａ is H, halogen, OH, CN, oxo, C １ to C ６ alkyl; halogen, OH, CN or C １ to C ６ alkyl substituted with alkoxy; C １ to C ６ alkyl; C ３ to C ６ cycloalkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkoxy, C １ to C ６ haloalkylamino, C １ to C ６ hydroxyalkylamino, (C ３ to 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 selected from the group consisting of saturated or partially unsaturated 4- to 10-membered heterocycloalkyl containing one or two 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; Cy ４ may be optionally replaced by 1 to 3 R ３ｂ ; R ３ｂ is H, deuterium, halogen, OH, CN, oxo, NR ｂ R ｃ , C １ ~C ６ alkyl, C substituted with deuterium 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 is haloalkoxy; R ｂ and R ｃ each independently is H or C １ to C ６ alkyl; R ｂ１ and R ｃ１ One of them is H or C １ ~C ６ alkyl, and R ｂ１ and R ｃ１ The other is H, C １ ~C ６ alkyl, C substituted with NR ｂ R ｃ ~C １ alkyl or C ６ substituted with C １ ~C ６ alkoxy is C １ ~C ６ alkyl]] a compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

2. In the formula I, [Chemical Formula 8] is 【Chemical Formula 9】 selected from the group consisting of, said R １ wherein the R are the same as or different from each other, the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1.

3. In the formula I, 【Chemical Formula 10】 is 【Chemical 11】 and said R １ The compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2, wherein they are the same as or different from each other.

4. Each R １ is independently selected from the group consisting of H, F, Br, Cl, I, CN, OH, OCH ３ , amino, methylamino, dimethylamino, ethylamino, acetylamino, methylsulfonylamino, ethylsulfonylamino, methyl, ethyl, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, phenoxy, benzyloxy or phenylamino, a compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3.

5. Two Rs substituted on the same ring １ The compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 4, characterized in that one of １ is H and the other is not H.

6. Two Rs substituted on the same ring １ The compound according to claim 4, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that both are H.

7. In the formula I, 【Chemical Formula 12】 is 【Chemical 13】 being as such, the compound according to Claim 2 or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

8. R' and R'' are each H or C １ -C ３ alkyl, and R' and R'' may optionally combine together with the carbon atom to which R' and R'' are attached to form C ３ -C ４ cycloalkyl, and the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1.

9. In formula I, 【Chemical Formula 14】 is 【Chemical 15】 being as such and R''' being methyl or ethyl, the compound according to Claim 8 or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

10. The compound is a compound represented by the following formula IA: 【Chemical 16】 (wherein A, Z １ , Z ２ , Z ３ and B are as defined in claim 1) being as such, the compound according to Claim 9 or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

11. A is Cy １ The compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that A is Cy.

12. Cy １ is C ６ -C １０ a 5- or 6-membered heteroaryl containing one or two heteroatoms selected from N and S, or an aryl, or the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 11.

13. A is Cy １ and Cy １ is phenyl, naphthalenyl, thiophenyl or pyridinyl, the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 12.

14. Cy １ is replaced optionally by 1 to 3 Rs ２ａ in the following ring structure: 【Chemical 17】 having any one of

15. Cy １ may be optionally substituted with 1 to 3 R ２ａ groups, and each R ２ａ is F, Cl, Br, I, OH, CN, SF ５ , -Si(CH ３ ) ３ , CH ３ SO ２ -, methyl, ethyl, propyl, isopropyl, CF ３ , CHF ２ , CH ２ F, NH ２ , CH ３ NH ２ (CH ３ ) ２ N-, methoxy, ethoxy, OCF ３ , OCHF ２ , OCH ２ F, cyclopropyl, cyclobutyl, cyclopentyl, 【Chemical Formula 18】 independently selected from the group consisting of, the compound according to Claim 11 or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

16. A is Cy １ -Y-Cy ２ The compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is as defined above.

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 to C １０ aryl, C ３ to C ５ a phenyl fused with C to C cycloalkyl or a 5- or 6-membered heteroaryl containing one or two heteroatoms selected from N and S, the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 16.

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 being as such, the compound according to Claim 17 or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

19. Y being a direct bond, the compound according to Claim 17 or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

20. Cy １ -Y-Cy ２ is R ２ａ and R ２ｂ optionally substituted by R and R with the following ring structure: 【Chemical 19】 having any one of

21. Cy １ is optionally replaced by one R ２ａ , where R ２ａ is selected from the group consisting of 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 is optionally substituted by 1 to 3 R ２ｂ wherein R ２ｂ is H, halogen, OH, CN, oxo, NR ｂ R ｃ ; C １ to C ６ alkyl; C substituted by halogen, CN, OH, NR ｂ R ｃ or C １ to C ６ alkoxy-substituted C １ to C ６ alkyl; C optionally interrupted by 1 to 3 oxygen atoms and / or nitrogen atoms １ to C ６ alkyl; and C substituted by hydroxy-(C １ to C ６ alkyl)amino- １ to C ６ alkyl, and the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 16, characterized in that it is selected from the group consisting of

22. R ２ａ The compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 21, wherein R is H.

23. R ２ａ is H; Each R ２ｂ is independently selected from the group consisting of 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 HOCH ２ H ４ NHCH ２ -, and the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 21, characterized in that it is independently selected from the group consisting of.

24. In formula I, A is the following structure 【Chemical 20】 【Chem.】 selected from, the compound according to Claim 1 or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

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 substituted C １ ~C ６ The compound according to claim 1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that it is alkyl.

26. B is -(CH ２ ) ｏ -Cy ３ wherein o is 0 or 1, and the compound according to claim 1 or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

27. Cy ３ is C ３ to C ８ cycloalkyl, C ３ to C ８ cycloalkenyl, a 6-membered saturated or partially unsaturated heterocycloalkyl containing one N, O or S, a bridged bicyclic C ５～８ cycloalkyl, C ６ to C １０ 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 1 to 3 N, and is selected from the group consisting of: the compound according to claim 26, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

28. Cy ３ is C ３ to C ６ cycloalkyl, C ３ to 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 aryl, thiophenyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, dihydroisobenzofuranyl, indolyl, indazolyl or benzotriazolyl, and a compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 27.

29. Cy ３ is replaced optionally by 1 to 3 R ３ａ in the following ring structure 【Chemical 21】 The compound according to claim 26, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, characterized by having any one of the following.

30. R ３ａ is selected from the group consisting of 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 , CH 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 The compound according to claim 26, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of

31. B is -(CH ２ ) ｏ -Cy ３ -W-Cy ４ wherein o is 0, the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1.

32. Cy ３ is C ６ -C １０ a 5- or 6-membered heteroaryl containing one or two heteroatoms selected from N or S or aryl; 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 a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and is selected from the group consisting of, a compound according to claim 31 or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

33. Cy ３ is C ６ -C １０ -aryl, and Cy ４ is a saturated or partially unsaturated 4- to 7-membered heterocycloalkyl containing one or two heteroatoms selected from N, O or S, and W is NH or C(O), a compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 32.

34. The compound according to claim 32, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that 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, and the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 32.

36. Cy ３ -W-Cy ４ is R ３ａ and R ３ｂ optionally substituted with R and R to form the following ring structure: 【Chemical 22】 The compound according to claim 31, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, characterized by having any one of the following.

37. Cy ３ may be replaced by one or two R ３ａ optionally, where R ３ａ is H, halogen, OH or CN; Cy ４ may be optionally substituted with 1 to 3 R ３ｂ groups, and R ３ｂ is H, deuterium, halogen, OH, CN, oxo, C １ to C ６ alkyl, C １ to C ６ alkyl substituted with deuterium or C １ to C ６ haloalkyl, the compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 31.

38. R ３ａ is H or F; R ３ｂ is H, F, oxo, methyl, ethyl, CHF ２ and CD ３ The compound or a solvate, stereoisomer or pharmaceutically acceptable salt thereof according to claim 37, characterized in that it is selected from the group consisting of

39. B has the following structure: H, CH ３ , 【Chemical 23】 【Chem.】 [Chemical] The compound according to claim 31, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, characterized by being any one of the following.

40. The compound is as follows: 【Chemical 24】 [Chemical] [Chemical] 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 [Chemical] [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 The compound according to claim 1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, characterized by being selected from the following.

41. A pharmaceutical composition comprising the compound according to any one of claims 1 to 40, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, as an active ingredient.

42. The pharmaceutical composition according to claim 41, characterized in that the pharmaceutical composition is for the prevention or treatment of a SOS1-mediated disease.

43. The pharmaceutical composition according to claim 42, characterized in that the SOS1-mediated disease is cancer or RAS opacity.

44. The pharmaceutical composition according to claim 43, characterized in that 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 cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma.

45. The pharmaceutical composition according to claim 43, characterized in that the RAS opacity is selected from the group consisting of neurofibromatosis type 1, Noonan syndrome, Leopard syndrome, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, CFC syndrome (heart-face-skin syndrome), Legius syndrome and hereditary gingival fibromatosis.

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