TYK2 inhibitor and use therof

Abstract

The present invention relates to: a compound represented by chemical formula 1 according to the present invention, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition comprising same. The compound or the pharmaceutically acceptable salt thereof according to the present invention can be effectively used for preventing, alleviating, or treating TYK2-related diseases.

Description

TYK2 inhibitors and uses thereof

[0001] The present invention relates to pyrrolopyridine and pyrrolopyrimidine compounds useful for modulating the activity of tyrosine kinase 2 (TYK2), and to a method for preparing the same. The present invention also relates to their use in the treatment of diseases mediated by tyrosine kinase 2, particularly autoimmune diseases, inflammatory diseases, and cancer.

[0002]

[0003] Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase that, together with Janus kinases 1, 2, and 3, constitutes the Janus kinase (JAK) family. The JAK family forms dimers in various combinations depending on the cytokine that binds to the receptor domain of the cell membrane, and regulates the activity of immune cells through signal transducer and activator of transcription (STAT) (Prior art documents 1 and 2). That is, JAK family dimers activate STAT, and the activated STAT enters the nucleus and promotes the production of new cytokines, thereby inducing immune cell activity.

[0004] TYK2 is particularly activated by interleukin-12, interleukin-23, and type 1 and type 3 interferons, which are inflammatory cytokines that are major causes of various autoimmune diseases, including psoriasis (Prior Art Document 3). Therefore, TYK2 activation causes various diseases. The results of several studies using TYK2-deficient mice support this. For example, in an experiment in which psoriasis was induced by IL-23, TYK2-deficient mice showed a reduced skin inflammatory response (Prior Art Document 4). Furthermore, TYK2-deficient mice showed resistance in models of colitis and multiple sclerosis (Prior Art Documents 5, 6). These findings suggest the importance of the TYK2 mechanism in autoimmune diseases.

[0005] TYK2 is known to cause or worsen various autoimmune diseases, including: That is, TYK2 is associated with various types of psoriasis (Plaque Psoriasis, Scalp Psoriasis, Nail Psoriasis, Palmoplantar Pustulosis), Psoriatic Arthritis, Various Forms of Lupus Erythematosus (Systemic Lupus Erythematosus, Discoid Lupus Erythematosus, Subacute Cutaneous Lupus Erythematosus), Lupus Nephritis, Ulcerative Colitis, Crohn's Disease, Alopecia Areata, Ankylosing Spondylitis, Multiple Sclerosis, Sjogren's Syndrome, Type 1 Diabetes, Temporal Arteritis, Tendonitis, Dermatomyositis, Polymyositis It is highly correlated with the development of polymyositis, eukocyte adhesion deficiency, uveitis, celiac disease, adenomatous polyp, lichen planus, hidradenitis supprativa, acute myeloid leukemia (AML), and COVID19.

[0006] Accordingly, the inventors of the present invention completed the present invention by studying a novel compound that can act as a TYK2 inhibitor and proving that it can be usefully used for various autoimmune diseases, inflammatory diseases, or cancer.

[0007] [Prior Art Literature]

[0008] 1. O'Shea, J.J., & Plenge, R. (2012). JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity, 36(4), 542-550.

[0009] 2. Teng, M. W. L., Bowman, E. P., McElwee, J. J., Smyth, M. J., Casanova, J.-L., Cooper, A. M., & Cua, D. J. (2015). IL-12 and IL-23 cytokines: From discovery to targeted therapies for immune-mediated inflammatory diseases. Nature Medicine, 21(7), 719-729.

[0010] 3. Garrido-Trigo, A., & Salas, A. Molecular Structure and Function of Janus Kinases: Implications for the Development of Inhibitors. (2020). Journal of Crohn’s & Colitis. 14(Supplement_2), S713-S724.

[0011] 4. Ishizaki, M., Muromoto, R., Akimoto, T., Sekine, Y., Kon, S., Diwan, M., Maeda, H., Togi, S., Shimoda, K., Oritani, K., & Matsuda, T. (2014). Tyk2 is a therapeutic target for psoriasis-like skin inflammation. International Immunology, 26(5):257-267.

[0012] 5. Hainzl, E., Stockinger, S., Rauch, I., Heider, S., Berry, D., Lassnig, C., Schwab, C., Rosebrock, F., Milinovich, G., Schlederer, M., Wagner, M., Schleper, C., Loy, A., Urich, T., Kenner, L., Han, X., Decker, T., Strobl, B., & M?ller, M., (2015). Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis. Journal of Immunology, 195(10), 5011-24.

[0013] 6. Oyamada, A., Ikebe, H., Itsumi, M., Saiwai, H., Okada, S., Shimoda, K., Iwakura, Y., Nakayama, K.I., Iwamoto, Y., Yoshikai, Y., & Yamada, H., (2009). Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis. Journal of Immunology, 183(11), 7539-7546.

[0014] 7. Lupardus, P. J., Ultsch, M., Wallweber, H., Bir Kohli, P., Johnson, A. R., & Eigenbrot, C. (2014). Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proceedings of the National Academy of Sciences of the United States of America, 111(22), 8025-8030.

[0015]

[0016] The purpose of the present invention is to provide a novel compound of the following chemical formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, which can be usefully used for the prevention, improvement, or treatment of TYK2-related diseases.

[0017] In addition, an object of the present invention is to provide a pharmaceutical composition for preventing, improving or treating a TYK2-related disease, which comprises a compound of the above chemical formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0018] Another object of the present invention is to provide a use of the compound for the manufacture of a medicament for preventing, improving or treating a TYK2-related disease.

[0019] Another object of the present invention is to provide a method for preventing, improving or treating a TYK2-related disease by administering the compound.

[0020]

[0021] Hereinafter, the present invention will be described in detail.

[0022]

[0023] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention pertains. Furthermore, numerical values ​​described herein are considered to include the meaning of "about" unless explicitly stated otherwise. All publications and other references mentioned herein are incorporated herein by reference in their entirety.

[0024]

[0025] The definitions of residues used in this specification are described below. In addition, if a residue is not separately defined, it is used in the sense generally understood by those skilled in the art.

[0026] The term "independently" as used herein means that when more than one substituent is selected from a plurality of possible substituents, these substituents may be the same or different from each other.

[0027] The term “optionally substituted” or “substituted” as used herein refers to the replacement of one or more hydrogen atoms with a monovalent or divalent radical. Suitable substituents include, for example, deutero, hydroxy, nitro, amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, lower alkyl, halo-lower alkyl, lower alkylamino, halo-lower alkylamino, lower alkoxy, halo-lower alkoxy, lower alkoxyalkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like. When the substituted substituent comprises a straight chain group, the substitution may occur within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, etc.) or at the chain terminus (e.g., 2-hydroxyethyl, 3-cyanopropyl, etc.). The substituted substituent may be a straight chain, branched chain, or cyclic arrangement of covalently bonded carbons or heteroatoms. It is to be understood that the above definition is not intended to encompass impermissible substitution patterns (e.g., a methyl substituted with five fluoro groups, or a halogen atom substituted with another halogen atom). Such impermissible substitution patterns are well known to those skilled in the art.

[0028] As used herein, the terms “halo,” “halogen,” and “halide(s)” include fluoro, chloro, bromo, and iodo.

[0029] As used herein, "alkyl" refers to an aliphatic hydrocarbon radical, including both linear and branched hydrocarbon radicals. For example, C1-C6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms and can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. For example, alkyl is C1- 10 Alkyl, preferably C1-6 alkyl, C1-4 alkyl, more preferably C1-3 alkyl.

[0030] The term "haloalkyl" as used herein means an alkyl group substituted with one or more, for example, 1 to 3, 1 to 4, halogen atoms, wherein said alkyl group is defined as above. "Halo" represents F, Cl, Br, or I, and the term is used interchangeably with the term "halogen." For example, haloalkyl means fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, and the like.

[0031] The term "alkenyl" as used herein refers to a hydrocarbon radical derived from a saturated alkyl having at least one double bond. Alkenyl can be in the E or Z configuration. For example, alkenyl is C2- 10 Alkenyl, preferably C2-6 alkenyl, C2-4 alkenyl, more preferably C2-3 alkenyl.

[0032] The term "alkynyl" as used herein refers to a hydrocarbon radical derived from a saturated alkyl having at least one triple bond. For example, alkynyl is C2- 10 Alkynyl, preferably C2-6 alkynyl, C2-4 alkynyl, more preferably C2-3 alkynyl.

[0033] The term "alkoxy" as used herein refers to an -O-alkyl or alkyl-O- group, wherein the alkyl group is defined as above. For example, it can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

[0034] The term “hydroxy” or “hydroxyl” as used herein, alone or in combination with other terms, means -OH.

[0035] The term “amino” as used herein means -NH2.

[0036] The term "cycloalkyl" as used herein refers to a cyclic alkyl which may be substituted or unsubstituted, for example, C3- 20 Cycloalkyl refers to a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms. A cycloalkyl group can be monocyclic or polycyclic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Preferably, the cycloalkyl can be C3-8 cycloalkyl or C3-6 cycloalkyl.

[0037] The term "cycloalkenyl" as used herein refers to a group which refers to a cyclic alkene derived from a saturated cycloalkyl having one double bond. The cycloalkenyl group can be monocyclic or polycyclic. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Preferably, the cycloalkenyl can be C3-8 cycloalkenyl or C3-6 cycloalkenyl.

[0038] The term "aryl" as used herein refers to an aromatic ring having from 6 to 20 carbon atoms (C6-) derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring. 20) refers to a monovalent aromatic hydrocarbon having an aromatic ring fused to a saturated or partially unsaturated ring. Aryl may include a bicyclic radical containing an aromatic ring fused to a saturated or partially unsaturated ring. Exemplary aryl groups may include radicals derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, indenyl, indanyl, and the like. As a specific example, aryl is C6- 12 Aryl, preferably C6- 10 It means aryl.

[0039] As used herein, "heterocycle" refers to an aromatic, saturated or partially unsaturated mono-, bi- or poly-cyclic system containing the specified number of ring atoms, and including one or more heteroatoms selected from N, O and S. The ring members, wherein the heterocyclic ring, may be connected to the base molecule via ring atoms (which may be C or N). The bicyclic system may be connected by 1,1-fused (spiro), 1,2-fused (fused) or 1,>2-fused (bridgehead). Preferably, the 1,1-fused (spiro) may be, but is not limited to, oxaspiro[3.3]heptanyl, oxaspiro[3.4]octanyl, azaspiro[3.3]heptanyl, azaspiro[3.4]octanyl, and the like.

[0040] As used herein, "heteroaryl" refers to a monovalent or divalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon containing one or more, preferably 1 to 4, 1 to 3 or 1 to 2, heteroatoms selected from N, O and S. Examples of heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxazole, 3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indolyl, and the like. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, furopyridinyl, and similar groups thereof. Unless otherwise defined, heteroaryl is a 4-12 membered heteroaryl, preferably a 4-10 membered heteroaryl, and more preferably a 4-7 membered heteroaryl.

[0041] As used herein, "heterocycloalkyl" refers to a monocyclic, bicyclic, tricyclic or higher cyclic alkyl having 3 to 10 carbon ring members containing one or more heteroatoms selected from N, O and S, for example 1 to 4, 1 to 3, or 1 to 2. In addition, the heterocycle according to the present invention may also be a fused or bridged heterocycloalkyl. Examples of heterocycloalkyl include azetidinyl, oxetanyl, tetrahydro, tetrahydrofuranyl, pyrrolidinyl, imidazolinyl, oxazolinyl, oxazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrazolopyridinyl, morpholinyl, indolinyl, azethiomorpholinyl, and the like.

[0042] Attachment of a heterocycloalkyl substituent can occur via a carbon atom or a heteroatom. The heterocycloalkyl group can be optionally substituted with one or more suitable groups via one or more of the aforementioned groups. Unless otherwise defined, heterocycloalkyl refers to a 4 to 12-membered heterocycloalkyl, preferably a 4 to 10-membered heterocycloalkyl, and more preferably a 4 to 7-membered heterocycloalkyl.

[0043] The above cyclic substituents (e.g., cycloalkyl, cycloalkenyl, aryl, heterocycle, heteroaryl, heterocycloalkyl, etc.) may be unsubstituted or substituted.

[0044]

[0045] The compound according to the present invention and its pharmaceutically acceptable salt have TYK2 inhibitory activity with superior cell activity and enzyme selectivity than the existing patented compound compared to the existing TYK2 inhibitor, and thus can be usefully used for the prevention, improvement or treatment of TYK2-related diseases, specifically, autoimmune diseases, inflammatory diseases, cancer or neurodegenerative diseases.

[0046] compound

[0047] To solve the above problem, the present invention provides a compound represented by the following chemical formula 1, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0048]

[0049] [Chemical Formula 1]

[0050]

[0051] In the above formula,

[0052] A1, A2, A3, A4 and A5 are each independently C, CH, CH2 or N;

[0053] The dotted line indicates the presence or absence of a bond, provided that the ring containing the dotted line is aromatic;

[0054] R1 is C1-C 10 Alkyl, C1-C 10 Haloalkyl, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl, wherein the C1-C 10 Alkyl, C1-C 10 Haloalkyl, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl is unsubstituted or substituted with oxo (=O), halo, C1-C 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 It may be substituted with one or more, preferably 1 to 4, substituents selected from the group consisting of haloalkyl;

[0055] R2 is H, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, OR' or NR'R", and the C1-C 10 Alkyl, C1-C 10 Alkoxy or 4-12 membered heterocycloalkyl is unsubstituted or substituted with halo, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 AlkoxyC1-C 10 Alkyl, 4-12 membered heterocycloalkyl, C6-C 10 It may be substituted with one or more, preferably 1 to 4, substituents selected from the group consisting of aryl and C3-C8 cycloalkyl,

[0056] At this time, R' and R” are each independently H, C1-C 10 Alkyl, and at this time, the above C1-C 10 Alkyl is unsubstituted or substituted with halo, cyano, 4-12 membered heterocycloalkyl, C6-C 10 Aryl, C3-C8 cycloalkyl and C1-C 10 which may be substituted with one or more, preferably 1 to 4, substituents selected from the group consisting of alkoxy, or

[0057] R' and R" together with N in the above NR'R" can form a 4- to 12-membered heterocycloalkyl, wherein the 4- to 12-membered heterocycloalkyl is unsubstituted or substituted with halo, C1-C 10 Alkoxy, or C1-C 10 AlkoxyC1-C 10 may be substituted with alkyl;

[0058] R3 is H, C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C2-C 10 Alkenyl, C3-C8 cycloalkyl, -C1-C 10Alkyl-C3-C8cycloalkyl, -C(=O)-C3-C8cycloalkyl, C3-C8cycloalkenyl, 4-12 membered heterocycloalkyl, or -C1-C 10 Alkyl-4-12 membered heterocycloalkyl, wherein the C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C2-C 10 Alkenyl, C3-C8 cycloalkyl, -C1-C 10 Alkyl-C3-C8cycloalkyl, -C(=O)-C3-C8cycloalkyl, C3-C8cycloalkenyl, 4-12 membered heterocycloalkyl, or -C1-C 10 Alkyl-4-12 membered heterocycloalkyl is unsubstituted or substituted with halo, cyano, oxo, C1-C 10 Alkyl, C2-C 10 which may be substituted with one or more, preferably 1 to 4, substituents selected from the group consisting of alkenyl, C1-C6 alkoxy, C3-C8 cycloalkyl which is unsubstituted or substituted with 1 to 3 halo groups, and 4-12 membered heterocycloalkyl;

[0059] R4 is C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, or amino, wherein the C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, or amino, is unsubstituted, or substituted with hydroxy and C1-C 10 It may be substituted with one or more, preferably 1 to 4, substituents selected from the group consisting of alkyl;

[0060] R5 is H, halo, nitro, cyano, amino, hydroxy, -C(=O)R”', -CO(=O)R”', -N(R”')2, -C(=O)NR”', -SO2R”', C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C2-C 10Alkenyl, C2-C 10 Alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C6-C 10 Aryl C1-C 10 Alkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkylC1-C 10 Alkyl, 4-12 membered heteroaryl or 4-12 membered heteroarylC1-C 10 Alkyl, and at this time, the above C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C6-C 10 Aryl C1-C 10 Alkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkylC1-C 10 Alkyl, 4-12 membered heteroaryl or 4-12 membered heteroarylC1-C 10 Alkyl is unsubstituted or substituted with halo, cyano, nitro, amino, hydroxy, C1-C 10 Alkyl, C2-C 10 Alkenyl. C1-C 10 Alkoxy, C6-C 10 It may be substituted with one or more, preferably 1 to 4, substituents selected from the group consisting of aryl, 4-12 membered heterocycloalkyl, 4-12 membered heteroaryl and C3-C8 cycloalkyl,

[0061] The above R”’ is H, halo, C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C8 cycloalkyl, C6-C10 Aryl, C6-C 10 Aryl C1-C 10 Alkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkylC1-C 10 Alkyl, 4-12 membered heteroaryl or 4-12 membered heteroarylC1-C 10 It could be an alkyl.

[0062]

[0063] Also, in one specific aspect of the present invention,

[0064] R1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl may be unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of oxo, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

[0065] In a more specific embodiment, the C3-C6 cycloalkyl of R1 can be cyclobutyl, cyclopentyl or cyclohexyl, and the 4- to 10-membered heterocycloalkyl can be oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

[0066] In a more specific embodiment, the C1-C6 alkyl of R1 can be methyl, ethyl, propyl, isopropyl, butyl, t-butyl.

[0067] In a more specific aspect, the above C1-C of R1 10 Alkyl, C1-C 10 Haloalkyl, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl may be unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, fluoro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, and methoxy.

[0068]

[0069] In a more specific embodiment, R1 may be selected from the following groups:

[0070] .

[0071]

[0072] Also, in one specific aspect of the present invention,

[0073] R2 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl, OR' or NR'R", wherein said C1-C6 alkyl, C1-C6 alkoxy or 4-10 membered heterocycloalkyl is unsubstituted or substituted with fluoro, chloro, bromo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkyl, 4-10 membered heterocycloalkyl, C6-C 10 which may be substituted with 1 to 4 substituents selected from the group consisting of aryl and C3-C6 cycloalkyl,

[0074] At this time, R' and R" are each independently H, C1-C6 alkyl, and at this time, the C1-C6 alkyl is unsubstituted or fluoro, chloro, bromo, cyano, 4-10 membered heterocycloalkyl, C6-C 10 It may be substituted with 1 to 4 substituents selected from the group consisting of aryl, C3-C6 cycloalkyl, and C1-C6 alkoxy.

[0075] Alternatively, R' and R" together with N in the above NR'R" may form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl may be unsubstituted or substituted with fluoro, chloro, bromo, C1-C6alkoxy, or C1-C6alkoxyC1-C6alkyl.

[0076] In a more specific embodiment, R2 may be selected from the following groups:

[0077] .

[0078] Also, in one specific aspect of the present invention,

[0079] R3 is H, C1-C6 alkyl, C1-C6 deuteroalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, -C1-C6 alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-10 membered heterocycloalkyl, or -C1-C6 alkyl-4-10 membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 deuteroalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, -C1-C6 alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-10 membered heterocycloalkyl, or -C1-C6 alkyl-4-10 membered heterocycloalkyl is, It may be unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of fluoro, chloro, bromo, cyano, oxo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C8 cycloalkyl which is unsubstituted or substituted with 1 to 3 halo groups and 4-10 membered heterocycloalkyl.

[0080] In a more specific embodiment, R3 may be selected from the following groups:

[0081] .

[0082]

[0083] In one specific embodiment of the present invention,

[0084] R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, or amino, wherein the C1-C6 alkyl, C1-C6 deuteroalkyl, or amino may be unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of hydroxy and C1-C6 alkyl.

[0085] In a more specific embodiment, R4 is CH3, CD3, CH2OH, NH2, or NHCH3.

[0086]

[0087] In one specific embodiment of the present invention,

[0088] R5 is H, halo, nitro, cyano, amino, hydroxy, -C(=O)R"', -CO(=O)R"', -N(R"')2, -C(=O)NR"', -SO2R"', C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C6-C 10 ArylC1-C6alkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylC1-C6alkyl, 4-10 membered heteroaryl or 4-10 membered heteroarylC1-C6alkyl, wherein the C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 10 Aryl, C6-C 10 ArylC1-C6alkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylC1-C6alkyl, 4-10 membered heteroaryl or 4-10 membered heteroarylC1-C6alkyl is unsubstituted or substituted with halo, cyano, nitro, amino, hydroxy, C1-C6alkyl, C2-C6alkenyl. C1-C6alkoxy, C6-C 10 which may be substituted with 1 to 4 substituents selected from the group consisting of aryl, 4-10 membered heterocycloalkyl, 4-10 membered heteroaryl and C3-C6 cycloalkyl,

[0089] The above R”’ is H, halo, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C6-C 10It may be arylC1-C6alkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylC1-C6alkyl, 4-10 membered heteroaryl or 4-10 membered heteroarylC1-C6alkyl.

[0090]

[0091] In a specific embodiment of the present invention, the heterocycloalkyl or heteroaryl may contain one or more heteroatoms, preferably 1 to 4, more preferably 1 to 3. The heteroatoms may be selected from the group consisting of N, O, and S.

[0092]

[0093] In a specific embodiment, the compounds of formula 1 according to the present invention may be one or more selected from the group consisting of compounds 1 to 117 below, but are not limited thereto.

[0094]

[0095] Compound 1: N-(1-methyl-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0096] Compound 2: N-(1-(3-cyanocyclobutyl)-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0097] Compound 3: N-(1-methyl-3-(1-(3-methyloxetan-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0098] Compound 4: 1-(1-methyl-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea,

[0099] Compound 5: N-(1-(3-cyanocyclobutyl)-3-(5-methyl-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0100] Compound 6: N-(1-(3-cyanocyclobutyl)-3-(1-(3-ethyltetrahydrofuran-3-yl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0101] Compound 7: 1-(3-(1-(3-ethyltetrahydrofuran-3-yl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea,

[0102] Compound 8: N-(1-(3-cyanocyclobutyl)-3-(5-cyclopropyl-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0103] Compound 9: N-(1-(3-cyanocyclobutyl)-3-(5-ethoxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0104] Compound 10: N-(1-(3-cyanocyclobutyl)-3-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0105] Compound 11: 1-(3-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea,

[0106] Compound 12: N-(1-(3-cyanocyclobutyl)-3-(5-cyclopropyl-6-oxo-1-(3-oxocyclobutyl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0107] Compound 13: N-(1-(3-cyanocyclobutyl)-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0108] Compound 14: 1-(1-methyl-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea,

[0109] Compound 15: N-(3-methyl-1-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide,

[0110] Compound 16: N-(5-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide,

[0111] Compound 17: N-(3-(5-(3-methoxyazetidin-1-yl)-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0112] Compound 18: N-(3-(1-(1-methoxy-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0113] Compound 19: N-(3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0114] Compound 20: N-(3-(1-isopropyl-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0115] Compound 21: N-(1-cyclopropyl-3-(1-isopropyl-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0116] Compound 22: N-(1-(3-cyanocyclobutyl)-3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0117] Compound 23: N-(3-(1-cyclobutyl-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0118] Compound 24: N-(3-(1-cyclobutyl-5-(3-(methoxymethyl)azetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0119] Compound 25: N-(3-(5-(isopentyloxy)-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0120] Compound 26: N-(3-(1-isopropyl-6-oxo-5-(2,2,2-trifluoroethoxy)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0121] Compound 27: N-(3-(5-(benzyloxy)-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0122] Compound 28: N-(3-(1-(tert-butyl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0123] Compound 29: N-(3-(1-(tert-butyl)-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0124] Compound 30: N-(3-(5-isobutoxy-1-(1-methylcyclopentyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0125] Compound 31: N-(3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclopentyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0126] Compound 32: N-(3-(5-isobutoxy-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0127] Compound 33: N-(1-cyclobutyl-3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0128] Compound 34: 1-(3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea,

[0129] Compound 35: 1-(1-cyclobutyl-3-(5-isobutoxy-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea,

[0130] Compound 36: N-(1-cyclobutyl-3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0131] Compound 37: 1-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea,

[0132] Compound 38: 1-(1-cyclobutyl-3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea,

[0133] Compound 39: N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0134] Compound 40: N-(3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0135] Compound 41: N-(1-cyclobutyl-3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0136] Compound 42: (S)-N-(3-(5-(3-methoxypyrrolidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0137] Compound 43: (S)-N-(1-cyclobutyl-3-(5-(3-methoxypyrrolidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0138] Compound 44: N-(1-cyclobutyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0139] Compound 45: N-(1-methyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0140] Compound 46: N-(1-methyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0141] Compound 47: N-(3-(5-(cyanomethoxy)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0142] Compound 48: N-(1-methyl-3-(1-(1-methylcyclobutyl)-5-(oxetan-3-ylmethoxy)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0143] Compound 49: N-(1-cyclopropyl-3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0144] Compound 50: (R)-N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0145] Compound 51: N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0146] Compound 52: N-(1-Cyclopropyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0147] Compound 53: N-(1-Cyclopropyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0148] Compound 54: (S)-N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0149] Compound 55: N-(3-(5-(cyclobutylmethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0150] Compound 56: N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0151] Compound 57: (R)-N-(3-(1-(1-ethylcyclobutyl)-5-(2-methoxypropoxy)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0152] Compound 58: (S)-N-(1-Cyclopropyl-3-(6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0153] Compound 59: N-(3-(1-(3,3-difluorobutan-2-yl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0154] Compound 60: N-(3-(1-(1-ethylcyclobutyl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0155] Compound 61: (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0156] Compound 62: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0157] Compound 63: N-(1-((1S,3R)-3-cyanocyclobutyl)-3-(5-isobutoxy-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0158] Compound 64: (S)-N-(1-Cyclopropyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0159] Compound 65: N-(1-Cyclopropyl-3-(5-((R)-2-methoxypropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0160] Compound 66: (S)-N-(1-Cyclopropyl-3-(5-(2-methoxyethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0161] Compound 67: (S)-N-(3-(5-(3,3-difluoropyrrolidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0162] Compound 68: N-(1-((1S,3R)-3-cyanocyclobutyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0163] Compound 69: (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3,

[0164] Compound 70: (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0165] Compound 71: (S)-N-(1-Cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0166] Compound 72: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3,

[0167] Compound 73: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(methyl-d3)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0168] Compound 74: (S)-N-(1-Cyclopropyl-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0169] Compound 75: (S)-N-(3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0170] Compound 76: (S)-N-(1-ethyl-3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0171] Compound 77: (S)-N-(1-Cyclopropyl-3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0172] Compound 78: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0173] Compound 79: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0174] Compound 80: (S)-N-(1-(cyclopropylmethyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0175] Compound 81: (S)-N-(1-((3,3-difluorocyclobutyl)methyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0176] Compound 82: (S)-N-(1-(2-fluoro-2-methylpropyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2 -yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0177] Compound 83: (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-methylallyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0178] Compound 84: (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0179] Compound 85: (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0180] Compound 86: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0181] Compound 87: (S)-N-(1-(2-cyanoethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0182] Compound 88: (S)-N-(1-(3-cyanopropyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0183] Compound 89: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3-oxocyclobutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0184] Compound 90: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-((3-methyloxetan-3-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0185] Compound 91: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-morpholinoethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0186] Compound 92: (S)-N-(1-(cyclopropylmethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0187] Compound 93: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(oxetan-3-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0188] Compound 94: N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0189] Compound 95: (S)-N-(1-(6,6-difluorospiro[3.3]heptan-2-yl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0190] Compound 96: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0191] Compound 97: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(7-oxaspiro[3.5]nonan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0192] Compound 98: (S)-N-(1-(cyclopropanecarbonyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0193] Compound 99: (S)-N-(1-(2,2-difluoroethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0194] Compound 100: N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3-fluorocyclobut-2-en-1-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0195] Compound 101: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0196] Compound 102: (S)-N-(1-ethyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0197] Compound 103: (S)-N-(3-(5-(2-Fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0198] Compound 104: (S)-N-(1-methyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0199] Compound 105: (S)-N-(1-ethyl-3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0200] Compound 106: (S)-N-(1-ethyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0201] Compound 107: (S)-N-(1-Cyclopropyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0202] Compound 108: (S)-N-(1-ethyl-3-(5-(3-fluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0203] Compound 109: (S)-N-(3-(5-(3-fluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0204] Compound 110: (S)-N-(1-Cyclopropyl-3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0205] Compound 111: N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0206] Compound 112: N-(1-Cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0207] Compound 113: (R)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0208] Compound 114: (R)-N-(1-Cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0209] Compound 115: (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide,

[0210] Compound 116: (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetamide, and

[0211] Compound 117: (S)-1-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea.

[0212] Unless otherwise specified, the chemical formulas or names given in the specification and claims encompass tautomers and all stereoisomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or mixtures of any of the above in which isomers and enantiomers are present, and pharmaceutically acceptable salts thereof and salts thereof, including solvates and hydrates of the free compounds or hydrates including solvates and hydrates of salts of the compounds.

[0213] In one embodiment, the compounds of the present invention may exist in the form of pharmaceutically acceptable salts. Useful salts include acid addition salts formed with pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound, which is relatively non-toxic and harmless to the patient, and which has an effective effect at a concentration that does not diminish the beneficial effects of the compound according to the present invention due to side effects caused by the salt.

[0214] Acid addition salts are prepared by conventional methods, for example, by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water can be heated, and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered off with suction.

[0215] At this time, organic acids and inorganic acids can be used as free acids, and inorganic acids such as hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid can be used, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, and hydroiodic acid can be used, but are not limited thereto.

[0216] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are particularly suitable for pharmaceutical purposes, but are not limited thereto. Furthermore, the corresponding silver salt can be prepared by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0217] Pharmaceutically acceptable salts of the compounds of the present invention include salts of acidic or basic groups that may be present in the compounds described in Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, and may be prepared by methods for preparing salts known in the art. In one specific embodiment, the pharmaceutically acceptable salt of the compounds of the present invention may be hydrochloride.

[0218] As a salt of the compound described in the above chemical formula 1 of the present invention, any salt of the compound described in the above chemical formula 1 that is pharmaceutically acceptable and exhibits pharmacological activity equivalent to that of the compound described in the above chemical formula 1 may be used without limitation.

[0219] In addition, the compound described in the above formula 1 according to the present invention includes, without limitation, not only its pharmaceutically acceptable salts but also solvates such as possible hydrates that can be prepared therefrom and all possible stereoisomers. All stereoisomers of the present invention, including enantiomeric forms and diastereomeric forms (e.g., those that can exist due to the asymmetric carbons in various substituents), are included in the scope of the present invention. Individual stereoisomers of the compounds of the present invention may be, for example, substantially free of other isomers (e.g., as pure or substantially pure optical isomers having a specific activity), or may be, for example, racemates or mixed with all other or other selected stereoisomers. The chiral center of the compounds of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendation. The racemic forms may be analyzed by physical methods such as separation by chiral column chromatography or separation or crystallization of diastereomeric derivatives, fractional shape crystallization. Individual optical isomers can be obtained from the racemate by any suitable method, including, but not limited to, salt formation with an optically active acid followed by crystallization.

[0220] Solvates and stereoisomers of the compound of the above formula 1 can be prepared from the compound using methods known in the art.

[0221] Furthermore, the compound of formula 1 according to the present invention can be prepared in crystalline or amorphous form, and when prepared in crystalline form, can be optionally hydrated or solvated. The present invention may include not only stoichiometric hydrates of the compound of formula 1 described above, but also compounds containing various amounts of water. The solvates of the compound of formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

[0222]

[0223] In a specific embodiment according to the present invention, the activity of TYK2 JH2, JAK1 JH1, JAK2 JH1, JAK3 JH1, and TYK2 JH1 enzymes was evaluated for the compound represented by chemical formula 1 according to the present invention, and excellent activity and selectivity were confirmed. In addition, IC in TYK2 / JAK1 cell activity 50 It showed excellent activity of < 50 nM.

[0224] Therefore, the compound according to the present invention and its pharmaceutically acceptable salt can be usefully used for the prevention, improvement or treatment of TYK2-related diseases, specifically autoimmune diseases, inflammatory diseases or cancer.

[0225]

[0226] Manufacturing method

[0227] In another aspect, the present invention relates to a method for producing the novel compound.

[0228] The compound of formula 1 can be synthesized using the synthetic routes described herein. In certain embodiments, methods well known in the chemical arts, either in light of the disclosure contained herein or in addition to it, can be used. Starting materials are generally available from commercial sources or readily prepared using methods well known to those skilled in the art.

[0229] The compounds of the present invention can be prepared from commercially available starting materials using the general methods exemplified herein. For illustrative purposes, Schemes 1 through 5 below provide routes for synthesizing compounds of Formula 1 as well as key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Those skilled in the art will recognize that other synthetic routes are available and can be utilized. Although specific starting materials and reagents are depicted in the schemes and described below, other starting materials and reagents can be substituted to provide various derivatives and / or reaction conditions. Furthermore, many of the compounds prepared by the methods described below can be further modified in light of the present disclosure using conventional chemicals known to those skilled in the art.

[0230] In a specific embodiment, the above manufacturing method is

[0231] It includes a first step of producing a compound represented by the chemical formula 1 by borylating a compound represented by the chemical formula 3 and then performing a Suzuki reaction or Ullmann reaction with a compound corresponding to the chemical formula 2.

[0232] As a specific example, in the first step, the compound represented by the chemical formula 3 is dissolved in 1,4-dioxane, and then bis(pinacolato)diboron, potassium acetate, Pd(dba)2, and 0.6 M PCy3 (PCy3in) in toluene are added as reaction reagents. Toluene) is used. Stir at 90-110℃ for 1 hour to overnight, then filter. Dissolve the reactant and the compound represented by chemical formula 2 in 1,4-dioxane and water, and then use Pd(dppf)2Cl2 as a reaction reagent. . Use DCM and K3PO4. Stir at 70-80℃ for 1 hour to overnight to prepare chemical formula 1.

[0233]

[0234] [Chemical Formula 2]

[0235]

[0236] [Chemical Formula 3]

[0237]

[0238] In the above formula,

[0239] A1, A2, A3, A4, A5, R1, R2, R3, R4, R5 and the dotted line are as defined in the above chemical formula 1,

[0240] X is halo, preferably fluoro, chloro, bromo or iodo.

[0241]

[0242] Specifically, the above manufacturing method can be represented by the following reaction scheme 1.

[0243] [Reaction Formula 1]

[0244]

[0245] In the above reaction formula,

[0246] A1, A2, A3, A4, A5, R1, R2, R3, R4, R5 and the dotted line are as defined in the above chemical formula 1,

[0247] X is halo, preferably fluoro, chloro, bromo or iodo.

[0248]

[0249] The compound of the above chemical formula 2 can be prepared by a preparation method comprising the following steps:

[0250] A second step of producing a compound represented by the following chemical formula 5 by reacting a compound represented by the following chemical formula 4 with NBS or NIS;

[0251] A compound represented by the following chemical formula 5 is S N Step 3: producing a compound represented by the following chemical formula 6 by performing a 2-reaction or a Chan-Lam reaction;

[0252] A fourth step of producing a compound represented by the chemical formula 2 by deacetylating the compound represented by the chemical formula 6 below with an acid, for example, hydrochloric acid, and then reacting it with isocyanate or acetyl chloride.

[0253]

[0254] As a specific example, in the second step, the compound represented by chemical formula 4 is dissolved in an appropriate solvent, for example, N,N-dimethylformamide, and then NBS or NIS as a halogen donor is added dropwise and stirred at room temperature overnight.

[0255] As a specific example, in the third step, the compound represented by the chemical formula 5 is dissolved in acetonitrile or N,N-dimethylformamide, and then cesium carbonate is used as a base and dimethyl sulfate, a halide alkyl, or mesyl alcohol is used as a reaction reagent. The chemical formula 6 is prepared by stirring at room temperature or 80°C overnight. Mesyl alcohol is prepared by dissolving the alcohol corresponding to R3 in dimethyl chloride, then adding triethylamine and methanesulfonyl chloride dropwise at 0°C, and stirring at room temperature for 2 to 4 hours. Alternatively, R3B(OH)2, 2,2'-bipyridyl, anhydrous copper(II) acetate, and sodium carbonate are used as reaction reagents for the Chan-Lam reaction, and N,N-dimethylformamide is used as a solvent. The chemical formula 6 is prepared by stirring at 70°C overnight.

[0256] As a specific example, in the fourth step, the compound represented by the chemical formula 6 is dissolved in methanol, 4N HCl in 1,4-dioxane is added dropwise, and the mixture is stirred at 80°C for 5 hours. The reactant is concentrated and dissolved in dimethyl chloride, and N,N-diisopropylethylamine and 2,2,2-trichloroacetyl isocyanate are added dropwise at 0°C. The mixture is stirred at room temperature for 30 minutes and concentrated. The reactant is dissolved in methanol, and a saturated aqueous sodium bicarbonate solution is added dropwise. The mixture is stirred at room temperature for 1 to 4 hours to prepare the chemical formula 2.

[0257]

[0258] Specifically, the above manufacturing method can be represented by the following reaction scheme 2.

[0259] [Reaction Formula 2]

[0260]

[0261]

[0262] In the above reaction formula,

[0263] A2, A3, A4, A5, R3, R4 and the dotted line are as defined in the above chemical formula 1,

[0264] X is halo, preferably fluoro, chloro, bromo or iodo.

[0265]

[0266] As a specific example, the compound of formula 3, wherein R5 is H and R2 is 4-12 membered heterocycloalkyl, OR' or NR'R", can be prepared by a preparation method comprising the following steps:

[0267] A compound represented by the following chemical formula 7 is prepared by the Mitsunobu reaction or S N Step 5 of producing a compound represented by the chemical formula 8 by a second reaction; and

[0268] This is the sixth step of producing a compound represented by the chemical formula 3 by reacting a compound represented by the chemical formula 8 below with a disilicide compound, NaHMDS, and an alcohol compound corresponding to R2, for example, HOR', or an amine compound corresponding to R2, for example, HNR'R" compound.

[0269]

[0270] As a specific example, in the fifth step, the compound represented by the chemical formula 7 is dissolved in N,N-dimethylformamide, and then cesium carbonate and an alkyl halide are added dropwise. The mixture is stirred at room temperature overnight to prepare the chemical formula 8. Alternatively, the compound represented by the chemical formula 7 is dissolved in tetrahydrofuran, and then R1OH, PhOPPh2 or PPh3, and DIAD or DEAD are added dropwise, and then stirred at room temperature overnight to prepare the chemical formula 8.

[0271] As a specific example, the following step 6 can be performed by dissolving the compound represented by chemical formula 8 in 1,4-dioxane or tetrahydrofuran, and then adding dropwise 2N NaHMDS in tetrahydrofuran and the alcohol (HOR') or amine (HNR'R") corresponding to R2. Stirring at room temperature or 50°C for 1 to 4 hours produces chemical formula 3.

[0272]

[0273] As a concrete example, R 5 The method for preparing the compound of the above chemical formula 3, wherein R is H and R2 is 4-12 membered heterocycloalkyl, OR' or NR'R" can be represented by the following reaction scheme 3.

[0274] [Reaction Formula 3]

[0275]

[0276] In the above formula,

[0277] A1, R1 and R2 are as defined in the above chemical formula 1,

[0278] X is halo, preferably fluoro, chloro, bromo or iodo.

[0279]

[0280] As a concrete example, R5 is H, R2 is H, C1-C 10 Alkyl, C1-C 10The compound of the above formula 3, which is an alkoxy or C3-C8 cycloalkyl, can be prepared by a preparation method comprising the following steps:

[0281] A compound represented by the following chemical formula 9 is prepared by the Mitsunobu reaction or S N Step 7 of producing a compound represented by the chemical formula 8 by a second reaction.

[0282]

[0283] As a specific example, in the seventh step, the compound represented by the chemical formula 9 is dissolved in N,N-dimethylformamide, and then cesium carbonate and an alkyl halide are added dropwise. The mixture is stirred at room temperature overnight to prepare the chemical formula 8. Alternatively, the compound represented by the chemical formula 9 is dissolved in tetrahydrofuran, and then R1OH, PhOPPh2 or PPh3, and DIAD or DEAD are added dropwise, and then stirred at room temperature overnight to prepare the chemical formula 8.

[0284]

[0285] As a concrete example, R5 is H, R2 is H, C1-C 10 Alkyl, C1-C 10 The method for preparing the compound of the above chemical formula 3, which is an alkoxy or C3-C8 cycloalkyl, can be represented by the following reaction scheme 4.

[0286] [Reaction Formula 4]

[0287]

[0288] In the above formula,

[0289] A1, R1 and R2 are as defined in the above chemical formula 1,

[0290] X is halo, preferably fluoro, chloro, bromo or iodo.

[0291]

[0292] As a specific example, the compound of the above chemical formula 1 can also be prepared by a preparation method comprising the following steps:

[0293] A first step of producing a compound represented by chemical formula 10 by subjecting a compound represented by chemical formula 3 to a Suzuki reaction or an Ulmann reaction with a compound corresponding to chemical formula 6; and

[0294] This is the second step of producing a compound represented by the chemical formula 1 by deacetylating the compound represented by the chemical formula 10 below with an acid, for example, hydrochloric acid, and then reacting it with acetoxyacetyl chloride or methylamine.

[0295]

[0296] As a specific example, in the above step 1, the compound represented by chemical formula 3 was dissolved in 1,4-dioxane, and then bis(pinacolato)diboron, potassium acetate, Pd(dba)2, and 0.6 M PCy3 (PCy3in) in toluene were added as reaction reagents. Toluene) is used. Stir at 90-110℃ for 1 hour to overnight, then filter. Dissolve the reactant and the compound represented by chemical formula 6 in 1,4-dioxane and water, and then use Pd(dppf)2Cl2 as a reaction reagent. . Use DCM and K3PO4. Stir at 70-80℃ for 1 hour to overnight to prepare chemical formula 10.

[0297] As a specific example, in the '2nd step', the compound represented by the chemical formula 10 synthesized in the '1st step' is dissolved in methanol, 4N HCl in 1,4-dioxane is added dropwise, and the mixture is stirred at 80°C for 5 hours. The reactant is concentrated, dissolved in dimethyl chloride, and acetoxyacetyl chloride and pyridine are added dropwise. The mixture is stirred at room temperature for 3 hours and concentrated. The reactant is dissolved in methanol, and potassium carbonate is added dropwise. The mixture is stirred at room temperature for 15 minutes to prepare chemical formula 1. Alternatively, the deacetylated reactant is concentrated, dissolved in tetrahydrofuran, and triphosgene is added dropwise at 0°C and stirred for 1 hour. Methylamine is added dropwise to the reactant at room temperature and stirred to prepare chemical formula 1.

[0298]

[0299] Specifically, the above manufacturing method can be represented by the following reaction scheme 5.

[0300] [Reaction Formula 5]

[0301]

[0302] In the above formula,

[0303] A1, A2, A3, A4, A5, R1, R2, R3, R4, R5 and the dotted line are as defined in the above chemical formula 1,

[0304] X is halo, preferably fluoro, chloro, bromo or iodo.

[0305]

[0306] Pharmaceutical compositions and medicinal uses

[0307] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be suitable for preventing, improving or treating various diseases caused by TYK2 activity due to their biological properties.

[0308] Accordingly, in another aspect, the present invention relates to a pharmaceutical composition for preventing, improving or treating various diseases related to TYK2, comprising a compound of the above chemical formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0309] A disease associated with TYK2 may include any disease, disorder, or condition directly or indirectly linked to the expression or activity of TYK2, including overexpression and / or abnormal activity levels. The abnormal activity level can be determined by comparing the activity level in normal healthy tissues or cells with the activity level in diseased cells. A disease mediated by TYK2 may also include any disease, disorder, or condition that can be prevented, ameliorated, inhibited, or cured by modulating TYK2 activity.

[0310] Diseases mediated by TYK2 that can be treated using the compound of the present invention may be autoimmune diseases, inflammatory diseases, cancers, or neurodegenerative diseases.

[0311]

[0312] In a specific embodiment, the autoimmune and inflammatory diseases are selected from the group consisting of asthma, alopecia areata, ankylosing spondylitis, lupus, lupus nephritis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis (plaque, scalp, nail psoriasis, etc.), Sjogren's syndrome, multiple sclerosis, palmar pustulosis, celiac disease, atopic dermatitis, contact dermatitis, delayed hypersensitivity reactions, ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and chorioconjunctivitis, diseases affecting the nose including allergic rhinitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis, endometriosis, leptospirosis, renal disease, cardiac hypertrophy, muscle wasting, catabolic disorders, fetal growth retardation, hypercholesterolemia, heart Disease, chronic heart failure, mesothelioma, indeterminate cutaneous dysplasia, Behcet's disease, pigmentary incontinence, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, nasal sinusitis, ocular allergy, silica-induced disease, chronic obstructive pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, COVID19, cataracts, myositis with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, or type 2 diabetes, temporal arteritis, tendinitis, dermatomyositis, appendicitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, , cystitis, dacryoadenitis, encephalitis, endocarditis, endometritis, Enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, leukocyte adhesion deficiency, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis,It may be one or more diseases selected from the group consisting of salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, , uveitis, vaginitis, vasculitis, and vulvitis, but is not limited thereto.

[0313] In a specific embodiment, the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary cancer, seminoma, esophageal cancer, laryngeal cancer, stomach cancer, gastrointestinal cancer, gastrointestinal cancer, skin cancer, keratoacanthoma, follicular carcinoma, melanoma, lung cancer, small cell lung carcinoma, non-small cell lung carcinoma (NSCLC), lung adenocarcinoma, squamous cell carcinoma of the lung, adenomatous polyp, colon cancer, pancreatic cancer, thyroid cancer, papillary cancer, bladder cancer, liver cancer, biliary tract cancer, kidney cancer, bone cancer, bone marrow disease, lymphatic disease, hairy cell cancer, oral cancer and pharyngeal cancer (oral), lip cancer, tongue cancer, oral cancer, salivary gland cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, colon cancer, endometrial cancer, uterine cancer, brain cancer, central nervous system system, cancer of the peritoneum, hepatocellular carcinoma, It may be one or more diseases selected from the group consisting of, but not limited to, head and neck cancer, cervical cancer, Hopkins disease, and leukemia (acute myeloid leukemia).

[0314] In a specific embodiment, the neurodegenerative disease may be one or more diseases from the group consisting of, but not limited to, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0315] All cancers mentioned above, characterized by specific sites / organs within the body, include both primary tumors and metastatic tumors derived from them. All cancers mentioned above can be further distinguished by their histopathologic classifications:

[0316] The terms “subject” or “patient”, as used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or primate, and most preferably a human.

[0317] The term "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, subject, or human being sought by a researcher, veterinarian, physician, or other clinician.

[0318] The term "treating" or "treatment" refers to one or more of (1) 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 development of the pathology and / or symptoms); and (2) 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), such as reducing the severity of the disease. In one embodiment, treating or treatment includes preventing or reducing the risk of developing a disease; e.g., preventing or reducing the risk of developing a disease, condition, or disorder in a subject who may be predisposed to the disease, condition, or disorder but who does not yet experience or exhibit the pathology or symptoms of the disease.

[0319]

[0320] In a specific embodiment, the compound according to the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same may be used in conjunction with non-pharmacological therapies known in the art for diseases associated with TYK2 activity. For example, in combination with radiotherapy, surgery, and / or other compounds, the compound may be used for the prevention, short-term, or long-term treatment of the diseases mentioned above.

[0321]

[0322] The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans via various routes. In the present invention, the routes of administration of the pharmaceutical composition include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal.

[0323] Additionally, oral and parenteral administration are preferred methods of administering the pharmaceutical composition. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0324] The pharmaceutical composition according to the present invention may additionally comprise one or more pharmaceutically acceptable carriers, one or more excipients and / or diluents.

[0325] Non-limiting examples of pharmaceutically suitable carriers include solids and / or liquids, such as ethanol, glycerol, water, and the like. The amount of carrier in the therapeutic composition can range from about 5 to about 99 weight percent, based on the total weight of the therapeutic composition or therapeutic combination. Non-limiting examples of suitable pharmaceutically acceptable excipients and diluents include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, wetting agents, bulking agents, antioxidants, lubricants, flavoring agents, thickening agents, coloring agents, surfactants, emulsifiers, thickening agents, and the like. Such excipients and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, and it will be apparent to those skilled in the art that any other pharmaceutically acceptable carrier, excipient and diluent may be used.

[0326] The composition comprising the compound of chemical formula 1 of the present invention or a salt thereof can be formulated and used in the form of oral formulations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, liquids, emulsions, syrups, external preparations, suppositories, or sterile injection solutions, each according to a conventional method.

[0327] The pharmaceutical composition according to the present invention may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Acceptable vehicles and solvents include mannitol, water, Ringer's solution, or isotonic sodium chloride solution. In addition, a sterile fixed oil is typically used as a solvent or suspending medium. For this purpose, any fixed oil with minimal irritation, including synthetic mono- or diglycerides, may be used. Fatty acids such as oleic acid and its glyceride derivatives are useful in injectable preparations, as are pharmaceutically acceptable natural oils (e.g., olive oil or castor oil), especially their polyoxyethylated forms.

[0328] The pharmaceutical composition according to the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions.

[0329] The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration. These compositions can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0330] Oral administration of the pharmaceutical composition according to the present invention is particularly useful when the desired treatment involves a site or organ easily accessible by topical application. When applied topically to the skin, the pharmaceutical composition should be formulated as a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the pharmaceutical composition may be formulated as a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present invention may also be applied topically to the lower intestinal tract by rectal suppository or as a suitable enema. Topically applied transdermal patches are also encompassed by the present invention.

[0331] The pharmaceutical composition of the present invention can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical field and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0332] The novel compound described above is contained in the pharmaceutical composition of the present invention in a therapeutically effective amount or a prophylactically effective amount. The preferred dosage of the compound according to the present invention varies depending on the patient's condition and body weight, the severity of the disease, the drug form, the route of administration, and the duration of administration, but can be appropriately selected by those skilled in the art. However, for a desirable effect, the compound of Chemical Formula 1 of the present invention can be administered once or several times daily in an amount of 0.0001 to 1000 mg / kg, preferably 0.01 to 500 mg / kg.

[0333] In the composition of the present invention, the compound of the above chemical formula 1 can be blended in an amount of 0.0001 to 50 wt% based on the total weight of the entire composition.

[0334]

[0335] In another aspect, the present invention relates to a method for preventing, improving or treating various diseases caused by the activity of TYK2, comprising a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0336] At this time, the compound of chemical formula 1 of the present invention, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" of the present invention means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dosage level can be determined according to factors including the patient's health condition, the type and severity of the disease, the activity and sensitivity of the drug, the administration method, the administration time, the administration route and the excretion rate, the treatment period, the drugs used in combination or simultaneously, and other factors well known in the medical field. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and this can be easily determined by those skilled in the art.

[0337] For example, the dosage may increase or decrease depending on the route of administration, severity of disease, gender, weight, age, etc., and thus the dosage does not limit the scope of the present invention in any way.

[0338] The preferred dosage of the compound of the present invention varies depending on the patient's condition and weight, the degree of the disease, the form of the drug, the route and period of administration, but can be appropriately selected by a person skilled in the art.

[0339]

[0340] combination therapy

[0341] The compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, may be used alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents).

[0342] Combination therapy may, for example, combine two therapies, three therapies (e.g., triple therapy with three therapeutic agents), or more. The dosage of one or more of the additional therapies (e.g., non-pharmacological or therapeutic agents) may be reduced from the standard dosage when administered alone.

[0343]

[0344] The compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, may be administered before, after, or simultaneously with one or more such additional therapies.

[0345]

[0346] In a specific embodiment, the compound of formula 1 may be combined with an additional therapeutic compound having anti-inflammatory or anti-hyperproliferative properties or useful for the treatment of autoimmune diseases, inflammatory diseases, or cancer. The additional therapeutic agent may be an NSAID or other anti-inflammatory agent. The additional therapeutic agent may be a chemotherapeutic agent.

[0347] In one specific embodiment, the compounds of the invention are administered in combination with any anti-IBD agent, including but not limited to anti-inflammatory drugs such as sulfasalazine, mesalamine or corticosteroids such as budesonide, prednisone, cortisone or hydrocortisone, immunosuppressants such as azathioprine, mercaptopurine, infliximab, adalimumab, certolizumab pegol, methotrexate, cyclosporine or natalizumab, antibiotics such as metronidazole or ciprofloxacin, antidiarrheals such as psyllium powder, loperamide or methylcellulose, lazatib, analgesics such as NSAIDs or acetaminophen, iron supplements, vitamin B supplements, vitamin D supplements and any combination of the foregoing. In another example, the compounds of the invention can be administered in combination with other anti-IBD treatments, such as surgery (e.g., before, during or after).

[0348] In one specific embodiment, the compounds of the invention are co-administered with any anti-psoriasis agent, including but not limited to topical corticosteroids, vitamin D analogs such as calcipotriene or calcitriol, anthralin, topical retinoids such as tazarotene, calcineurin inhibitors such as tacrolimus or pimecrolinus, salicylic acid, coal tar, NSAIDs, moisturizing creams and ointments, oral or injectable retinoids such as acitretin, methotrexate, cyclosporine, hydroxyurea, immunomodulatory drugs such as alefacept, etanercept, infliximab or ustekinumab, thioguanine, and any combination of the foregoing. In another example, the compounds of the present invention may be administered in combination with other antipsoriatic treatments, such as phototherapy, solar therapy, UVB therapy, narrow-band UVB therapy, Goeckerman therapy, photochemotherapy, such as psoralen plus ultraviolet A (PUVA), excimer and pulsed dye laser therapy, or any combination (e.g., before, during or after) of antipsoriatic agents and antipsoriatic treatments.

[0349] In one specific embodiment, the compounds of the invention are co-administered with any antiasthmatic agent, including but not limited to β2-adrenergic agonists, inhaled and oral corticosteroids, leukotriene receptor antagonists, and omalizumab. In another embodiment, the compounds of the invention can be co-administered with an antiasthmatic agent selected from a combination of an NSAID, fluticasone and salmeterol, a combination of budesonide and formoterol, omalizumab, lebrikizumab, and a corticosteroid selected from fluticasone, budesonide, mometasone, flunisolide, and beclomethasone.

[0350]

[0351] Hereinafter, preferred examples are presented to aid in understanding the present invention. However, the following examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited by the examples.

[0352]

[0353] Various synthetic methods for the starting materials for synthesizing the compounds of the present invention are known, and if the starting materials are commercially available, they can be purchased and used from a supplier. Reagent suppliers include, but are not limited to, Sigma-Aldrich, TCI, an-gene, chemspace, chemscene, BLD, Alfa, combi-blocks, and Dae-Jung. In addition, all commercially available materials were used without further purification, except where otherwise specified.

[0354]

[0355] First, the compounds used in the synthesis in the examples below were prepared as in the following manufacturing examples. The following manufacturing examples are examples of compounds represented by Chemical Formula 1 in Scheme 1 above, and can be appropriately modified to correspond to the structure of the example to be prepared.

[0356]

[0357] Manufacturing Example 1) Manufacturing of N-(3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Compound Example 19)

[0358] Step 1) Preparation of 4-bromo-6-chloro-2-isopropylpyridazin-3(2H)-one

[0359]

[0360] 500 mg (2.39 mmol) of 5-bromo-3-chloro-1H-pyridazin-6-one was dissolved in 10 mL of N,N-dimethylformamide, and 1556 mg (4.77 mmol) of cesium carbonate and 0.360 mL (3.58 mmol) of 2-iodopropane were added dropwise. After stirring at room temperature for 16 hours, 30 mL of water and 30 mL of ethyl acetate were added, and the layers were separated. Extraction was performed with 200 mL of ethyl acetate. The organic layer was treated with anhydrous magnesium sulfate and concentrated. The target compound was obtained by separation using column chromatography. (550 mg, 92%)

[0361] LC-MS (ESI) calcd. for C7H8BrClN2O: 249.95, m / z found, 250.62[M+H] + .

[0362]

[0363] Step 2) Preparation of 6-chloro-4-isobutoxy-2-isopropyl-pyridazin-3-one

[0364]

[0365] 275 mg (1.09 mmol) of 4-bromo-6-chloro-2-isopropylpyridazin-3(2H)-one and 82 mg (1.09 mmol) of 2-methylpropan-1-ol were dissolved in 5 mL of 1,4-dioxane, and 2M NaHMDS (0.71 mL, 1.42 mmol) was slowly added dropwise. The mixture was stirred at 50°C for 1 hour, and 10 mL of water was added to terminate the reaction. The organic layer, extracted with 100 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound was obtained by separation using column chromatography. (179 mg, 67%)

[0366] LC-MS (ESI) calcd. for C 11 H 17 ClN2O2: 244.10, m / z found, 245.10 [M+H] + .

[0367]

[0368] Step 3) Preparation of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0369]

[0370] N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (10 g, 54.23 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and then NBS (12.19 g, 81.34 mmol) was added dropwise. The mixture was stirred at room temperature until the reaction was complete, and then 100 mL of water and 100 mL of ethyl acetate were added dropwise. The organic layer, extracted with 200 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained compound was proceeded to the next reaction without any purification step.

[0371] LC-MS (ESI) calcd. for C9H8BrN3O: 252.99, m / z found, 254.27 [M+H] + .

[0372] 1 H NMR (DMSO-d6, 400 MHz) δ 11.72 (s, 1H), 10.16 (s, 1H), 8.43 (s, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 2.19 (s, 3H).

[0373]

[0374] Step 4) Preparation of N-(3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0375]

[0376] N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide 7.4 g (29.13 mmol) was dissolved in 200 mL of acetonitrile, and cesium carbonate 18.98 g (58.25 mmol) and dimethyl sulfate 3.038 mL (32.04 mmol) were added dropwise. The mixture was stirred at room temperature until the reaction was complete, and then 100 mL of water and 100 mL of ethyl acetate were added dropwise. The organic layer, extracted with 200 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained compound was proceeded to the next reaction without any purification step. (7.74 g, 99%)

[0377] LC-MS (ESI) calcd. for C 10 H 10 BrN3O: 267.00, m / z found, 268.20 [M+H] + .

[0378] 1 H NMR (DMSO-d6, 400 MHz) δ 10.36 (s, 1H), 8.63 (s, 1H), 8.13 (s, 1H), 7.76 (s, 1H), 3.88 (s, 3H), 2.09 (s, 3H).

[0379]

[0380] Step 5) Preparation of N-[3-(5-isobutoxy-1-isopropyl-6-oxo-pyridazin-3-yl)-1-methyl-pyrrolo[2,3-c]pyridin-5-yl]acetamide

[0381]

[0382] 45 mg (0.18 mmol) of 6-chloro-4-isobutoxy-2-isopropyl-pyridazin-3-one, 93 mg (0.37 mmol) of bis(pinacolato)diboron, 36 mg (0.37 mmol) of potassium acetate, 16 mg (0.028 mmol) of Pd(dba), and 0.092 mL (0.055 mmol) of 0.6 M PCy3in toluene were dissolved in 1 mL of 1,4-dioxane and stirred at 90°C for 2 hours. After cooling to room temperature, the mixture was filtered using Celite. The mixture was dissolved in 1 mL of 1,4-dioxane and 0.1 mL of water, and then 58 mg (0.18 mmol) of N-(3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide and Pd(dppf)2Cl2 . 15 mg (0.018 mmol) of DCM and 78 mg (0.37 mmol) of K3PO4 were added dropwise and stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was filtered using Celite. The target compound was obtained by separation using Prep-HPLC (10.5 mg, 14%).

[0383] LC-MS (ESI) calcd. for C 21 H 27 N5O3: 397.21, m / z found, 398.25[M+H] + .

[0384] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.08 (s, 1H), 8.45 (s, 1H), 7.95 (br s, 1H), 7.54 (s, 1H), 6.71 (s, 1H), 5.4-5.6 (m, 1H), 3.95 (s, 3H), 3.84 (d, 2H, J=6.6 Hz), 2.2-2.3 (m, 4H), 1.6-1.6 (m, 6H), 1.12 (d, 6H, J=6.8 Hz).

[0385]

[0386] Manufacturing Example 2) Manufacturing of 1-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea (Example 37 compound)

[0387] Step 1) Preparation of 4-bromo-6-chloro-2-(2,2,2-trifluoro-1-methyl-ethyl)pyridazin-3-one

[0388]

[0389] 5-Bromo-3-chloro-1H-pyridazin-6-one 500 mg (2.39 mmol), 1,1,1-trifluoropropan-2-ol 409 mg (3.58 mmol), PPh31252 mg (4.77 mmol) were dissolved in 10 mL of tetrahydrofuran, and then DIAD 0.937 mL (4.77 mmol) was slowly added dropwise at 0°C. The temperature was raised to room temperature, stirred for 16 hours, and then 20 mL of water and 20 mL of ethyl acetate were added dropwise. The organic layer extracted with 100 mL of ethyl acetate was dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound was obtained by separation using column chromatography. (182 mg, 25%)

[0390] LC-MS (ESI) calcd. for C7H5BrClF3N2O: 303.92, m / z found, 305.21[M+H] + .

[0391] 1 H NMR (DMSO-d, 400 MHz) δ 8.31 (s, 1H), 5.73-5.80 (m, 1H), 1.54-1.56 (d, 3H).

[0392]

[0393] Step 2) Preparation of 6-chloro-4-isobutoxy-2-(2,2,2-trifluoro-1-methyl-ethyl)pyridazin-3-one

[0394]

[0395] The title compound was prepared using the same method as in step 2 of Manufacturing Example 1.

[0396] LC-MS (ESI) calcd. for C 11 H 14 ClF3N2O2: 298.07, m / z found, 299.28[M+H] + .

[0397] 1 H NMR (DMSO-d, 400 MHz) δ 7.02 (s, 1H), 5.71-5.79 (m, 1H), 3.84-3.92 (m, 2H), 2.02-2.11 (m, 1H), 1.52-1.54 (d, 3H), 0.96-0.97 (d, 6H).

[0398]

[0399] Step 3) Preparation of (3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)urea

[0400]

[0401] N-(3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide 2500 mg (9.32 mmol) was dissolved in 10 mL of methanol, and 4N HCl 11 mL (46.6 mmol) was added dropwise. After reacting at 80°C for 1 hour, the mixture was concentrated under reduced pressure. The reaction mixture was dissolved in 10 mL of dimethyl chloride, and at 0°C, 4.61 mL (27.97 mmol) of N,N-diisopropylethylamine and 2.78 mL (23.31 mmol) of 2,2,2-trichloroacetyl isocyanate were slowly added dropwise. The reaction mixture was stirred at room temperature until the reaction was complete, and then the reaction mixture was concentrated under reduced pressure. The reaction mixture was dissolved in 10 mL of methanol, and 10 mL of a saturated aqueous sodium bicarbonate solution was added dropwise, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was filtered and dried to obtain the target compound (2200 mg, 88%).

[0402] 1H NMR (DMSO-d, 400 MHz) δ 8.84 (s, 1H), 8.54 (s, 1H), 7.72 (s, 1H), 6.39-6.62 (m, 2H), 3.84 (s, 3H).

[0403]

[0404] Step 4) Preparation of 1-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0405]

[0406] 37 mg (0.12 mmol) of 6-chloro-4-isobutoxy-2-(2,2,2-trifluoro-1-methyl-ethyl)pyridazin-3-one, 63 mg (0.25 mmol) of bis(pinacolato)diboron, 24 mg (0.25 mmol) of potassium acetate, 211 mg (0.019 mmol) of Pd(dba), and 0.062 mL (0.037 mmol) of 0.6 M PCy3in toluene were dissolved in 1 mL of 1,4-dioxane and stirred at 90°C for 2 hours. After lowering the temperature to room temperature, filter using Celite. The mixture was dissolved in 1 mL of 1,4-dioxane, 0.1 mL of water, and 33 mg (0.12 mmol) of (3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)urea, Pd(dppf)2Cl2 . 10 mg (0.012 mmol) of DCM and 53 mg (0.25 mmol) of K3PO4 were added dropwise and stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was filtered using Celite. The target compound was obtained using Prep-HPLC (1.5 mg, 2.6%).

[0407] LC-MS (ESI) calcd. for C 20 H 23 F3N6O3: 452.18, m / z found, 453.32[M+H] + .

[0408] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.4-8.5 (m, 1H), 7.6-7.6 (m, 1H), 7.5-7.6 (m, 1H), 6.9-7.0 (m, 1H), 6.67 (s, 1H), 5.9-6.0 (m, 1H), 3.9-4.0 (m, 3H), 3.8-3.9 (m, 2H), 2.2-2.4 (m, 1H), 1.7-1.8 (m, 3H), 1.0-1.1 (m, 6H).

[0409]

[0410] Manufacturing Example 3) Manufacturing of N-(1-cyclopropyl-3-(1-isopropyl-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Compound Example 21)

[0411] Step 1) Preparation of 4-bromo-6-chloro-2-isopropylpyridazin-3(2H)-one

[0412]

[0413] The title compound was obtained by the same method as step 1 of manufacturing example 1.

[0414]

[0415] Step 2) Preparation of 6-chloro-2-isopropyl-4-(3-methoxyazetidin-1-yl)pyridazin-3-one

[0416]

[0417] 3-Methoxyazetidine hydrochloride (135 mg, 1.09 mmol) was dissolved in 5 mL of 1,4-dioxane, N,N-diisopropylethylamine (0.36 mL, 2.19 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 minutes. 275 mg, 1.09 mmol) of 4-bromo-6-chloro-2-isopropylpyridazin-3(2H)-one and 0.71 mL, 1.42 mmol) of 2 M NaHMDS were added dropwise to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After cooling to room temperature, 10 mL of water was added dropwise, and the mixture was neutralized to pH 7-8 with 1 N HCl aqueous solution. The organic layer, extracted with 100 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound was obtained by separation using column chromatography. (70 mg, 25%)

[0418] LC-MS (ESI) calcd. for C 11 H 16 ClN3O2: 257.09, m / z found, 257.93[M+H] + .

[0419]

[0420] Step 3) Preparation of N-(3-bromo-1-cyclopropyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0421]

[0422] 1430 mg (7.87 mmol) of anhydrous copper(II) acetate was dissolved in 12 mL of N,N-dimethylformamide, and then 1229 mg (7.87 mmol) of 2,2'-bipyridyl, 962 mg (7.87 mmol) of sodium carbonate, 1392 mg (7.87 mmol) of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 1000 mg (3.94 mmol) of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide were added dropwise in sequence. The mixture was stirred at 70°C for 16 hours. After cooling to room temperature, 100 mL of water and 100 mL of ethyl acetate were added dropwise. The organic layer, extracted with 200 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound was obtained by separation using column chromatography. (951 mg, 82%)

[0423] LC-MS (ESI) calcd. for C 12 H 12 BrN3O: 293.02, m / z found, 294.30[M+H] + .

[0424]

[0425] Step 4) Preparation of N-(1-cyclopropyl-3-(1-isopropyl-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0426]

[0427] 35 mg (0.14 mmol) of 6-chloro-2-isopropyl-4-(3-methoxyazetidin-1-yl)pyridazin-3-one, 69 mg (0.27 mmol) of bis(pinacolato)diboron, 27 mg (0.27 mmol) of potassium acetate, 212 mg (0.020 mmol) of Pd(dba), and 0.068 mL (0.041 mmol) of 0.6 M PCy3in toluene were dissolved in 1 mL of 1,4-dioxane and stirred at 90°C for 2 hours. After cooling to room temperature, the mixture was filtered using Celite. The mixture was dissolved in 1 mL of 1,4-dioxane and 0.1 mL of water, and then 40 mg (0.14 mmol) of N-(3-bromo-1-cyclopropyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Pd(dppf)2Cl2 . 11 mg (0.014 mmol) of DCM and 58 mg (0.27 mmol) of K3PO4 were added dropwise and stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was filtered using Celite. The target compound was obtained by separation using Prep-HPLC (2.4 mg, 4%).

[0428] LC-MS (ESI) calcd. for C 23 H 28 N6O3: 436.22, m / z found, 437.32[M+H] + .

[0429] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.01 (s, 1H), 8.5-8.7 (m, 1H), 7.99 (br s, 1H), 7.56 (s, 1H), 6.07 (s, 1H), 5.3-5.4 (m, 1H), 4.53 (br s, 2H), 4.35 (s, 1H), 4.1-4.3 (m, 2H), 3.48 (s, 1H), 3.36 (s, 3H), 2.2-2.3 (m, 4H), 1.5-1.6 (m, 6H), 1.2-1.2 (m, 2H), 1.12 (br d, 2H, J=4.4 Hz).

[0430]

[0431] Manufacturing Example 4) Manufacturing of N-(5-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide (Compound Example 16)

[0432] Step 1) Preparation of 7-methylpyrrolo[1,2-c]pyrimidin-3-amine

[0433]

[0434] 200 mg (0.81 mmol) of tert-butyl N-{7-methylpyrrolo[1,2-c]pyrimidin-3-yl}carbamate was dissolved in 2 mL of dimethyl chloride, and 0.1 mL of TFA was added dropwise. The mixture was stirred at room temperature until the reaction was complete, and the reaction mixture was concentrated under reduced pressure. The obtained compound was proceeded to the next reaction without purification.

[0435] LC-MS (ESI) calcd. for C8H9N3: 147.08, m / z found, 147.72[M+H] + .

[0436]

[0437] Step 2) Preparation of N-(7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide

[0438]

[0439] 118 mg (0.80 mmol) of 7-methylpyrrolo[1,2-c]pyrimidin-3-amine was dissolved in 2 mL of tetrahydrofuran, and 0.091 mL (0.96 mmol) of acetic anhydride and 1.39 mL (8.00 mmol) of N,N-diisopropylethylamine were added dropwise. The mixture was stirred at room temperature until the reaction was complete, and then 10 mL of water and 10 mL of ethyl acetate were added dropwise. The organic layer, extracted with 100 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained compound was proceeded to the next reaction without any purification step.

[0440] LC-MS (ESI) calcd. for C 10 H 11 N3O: 189.09, m / z found, 190.13[M+H] + .

[0441]

[0442] Step 3) Preparation of N-(5-bromo-7-methyl-pyrrolo[1,2-c]pyrimidin-3-yl)acetamide

[0443]

[0444] N-(7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide (60 mg, 0.32 mmol) was dissolved in 2 mL of dimethyl chloride, and NBS (85 mg, 0.48 mmol) was added dropwise. The mixture was stirred at room temperature until the reaction was complete, and then 10 mL of water and 10 mL of ethyl acetate were added dropwise. The organic layer, extracted with 100 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound was obtained by separation using column chromatography. (40 mg, 47%)

[0445] LC-MS (ESI) calcd. for C 10 H 10 BrN3O: 267.00, m / z found, 268.01[M+H] + .

[0446]

[0447] Step 4) Preparation of N-[5-[5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-pyridazin-3-yl]-7-methyl-pyrrolo[1,2-c]pyrimidin-3-yl]acetamide

[0448]

[0449] 50 mg (0.17 mmol) of 6-chloro-4-(3-methoxyazetidin-1-yl)-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one, 86 mg (0.33 mmol) of bis(pinacolato)diboron, 33 mg (0.33 mmol) of potassium acetate, 214 mg (0.025 mmol) of Pd(dba), and 0.083 mL (0.051 mmol) of 0.6 M PCy3in toluene were dissolved in 1 mL of 1,4-dioxane and stirred at 130°C for 4 hours. After lowering the temperature to room temperature, the mixture was filtered using Celite. The mixture was dissolved in 1 mL of 1,4-dioxane and 0.1 mL of water, and then 40 mg (0.15 mmol) of N-(5-bromo-7-methyl-pyrrolo[1,2-c]pyrimidin-3-yl)acetamide and Pd(dppf)2Cl2 . 14 mg (0.017 mmol) of DCM and 71 mg (0.33 mmol) of K3PO4 were added dropwise and stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was filtered using Celite. The target compound was obtained using Prep-HPLC (1 mg, 1%).

[0450] LC-MS (ESI) calcd. for C 23 H 28 N6O4: 452.22, m / z found, 453.45[M+H] +

[0451] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.6-8.7 (m, 1H), 8.4-8.5 (m, 1H), 7.5-7.6 (m, 1H), 6.8-6.8 (m, 1H), 6.10 (s, 1H), 4.4-4.6 (m, 3H), 4.3-4.4 (m, 1H), 4.2-4.3 (m, 1H), 4.1-4.2 (m, 2H), 4.0-4.1 (m, 2H), 3.3 (s, 3H), 2.8-2.9 (m, 1H), 2.6-2.7 (m, 1H), 2.5 (s, 3H), 2.2 (s, 3H), 1.7 (s, 3H).

[0452]

[0453] Manufacturing Example 5) Manufacturing of N-(3-methyl-1-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (Compound Example 15)

[0454] Step 1) Preparation of 6-(6-chloro-3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one

[0455]

[0456] 68 mg (0.26 mmol) of 6-bromo-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one was dissolved in 2 mL of N,N-dimethylformamide, and then 69 mg (0.39 mmol) of 6-chloro-3-methyl-1H-pyrrolo[3,2-c]pyridine, 5.0 mg (0.026 mmol) of CuI, 5.6 μL (0.053 mmol) of N,N'-dimethylethylenediamine, and 108 mg (0.79 mmol) of potassium carbonate were added dropwise, and the mixture was stirred at 130°C for 16 hours. After cooling to room temperature, the mixture was filtered using Celite. The target compound was obtained using Prep-HPLC. (10 mg, 11%)

[0457] LC-MS (ESI) calcd. for C 17 H 17 ClN4O2: 344.10, m / z found, 345.07[M+H] + .

[0458]

[0459] Step 2) Preparation of N-(3-methyl-1-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide

[0460]

[0461] 6-(6-chloro-3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one (10 mg, 0.029 mmol), acetamide (3.5 mg, 0.058 mmol), Brettphos Pd(II) G3 (2.7 mg, 0.0029 mmol), and cesium carbonate (28 mg, 0.087 mmol) were dissolved in 2 mL of tert-butanol and stirred at 130°C for 3 hours. After cooling to room temperature, the mixture was filtered using Celite. The target compound was obtained by separation using Prep-HPLC (1.5 mg, 14%).

[0462] LC-MS (ESI) calcd. for C 19 H 21 N5O3: 367.16, m / z found, 368.26[M+H] + .

[0463] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.68 (s, 1H), 8.56 (s, 1H), 8.09 (br s, 1H), 7.56 (d, 1H, J=9.9 Hz), 7.1-7.2 (m, 2H), 4.2-4.4 (m, 2H), 4.0-4.1 (m, 2H), 2.8-2.9 (m, 1H), 2.5-2.6 (m, 1H), 2.4 (s, 3H), 2.2 (s, 3H), 1.8 (s, 3H).

[0464]

[0465] Manufacturing Example 6) Manufacturing of N-(3-methyl-1-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (Compound of Example 5)

[0466] Step 1) Preparation of 6-chloro-4-methyl-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one

[0467]

[0468] 100 mg (0.692 mmol) of 3-chloro-5-methyl-1H-pyridazin-6-one, 141 mg (1.38 mmol) of tetrahydro-3-methyl-3-furanol, and 417 mg (1.59 mmol) of PPh3 were dissolved in 5 mL of tetrahydrofuran, and then 0.312 mL (1.59 mmol) of DIAD was slowly added dropwise at 0°C. The temperature was raised to room temperature, stirred for 16 hours, and then 20 mL of water and 20 mL of ethyl acetate were added dropwise. The organic layer, extracted with 100 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound was obtained by separation using column chromatography. (30 mg, 19%)

[0469] LC-MS (ESI) calcd. for C 10 H 13 ClN2O2: 228.68, m / z found, 229.13[M+H] + .

[0470]

[0471] Step 2) Preparation of N-(3-iodo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0472]

[0473] N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (5 g, 28.54 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and NIS (7.7 g, 34.25 mmol) was added dropwise. The mixture was stirred at room temperature until the reaction was complete, and then 100 mL of water and 100 mL of ethyl acetate were added dropwise. The organic layer, extracted with 200 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained compound was proceeded to the next reaction without any purification step.

[0474] LC-MS (ESI) calcd. for C9H8IN3O: 300.97, m / z found, 301.67 [M+H] + .

[0475]

[0476] Step 3) Preparation of N-(1-(3-cyanocyclobutyl)-3-iodo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0477]

[0478] To 631 mg (6.50 mmol) of 3-hydroxycyclobutanecarbonitrile was dissolved 7 mL of dimethyl chloride, and then at -10°C, 1.09 mL (7.80 mmol) of triethylamine and 0.550 mL (7.15 mmol) of methanesulfonyl chloride were slowly added dropwise. After stirring at 0°C for 4 hours, 20 mL of water and 20 mL of ethyl acetate were added dropwise, and the mixture was washed with a saturated aqueous sodium bicarbonate solution. The organic layer, extracted with 200 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained compound was proceeded to the next reaction without any purification step. N-(3-iodo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide 1505 mg (5.0 mmol) and cesium carbonate 3258 mg (10.0 mmol) were dissolved in 20 mL of N,N-dimethylformamide, and the (3-cyanocyclobutyl)methanesulfonate prepared above was added dropwise. After stirring overnight at 80°C, 100 mL of water and 100 mL of ethyl acetate were added dropwise. The organic layer extracted with 200 mL of ethyl acetate was dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound was obtained by separation using column chromatography. (200 mg, 11%)

[0479] LC-MS (ESI) calcd. for C 14 H 13 IN4O: 380.01, m / z found, 381.06 [M+H] + .

[0480]

[0481] Step 4) Preparation of N-(1-(3-cyanocyclobutyl)-3-(5-methyl-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0482]

[0483] 6-chloro-4-methyl-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one 30 mg (0.13 mmol), bis(pinacolato)diboron 66 mg (0.26 mmol), potassium acetate 26 mg (0.26 mmol), Pd(dppf)2Cl2 . 11 mg (0.013 mmol) of DCM was dissolved in 1 mL of 1,4-dioxane and stirred at 100°C for 2 hours. The temperature was lowered to room temperature and filtered using Celite. The mixture was dissolved in 1 mL of 1,4-dioxane and 0.1 mL of water, and 49 mg (0.13 mmol) of N-[1-(3-cyanocyclobutyl)-3-iodo-pyrrolo[2,3-c]pyridin-5-yl]acetamide and Pd(dppf)2Cl2 were added. . 11 mg (0.013 mmol) of DCM and 55 mg (0.26 mmol) of K3PO4 were added dropwise and stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was filtered using Celite. The target compound was obtained by separation using Prep-HPLC (13 mg, 22%).

[0484] LC-MS (ESI) calcd. for C 24 H 26 N6O3: 446.21, m / z found, 447.27 [M+H] + .

[0485] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.96 (s, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 7.4-7.5 (m, 1H), 4.97 (br d, 1H, J=9.0 Hz), 4.50 (d, 1H, J=9.3 Hz), 4.30 (d, 1H, J=9.4 Hz), 4.0-4.1 (m, 2H), 3.1-3.2 (m, 3H), 2.8-3.0 (m, 3H), 2.72 (br d, 1H, J=6.1 Hz), 2.3-2.3 (m, 3H), 2.24 (s, 3H), 1.77 (s, 3H).

[0486]

[0487] Manufacturing Example 7) Manufacturing of N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Compound Example 39)

[0488] Step 1) Preparation of 4-bromo-6-chloro-2-(2,2,2-trifluoro-1-methyl-ethyl)pyridazin-3-one

[0489]

[0490] The title compound was obtained by the same method as step 1 of Manufacturing Example 2.

[0491]

[0492] Step 2) Preparation of 6-chloro-4-(3-methoxyazetidin-1-yl)-2-(1,1,1-trifluoropropan-2-yl)pyridazin-3(2H)-one

[0493]

[0494] 3-Methoxyazetidine hydrochloride (97 mg, 0.79 mmol) was dissolved in 1 mL of 1,4-dioxane, N,N-diisopropylethylamine (0.22 mL, 1.31 mmol) was added dropwise, and the mixture was stirred at room temperature for 15 minutes. 200 mg, 0.65 mmol) of 4-bromo-6-chloro-2-(2,2,2-trifluoro-1-methyl-ethyl)pyridazin-3-one and 0.42 mL, 0.85 mmol) of 2 M NaHMDS were added dropwise to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. After cooling to room temperature, 10 mL of water was added dropwise, and the mixture was neutralized to pH 7-8 with 1 N HCl aqueous solution. The organic layer, extracted with 100 mL of ethyl acetate, was dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound was obtained by separation using column chromatography. (56 mg, 27%)

[0495] LC-MS (ESI) calcd. for C 11 H 13 ClF3N3O2: 311.06, m / z found, 311.95[M+H] + .

[0496]

[0497] Step 3) Preparation of N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0498]

[0499] 6-chloro-4-(3-methoxyazetidin-1-yl)-2-(1,1,1-trifluoropropan-2-yl)pyridazin-3(2H)-one 62 mg (0.20 mmol), bis(pinacolato)diboron 101 mg (0.40 mmol), potassium acetate 39 mg (0.40 mmol), Pd(dppf)2Cl2 .16 mg (0.020 mmol) of DCM was dissolved in 1 mL of 1,4-dioxane and stirred at 100°C for 2 hours. The temperature was lowered to room temperature and filtered using Celite. The mixture was dissolved in 1 mL of 1,4-dioxane and 0.1 mL of water, and 63 mg (0.20 mmol) of N-(3-iodo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide and Pd(dppf)2Cl2 were added. . 16 mg (0.020 mmol) of DCM and 84 mg (0.40 mmol) of K3PO4 were added dropwise and stirred overnight at 80°C. After cooling to room temperature, the mixture was filtered using Celite. The target compound was obtained by separation using Prep-HPLC (8 mg, 9%).

[0500] LC-MS (ESI) calcd. for C 21 H 23 F3N6O3: 464.18, m / z found, 465.54 [M+H] + .

[0501] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.91 (s, 1H), 8.42 (s, 1H), 7.9-8.0 (m, 1H), 7.53 (s, 1H), 6.1-6.1 (m, 1H), 5.8-5.9 (m, 1H), 4.5-4.6 (m, 2H), 4.3-4.4 (m, 1H), 4.2-4.2 (m, 2H), 3.9-4.0 (m, 3H), 3.9-4.0 (m, 4H), 3.37 (s, 3H), 2.25 (s, 4H), 1.8-1.9 (m, 3H)

[0502]

[0503] Manufacturing Example 8) Manufacturing of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 115 compound)

[0504] Step 1) Preparation of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0505]

[0506] The title compound was obtained by the same method as step 3 of Manufacturing Example 1.

[0507]

[0508] Step 2) Preparation of 4-(2,2-difluoroethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]pyridazin-3-one

[0509]

[0510] 6-Chloro-4-(2,2-difluoroethoxy)-2-[(2S)-1,1,1-trifluoropropan-2-yl]pyridazin-3-one (1000 mg, 3.26 mmol), bis(pinacolato)diboron (1004 mg, 3.91 mmol), Pd(OAc) (214.6 mg, 0.065 mmol), CyJohnPhos (22.9 mg, 0.065 mmol), and potassium acetate (384 mg, 3.91 mmol) were dissolved in monoglyme and stirred at 60°C for 1 hour. 15 mL of ethyl acetate and 7 mL of water were added, stirred, and filtered using Celite. Drying over anhydrous magnesium sulfate, filtering, and concentrating, 5 mL of diisopropyl ether was added dropwise, and stirred overnight. The crystals were filtered to obtain the target compound. (800 mg, 62%)

[0511] 1 H NMR (DMSO-d6, 400 MHz) δ 6.88 (s, 1H), 6.3-6.6 (m, 1H), 5.8-5.9 (m, 1H), 4.4-4.5 (m, 2H), 1.57 (d, 3H, J=7.0 Hz), 1.31 (s, 12H)

[0512]

[0513] Step 3) Preparation of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0514]

[0515] N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide 50 mg (0.20 mmol), 4-(2,2-difluoroethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(2S)-1,1,1-trifluoropropan-2-yl]pyridazin-3-one 94 mg (0.24 mmol), Pd(dppf)2Cl2 . 16 mg (0.020 mmol) of DCM and 84 mg (0.39 mmol) of K3PO4 were dissolved in 2 mL of 1,4-dioxane and 0.4 mL of water, and stirred at 80°C for 2 hours. After cooling to room temperature, the solution was filtered using Celite. The target compound was obtained using Prep-HPLC. (11.8 mg, 13%)

[0516] LC-MS (ESI) calcd. for C 18 H 16 F5N5O3: 445.34, m / z found, 446.49 [M+H] + .

[0517] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.0 (s, 1H), 8.5-8.7 (m, 2H), 7.9 (s, 1H), 7.7 (s, 1H), 6.94 (br s, 1H), 6.2-6.3 (m, 1H), 5.9-6.0 (m, 1H), 4.2-4.5 (m, 4H), 2.26 (br s, 3H), 1.8-2.0 (m, 3H)

[0518]

[0519] Manufacturing Example 9) Manufacturing of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetamide (Compound Example 116)

[0520] Step 1) Preparation of (S)-6-(5-amino-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-(2,2-difluoroethoxy)-2-(1,1,1-trifluoropropan-2-yl)pyridazin-3(2H)-one

[0521]

[0522] (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 85) 150 mg (0.32 mmol) was dissolved in 1 mL of dimethyl chloride, 0.3 mL of 4N HCl in 1,4-dioxane was added dropwise, and the mixture was stirred at 80°C overnight. After lowering the temperature to room temperature, concentration was performed, and the target compound was obtained using Prep-HPLC. (130 mg, 95%)

[0523] LC-MS (ESI) calcd. for C 18 H 18 F5N5O2: 431.36, m / z found, 432.12 [M+H] + .

[0524] 1H NMR (METHANOL-d4, 400 MHz) δ 8.27 (br s, 1H), 8.09 (br s, 1H), 7.46 (br s, 1H), 7.30 (br s, 1H), 6.46 (br s, 1H), 6.32 (br s, 1H), 6.19 (br s, 1H), 5.9-6.0 (m, 1H), 4.48 (br t, 2H, J=12.6 Hz), 4.24 (br d, 2H, J=6.6 Hz), 1.80 (br d, 3H, J=6.3 Hz), 1.51 (br t, 3H, J=6.3 Hz)

[0525]

[0526] Step 2) Preparation of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetamide

[0527]

[0528] (S)-6-(5-amino-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-(2,2-difluoroethoxy)-2-(1,1,1-trifluoropropan-2-yl)pyridazin-3(2H)-one 30 mg (0.0695 mmol) was dissolved in 1 mL of dimethyl chloride, and 14.2 mg (0.104 mmol) of acetoxyacetyl chloride and 0.028 mL (0.348 mmol) of pyridine were added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved in 1 mL of methanol, and 19.2 mg (0.139 mmol) of potassium carbonate was added dropwise and stirred at room temperature for 15 minutes. After concentration under reduced pressure, the target compound was obtained using Prep-HPLC. (10.7 mg, 31%)

[0529] LC-MS (ESI) calcd. for C 20 H 20 F5N5O4: 489.40, m / z found, 490.21 [M+H] + .

[0530] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.31 (br s, 1H), 9.02 (br s, 1H), 8.46 (s, 1H), 7.61 (s, 1H), 6.88 (s, 1H), 6.1-6.4 (m, 1H), 5.94 (br s, 1H), 5.32 (s, 6H), 4.2-4.5 (m, 6H), 1.89 (br d, 3H, J=6.5 Hz), 1.5-1.6 (m, 3H)

[0531]

[0532] Manufacturing Example 10) Manufacturing of (S)-1-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea (Example 117 compound)

[0533] Step 1) Preparation of (S)-6-(5-amino-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-(2,2-difluoroethoxy)-2-(1,1,1-trifluoropropan-2-yl)pyridazin-3(2H)-one

[0534]

[0535] The title compound was obtained in the same manner as in step 1 of Manufacturing Example 9.

[0536]

[0537] Step 2) Preparation of (S)-1-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea

[0538]

[0539] (S)-6-(5-amino-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-(2,2-difluoroethoxy)-2-(1,1,1-trifluoropropan-2-yl)pyridazin-3(2H)-one 30 mg (0.0695 mmol) was dissolved in 1 mL of tetrahydrofuran, and 21 mg (0.0695 mmol) of triphosgene was added dropwise at 0°C and stirred for 1 hour. After the temperature was raised to room temperature, 0.278 mL (0.556 mmol) of 2M methylamine in tetrahydrofuran was added dropwise and stirred for 2 hours. After concentration under reduced pressure, the target compound was obtained using Prep-HPLC. (7 mg, 21%)

[0540] 1 H NMR (METHANOL-d4, 400 MHz) δ 8.54 (d, 1H, J=0.9 Hz), 8.2 (s, 1H), 8.1 (s, 1H), 7.84 (d, 1H, J=0.9 Hz), 7.37 (s, 1H), 6.2-6.5 (m, 1H), 5.9-6.0 (m, 1H), 4.50 (dt, 2H, J=3.9, 13.3 Hz), 4.3-4.4 (m, 2H), 3.13 (br s, 3H), 1.83 (d, 3H, J=7.0 Hz), 1.5-1.6 (m, 3H)

[0541]

[0542] The following examples were synthesized with reference to the above manufacturing examples.

[0543]

[0544] Example 1: Synthesis of N-(1-methyl-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0545]

[0546] The above compound was obtained by the method of Preparation Example 7.

[0547] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.91 (s, 1H), 8.43 (s, 1H), 7.9-8.0 (m, 1H), 7.5-7.6 (m, 2H), 6.94 (d, 1H, J=9.6 Hz), 4.4-4.5 (m, 1H), 4.30 (d, 1H, J=9.5 Hz), 4.0-4.1 (m, 2H), 3.9 (s, 3H), 2.8-2.9 (m, 1H), 2.6-2.7 (m, 1H), 2.2 (s, 3H), 1.7 (s, 3H)

[0548]

[0549] Example 2: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0550]

[0551] The above compound was obtained by the method of Preparation Example 6.

[0552] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.9-9.0 (m, 1H), 8.4-8.5 (m, 1H), 7.9-7.9 (m, 1H), 7.7-7.7 (m, 1H), 7.6-7.7 (m, 1H), 6.9-7.1 (m, 1H), 4.9-5.0 (m, 1H), 4.4-4.5 (m, 1H), 4.2-4.4 (m, 1H), 4.0-4.2 (m, 2H), 3.1-3.3 (m, 3H), 2.8-3.0 (m, 3H), 2.7-2.8 (m, 1H), 2.2 (s, 3H), 1.7-1.8 (s, 3H)

[0553]

[0554] Example 3: Synthesis of N-(1-methyl-3-(1-(3-methyloxetan-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0555]

[0556] The above compound was obtained by the method of Preparation Example 7.

[0557] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.9-8.9 (m, 1H), 8.46 (s, 1H), 8.0-8.0 (m, 1H), 7.5-7.6 (m, 2H), 6.9-7.0 (m, 1H), 6.3-6.4 (m, 2H), 5.2-5.3 (m, 2H), 4.9-5.1 (m, 3H), 4.7-4.8 (m, 2H), 3.9-4.1 (m, 5H), 2.2-2.3 (m, 6H), 2.0-2.0 (s, 3H)

[0558]

[0559] Example 4: Synthesis of 1-(1-methyl-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0560]

[0561] The above compound was obtained by the method of Preparation Example 2.

[0562] 1 H NMR (METHANOL-d4, 400 MHz) δ 8.55 (s, 1H), 8.1-8.1 (m, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 6.99 (d, 1H, J=9.6 Hz), 4.4-4.4 (m, 1H), 4.2-4.3 (m, 1H), 4.0-4.1 (m, 2H), 3.9-4.0 (s, 3H), 3.59 (d, 1H, J=4.8 Hz), 3.5-3.6 (m, 1H), 2.8-2.9 (m, 1H), 2.7-2.7 (m, 1H), 2.0-2.1 (m, 3H)

[0563]

[0564] Example 5: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(5-methyl-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0565]

[0566] The above compound was obtained by the method of Preparation Example 6.

[0567] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.96 (s, 1H), 8.43 (s, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 7.4-7.5 (m, 1H), 4.97 (br d, 1H, J=9.0 Hz), 4.50 (d, 1H, J=9.3 Hz), 4.30 (d, 1H, J=9.4 Hz), 4.0-4.1 (m, 2H), 3.1-3.2 (m, 3H), 2.8-3.0 (m, 3H), 2.72 (br d, 1H, J=6.1 Hz), 2.3-2.3 (m, 3H), 2.24 (s, 3H), 1.77 (s, 3H)

[0568]

[0569] Example 6: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(1-(3-ethyltetrahydrofuran-3-yl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0570]

[0571] The above compound was obtained by the method of Preparation Example 6.

[0572] 1H NMR (DMSO-d6, 400 MHz) δ 10.2-10.3 (m, 1H), 8.8-8.9 (m, 1H), 8.6-8.7 (m, 2H), 8.0-8.0 (m, 1H), 5.1-5.3 (m, 1H), 4.3-4.4 (m, 1H), 4.0-4.1 (m, 1H), 3.8-3.9 (m, 2H), 2.8-3.0 (m, 4H), 2.7-2.8 (m, 1H), 2.6-2.7 (m, 1H), 2.1-2.2 (m, 3H), 2.1-2.1 (s, 3H), 1.9-2.0 (m, 1H), 0.9 (s, 3H)

[0573]

[0574] Example 7: Synthesis of 1-(3-(1-(3-ethyltetrahydrofuran-3-yl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0575]

[0576] The above compound was obtained by the method of Preparation Example 2.

[0577] 1 H NMR (DMSO-d6, 400 MHz) δ 8.9-8.9 (m, 1H), 8.54 (d, 1H, J=0.8 Hz), 8.3-8.4 (m, 1H), 8.17 (s, 1H), 7.8-7.9 (m, 1H), 6.4-6.6 (m, 2H), 4.3-4.4 (m, 1H), 4.0-4.1 (m, 1H), 3.8-3.9 (m, 5H), 2.6-2.7 (m, 3H), 2.1-2.2 (m, 4H), 1.9-2.0 (m, 1H), 0.8 (s, 3H)

[0578]

[0579] Example 8: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(5-cyclopropyl-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0580]

[0581] The above compound was obtained by the method of Preparation Example 6.

[0582] 1 H NMR (400 MHz, METHANOL-d4) δ 8.74 (s, 1 H) 8.59 - 8.66 (s, 1 H) 8.40 - 8.44 (s, 1 H) 7.50 - 7.55 (m, 1 H) 4.38 - 4.44 (m, 1 H) 3.95 - 4.06 (m, 3 H) 3.07 - 3.17 (m, 2 H) 2.92 - 3.04 (m, 2 H) 2.69 - 2.79 (m, 1 H) 2.25 - 2.33 (m, 1 H) 2.21 - 2.23 (s, 3 H) 2.17 - 2.20 (m, 1 H) 1.92 - 1.94 (m, 1 H) 1.90 - 1.92 (s, 3 H) 1.17 - 1.21 (m, 2 H) 1.01 - 1.07 (m, 2 H)

[0583]

[0584] Example 9: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(5-ethoxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0585]

[0586] The above compound was obtained by the method of Preparation Example 6.

[0587] 1H NMR (400 MHz, METHANOL-d4) δ 8.84 - 8.89 (s, 1 H) 8.57 - 8.60 (s, 1 H) 8.53 - 8.56 (s, 1 H) 7.34 - 7.38 (s, 1 H) 5.13 - 5.22 (m, 1 H) 4.40 - 4.45 (m, 1 H) 4.23 - 4.32 (m, 3 H) 4.01 - 4.08 (m, 2 H) 3.36 - 3.38 (m, 2 H) 3.07 - 3.16 (m, 2 H) 2.96 - 3.03 (m, 2 H) 2.86 - 2.95 (m, 1) H) 2.68 - 2.75 (m, 1 H) 2.21 - 2.23 (s, 3 H) 1.71 - 1.74 (s, 3 H) 1.52 - 1.58 (t, 3 H)

[0588]

[0589] Example 10: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0590]

[0591] The above compound was obtained by the method of Preparation Example 6.

[0592] 1 H NMR (METHANOL-d4, 400 MHz) δ 8.83 (s, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 6.58 (s, 1H), 5.1-5.2 (m, 1H), 4.5-4.5 (m, 1H), 4.3-4.5 (m, 2H), 4.22 (br d, 1H, J=9.8 Hz), 4.12 (br s, 1H), 4.02 (br d, 2H, J=7.5 Hz), 3.50 (br s, 1H), 2.8-3.2 (m, 5H), 2.6-2.7 (m, 1H), 2.21 (s, 2H), 1.69 (s, 2H)

[0593]

[0594] Example 11: Synthesis of 1-(3-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0595]

[0596] The above compound was obtained by the method of Preparation Example 2.

[0597] 1 H NMR (DMSO-d6, 400 MHz) δ 8.89 (br s, 1H), 8.51 (s, 1H), 8.22 (br s, 1H), 8.14 (s, 1H), 6.38 (s, 1H), 4.38 (br s, 2H), 4.27 (br d, 2H, J=9.1 Hz), 3.9-4.1 (m, 3H), 3.8-3.9 (m, 4H), 3.2-3.3 (m, 1H), 2.61 (br d, 2H, J=18.3 Hz), 1.54 (s, 3H)

[0598]

[0599] Example 12: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(5-cyclopropyl-6-oxo-1-(3-oxocyclobutyl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0600]

[0601] The above compound was obtained by the method of Preparation Example 6.

[0602] 1H NMR (400 MHz, DMSO-d6) δ 10.23 - 10.31 (br s, 1 H) 8.84 - 8.93 (s, 1 H) 8.61 - 8.69 (m, 2 H) 7.45 - 7.52 (s, 1 H) 5.50 - 5.63 (s, 1 H) 5.10 - 5.25 (m, 1 H) 3.92 - 3.95 (m, 1 H) 3.74 - 3.83 (m, 2 H) 3.47 - 3.50 (m, 2 H) 2.96 - 3.05 (m, 2 H) 2.85 - 2.92 (m, 2 H) 2.21 - 2.28 (m, 1H) 2.06 - 2.09 (s, 3 H) 1.10 - 1.14 (m, 2 H) 1.00 - 1.04 (m, 2 H)

[0603]

[0604] Example 13: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0605]

[0606] The above compound was obtained by the method of Preparation Example 6.

[0607] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.61 (s, 1H), 8.44 (s, 1H), 8.39 (s, 1H), 8.02 (s, 1H), 7.82 (br d, 1H, J=8.5 Hz), 7.50 (s, 1H), 6.82 (d, 1H, J=8.5 Hz), 4.97 (br t, 1H, J=7.9 Hz), 4.29 (d, 1H, J=9.8 Hz), 3.9-4.0 (m, 3H), 3.1-3.2 (m, 3H), 2.9-3.0 (m, 2H), 2.6-2.7 (m, 1H), 2.24 (s, 3H), 2.1-2.2 (m, 1H), 1.82 (s, 3H)

[0608]

[0609] Example 14: Synthesis of 1-(1-methyl-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0610]

[0611] The above compound was obtained by the method of Preparation Example 2.

[0612] 1 H NMR (METHANOL-d4, 400 MHz) δ 8.5-8.6 (m, 1H), 8.4-8.4 (m, 1H), 7.9-8.0 (m, 1H), 7.68 (s, 3H), 6.8-6.9 (m, 1H), 4.2-4.3 (m, 1H), 3.9-4.0 (m, 6H), 2.6-2.7 (m, 1H), 2.1-2.2 (m, 1H), 1.8 (s, 3H)

[0613]

[0614] Example 15: Synthesis of N-(3-methyl-1-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide

[0615]

[0616] The above compound was obtained by the method of Preparation Example 5.

[0617] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.68 (s, 1H), 8.56 (s, 1H), 8.09 (br s, 1H), 7.56 (d, 1H, J=9.9 Hz), 7.1-7.2 (m, 2H), 4.2-4.4 (m, 2H), 4.0-4.1 (m, 2H), 2.8-2.9 (m, 1H), 2.5-2.6 (m, 1H), 2.4 (s, 3H), 2.2 (s, 3H), 1.8 (s, 3H)

[0618]

[0619] Example 16: Synthesis of N-(5-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide

[0620]

[0621] The above compound was obtained by the method of Preparation Example 4.

[0622] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.6-8.7 (m, 1H), 8.4-8.5 (m, 1H), 7.5-7.6 (m, 1H), 6.8-6.8 (m, 1H), 6.10 (s, 1H), 4.4-4.6 (m, 3H), 4.3-4.4 (m, 1H), 4.2-4.3 (m, 1H), 4.1-4.2 (m, 2H), 4.0-4.1 (m, 2H), 3.3 (s, 3H), 2.8-2.9 (m, 1H), 2.6-2.7 (m, 1H), 2.5 (s, 3H), 2.2 (s, 3H), 1.7 (s, 3H)

[0623]

[0624] Example 17: Synthesis of N-(3-(5-(3-methoxyazetidin-1-yl)-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0625]

[0626] The above compound was obtained by the method of Preparation Example 1.

[0627] 1H NMR (400 MHz, METHANOL-d4) δ 8.54 (s, 1 H) 8.85 (s, 1 H) 6.37 (s, 1 H) 7.96 (s, 1 H) 4.45 - 4.52 (m, 2 H) 4.37 - 4.42 (t, 2 H) 4.32 - 4.37 (m, 1 H) 4.07 - 4.15 (m, 2 H) 3.97 - 4.02 (m, 2 H) 3.95 (s, 3 H) 3.41 (s, 3 H) 3.37 (s, 3 H) 2.22 (s, 3 H)

[0628]

[0629] Example 18: Synthesis of N-(3-(1-(1-methoxy-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0630]

[0631] The above compound was obtained by the method of Preparation Example 1.

[0632] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.77 (s, 1H), 8.48 (s, 1H), 8.0-8.1 (m, 2H), 7.8-7.9 (m, 1H), 7.02 (d, 1H, J=9.1 Hz), 3.9-4.0 (m, 3H), 3.8-3.9 (m, 2H), 3.4-3.5 (m, 3H), 2.2-2.3 (m, 4H), 1.70 (s, 6H)

[0633]

[0634] Example 19: Synthesis of N-(3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0635]

[0636] The above compound was obtained by the method of Preparation Example 1.

[0637] 1H NMR (CHLOROFORM-d, 400 MHz) δ 9.08 (s, 1H), 8.45 (s, 1H), 7.95 (br s, 1H), 7.54 (s, 1H), 6.71 (s, 1H), 5.4-5.6 (m, 1H), 3.95 (s, 3H), 3.84 (d, 2H, J=6.6 Hz), 2.2-2.3 (m, 4H), 1.6-1.6 (m, 6H), 1.12 (d, 6H, J=6.8 Hz)

[0638]

[0639] Example 20: Synthesis of N-(3-(1-isopropyl-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0640]

[0641] The above compound was obtained by the method of Preparation Example 1.

[0642] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.03 (s, 1H), 8.4-8.5 (m, 1H), 7.9-8.0 (m, 1H), 7.51 (s, 1H), 6.09 (s, 1H), 5.3-5.4 (m, 1H), 4.53 (br s, 2H), 4.3-4.4 (m, 1H), 4.17 (br d, 2H, J=6.6 Hz), 3.92 (s, 3H), 3.36 (s, 3H), 2.25 (s, 3H), 1.5-1.6 (m, 6H)

[0643]

[0644] Example 21: Synthesis of N-(1-cyclopropyl-3-(1-isopropyl-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0645]

[0646] The above compound was obtained by the method of Preparation Example 3.

[0647] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.01 (s, 1H), 8.5-8.7 (m, 1H), 7.99 (br s, 1H), 7.56 (s, 1H), 6.07 (s, 1H), 5.3-5.4 (m, 1H), 4.53 (br s, 2H), 4.35 (s, 1H), 4.1-4.3 (m, 2H), 3.48 (s, 1H), 3.36 (s, 3H), 2.2-2.3 (m, 4H), 1.5-1.6 (m, 6H), 1.2-1.2 (m, 2H), 1.12 (br d, 2H, J=4.4 Hz)

[0648]

[0649] Example 22: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0650]

[0651] The above compound was obtained by the method of Preparation Example 6.

[0652] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.11 (s, 1H), 8.43 (s, 1H), 7.97 (s, 1H), 7.70 (s, 1H), 6.74 (s, 1H), 5.4-5.6 (m, 1H), 5.00 (s, 1H), 3.90 (d, 2H, J=6.6 Hz), 3.1-3.2 (m, 3H), 2.9-3.1 (m, 2H), 2.3-2.4 (m, 1H), 2.26 (s, 3H), 1.5-1.6 (m, 6H), 1.14 (d, 6H, J=6.8 Hz)

[0653]

[0654] Example 23: Synthesis of N-(3-(1-cyclobutyl-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0655]

[0656] The above compound was obtained by the method of Preparation Example 7.

[0657] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.12 (s, 1H), 8.46 (s, 1H), 7.9-8.0 (m, 1H), 7.5-7.6 (m, 1H), 6.72 (s, 1H), 5.6-5.7 (m, 1H), 3.9 (s, 3H), 3.8-3.9 (m, 2H), 2.7-2.9 (m, 2H), 2.4-2.6 (m, 2H), 2.2-2.3 (m, 4H), 2.0-2.2 (m, 1H), 1.8-2.0 (m, 1H), 1.0-1.2 (m, 6H)

[0658] "

[0659] Example 24: Synthesis of N-(3-(1-cyclobutyl-5-(3-(methoxymethyl)azetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0660]

[0661] The above compound was obtained by the method of Preparation Example 7.

[0662] 1H NMR (CHLOROFORM-d, 400 MHz) δ 9.05 (s, 1H), 8.42 (s, 1H), 7.99 (br s, 1H), 7.52 (s, 1H), 6.05 (s, 1H), 5.50 (t, 1H, J=8.4 Hz), 4.39 (br s, 2H), 4.08 (br s, 2H), 3.92 (s, 3H), 3.62 (d, 2H, J=6.6 Hz), 3.41 (s, 3H), 2.97 (br s, 1H), 2.80 (br t, 2H, J=10.4 Hz), 2.41 (br d, 2H, J=8.5 Hz), 2.24 (s, 3H), 2.05 (br d, 1H, J=9.9 Hz), 1.7-1.9 (m, 1H)

[0663]

[0664] Example 25: Synthesis of N-(3-(5-(isopentyloxy)-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0665]

[0666] The above compound was obtained by the method of Preparation Example 1.

[0667] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.08 (s, 1H), 8.45 (s, 1H), 8.06 (s, 1H), 7.54 (s, 1H), 6.72 (s, 1H), 5.4-5.5 (m, 1H), 4.12 (t, 2H, J=6.6 Hz), 3.94 (s, 3H), 2.26 (s, 3H), 1.8-2.0 (m, 4H), 1.57 (d, 6H, J=6.6 Hz), 1.01 (d, 6H, J=6.5 Hz)

[0668]

[0669] Example 26: Synthesis of N-(3-(1-isopropyl-6-oxo-5-(2,2,2-trifluoroethoxy)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0670]

[0671] The above compound was obtained by the method of Preparation Example 1.

[0672] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.08 (s, 1H), 8.46 (s, 1H), 7.99 (br s, 1H), 7.52 (s, 1H), 7.01 (s, 1H), 5.4-5.5 (m, 1H), 4.78 (q, 2H, J=8.2 Hz), 3.95 (s, 3H), 2.27 (s, 3H), 1.60 (d, 6H, J=6.6 Hz)

[0673]

[0674] Example 27: Synthesis of N-(3-(5-(benzyloxy)-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0675]

[0676] The above compound was obtained by the method of Preparation Example 1.

[0677] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.05 (s, 1H), 8.43 (s, 1H), 8.08 (br s, 1H), 7.52 (d, 2H, J=7.3 Hz), 7.3-7.5 (m, 4H), 6.78 (s, 1H), 5.4-5.6 (m, 1H), 5.27 (s, 2H), 3.92 (s, 3H), 2.26 (s, 3H), 1.57 (d, 6H, J=6.6 Hz)

[0678]

[0679] Example 28: Synthesis of N-(3-(1-(tert-butyl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0680]

[0681] The above compound was obtained by the method of Preparation Example 7.

[0682] 1 H NMR (DMSO-d6, 400 MHz) δ 10.20 (s, 1H), 8.85 (s, 1H), 8.63 (d, 1H, J=1.0 Hz), 8.30 (s, 1H), 7.15 (s, 1H), 3.92 (s, 3H), 3.84 (d, 2H, J=6.6 Hz), 2.1-2.1 (m, 4H), 1.72 (s, 9H), 1.03 (d, 6H, J=6.8 Hz)

[0683]

[0684] Example 29: Synthesis of N-(3-(1-(tert-butyl)-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0685]

[0686] The above compound was obtained by the method of Preparation Example 7.

[0687] 1 H NMR (DMSO-d6, 400 MHz) δ 10.17 (s, 1H), 8.81 (s, 1H), 8.59 (d, 1H, J=0.9 Hz), 8.12 (s, 1H), 6.38 (s, 1H), 4.3-4.4 (m, 2H), 4.3-4.3 (m, 1H), 3.9-4.0 (m, 2H), 3.90 (s, 3H), 3.25 (s, 3H), 2.07 (s, 3H), 1.68 (s, 9H)

[0688]

[0689] Example 30: Synthesis of N-(3-(5-isobutoxy-1-(1-methylcyclopentyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0690]

[0691] The above compound was obtained by the method of Preparation Example 7.

[0692] 1 H NMR (DMSO-d6, 400 MHz) δ 10.19 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H, J=0.9 Hz), 8.30 (s, 1H), 7.15 (s, 1H), 3.92 (s, 3H), 3.85 (d, 2H, J=6.6 Hz), 2.4-2.4 (m, 2H), 2.2-2.3 (m, 2H), 2.1-2.2 (m, 4H), 1.6-1.7 (m, 4H), 1.53 (s, 3H), 1.03 (d, 6H, J=6.8 Hz)

[0693]

[0694] Example 31: Synthesis of N-(3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclopentyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0695]

[0696] The above compound was obtained by the method of Preparation Example 7.

[0697] 1H NMR (DMSO-d6, 400 MHz) δ 10.15 (s, 1H), 8.81 (s, 1H), 8.59 (d, 1H, J=1.0 Hz), 8.13 (s, 1H), 6.37 (s, 1H), 4.3-4.4 (m, 2H), 4.2-4.3 (m, 1H), 3.9-4.0 (m, 2H), 3.90 (s, 3H), 3.25 (s, 3H), 2.4-2.4 (m, 2H), 2.2-2.2 (m, 2H), 2.08 (s, 3H), 1.6-1.7 (m, 4H), 1.51 (s, 3H)

[0698]

[0699] Example 32: Synthesis of N-(3-(5-isobutoxy-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0700]

[0701] The above compound was obtained by the method of Preparation Example 7.

[0702] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.9-9.0 (m, 1H), 8.4-8.5 (m, 1H), 8.1-8.1 (m, 1H), 7.53 (s, 1H), 6.70 (s, 1H), 5.32 (s, 12H), 3.94 (s, 3H), 3.82 (d, 2H, J=6.8 Hz), 3.51 (s, 3H), 2.7-2.8 (m, 2H), 2.5-2.6 (m, 2H), 2.25 (s, 3H), 1.9-2.0 (m, 1H), 1.8-1.9 (m, 1H), 1.11 (d, 7H, J=6.8 Hz)

[0703]

[0704] Example 33: Synthesis of N-(1-cyclobutyl-3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0705]

[0706] The above compound was obtained by the method of Preparation Example 1.

[0707] 1 H NMR (DMSO-d6, 400 MHz) δ 10.22 (s, 1H), 9.06 (s, 1H), 8.66 (d, 1H, J=0.9 Hz), 8.55 (s, 1H), 7.28 (s, 1H), 5.26 (quin, 1H, J=6.7 Hz), 5.14 (quin, 1H, J=8.4 Hz), 3.90 (d, 2H, J=6.5 Hz), 2.6-2.6 (m, 1H), 2.6-2.6 (m, 1H), 2.1-2.2 (m, 1H), 2.10 (s, 3H), 1.9-2.0 (m, 2H), 1.43 (d, 6H, J=6.6 Hz), 1.05 (d, 6H, J=6.8 Hz)

[0708]

[0709] Example 34: Synthesis of 1-(3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0710]

[0711] The above compound was obtained by the method of Preparation Example 2.

[0712] 1 H NMR (DMSO-d6, 400 MHz) δ 8.93 (s, 1H), 8.54 (d, 1H, J=1.0 Hz), 8.48 (br s, 1H), 8.29 (s, 1H), 7.14 (s, 1H), 6.5-6.6 (m, 2H), 5.25 (td, 1H, J=6.6, 13.4 Hz), 3.89 (s, 5H), 2.1-2.2 (m, 2H), 2.0-2.0 (m, 1H), 1.42 (d, 6H, J=6.6 Hz), 1.03 (d, 6H, J=6.8 Hz)

[0713]

[0714] Example 35: Synthesis of 1-(1-cyclobutyl-3-(5-isobutoxy-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0715]

[0716] The above compound was obtained by the method of Preparation Example 2.

[0717] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.45 (s, 1H), 7.5-7.7 (m, 2H), 6.99 (s, 1H), 6.65 (s, 1H), 4.92 (s, 1H), 3.82 (d, 2H, J=6.8 Hz), 2.6-2.8 (m, 4H), 2.55 (dt, 2H, J=2.4, 9.5 Hz), 2.4-2.5 (m, 2H), 2.2-2.4 (m, 1H), 1.9-2.1 (m, 3H), 1.88 (br s, 1H), 1.73 (s, 3H), 1.13 (d, 6H, J=6.6 Hz)

[0718]

[0719] Example 36: Synthesis of N-(1-cyclobutyl-3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0720]

[0721] The above compound was obtained by the method of Preparation Example 7.

[0722] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.95 (s, 1H), 8.47 (s, 1H), 8.04 (s, 1H), 7.69 (s, 1H), 6.77 (s, 1H), 5.9-6.1 (m, 1H), 4.94 (s, 1H), 4.23 (s, 1H), 3.89 (br d, 1H, J=3.3 Hz), 3.88 (br d, 1H, J=3.5 Hz), 2.6-2.8 (m, 2H), 2.5-2.6 (m, 2H), 2.2-2.3 (m, 4H), 2.05 (td, 2H, J=5.0, 9.9 Hz), 1.89 (d, 3H, J=7.1 Hz), 1.27 (s, 2H), 1.12 (d, 6H, J=6.8 Hz)

[0723]

[0724] Example 37: Synthesis of 1-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0725]

[0726] The above compound was obtained by the method of Preparation Example 2.

[0727] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.4-8.5 (m, 1H), 7.6-7.6 (m, 1H), 7.5-7.6 (m, 1H), 6.9-7.0 (m, 1H), 6.67 (s, 1H), 5.9-6.0 (m, 1H), 3.9-4.0 (m, 3H), 3.8-3.9 (m, 2H), 2.2-2.4 (m, 1H), 1.7-1.8 (m, 3H), 1.0-1.1 (m, 6H)

[0728]

[0729] Example 38: Synthesis of 1-(1-cyclobutyl-3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0730]

[0731] The above compound was obtained by the method of Preparation Example 2.

[0732] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.4-8.5 (m, 1H), 7.6-7.7 (m, 2H), 7.0-7.0 (m, 1H), 6.6-6.7 (m, 1H), 5.4-5.5 (m, 1H), 4.9-5.0 (m, 1H), 3.8-3.9 (m, 2H), 2.6-2.8 (m, 2H), 2.5-2.6 (m, 2H), 2.3-2.4 (m, 1H), 2.0-2.1 (m, 2H), 1.50 (d, 6H, J=6.6 Hz), 1.13 (d, 6H, J=6.8 Hz)

[0733]

[0734] Example 39: Synthesis of N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0735]

[0736] The above compound was obtained by the method of Preparation Example 7.

[0737] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.91 (s, 1H), 8.42 (s, 1H), 7.9-8.0 (m, 1H), 7.53 (s, 1H), 6.1-6.1 (m, 1H), 5.8-5.9 (m, 1H), 4.5-4.6 (m, 2H), 4.3-4.4 (m, 1H), 4.2-4.2 (m, 2H), 3.9-4.0 (m, 3H), 3.9-4.0 (m, 4H), 3.37 (s, 3H), 2.25 (s, 4H), 1.8-1.9 (m, 3H)

[0738]

[0739] Example 40: Synthesis of N-(3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0740]

[0741] The above compound was obtained by the method of Preparation Example 7.

[0742] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.91 (s, 1H), 8.41 (s, 1H), 8.02 (br s, 1H), 7.48 (s, 1H), 6.08 (s, 1H), 4.51 (br s, 2H), 4.3-4.4 (m, 1H), 4.0-4.2 (m, 2H), 3.91 (s, 3H), 3.3-3.4 (m, 3H), 2.6-2.8 (m, 2H), 2.47 (br t, 2H, J=9.1 Hz), 2.24 (s, 3H), 1.95 (br d, 1H, J=10.3 Hz), 1.8-1.9 (m, 2H)

[0743]

[0744] Example 41: Synthesis of N-(1-cyclobutyl-3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0745]

[0746] The above compound was obtained by the method of Preparation Example 7.

[0747] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.90 (s, 1H), 8.43 (s, 1H), 8.12 (s, 1H), 7.62 (s, 1H), 6.10 (s, 1H), 4.91 (s, 1H), 4.52 (br s, 2H), 4.34 (s, 1H), 4.16 (br d, 2H, J=6.1 Hz), 3.34 (s, 3H), 2.7-2.8 (m, 2H), 2.66 (br dd, 2H, J=3.0, 5.6 Hz), 2.4-2.6 (m, 4H), 2.23 (s, 3H), 1.9-2.1 (m, 4H), 1.85 (br s, 1H), 1.79 (br s, 2H)

[0748]

[0749] Example 42: Synthesis of (S)-N-(3-(5-(3-methoxypyrrolidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0750]

[0751] The above compound was obtained by the method of Preparation Example 7.

[0752] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.9-8.9 (m, 1H), 8.4-8.5 (m, 1H), 7.9-7.9 (m, 1H), 7.51 (s, 1H), 6.2-6.2 (m, 1H), 4.0-4.1 (m, 3H), 3.9-4.0 (m, 3H), 3.7-3.8 (m, 2H), 3.3-3.4 (m, 3H), 2.7-2.8 (m, 2H), 2.4-2.5 (m, 2H), 2.2-2.3 (m, 2H), 2.2-2.3 (m, 1H), 1.7-1.8 (m, 3H), 0.8-0.9 (m, 4H)

[0753]

[0754] Example 43: Synthesis of (S)-N-(1-cyclobutyl-3-(5-(3-methoxypyrrolidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0755]

[0756] The above compound was obtained by the method of Preparation Example 7.

[0757] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.90 (s, 1H), 8.43 (s, 1H), 7.91 (br s, 1H), 7.64 (s, 1H), 6.21 (s, 1H), 4.92 (s, 1H), 4.0-4.1 (m, 3H), 3.6-3.8 (m, 2H), 3.38 (s, 3H), 2.75 (br d, 2H, J=10.4 Hz), 2.6-2.7 (m, 2H), 2.4-2.6 (m, 4H), 2.24 (s, 3H), 2.03 (dt, 4H, J=4.9, 10.3 Hz), 1.85 (s, 1H), 1.73 (s, 3H)

[0758]

[0759] Example 44: Synthesis of N-(1-cyclobutyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0760]

[0761] The above compound was obtained by the method of Preparation Example 7.

[0762] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.90 (s, 1H), 8.44 (s, 1H), 8.02 (s, 1H), 7.64 (s, 1H), 6.21 (s, 1H), 4.92 (br t, 1H, J=8.4 Hz), 4.6-4.8 (m, 5H), 4.12 (s, 2H), 3.70 (br t, 2H, J=6.8 Hz), 2.6-2.8 (m, 4H), 2.4-2.6 (m, 4H), 2.2-2.3 (m, 5H), 1.9-2.1 (m, 4H), 1.8-1.9 (m, 1H), 1.34 (d, 1H, J=6.6 Hz)

[0763]

[0764] Example 45: Synthesis of N-(1-methyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0765]

[0766] The above compound was obtained by the method of Preparation Example 7.

[0767] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.91 (s, 1H), 8.42 (s, 1H), 7.96 (br s, 1H), 7.51 (s, 1H), 6.21 (s, 1H), 5.32 (s, 1H), 4.74 (d, 2H, J=6.1 Hz), 4.64 (d, 2H, J=6.0 Hz), 4.11 (s, 2H), 3.92 (s, 3H), 3.69 (br t, 2H, J=6.8 Hz), 2.7-2.8 (m, 2H), 2.4-2.6 (m, 2H), 2.2-2.3 (m, 5H), 1.95 (br d, 1H, J=10.5 Hz), 1.84 (br d, 1H, J=10.5 Hz), 1.73 (s, 3H), 1.28 (s, 1H)

[0768]

[0769] Example 46: Synthesis of N-(1-methyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0770]

[0771] The above compound was obtained by the method of Preparation Example 7.

[0772] 1 H NMR (DMSO-d6, 400 MHz) δ 10.15 (s, 1H), 8.85 (s, 1H), 8.58 (d, 1H, J=1.0 Hz), 8.15 (s, 1H), 6.34 (s, 1H), 4.72 (s, 4H), 4.33 (br s, 3H), 3.90 (s, 3H), 2.07 (s, 3H), 2.0-2.0 (m, 3H), 1.8-1.9 (m, 1H), 1.7-1.7 (m, 1H), 1.55 (s, 3H), 1.4-1.5 (m, 2H)

[0773]

[0774] Example 47: Synthesis of N-(3-(5-(cyanomethoxy)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0775]

[0776] The above compound was obtained by the method of Preparation Example 7.

[0777] 1H NMR (DMSO-d6, 400 MHz) δ 10.22 (s, 1H), 8.89 (s, 1H), 8.65 (d, 1H, J=1.0 Hz), 8.26 (s, 1H), 7.44 (s, 1H), 5.31 (s, 2H), 3.94 (s, 3H), 2.6-2.6 (m, 2H), 2.4-2.4 (m, 2H), 2.09 (s, 3H), 1.8-1.9 (m, 1H), 1.7-1.8 (m, 1H), 1.60 (s, 3H)

[0778] Example 48: Synthesis of N-(1-methyl-3-(1-(1-methylcyclobutyl)-5-(oxetan-3-ylmethoxy)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0779]

[0780] The above compound was obtained by the method of Preparation Example 7.

[0781] 1 H NMR (400 MHz, CHLOROFORM- d) δ 8.96 (s, 1 H) 8.45 (s, 1 H) 7.58 (s, 1 H) 6.82 (s, 1 H) 4.93 - 5.01 (m, 2 H) 4.55 - 4.61 (m, 2 H) 4.38 (d, J=7.25 Hz, 2 H) 3.93 - 3.97 (m, 3 H) 3.58 - 3.67 (m, 1 H) 2.68 - 2.80 (m, 2 H) 2.46 - 2.56 (m, 2 H) 1.84 - 2.00 (m, 2 H) 1.75 (s, 3 H) 1.28 (s, 3H)

[0782]

[0783] Example 49: Synthesis of N-(1-cyclopropyl-3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0784]

[0785] The above compound was obtained by the method of Preparation Example 3.

[0786] 1 H NMR (DMSO-d6, 400 MHz) δ 10.25 (s, 1H), 8.95 (s, 1H), 8.69 (d, 1H, J=1.1 Hz), 8.43 (s, 1H), 7.32 (s, 1H), 5.8-5.9 (m, 1H), 3.9-4.0 (m, 2H), 3.6-3.7 (m, 1H), 2.1-2.2 (m, 1H), 2.09 (s, 3H), 1.81 (d, 3H, J=7.1 Hz), 1.1-1.2 (m, 2H), 1.1-1.1 (m, 2H), 1.04 (d, 6H, J=6.6 Hz)

[0787]

[0788] Example 50: Synthesis of (R)-N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0789]

[0790] The above compound was obtained by the method of Preparation Example 7.

[0791] 1 H NMR (DMSO-d6, 400 MHz) δ 10.22 (s, 1H), 8.94 (s, 1H), 8.65 (d, 1H, J=1.0 Hz), 8.40 (s, 1H), 7.25 (s, 1H), 5.8-5.9 (m, 1H), 3.9-4.0 (m, 5H), 2.1-2.2 (m, 4H), 2.0-2.0 (m, 1H), 1.81 (d, 3H, J=7.1 Hz), 1.04 (d, 6H, J=6.6 Hz)

[0792]

[0793] Example 51: Synthesis of N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0794]

[0795] The above compound was obtained by the method of Preparation Example 7.

[0796] 1 H NMR (DMSO-d6, 400 MHz) δ 10.22 (s, 1H), 8.94 (s, 1H), 8.65 (d, 1H, J=1.0 Hz), 8.40 (s, 1H), 7.25 (s, 1H), 5.85 (quin, 1H, J=7.3 Hz), 3.9-4.0 (m, 5H), 2.1-2.2 (m, 4H), 1.9-2.1 (m, 1H), 1.81 (d, 3H, J=7.1 Hz), 1.04 (d, 6H, J=6.6 Hz)

[0797]

[0798] Example 52: Synthesis of N-(1-cyclopropyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0799]

[0800] The above compound was obtained by the method of Preparation Example 3.

[0801] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.90 (s, 1H), 8.62 (s, 1H), 8.04 (br s, 1H), 7.57 (s, 1H), 6.08 (s, 1H), 5.84 (br d, 1H, J=7.3 Hz), 5.32 (s, 2H), 4.5-4.7 (m, 2H), 4.35 (s, 1H), 4.20 (br s, 2H), 3.47 (s, 1H), 3.36 (s, 3H), 2.25 (s, 3H), 1.8-1.9 (m, 3H), 1.2-1.4 (m, 5H), 1.0-1.2 (m, 5H), 0.90 (br s, 2H)

[0802]

[0803] Example 53: Synthesis of N-(1-cyclopropyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0804]

[0805] The above compound was obtained by the method of Preparation Example 3.

[0806] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.89 (s, 1H), 8.61 (s, 1H), 7.93 (br s, 1H), 7.56 (s, 1H), 6.18 (s, 1H), 4.75 (d, 2H, J=6.1 Hz), 4.64 (d, 2H, J=6.1 Hz), 4.11 (s, 2H), 3.69 (br t, 2H, J=6.8 Hz), 3.4-3.6 (m, 1H), 2.73 (br d, 2H, J=12.1 Hz), 2.4-2.6 (m, 2H), 2.2-2.3 (m, 5H), 1.95 (br d, 1H, J=10.4 Hz), 1.84 (br d, 1H, J=9.8 Hz), 1.73 (s, 3H), 1.1-1.2 (m, 4H)

[0807]

[0808] Example 54: Synthesis of (S)-N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0809]

[0810] The above compound was obtained by the method of Preparation Example 7.

[0811] 1 H NMR (DMSO-d6, 400 MHz) δ 10.22 (s, 1H), 8.94 (s, 1H), 8.65 (d, 1H, J=0.9 Hz), 8.40 (s, 1H), 7.25 (s, 1H), 5.8-5.9 (m, 1H), 3.9-4.0 (m, 5H), 2.1-2.2 (m, 4H), 1.81 (d, 3H, J=7.1 Hz), 1.03 (d, 6H, J=6.6 Hz)

[0812]

[0813] Example 55: Synthesis of N-(3-(5-(cyclobutylmethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0814]

[0815] The above compound was obtained by the method of Preparation Example 7.

[0816] 1 H NMR (DMSO-d6, 400 MHz) δ 10.22 (s, 1H), 8.94 (s, 1H), 8.65 (d, 1H, J=1.0 Hz), 8.40 (s, 1H), 7.27 (s, 1H), 5.84 (td, 1H, J=7.1, 14.6 Hz), 4.1-4.2 (m, 2H), 3.94 (s, 3H), 2.8-2.9 (m, 1H), 2.1-2.2 (m, 5H), 1.8-2.0 (m, 7H)

[0817]

[0818] Example 56: Synthesis of N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0819]

[0820] The above compound was obtained by the method of Preparation Example 7.

[0821] 1 H NMR (DMSO-d6, 400 MHz) δ 10.24 (s, 1H), 8.95 (s, 1H), 8.66 (d, 1H, J=1.0 Hz), 8.37 (s, 1H), 7.42 (s, 1H), 5.86 (quin, 1H, J=7.3 Hz), 4.49 (t, 2H, J=12.3 Hz), 3.94 (s, 3H), 2.10 (s, 3H), 1.7-1.9 (m, 6H)

[0822]

[0823] Example 57: Synthesis of (R)-N-(3-(1-(1-ethylcyclobutyl)-5-(2-methoxypropoxy)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0824]

[0825] The above compound was obtained by the method of Preparation Example 7.

[0826] 1H NMR (CHLOROFORM-d, 400 MHz) δ 9.00 (s, 1H), 8.41 (s, 2H), 7.51 (s, 1H), 6.76 (s, 1H), 4.0-4.2 (m, 1H), 3.9-4.0 (m, 5H), 3.5-3.5 (m, 3H), 2.7-2.8 (m, 2H), 2.5-2.6 (m, 2H), 2.2-2.3 (m, 5H), 1.8-2.0 (m, 3H), 1.3-1.4 (m, 5H), 0.8-0.9 (m, 6H)

[0827]

[0828] Example 58: Synthesis of (S)-N-(1-cyclopropyl-3-(6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0829]

[0830] The above compound was obtained by the method of Preparation Example 3.

[0831] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.8-9.0 (m, 1H), 8.6-8.7 (m, 1H), 7.9-8.0 (m, 1H), 7.5-7.7 (m, 1H), 6.2-6.3 (m, 1H), 5.8-6.0 (m, 1H), 4.6-4.8 (m, 4H), 4.0-4.2 (m, 2H), 3.7-3.9 (m, 2H), 3.4-3.6 (m, 1H), 2.2-2.4 (m, 5H), 1.8-1.9 (m, 3H), 1.1-1.3 (m, 4H)

[0832]

[0833] Example 59: Synthesis of N-(3-(1-(3,3-difluorobutan-2-yl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0834]

[0835] The above compound was obtained by the method of Preparation Example 7.

[0836] 1 H NMR (DMSO-d6, 400 MHz) δ 10.26 (s, 1H), 9.00 (s, 1H), 8.65 (d, 1H, J=1.0 Hz), 8.39 (s, 1H), 7.22 (s, 1H), 5.5-5.6 (m, 1H), 3.8-4.0 (m, 5H), 2.1-2.2 (m, 4H), 1.7-1.8 (m, 6H), 1.03 (d, 6H, J=6.8 Hz)

[0837]

[0838] Example 60: Synthesis of N-(3-(1-(1-ethylcyclobutyl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0839]

[0840] The above compound was obtained by the method of Preparation Example 7.

[0841] 1 H NMR (DMSO-d6, 400 MHz) δ 10.18 (s, 1H), 8.91 (s, 1H), 8.61 (d, 1H, J=1.1 Hz), 8.30 (s, 1H), 7.16 (s, 1H), 3.91 (s, 3H), 3.85 (d, 2H, J=6.6 Hz), 2.5-2.6 (m, 2H), 2.4-2.5 (m, 2H), 2.0-2.2 (m, 6H), 1.7-1.9 (m, 2H), 1.03 (d, 6H, J=6.6 Hz), 0.79 (t, 3H, J=7.4 Hz)

[0842]

[0843] Example 61: Synthesis of (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0844]

[0845] The above compound was obtained by the method of Preparation Example 7.

[0846] 1 H NMR (DMSO-d6, 400 MHz) δ 10.18 (s, 1H), 8.90 (s, 1H), 8.61 (d, 1H, J=1.0 Hz), 8.22 (s, 1H), 6.43 (s, 1H), 5.7-5.8 (m, 1H), 4.4-4.5 (m, 2H), 4.3-4.3 (m, 1H), 4.02 (br d, 2H, J=2.3 Hz), 3.91 (s, 3H), 3.26 (s, 3H), 2.08 (s, 3H), 1.77 (d, 3H, J=7.0 Hz)

[0847]

[0848] Example 62: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0849]

[0850] The above compound was obtained by the method of Preparation Example 7.

[0851] 1 H NMR (DMSO-d6, 400 MHz) δ 10.24 (s, 1H), 8.95 (s, 1H), 8.66 (d, 1H, J=1.0 Hz), 8.37 (s, 1H), 7.42 (s, 1H), 5.8-5.9 (m, 1H), 4.49 (t, 2H, J=12.3 Hz), 3.94 (s, 3H), 2.10 (s, 3H), 1.7-1.9 (m, 6H)

[0852]

[0853] Example 63: Synthesis of N-(1-((1S,3R)-3-cyanocyclobutyl)-3-(5-isobutoxy-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0854]

[0855] The above compound was obtained by the method of Preparation Example 6.

[0856] 1 H NMR (DMSO-d6, 400 MHz) δ 10.24 (s, 1H), 8.96 (s, 1H), 8.68 (s, 1H), 8.65 (d, 1H, J=0.9 Hz), 7.35 (s, 1H), 5.86 (quin, 1H, J=7.3 Hz), 5.1-5.2 (m, 1H), 3.97 (dq, 2H, J=6.6, 9.4 Hz), 3.2-3.3 (m, 1H), 3.01 (dq, 2H, J=2.4, 8.0 Hz), 2.8-3.0 (m, 2H), 2.16 (td, 1H, J=6.6, 13.3 Hz), 2.09 (s, 3H), 1.82 (d, 3H, J=7.0 Hz), 1.07 (d, 6H, J=6.8 Hz)

[0857]

[0858] Example 64: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0859]

[0860] The above compound was obtained by the method of Preparation Example 3.

[0861] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.89 (s, 1H), 8.62 (s, 1H), 8.00 (br s, 1H), 7.57 (s, 1H), 6.08 (s, 1H), 5.8-5.9 (m, 1H), 4.5-4.6 (m, 2H), 4.3-4.4 (m, 1H), 4.20 (br s, 2H), 3.48 (br d, 1H, J=3.8 Hz), 3.36 (s, 3H), 2.25 (s, 3H), 1.7-1.9 (m, 3H), 1.37 (s, 1H), 1.1-1.3 (m, 5H)

[0862]

[0863] Example 65: Synthesis of N-(1-cyclopropyl-3-(5-((R)-2-methoxypropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0864]

[0865] The above compound was obtained by the method of Preparation Example 3.

[0866] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.95 (s, 1H), 8.65 (s, 1H), 8.00 (br s, 1H), 7.61 (s, 1H), 6.83 (s, 1H), 5.9-6.0 (m, 1H), 4.17 (dd, 1H, J=6.2, 9.7 Hz), 4.01 (dd, 1H, J=4.8, 9.8 Hz), 3.91 (br d, 1H, J=5.4 Hz), 3.50 (s, 4H), 2.25 (s, 3H), 1.7-1.9 (m, 3H), 1.35 (d, 3H, J=6.3 Hz), 1.2-1.3 (m, 2H), 1.1-1.2 (m, 2H)

[0867]

[0868] Example 66: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(2-methoxyethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0869]

[0870] The above compound was obtained by the method of Preparation Example 3.

[0871] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.94 (s, 1H), 8.64 (s, 1H), 8.19 (br s, 1H), 7.61 (s, 1H), 6.87 (s, 1H), 5.9-6.0 (m, 1H), 4.31 (t, 2H, J=4.8 Hz), 4.14 (d, 1H, J=7.1 Hz), 3.8-4.0 (m, 2H), 3.5-3.5 (m, 4H), 2.25 (s, 3H), 2.06 (s, 1H), 1.87 (d, 3H, J=7.1 Hz), 1.2-1.3 (m, 3H), 1.12 (br d, 2H, J=3.3 Hz), 0.90 (s, 2H)

[0872]

[0873] Example 67: Synthesis of (S)-N-(3-(5-(3,3-difluoropyrrolidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0874]

[0875] The above compound was obtained by the method of Preparation Example 7.

[0876] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.90 (s, 1H), 8.43 (s, 1H), 8.00 (br s, 1H), 7.54 (s, 1H), 6.28 (s, 1H), 5.8-6.0 (m, 1H), 4.29 (br t, 2H, J=13.5 Hz), 3.8-3.9 (m, 5H), 2.4-2.6 (m, 2H), 2.25 (s, 3H), 2.03 (s, 1H), 1.7-1.9 (m, 3H)

[0877]

[0878] Example 68: Synthesis of N-(1-((1S,3R)-3-cyanocyclobutyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0879]

[0880] The above compound was obtained by the method of Preparation Example 6.

[0881] 1 H NMR (DMSO-d6, 400 MHz) δ 10.25 (s, 1H), 8.96 (s, 1H), 8.66 (s, 2H), 7.49 (s, 1H), 5.8-5.9 (m, 1H), 5.1-5.2 (m, 1H), 4.52 (t, 2H, J=12.0 Hz), 3.0-3.1 (m, 1H), 2.8-2.9 (m, 1H), 2.09 (s, 3H), 2.01 (q, 1H, J=7.1 Hz), 1.8-1.9 (m, 6H)

[0882]

[0883] Example 69: Synthesis of (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3

[0884]

[0885] The above compound was obtained by the method of Preparation Example 7.

[0886] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.90 (s, 1H), 8.39 (s, 1H), 8.00 (br s, 1H), 7.49 (s, 1H), 6.07 (s, 1H), 5.8-6.0 (m, 1H), 4.53 (br s, 2H), 4.3-4.4 (m, 1H), 4.19 (br s, 2H), 3.89 (s, 3H), 3.36 (s, 3H), 1.7-1.9 (m, 3H)

[0887]

[0888] Example 70: Synthesis of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0889]

[0890] The above compound was obtained by the method of Preparation Example 7.

[0891] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.9-9.1 (m, 1H), 8.8-8.9 (m, 1H), 8.4-8.5 (m, 1H), 7.9-8.0 (m, 1H), 7.5-7.6 (m, 1H), 6.8-7.0 (m, 1H), 6.1-6.4 (m, 1H), 5.9-6.0 (m, 1H), 5.9-5.9 (m, 1H), 4.3-4.5 (m, 2H), 3.8-4.0 (m, 3H), 2.2-2.3 (m, 3H), 1.8-2.0 (m, 3H)

[0892]

[0893] Example 71: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0894]

[0895] The above compound was obtained by the method of Preparation Example 3.

[0896] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.9-9.0 (m, 1H), 8.6-8.7 (m, 1H), 7.8-8.0 (m, 1H), 7.5-7.7 (m, 1H), 6.8-7.0 (m, 1H), 6.1-6.4 (m, 1H), 5.9-6.0 (m, 1H), 4.4-4.5 (m, 2H), 3.4-3.6 (m, 1H), 2.1-2.3 (m, 3H), 1.8-2.0 (m, 3H), 1.0-1.3 (m, 4H)

[0897]

[0898] Example 72: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3

[0899]

[0900] The above compound was obtained by the method of Preparation Example 7.

[0901] 1 H NMR (DMSO-d6, 400 MHz) δ 10.24 (s, 1H), 8.95 (s, 1H), 8.66 (d, 1H, J=1.0 Hz), 8.37 (s, 1H), 7.42 (s, 1H), 5.86 (quin, 1H, J=7.3 Hz), 4.49 (t, 2H, J=12.3 Hz), 3.94 (s, 3H), 1.7-1.9 (m, 6H)

[0902]

[0903] Example 73: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(methyl-d3)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0904]

[0905] The above compound was obtained by the method of Preparation Example 7.

[0906] 1 H NMR (DMSO-d6, 400 MHz) δ 10.24 (s, 1H), 8.95 (s, 1H), 8.66 (d, 1H, J=1.0 Hz), 8.37 (s, 1H), 7.42 (s, 1H), 5.8-5.9 (m, 1H), 4.49 (t, 2H, J=12.3 Hz), 2.10 (s, 3H), 1.7-1.9 (m, 6H)

[0907]

[0908] Example 74: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0909]

[0910] The above compound was obtained by the method of Preparation Example 3.

[0911] 1H NMR (DMSO-d6, 400 MHz) δ 10.27 (s, 1H), 8.95 (s, 1H), 8.70 (d, 1H, J=1.0 Hz), 8.42 (s, 1H), 7.47 (s, 1H), 5.85 (quin, 1H, J=7.4 Hz), 4.49 (t, 2H, J=12.3 Hz), 3.68 (tt, 1H, J=3.7, 7.1 Hz), 2.10 (s, 3H), 1.7-1.9 (m, 6H), 1.2-1.3 (m, 1H), 1.1-1.2 (m, 2H), 1.0-1.1 (m, 2H)

[0912]

[0913] Example 75: Synthesis of (S)-N-(3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0914]

[0915] The above compound was obtained by the method of Preparation Example 7.

[0916] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.91 (s, 1H), 8.41 (s, 1H), 7.93 (br s, 1H), 7.51 (s, 1H), 6.09 (s, 1H), 5.86 (s, 1H), 4.51 (br d, 3H, J=6.3 Hz), 4.1-4.3 (m, 2H), 3.91 (s, 3H), 3.6-3.8 (m, 1H), 2.25 (s, 3H), 1.8-1.9 (m, 3H), 1.20 (d, 6H, J=6.1 Hz)

[0917]

[0918] Example 76: Synthesis of (S)-N-(1-ethyl-3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0919]

[0920] The above compound was obtained by the method of Preparation Example 7.

[0921] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.91 (s, 1H), 8.45 (s, 1H), 7.92 (br s, 1H), 7.58 (s, 1H), 6.10 (s, 1H), 5.85 (br d, 1H, J=7.3 Hz), 4.4-4.6 (m, 3H), 4.28 (q, 4H, J=7.4 Hz), 3.6-3.7 (m, 1H), 2.25 (s, 3H), 1.8-1.9 (m, 3H), 1.5-1.6 (m, 3H), 1.2-1.2 (m, 6H)

[0922]

[0923] Example 77: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0924]

[0925] The above compound was obtained by the method of Preparation Example 3.

[0926] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.8-8.9 (m, 1H), 8.6-8.7 (m, 1H), 7.9-8.0 (m, 1H), 7.57 (s, 1H), 6.0-6.1 (m, 1H), 5.8-5.9 (m, 1H), 4.4-4.7 (m, 3H), 4.23 (s, 2H), 3.6-3.7 (m, 1H), 3.4-3.5 (m, 1H), 2.2-2.3 (m, 3H), 1.8-1.9 (m, 3H), 1.0-1.3 (m, 10H)

[0927]

[0928] Example 78: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0929]

[0930] The above compound was obtained by the method of Preparation Example 7.

[0931] 1 H NMR (DMSO-d6, 400 MHz) δ 10.23 (s, 1H), 8.95 (s, 1H), 8.71 (d, 1H, J=1.0 Hz), 8.45 (s, 1H), 7.43 (s, 1H), 5.86 (quin, 1H, J=7.2 Hz), 4.49 (t, 2H, J=12.3 Hz), 4.35 (q, 2H, J=7.3 Hz), 2.10 (s, 3H), 1.7-1.9 (m, 6H), 1.48 (t, 3H, J=7.3 Hz)

[0932]

[0933] Example 79: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0934]

[0935] The above compound was obtained by the method of Preparation Example 7.

[0936] 1H NMR (DMSO-d6, 400 MHz) δ 10.25 (s, 1H), 8.94 (s, 1H), 8.65 (d, 1H, J=1.0 Hz), 8.51 (s, 1H), 7.46 (s, 1H), 5.8-5.9 (m, 1H), 5.0-5.1 (m, 1H), 4.79 (s, 2H), 4.62 (s, 2H), 4.50 (t, 2H, J=12.0 Hz), 2.9-3.0 (m, 2H), 2.7-2.7 (m, 1H), 2.6-2.7 (m, 1H), 2.09 (s, 3H), 1.7-1.9 (m, 6H)

[0937]

[0938] Example 80: Synthesis of (S)-N-(1-(cyclopropylmethyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0939]

[0940] The above compound was obtained by the method of Preparation Example 7.

[0941] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.92 (s, 1H), 8.46 (s, 1H), 7.93 (br s, 1H), 7.65 (s, 1H), 6.12 (s, 1H), 5.86 (s, 1H), 4.5-4.6 (m, 2H), 4.3-4.4 (m, 1H), 4.1-4.3 (m, 2H), 4.0-4.1 (m, 1H), 4.08 (d, 3H, J=6.9 Hz), 3.37 (s, 3H), 2.25 (s, 3H), 1.8-1.9 (m, 3H), 1.3-1.4 (m, 1H), 0.7-0.8 (m, 2H), 0.45 (d, 2H, J=5.8 Hz)

[0942]

[0943] Example 81: Synthesis of (S)-N-(1-((3,3-difluorocyclobutyl)methyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0944]

[0945] The above compound was obtained by the method of Preparation Example 7.

[0946] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.93 (s, 1H), 8.44 (s, 1H), 7.8-8.0 (m, 1H), 7.4-7.6 (m, 1H), 6.0-6.2 (m, 1H), 5.7-6.0 (m, 1H), 4.4-4.7 (m, 2H), 4.1-4.4 (m, 5H), 3.3-3.4 (m, 3H), 2.6-2.9 (m, 3H), 2.3-2.6 (m, 2H), 2.1-2.3 (m, 3H), 1.7-1.9 (m, 3H)

[0947]

[0948] Example 82: Synthesis of (S)-N-(1-(2-fluoro-2-methylpropyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0949]

[0950] The above compound was obtained by the method of Preparation Example 7.

[0951] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.95 (s, 1H), 8.42 (s, 1H), 7.9-8.0 (m, 1H), 7.58 (d, 1H, J=1.3 Hz), 6.10 (s, 1H), 5.8-6.0 (m, 1H), 4.4-4.6 (m, 2H), 4.1-4.4 (m, 5H), 3.36 (s, 3H), 2.25 (s, 3H), 1.86 (d, 3H, J=7.0 Hz), 1.3-1.5 (m, 6H)

[0952]

[0953] Example 83: Synthesis of (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-methylallyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0954]

[0955] The above compound was obtained by the method of Preparation Example 7.

[0956] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.9-9.0 (m, 1H), 8.4-8.5 (m, 1H), 7.8-7.9 (m, 1H), 7.54 (s, 1H), 6.1-6.1 (m, 1H), 5.8-6.0 (m, 1H), 5.0-5.1 (m, 1H), 4.8-4.9 (m, 1H), 4.74 (s, 2H), 4.5-4.6 (m, 2H), 4.3-4.4 (m, 1H), 4.1-4.3 (m, 2H), 3.3-3.4 (m, 3H), 2.2-2.3 (m, 3H), 2.1-2.3 (m, 3H), 1.85 (br d, 3H, J=7.0 Hz), 1.7-1.8 (m, 3H)

[0957]

[0958] Example 84: Synthesis of (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0959]

[0960] The above compound was obtained by the method of Preparation Example 7.

[0961] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.94 (s, 1H), 8.42 (s, 1H), 7.9-8.0 (m, 1H), 7.53 (s, 1H), 6.07 (s, 1H), 5.8-5.9 (m, 1H), 4.4-4.6 (m, 4H), 4.3-4.4 (m, 1H), 4.1-4.3 (m, 2H), 3.37 (s, 3H), 2.6-2.8 (m, 2H), 2.2-2.3 (m, 1H), 2.26 (s, 3H), 1.8-1.9 (m, 4H)

[0962]

[0963] Example 85: Synthesis of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0964]

[0965] The above compound was obtained by the method of Preparation Example 7.

[0966] 1H NMR (DMSO-d6, 400 MHz) δ 10.23 (s, 1H), 8.95 (s, 1H), 8.71 (d, 1H, J=1.0 Hz), 8.45 (s, 1H), 7.44 (s, 1H), 6.4-6.7 (m, 1H), 5.86 (quin, 1H, J=7.3 Hz), 4.5-4.6 (m, 2H), 4.35 (q, 2H, J=7.2 Hz), 2.10 (s, 3H), 1.82 (d, 3H, J=7.0 Hz), 1.48 (t, 3H, J=7.3 Hz)

[0967]

[0968] Example 86: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0969]

[0970] The above compound was obtained by the method of Preparation Example 7.

[0971] 1 H NMR (DMSO-d6, 400 MHz) δ 10.22 (s, 1H), 8.94 (s, 1H), 8.71 (d, 1H, J=0.9 Hz), 8.40 (s, 1H), 7.43 (s, 1H), 5.8-5.9 (m, 1H), 4.4-4.6 (m, 4H), 3.74 (t, 2H, J=5.1 Hz), 3.24 (s, 3H), 2.10 (s, 5H), 1.7-1.9 (m, 6H)

[0972]

[0973] Example 87: Synthesis of (S)-N-(1-(2-cyanoethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0974]

[0975] The above compound was obtained by the method of Preparation Example 7.

[0976] 1 H NMR (DMSO-d6, 400 MHz) δ 10.27 (s, 1H), 8.96 (s, 1H), 8.80 (d, 1H, J=1.0 Hz), 8.47 (s, 1H), 7.40 (s, 1H), 5.8-5.9 (m, 1H), 4.63 (dt, 2H, J=1.7, 6.5 Hz), 4.50 (br t, 2H, J=12.1 Hz), 3.19 (t, 2H, J=6.4 Hz), 2.10 (s, 3H), 1.7-1.9 (m, 6H)

[0977]

[0978] Example 88: Synthesis of (S)-N-(1-(3-cyanopropyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0979]

[0980] The above compound was obtained by the method of Preparation Example 7.

[0981] 1 H NMR (DMSO-d6, 400 MHz) δ 10.25 (s, 1H), 8.96 (s, 1H), 8.72 (d, 1H, J=1.0 Hz), 8.44 (s, 1H), 7.42 (s, 1H), 5.86 (td, 1H, J=7.5, 14.7 Hz), 4.49 (t, 2H, J=12.2 Hz), 4.38 (br t, 2H, J=7.3 Hz), 2.6-2.6 (m, 2H), 2.19 (quin, 2H, J=7.1 Hz), 2.10 (s, 3H), 1.8-1.9 (m, 6H)

[0982]

[0983] Example 89: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3-oxocyclobutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0984]

[0985] The above compound was obtained by the method of Preparation Example 7.

[0986] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.00 (s, 1H), 8.48 (s, 1H), 7.94 (br s, 1H), 7.70 (s, 1H), 6.92 (s, 1H), 5.7-6.0 (m, 1H), 5.1-5.3 (m, 1H), 4.38 (t, 2H, J=11.1 Hz), 3.8-3.9 (m, 1H), 3.5-3.8 (m, 2H), 2.27 (s, 2H), 1.8-1.9 (m, 3H)

[0987]

[0988] Example 90: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-((3-methyloxetan-3-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0989]

[0990] The above compound was obtained by the method of Preparation Example 7.

[0991] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.97 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 6.89 (s, 1H), 5.8-6.0 (m, 1H), 4.67 (dd, 2H, J=2.6, 6.1 Hz), 4.4-4.5 (m, 4H), 4.37 (t, 2H, J=11.1 Hz), 2.25 (s, 3H), 2.03 (s, 1H), 1.8-1.9 (m, 6H), 1.37 (s, 3H)

[0992]

[0993] Example 91: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-morpholinoethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0994]

[0995] The above compound was obtained by the method of Preparation Example 7.

[0996] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.95 (s, 1H), 8.50 (s, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 6.92 (s, 1H), 5.8-6.0 (m, 1H), 4.3-4.4 (m, 4H), 3.7-3.8 (m, 4H), 2.83 (t, 2H, J=6.3 Hz), 2.5-2.6 (m, 4H), 2.26 (s, 3H), 1.8-1.9 (m, 6H)

[0997]

[0998] Example 92: Synthesis of (S)-N-(1-(cyclopropylmethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0999]

[1000] The above compound was obtained by the method of Preparation Example 7.

[1001] 1H NMR (DMSO-d6, 400 MHz) δ 10.23 (s, 1H), 8.95 (s, 1H), 8.74 (d, 1H, J=1.0 Hz), 8.46 (s, 1H), 7.42 (s, 1H), 5.86 (quin, 1H, J=7.3 Hz), 4.50 (t, 2H, J=12.2Hz), 4.1-4.2 (m, 2H), 2.10 (s, 3H), 1.7-1.9 (m, 6H), 1.3-1.4 (m, 1H), 0.5-0.6 (m, 2H), 0.4-0.5 (m, 2H)

[1002]

[1003] Example 93: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(oxetan-3-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1004]

[1005] The above compound was obtained by the method of Preparation Example 7.

[1006] 1 H NMR (DMSO-d6, 400 MHz) δ 10.25 (s, 1H), 8.94 (s, 1H), 8.76 (d, 1H, J=1.0 Hz), 8.48 (s, 1H), 7.41 (s, 1H), 5.86 (quin, 1H, J=7.3 Hz), 4.6-4.7 (m, 4H), 4.4-4.5 (m, 4H), 3.5-3.6 (m, 1H), 2.09 (s, 3H), 1.7-1.9 (m, 6H)

[1007]

[1008] Example 94: Synthesis of N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1009]

[1010] The above compound was obtained by the method of Preparation Example 7.

[1011] 1 H NMR (DMSO-d6, 400 MHz) δ 10.25 (s, 1H), 8.96 (s, 1H), 8.77 (d, 1H, J=0.9 Hz), 8.42 (s, 1H), 7.48 (s, 1H), 5.86 (quin, 1H, J=7.3 Hz), 5.4-5.5 (m, 1H), 4.51 (t, 2H, J=12.2 Hz), 4.15 (dt, 1H, J=6.2, 8.2 Hz), 4.0-4.1 (m, 2H), 3.88 (dt, 1H, J=6.5, 8.4 Hz), 2.6-2.6 (m, 1H), 2.2-2.3 (m, 1H), 2.10 (s, 3H), 1.7-1.9 (m, 6H)

[1012]

[1013] Example 95: Synthesis of (S)-N-(1-(6,6-difluorospiro[3.3]heptan-2-yl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1014]

[1015] The above compound was obtained by the method of Preparation Example 7.

[1016] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.90 (s, 1H), 8.39 (s, 1H), 7.93 (s, 1H), 7.57 (s, 1H), 6.09 (s, 1H), 5.86 (s, 1H), 5.69 (s, 1H), 4.87 (s, 1H), 4.5-4.6 (m, 2H), 4.36 (s, 4H), 3.3-3.4 (m, 4H), 2.8-2.9 (m, 4H), 2.6-2.8 (m, 4H), 2.24 (s, 3H), 1.83 (d, 3H, J=7.1 Hz)

[1017]

[1018] Example 96: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1019]

[1020] The above compound was obtained by the method of Preparation Example 7.

[1021] 1 H NMR (DMSO-d6, 400 MHz) δ 10.23 (s, 1H), 8.95 (s, 1H), 8.71 (d, 1H, J=1.0 Hz), 8.44 (s, 1H), 7.43 (s, 1H), 5.86 (quin, 1H, J=7.3 Hz), 4.49 (t, 2H, J=12.3Hz), 4.27 (t, 2H, J=7.1 Hz), 2.10 (s, 3H), 1.7-1.9 (m, 8H), 0.89 (t, 3H, J=7.4 Hz)

[1022]

[1023] Example 97: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(7-oxaspiro[3.5]nonan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1024]

[1025] The above compound was obtained by the method of Preparation Example 7.

[1026] 1 H NMR (DMSO-d6, 400 MHz) δ 10.25 (s, 1H), 8.95 (s, 1H), 8.67 (d, 1H, J=1.0 Hz), 8.52 (s, 1H), 7.49 (s, 1H), 5.86 (td, 1H, J=7.2, 14.6 Hz), 5.19 (quin, 1H, J=8.4 Hz), 4.51 (t, 2H, J=12.1 Hz), 3.6-3.7 (m, 2H), 3.5-3.6 (m, 2H), 2.6-2.7 (m, 2H), 2.2-2.3 (m, 2H), 2.09 (s, 3H), 1.7-1.9 (m, 8H), 1.6-1.7 (m, 2H)

[1027]

[1028] Example 98: Synthesis of (S)-N-(1-(cyclopropanecarbonyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1029]

[1030] The above compound was obtained by the method of Preparation Example 7.

[1031] 1 H NMR (DMSO-d6, 400 MHz) δ 10.51 (s, 1H), 9.30 (d, 1H, J=1.0 Hz), 9.16 (s, 1H), 9.08 (s, 1H), 7.62 (s, 1H), 5.9-6.0 (m, 1H), 4.52 (t, 2H, J=12.1 Hz), 2.81 (quin, 1H, J=6.1 Hz), 2.12 (s, 3H), 1.8-1.9 (m, 6H), 1.25 (d, 4H, J=5.9 Hz)

[1032]

[1033] Example 99: Synthesis of (S)-N-(1-(2,2-difluoroethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1034]

[1035] The above compound was obtained by the method of Preparation Example 7.

[1036] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.00 (s, 1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.60 (s, 1H), 6.89 (s, 1H), 6.12 (s, 1H), 5.9-6.0 (m, 1H), 4.57 (dt, 2H, J=3.4, 14.4 Hz), 4.36 (t, 2H, J=11.1 Hz), 2.26 (s, 3H), 1.8-1.9 (m, 6H)

[1037]

[1038] Example 100: Synthesis of N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3-fluorocyclobut-2-en-1-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1039]

[1040] The above compound was obtained by the method of Preparation Example 7.

[1041] 1H NMR (CHLOROFORM-d, 400 MHz) δ 9.00 (s, 1H), 8.63 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 7.4-7.5 (m, 1H), 6.92 (s, 1H), 6.2-6.4 (m, 1H), 5.8-6.1 (m, 1H), 4.87 (dd, 1H, J=3.3, 16.8 Hz), 4.71 (d, 1H, J=3.3 Hz), 4.59 (d, 1H, J=3.4 Hz), 4.38 (t, 2H, J=11.0 Hz), 2.27 (s, 3H), 1.8-2.0 (m, 6H)

[1042]

[1043] Example 101: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1044]

[1045] The above compound was obtained by the method of Preparation Example 7.

[1046] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.97 (s, 1H), 8.52 (s, 1H), 7.92 (br s, 1H), 7.67 (s, 1H), 6.91 (s, 1H), 5.9-6.1 (m, 1H), 4.7-4.9 (m, 1H), 4.37 (t, 2H, J=11.1 Hz), 2.26 (s, 3H), 1.8-1.9 (m, 6H), 1.6-1.7 (m, 6H)

[1047]

[1048] Example 102: Synthesis of (S)-N-(1-ethyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1049]

[1050] The above compound was obtained by the method of Preparation Example 7.

[1051] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.92 (s, 1H), 8.45 (s, 1H), 7.9-8.0 (s, 1H), 7.59 (s, 1H), 6.12 (s, 1H), 5.86 (s, 1H), 4.4-4.6 (m, 2H), 4.1-4.4 (m, 4H), 3.37 (s, 2H), 2.25 (s, 2H), 1.84 (d, 3H, J=7.1 Hz)

[1052]

[1053] Example 103: Synthesis of (S)-N-(3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1054]

[1055] The above compound was obtained by the method of Preparation Example 7.

[1056] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.96 (br s, 1H), 8.45 (br s, 1H), 7.94 (br s, 1H), 7.55 (s, 1H), 6.89 (s, 1H), 5.8-6.0 (m, 1H), 4.16 (br d, 2H, J=16.6 Hz), 3.94 (s, 3H), 2.25 (s, 3H), 1.8-2.0 (m, 3H), 1.5-1.6 (m, 6H)

[1057]

[1058] Example 104: Synthesis of (S)-N-(1-methyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1059]

[1060] The above compound was obtained by the method of Preparation Example 7.

[1061] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.95 (br s, 1H), 8.46 (br s, 1H), 8.00 (br s, 1H), 7.55 (s, 1H), 7.04 (s, 1H), 5.9-6.0 (m, 1H), 4.7-4.8 (m, 2H), 3.95 (s, 3H), 2.26 (s, 3H), 1.91 (br d, 3H, J=6.8 Hz)

[1062]

[1063] Example 105: Synthesis of (S)-N-(1-ethyl-3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1064]

[1065] The above compound was obtained by the method of Preparation Example 7.

[1066] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.97 (br s, 1H), 8.47 (br s, 1H), 8.00 (br s, 1H), 7.61 (s, 1H), 6.89 (s, 1H), 5.9-6.0 (m, 1H), 4.30 (br d, 2H, J=6.9 Hz), 4.16 (br d, 2H, J=16.6 Hz), 2.25 (br s, 3H), 1.89 (br d, 3H, J=6.3 Hz), 1.5-1.6 (m, 6H)

[1067]

[1068] Example 106: Synthesis of (S)-N-(1-ethyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1069]

[1070] The above compound was obtained by the method of Preparation Example 7.

[1071] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.96 (br s, 1H), 8.49 (br s, 1H), 7.97 (br s, 1H), 7.6-7.6 (s, 1H), 7.4 (s, 1H), 7.05 (s, 1H), 5.8-6.0 (m, 1H), 4.76 (q, 2H, J=7.7 Hz), 4.2-4.4 (m, 2H), 2.26 (s, 3H), 1.7-2.0 (m, 3H), 1.5-1.6 (m, 3H)

[1072]

[1073] Example 107: Synthesis of (S)-N-(1-cyclopropyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1074]

[1075] The above compound was obtained by the method of Preparation Example 3.

[1076] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.94 (br s, 1H), 8.66 (br s, 1H), 7.95 (br s, 1H), 7.61 (s, 1H), 7.03 (s, 1H), 5.8-6.0 (m, 1H), 4.76 (br d, 2H, J=7.9 Hz), 3.51 (br s, 1H), 2.26 (s, 3H), 2.03 (s, 1H), 1.91 (br d, 3H, J=6.4 Hz), 1.2-1.3 (m, 2H), 1.13 (br s, 2H)

[1077]

[1078] Example 108: Synthesis of (S)-N-(1-ethyl-3-(5-(3-fluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1079]

[1080] The above compound was obtained by the method of Preparation Example 7.

[1081] 1 H NMR (DMSO-d6, 400 MHz) δ 10.21 (s, 1H), 8.95 (s, 1H), 8.69 (s, 1H), 8.48 (s, 1H), 7.34 (s, 1H), 5.84 (br d, 1H, J=7.4 Hz), 4.71 (t, 1H, J=5.8 Hz), 4.59 (t, 1H, J=5.8 Hz), 4.2-4.4 (m, 4H), 2.1-2.3 (m, 2H), 2.09 (s, 3H), 1.81 (d, 3H, J=7.0 Hz), 1.48 (t, 3H, J=7.2 Hz)

[1082]

[1083] Example 109: Synthesis of (S)-N-(3-(5-(3-fluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1084]

[1085] The above compound was obtained by the method of Preparation Example 7.

[1086] 1 H NMR (DMSO-d6, 400 MHz) δ 10.23 (s, 1H), 8.95 (s, 1H), 8.65 (d, 1H, J=1.0 Hz), 8.41 (s, 1H), 7.32 (s, 1H), 5.85 (td, 1H, J=7.3, 14.6 Hz), 4.71 (t, 1H,

[1087] J=5.8 Hz), 4.59 (t, 1H, J=5.8 Hz), 4.2-4.3 (m, 2H), 3.94 (s, 3H), 2.26 (t, 1H, J=6.0 Hz), 2.2-2.2 (m, 1H), 2.10 (s, 3H), 1.81 (d, 3H, J=7.1 Hz)

[1088]

[1089] Example 110: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1090]

[1091] The above compound was obtained by the method of Preparation Example 3.

[1092] 1H NMR (CHLOROFORM-d, 400 MHz) δ 8.95 (s, 1H), 8.64 (s, 1H), 8.07 (br s, 1H), 7.61 (s, 1H), 6.86 (s, 1H), 5.9-6.0 (m, 1H), 4.16 (d, 2H, J=16.6 Hz), 3.50 (br d, 1H, J=3.5 Hz), 2.25 (s, 3H), 1.89 (br d, 3H, J=6.9 Hz), 1.74 (br s, 1H), 1.6 (s, 3H), 1.5 (s, 3H), 1.2-1.3 (m, 4H), 1.13 (br s, 2H)

[1093]

[1094] Example 111: Synthesis of N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1095]

[1096] The above compound was obtained by the method of Preparation Example 7.

[1097] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.95 (br s, 1H), 8.49 (br s, 1H), 8.00 (br s, 1H), 7.62 (s, 1H), 6.91 (s, 1H), 6.1-6.4 (m, 1H), 5.8-6.0 (m, 1H), 4.43 (dt, 2H, J=3.4, 12.5 Hz), 4.31 (q, 2H, J=7.0 Hz), 2.26 (s, 3H), 1.7-1.9 (m, 4H), 1.4-1.6 (m, 3H)

[1098]

[1099] Example 112: Synthesis of N-(1-cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1100]

[1101] The above compound was obtained by the method of Preparation Example 3.

[1102] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 8.94 (br s, 1H), 8.66 (br s, 1H), 7.95 (br s, 1H), 7.62 (s, 1H), 6.89 (s, 1H), 6.1-6.4 (m, 1H), 5.8-6.0 (m, 1H), 4.43 (dt, 2H, J=3.8, 12.7 Hz), 4.26 (br d, 1H, J=8.8 Hz), 3.51 (br s, 1H), 2.26 (s, 2H), 1.90 (br d, 3H, J=6.6 Hz), 1.23 (br d, 2H, J=5.0 Hz), 1.14 (br s, 2H)

[1103]

[1104] Example 113: Synthesis of (R)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1105]

[1106] The above compound was obtained by the method of Preparation Example 7.

[1107] 1H NMR (DMSO-d6, 400 MHz) δ 10.23 (s, 1H), 8.95 (s, 1H), 8.71 (d, 1H, J=0.9 Hz), 8.45 (s, 1H), 7.44 (s, 1H), 6.4-6.7 (m, 1H), 5.86 (quin, 1H, J=7.3 Hz), 4.5-4.6 (m, 2H), 4.35 (q, 2H, J=7.3 Hz), 2.10 (s, 3H), 1.82 (d, 3H, J=7.0 Hz), 1.48 (t, 3H, J=7.3 Hz)

[1108]

[1109] Example 114: Synthesis of (R)-N-(1-cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1110]

[1111] The above compound was obtained by the method of Preparation Example 3.

[1112] 1 H NMR (DMSO-d6, 400 MHz) δ 10.27 (s, 1H), 8.95 (s, 1H), 8.70 (d, 1H, J=1.0 Hz), 8.42 (s, 1H), 7.48 (s, 1H), 6.6-6.6 (m, 1H), 6.4-6.7 (m, 1H), 5.8-5.9 (m, 1H), 4.51 (tt, 2H, J=3.5, 14.1 Hz), 3.68 (tt, 1H, J=3.6, 7.0 Hz), 2.10 (s, 3H), 1.81 (d, 3H, J=7.0 Hz), 1.1-1.2 (m, 2H), 1.1-1.1 (m, 2H)

[1113]

[1114] Example 115: Synthesis of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[1115]

[1116] The above compound was obtained by the method of Preparation Example 8.

[1117] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.0 (s, 1H), 8.5-8.7 (m, 2H), 7.9 (s, 1H), 7.7 (s, 1H), 6.94 (br s, 1H), 6.2-6.3 (m, 1H), 5.9-6.0 (m, 1H), 4.2-4.5 (m, 4H), 2.26 (br s, 3H), 1.8-2.0 (m, 3H)

[1118]

[1119] Example 116: Synthesis of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetamide

[1120]

[1121] The above compound was obtained by the method of Preparation Example 9.

[1122] 1 H NMR (CHLOROFORM-d, 400 MHz) δ 9.31 (br s, 1H), 9.02 (br s, 1H), 8.46 (s, 1H), 7.61 (s, 1H), 6.88 (s, 1H), 6.1-6.4 (m, 1H), 5.94 (br s, 1H), 5.32 (s, 6H), 4.2-4.5 (m, 6H), 1.89 (br d, 3H, J=6.5 Hz), 1.5-1.6 (m, 3H)

[1123]

[1124] Example 117: Synthesis of (S)-1-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea

[1125]

[1126] The above compound was obtained by the method of Preparation Example 10.

[1127] 1 H NMR (METHANOL-d4, 400 MHz) δ 8.54 (d, 1H, J=0.9 Hz), 8.2 (s, 1H), 8.1 (s, 1H), 7.84 (d, 1H, J=0.9 Hz), 7.37 (s, 1H), 6.2-6.5 (m, 1H), 5.9-6.0 (m, 1H), 4.50 (dt, 2H, J=3.9, 13.3 Hz), 4.3-4.4 (m, 2H), 3.13 (br s, 3H), 1.83 (d, 3H, J=7.0 Hz), 1.5-1.6 (m, 3H)

[1128]

[1129] TYK2 pseudokinase ligand

[1130] TYK2, like other JAK family proteins, is composed of four domains (FERM, SH2, JH2, and JH1 domains) (Prior document 7). The JH1 domain is a kinase domain with active function that actually transmits intracellular signals, and the JH2 domain is a pseudokinase domain that has a regulatory function that inhibits the activation of the JH1 domain until an external stimulus is applied (Prior document 7). In other words, the TYK2 pseudokinase domain stabilizes the structurally inactive state of the kinase domain. Therefore, small molecule pseudokinase ligands can inhibit the activity of TYK2 by stabilizing this inactive structure.

[1131]

[1132] Experimental example)

[1133] The following experiments were conducted using the example compounds manufactured as described above.

[1134] Experimental Example 1: Analysis of TYK2 pseudokinase domain binding affinity

[1135] To analyze the binding affinity of test compounds to the TYK2 pseudokinase domain, a polarized fluorescence-based TYK2 JH2 Pseudokinase Domain Inhibitor Screening Assay Kit (BPS bioscience) was used. Compound evaluation was performed according to the manufacturer's protocol, and the method is as follows.

[1136] Test compounds or control compounds (Deucravacitnib) were serially diluted in DMSO, and then diluted 1 / 10 with distilled water to prepare a 10x compound solution. The compound solution was mixed with Probe 1 prepared in binding reaction buffer (JH2 binding buffer), and the reaction was performed at 25°C for 10 minutes. Next, the reaction was initiated by adding the TYK2 pseudokinase domain enzyme prepared in binding reaction buffer. The reaction was performed in a black 384-well plate at 25°C for 1 hour. Polarized fluorescence was measured using Synergy neo (BioTek Instruments, Inc.). The reaction mixture containing no enzyme served as a negative control, and the mixture without any compound served as a positive control.

[1137]

[1138] Experimental Example 2: JAK Kinase Domain Activity Analysis

[1139] Kinase domain activity of the JAK family was assayed using the ADP-Glo ​​kinase assay kit (Promega). Compound evaluation was performed according to the manufacturer's protocol, as follows.

[1140] 10 mM test compounds were diluted to 0.5 mM using DMSO in a 96-well plate, and then serially diluted 5-fold in DMSO. The diluted compounds were diluted 1 / 10 with 1x reaction buffer (composition) to prepare a 5x compound solution. 5 uL of the 5x compound solution was mixed with a substrate and ATP mixture (10 uL) prepared in reaction buffer (40 mM Tris, 20 mM MgCl2, and 0.1 mg / ml BSA, 0.05 mM DTT, pH 7.5). Next, the enzyme reaction was initiated by adding JAK family enzymes (10 uL) prepared in reaction buffer. A brief spin was performed to allow all solutions to settle to the bottom of the plate. The final concentrations of the test compounds in the reaction mixtures were 10,000, 2,000, 400, 80, 16, and 3.2 nM. The concentration of the control compound (Brepocitinib or Tofacitinib) was 10-fold lower. The enzyme reaction was performed at 25°C for 1 hour. 25 μL of ADP-Glo ​​reagent was added, and the reaction was performed at 25°C for 1 hour. The reaction was stopped by mixing 50 μL of kinase detection reagent, and the luminescence signal was measured using Synergy neo (BioTek Instruments, Inc.). The reaction mixture containing no enzyme served as a negative control, and the mixture containing no compound served as a positive control. The enzymes, substrates, and control drugs used are summarized in Table 1 below. The experimental results are shown in Table 2.

[1141]

[1142] Enzyme substrate control drugJAK1IRS1 (Y608) peptideBrepocitinibJAK2IGF1R peptideTofacitinibJAK3Poly (4:1 Glu-Tyr) peptideTofacitinibTYK2IRS1 (Y608) peptideBrepocitinib

[1143] TYK2 pseudokinase and JAK kinase domain activity confirmation results Example TYK2 JH2 IC 50 (nM)JAK1 JH1 IC 50 (nM)JAK2 JH1 IC 50 (nM)JAK3 JH1 IC 50 (nM)TYK2 JH1 IC 50

[1144] ND: Not determined Experimental Example 3: Analysis of TYK2 / JAK1 cell activity by IFNα2B stimulation

[1145] The inhibitory activity of test compounds on TYK2 / JAK1 activity was analyzed using HEK-blue IFNα / β cell lines (InvivoGen) that secrete SEAP (Secreted embryonic alkaline phosphatase) depending on the degree of cell stimulation. Cell culture and evaluation were performed according to the manufacturer's recommendations, and the method is as follows. Cells cultured in growth medium (Dulbecco's Modified Eagle Medium, 10% Fetal bovine serum, 1% Penicillin-Streptomycin, 100 ug / mL Normocin, 10 mg / mL Blasticidin, 100 mg / mL Zeocin) were harvested and resuspended in test medium (DMEM, 10% FBS, 1% Penicillin-Streptomycin), and then 3.5 x 10 (160 uL) were added to each well of a 96-well plate. 4Cells were seeded. After culturing for 24 hours in a 37°C CO2 incubator, 20 μL of test compound or control compound (Deucravacitinib) diluted in test medium was added and incubated for 1 hour and 30 minutes at 37°C. Next, 20 μL of human IFNα2B recombinant protein (PBL assay science) prepared in test medium was added to each well (final concentration 1 U / mL) and incubated for 24 hours at 37°C. 20 μL and 180 μL of cell supernatant were mixed with QUANTI-blue reagent (InvivoGen) and reacted at 37°C for 20–30 minutes. The absorbance at 630 nm was measured using Synergy neo (BioTek Instruments, Inc.). The reaction mixture without IFNα2B was the negative control, and the mixture without any compound was the positive control. The experimental results are shown in Table 3.

[1146] Results of TYK2 / JAK1 cell activation test by IFNα2B stimulation (A: IC 50 <50 nM; B: IC50 >50 nM and <500 nM; C:IC 50 > 500Nm; ; ND: Not determined) Example IC 50<h2 style=";text-align:left;direction:ltr">1A2B3ND4ND5A6A7A8A9ND10A11A12ND13ND14ND15ND16A17ND18C19B20B21B22A23A24A25A26B27B28B29B30B31A32A33A34A35A36A37A38A39A40A41A42B43A44A45A46B47B48B49A50C51A52A53A54A55A56A57A58A59ND60A61A62A 63A64A65A66A67A68A69A70A71A72A73A74A75A76A77A78A79A80A81A82B83B84A85A86B87B88A89B90B91B92ND93ND94ND95A96A97A98B99A100A101A102A103A104A105A106A107A108A109A110A111A112A113C114C115C116A117ND

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; [Chemical Formula 1] In the above formula, A1, A2, A3, A4 and A5 are each independently C, CH, CH2 or N; Dotted lines indicate bonds or absence of bonds, provided that the ring containing the dotted line is aromatic; R1 is C1-C 10 Alkyl, C1-C 10 Haloalkyl, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl, wherein the C1-C 10 Alkyl, C1-C 10 Haloalkyl, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl is unsubstituted or substituted with oxo, halo, C1-C 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 substituted with one or more substituents selected from the group consisting of haloalkyl; R2 is H, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, OR' or NR'R", and the C1-C 10 Alkyl, C1-C 10 Alkoxy or 4- to 12-membered heterocycloalkyl is unsubstituted or substituted with halo, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkoxy C1-C 10 Alkyl, 4-12 membered heterocycloalkyl, C6-C 10 Substituted with one or more, preferably 1 to 4, substituents selected from the group consisting of aryl and C3-C8 cycloalkyl, At this time, R' and R” are each independently H, or C1-C 10 Alkyl, and at this time, the C1-C 10 Alkyl is unsubstituted or substituted with halo, cyano, 4-12 membered heterocycloalkyl, C6-C 10 Aryl, C3-C8 cycloalkyl and C1-C 10 substituted with one or more substituents selected from the group consisting of alkoxy, or R' and R" together with N in the above NR'R" may form a 4- to 12-membered heterocycloalkyl, wherein the 4- to 12-membered heterocycloalkyl is unsubstituted or substituted with halo, C1-C 10 Alkoxy, or C1-C 10 Alkoxy C1-C 10 substituted with alkyl; R3 is H, C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C2-C 10 Alkenyl, C3-C8 cycloalkyl, -C1-C 10 Alkyl-C3-C8cycloalkyl, -C(=O)-C3-C8cycloalkyl, C3-C8cycloalkenyl, 4-12 membered heterocycloalkyl, or -C1-C 10 Alkyl-4-membered-12-membered heterocycloalkyl, wherein the C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C2-C 10 Alkenyl, C3-C8 cycloalkyl, -C1-C 10 Alkyl-C3-C8cycloalkyl, -C(=O)-C3-C8cycloalkyl, C3-C8cycloalkenyl, 4-12 membered heterocycloalkyl, or -C1-C 10 Alkyl-4-12 membered heterocycloalkyl is unsubstituted or substituted with halo, cyano, oxo, C1-C 10 Alkyl, C2-C 10 substituted with one or more substituents selected from the group consisting of alkenyl, C1-C6 alkoxy, C3-C8 cycloalkyl which is unsubstituted or substituted with 1 to 3 halo, and 4-12 membered heterocycloalkyl; R4 is C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, or amino, wherein the C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, or amino is unsubstituted, or hydroxy and C1-C 10 which may be substituted with one or more, preferably 1 to 4, substituents selected from the group consisting of alkyl; R5 is H, halo, nitro, cyano, amino, hydroxy, -C(=O)R”', -CO(=O)R”', -N(R”')2, -C(=O)NR”', -SO2R”', C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C6-C 10 Aryl C1-C 10 Alkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkylC1-C 10 Alkyl, 4-12 membered heteroaryl or 4-12 membered heteroarylC1-C 10 Alkyl, and at this time, the C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C6-C 10 Aryl C1-C 10 Alkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkylC1-C 10 Alkyl, 4-12 membered heteroaryl or 4-12 membered heteroarylC1-C 10 Alkyl is unsubstituted or substituted with halo, cyano, nitro, amino, hydroxy, C1-C 10 Alkyl, C2-C 10 Alkenyl. C1-C 10 Alkoxy, C6-C 10 Substituted with at least one selected from the group consisting of aryl, 4-12 membered heterocycloalkyl, 4-12 membered heteroaryl and C3-C8 cycloalkyl, The above R”’ is H, halo, C1-C 10 Alkyl, C1-C 10 Deuteroalkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C3-C8 cycloalkyl, C6-C 10 Aryl, C6-C 10 Aryl C1-C 10 Alkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkylC1-C 10 Alkyl, 4-12 membered heteroaryl or 4-12 membered heteroarylC1-C 10 It's alkyl.

2. In paragraph 1, A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 10-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 10-membered heterocycloalkyl is unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of oxo, fluoro, chloro, bromo, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

3. In paragraph 1, A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the C3-C6 cycloalkyl of the above R1 is cyclobutyl, cyclopentyl or cyclohexyl.

4. In paragraph 1, A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the 4- to 10-membered heterocycloalkyl of R1 is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

5. In paragraph 1, C1-C of the above R1 10 Alkyl, C1-C 10 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein haloalkyl, C3-C8 cycloalkyl, or 4- to 12-membered heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, fluoro, methyl, ethyl, propyl, isopropyl, trifluoromethyl, and methoxy.

6. In paragraph 1, wherein R1 is selected from the following groups, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: .

7. In paragraph 1, The above R2 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, OR' or NR'R", and the C1-C6 alkyl, C1-C6 alkoxy or 4-10 membered heterocycloalkyl is unsubstituted or substituted with fluoro, chloro, bromo, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkyl, 4-10 membered heterocycloalkyl, C6-C 10 Substituted with 1 to 4 substituents selected from the group consisting of aryl and C3-C6 cycloalkyl, At this time, R' and R" are each independently H, or C1-C6 alkyl, and at this time, the C1-C6 alkyl is unsubstituted, or fluoro, chloro, bromo, cyano, 4-10 membered heterocycloalkyl, C6-C 10 substituted with 1 to 4 substituents selected from the group consisting of aryl, C3-C6 cycloalkyl, and C1-C6 alkoxy, or A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R' and R" together with N in said NR'R" can form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is unsubstituted or substituted with fluoro, chloro, bromo, C1-C6alkoxy, or C1-C6alkoxyC1-C6alkyl.

8. In paragraph 1, wherein R2 is selected from the following groups, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: .

9. In paragraph 1, The above R3 is H, C1-C6 alkyl, C1-C6 deuteroalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, -C1-C6 alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-10 membered heterocycloalkyl, or -C1-C6 alkyl-4-10 membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 deuteroalkyl, C2-C6 alkenyl, C3-C8 cycloalkyl-C1-C6 alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-10 membered heterocycloalkyl, or -C1-C6 alkyl-4-10 membered heterocycloalkyl is unsubstituted or Or a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is substituted with 1 to 4 substituents selected from the group consisting of fluoro, chloro, bromo, cyano, oxo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C8 cycloalkyl which is unsubstituted or substituted with 1 to 3 halo, and 4-10 membered heterocycloalkyl.

10. In paragraph 1, wherein R3 is selected from the following groups, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: .

11. In paragraph 1, A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R4 is C1-C6 alkyl, C1-C6 deuteroalkyl, or amino, wherein the C1-C6 alkyl, C1-C6 deuteroalkyl, or amino is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of hydroxy and C1-C6 alkyl.

12. In paragraph 1, A compound wherein R4 is CH3, CD3, CH2OH, NH2 or NHCH3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. In paragraph 1, The above R5 is H, halo, nitro, cyano, amino, hydroxy, -C(=O)R"', -CO(=O)R"', -N(R"')2, -C(=O)NR"', -SO2R"', C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C6-C 10 ArylC1-C6alkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylC1-C6alkyl, 4-10 membered heteroaryl or 4-10 membered heteroarylC1-C6alkyl, wherein the C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C6-C 10 Aryl, C6-C 10 ArylC1-C6alkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylC1-C6alkyl, 4-10 membered heteroaryl or 4-10 membered heteroarylC1-C6alkyl is unsubstituted or substituted with halo, cyano, nitro, amino, hydroxy, C1-C6alkyl, C2-C6alkenyl. C1-C6alkoxy, C6-C 10 Substituted with 1 to 4 substituents selected from the group consisting of aryl, 4-10 membered heterocycloalkyl, 4-10 membered heteroaryl and C3-C6 cycloalkyl, The above R”’ is H, halo, C1-C6 alkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C6-C 10 A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is arylC1-C6alkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkylC1-C6alkyl, 4-10 membered heteroaryl or 4-10 membered heteroarylC1-C6alkyl.

14. In paragraph 1, A compound selected from the group consisting of compounds 1 to 117, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Compound 1: N-(1-methyl-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 2: N-(1-(3-cyanocyclobutyl)-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 3: N-(1-methyl-3-(1-(3-methyloxetan-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 4: 1-(1-methyl-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea, Compound 5: N-(1-(3-cyanocyclobutyl)-3-(5-methyl-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 6: N-(1-(3-cyanocyclobutyl)-3-(1-(3-ethyltetrahydrofuran-3-yl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 7: 1-(3-(1-(3-ethyltetrahydrofuran-3-yl)-5-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea, Compound 8: N-(1-(3-cyanocyclobutyl)-3-(5-cyclopropyl-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 9: N-(1-(3-cyanocyclobutyl)-3-(5-ethoxy-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 10: N-(1-(3-cyanocyclobutyl)-3-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 11: 1-(3-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea, Compound 12: N-(1-(3-cyanocyclobutyl)-3-(5-cyclopropyl-6-oxo-1-(3-oxocyclobutyl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 13: N-(1-(3-cyanocyclobutyl)-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 14: 1-(1-methyl-3-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea, Compound 15: N-(3-methyl-1-(1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide, Compound 16: N-(5-(5-(3-methoxyazetidin-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide, Compound 17: N-(3-(5-(3-methoxyazetidin-1-yl)-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 18: N-(3-(1-(1-methoxy-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 19: N-(3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 20: N-(3-(1-isopropyl-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 21: N-(1-cyclopropyl-3-(1-isopropyl-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 22: N-(1-(3-cyanocyclobutyl)-3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 23: N-(3-(1-cyclobutyl-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 24: N-(3-(1-cyclobutyl-5-(3-(methoxymethyl)azetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 25: N-(3-(5-(isopentyloxy)-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 26: N-(3-(1-isopropyl-6-oxo-5-(2,2,2-trifluoroethoxy)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 27: N-(3-(5-(benzyloxy)-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 28: N-(3-(1-(tert-butyl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 29: N-(3-(1-(tert-butyl)-5-(3-methoxyazetidin-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 30: N-(3-(5-isobutoxy-1-(1-methylcyclopentyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 31: N-(3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclopentyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 32: N-(3-(5-isobutoxy-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 33: N-(1-cyclobutyl-3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 34: 1-(3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea, Compound 35: 1-(1-cyclobutyl-3-(5-isobutoxy-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea, Compound 36: N-(1-cyclobutyl-3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 37: 1-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea, Compound 38: 1-(1-cyclobutyl-3-(5-isobutoxy-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)urea, Compound 39: N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 40: N-(3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 41: N-(1-cyclobutyl-3-(5-(3-methoxyazetidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 42: (S)-N-(3-(5-(3-methoxypyrrolidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 43: (S)-N-(1-Cyclobutyl-3-(5-(3-methoxypyrrolidin-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 44: N-(1-cyclobutyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 45: N-(1-methyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 46: N-(1-methyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,6-dihydropyridazin-3- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 47: N-(3-(5-(cyanomethoxy)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 48: N-(1-methyl-3-(1-(1-methylcyclobutyl)-5-(oxetan-3-ylmethoxy)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 49: N-(1-cyclopropyl-3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 50: (R)-N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 51: N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 52: N-(1-Cyclopropyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 53: N-(1-Cyclopropyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 54: (S)-N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 55: N-(3-(5-(cyclobutylmethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 56: N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 57: (R)-N-(3-(1-(1-ethylcyclobutyl)-5-(2-methoxypropoxy)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 58: (S)-N-(1-Cyclopropyl-3-(6-oxo-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 59: N-(3-(1-(3,3-difluorobutan-2-yl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 60: N-(3-(1-(1-ethylcyclobutyl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 61: (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3- yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 62: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 63: N-(1-((1S,3R)-3-cyanocyclobutyl)-3-(5-isobutoxy-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 64: (S)-N-(1-Cyclopropyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 65: N-(1-Cyclopropyl-3-(5-((R)-2-methoxypropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 66: (S)-N-(1-Cyclopropyl-3-(5-(2-methoxyethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 67: (S)-N-(3-(5-(3,3-difluoropyrrolidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 68: N-(1-((1S,3R)-3-cyanocyclobutyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 69: (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3, Compound 70: (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 71: (S)-N-(1-Cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 72: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3, Compound 73: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(methyl-d3)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 74: (S)-N-(1-Cyclopropyl-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 75: (S)-N-(3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3- yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 76: (S)-N-(1-ethyl-3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 77: (S)-N-(1-Cyclopropyl-3-(5-(3-isopropoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 78: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 79: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-oxaspiro[3.3]heptan-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 80: (S)-N-(1-(cyclopropylmethyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 81: (S)-N-(1-((3,3-difluorocyclobutyl)methyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 82: (S)-N-(1-(2-fluoro-2-methylpropyl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 83: (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-methylallyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 84: (S)-N-(3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, and Compound 85: (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 86: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 87: (S)-N-(1-(2-cyanoethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 88: (S)-N-(1-(3-cyanopropyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 89: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3-oxocyclobutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 90: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-((3-methyloxetan-3-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 91: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-morpholinoethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 92: (S)-N-(1-(cyclopropylmethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 93: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(oxetan-3-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 94: N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 95: (S)-N-(1-(6,6-difluorospiro[3.3]heptan-2-yl)-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 96: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 97: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(7-oxaspiro[3.5]nonan-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 98: (S)-N-(1-(cyclopropanecarbonyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 99: (S)-N-(1-(2,2-difluoroethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 100: N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3-fluorocyclobut-2-en-1-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 101: (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 102: (S)-N-(1-ethyl-3-(5-(3-methoxyazetidin-1-yl)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 103: (S)-N-(3-(5-(2-Fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3- yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 104: (S)-N-(1-methyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 105: (S)-N-(1-ethyl-3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 106: (S)-N-(1-ethyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 107: (S)-N-(1-Cyclopropyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 108: (S)-N-(1-ethyl-3-(5-(3-fluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3- yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 109: (S)-N-(3-(5-(3-fluoropropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 110: (S)-N-(1-Cyclopropyl-3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 111: N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 112: N-(1-cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 113: (R)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 114: (R)-N-(1-Cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 115: (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 116: (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetamide, and Compound 117: (S)-1-(3-(5-(2,2-Difluoroethoxy)-6-oxo-1-(1,1,1-trifluoropropan-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea.

15. A pharmaceutical composition for preventing, improving or treating a TYK2-related disease, comprising a TYK2 inhibitory compound of any one of claims 1 to 14, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition according to claim 15, wherein the TYK2-related disease is an autoimmune disease, an inflammatory disease, cancer, or a neurodegenerative disease.

17. In the 16th paragraph, the autoimmune and inflammatory diseases are asthma, inflammatory bowel disease, alopecia areata, ankylosing spondylitis, lupus, lupus nephritis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis (plaque, scalp, nail psoriasis, etc.), Sjogren's syndrome, multiple sclerosis, palmar pustulosis, celiac disease, atopic dermatitis, contact dermatitis, delayed hypersensitivity reactions, ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and treatment of ocular diseases and conditions such as chorioconjunctivitis, diseases affecting the nose including allergic rhinitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis, endometriosis, leptospirosis renal disease, cardiac hypertrophy, muscle wasting, catabolic disorders, fetal growth retardation, Hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, indefinite cutaneous dysplasia, Behcet's disease, pigmentary incontinence, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, nasal sinusitis, ocular allergy, silica-induced disease, COPD, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, COVID19, cataracts, myositis with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, or type 2 diabetes, temporal arteritis, tendonitis, dermatomyositis, appendicitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, Encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, leukocyte adhesion deficiency, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis,One or more diseases selected from the group consisting of proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, and vulvitis, pharmaceutical composition.

18. In paragraph 16, The above cancers are breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary cancer, seminoma, esophageal cancer, laryngeal cancer, stomach cancer, gastrointestinal cancer, gastrointestinal cancer, skin cancer, keratoacanthoma, follicular carcinoma, melanoma, lung cancer, small cell lung carcinoma, non-small cell lung carcinoma (NSCLC), lung adenocarcinoma, squamous cell carcinoma of the lung, adenomatous polyp, colon cancer, pancreatic cancer, thyroid cancer, papillary cancer, bladder cancer, liver cancer, biliary tract cancer, kidney cancer, bone cancer, bone marrow disease, lymphatic disease, hairy cell cancer, oral cancer and pharyngeal cancer (oral), lip cancer, tongue cancer, oral cavity cancer, salivary gland cancer, pharyngeal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, kidney cancer, prostate cancer, vulval cancer, thyroid cancer, colon cancer, endometrial cancer, uterine cancer, brain cancer, central nervous system system, peritoneal cancer, hepatocellular carcinoma, head cancer, A pharmaceutical composition comprising at least one selected from the group consisting of cervical cancer, Hopkins disease and leukemia (acute myeloid leukemia).

19. In Article 16, A pharmaceutical composition wherein the neurodegenerative disease is at least one selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

20. A method comprising the steps of producing a compound represented by the following chemical formula 1 by performing a Suzuki reaction or Ullmann reaction with a compound corresponding to the chemical formula 2 after borylation of the compound represented by the following chemical formula 3. Method for producing a compound represented by chemical formula 1 according to Article 1: [Chemical Formula 1] [Chemical formula 2] [Chemical Formula 3] In the above formula, A1, A2, A3, A4, A5, R1, R2, R3, R4, R5 and the dotted line are as defined in Article 1, X is halo.

21. In paragraph 20, The compound of the above chemical formula 2 is manufactured by a manufacturing method comprising the following steps: A step of producing a compound represented by the following chemical formula 5 by reacting a compound represented by the following chemical formula 4 with NBS or NIS; A compound represented by the following chemical formula 5 is S N A step of producing a compound represented by the following chemical formula 6 by performing a 2-reaction or a Chan-Lam reaction; A step for producing a compound represented by the chemical formula 2 by deacetylating a compound represented by the chemical formula 6 with an acid and then reacting it with isocyanate or acetyl chloride: [Chemical Formula 4] [Chemical Formula 5] [Chemical formula 6] In the above formula, A2, A3, A4, A5, R3, R4 and the dotted line are as defined in the chemical formula 1 above, X is halo.

22. In paragraph 20, The compound of the above chemical formula 3 is manufactured by a manufacturing method comprising the following steps: A compound represented by the following chemical formula 7 is prepared by the Mitsunobu reaction or S N Step 2 of producing a compound represented by the chemical formula 8 by a reaction; and A step for producing a compound represented by the chemical formula 3 by reacting a compound represented by the chemical formula 8 below with a HOR' or HNR'R" compound as a base: [Chemical formula 7] [Chemical formula 8] In the above formula, A1 and R1 are as defined in the chemical formula 1 above, X is halo.

23. In paragraph 20, The compound of the above chemical formula 3 is manufactured by a manufacturing method comprising the following steps: A compound represented by the following chemical formula 9 is prepared by the Mitsunobu reaction or S N Step 2 for producing a compound represented by the chemical formula 8 by reaction: [Chemical formula 9] In the above formula, A1 and R1 are as defined in the chemical formula 1 above, X is halo.

24. A step of producing a compound represented by the following chemical formula 10 by performing a Suzuki reaction or Ullmann reaction with a compound corresponding to the chemical formula 6 after borylation of the compound represented by the following chemical formula 3; and A method comprising the steps of deacetylating a compound represented by the following chemical formula 10 with an acid and then reacting it with acetoxyacetyl chloride or methylamine to produce a compound represented by the following chemical formula 1. Method for producing a compound represented by chemical formula 1 according to Article 1: [Chemical Formula 1] [Chemical Formula 3] [Chemical Formula 10] In the above formula, A1, A2, A3, A4, A5, R1, R2, R3, R4, R5 and the dotted line are as defined in paragraph 1.

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