Tyk2 inhibitors and uses thereof

Abstract

The present disclosure relates to a 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, and a pharmaceutical composition comprising the same, and the compound of the present disclosure or a pharmaceutically acceptable salt thereof is effective for preventing, ameliorating, or treating a TYK2-related disease.[Formula 1]

Description

background Technical Field

[0001] This disclosure relates to pyrrolopyridine and pyrrolopyrimidine compounds and methods for their preparation; said compounds can be used to regulate tyrosine kinase 2 (TYK2) activity. This disclosure also relates to the use of these compounds in the treatment of TYK2-mediated diseases, particularly autoimmune diseases, inflammatory diseases, and cancer.

[0002] Relevant Existing Technology Description

[0003] Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase that, along with Janus kinases 1, 2, and 3, constitutes the Janus kinase (JAK) family. The JAK family forms dimers in various combinations based on cytokines bound to their cell membrane receptor domains, thereby regulating immune cell activity through signal transduction and activating transcription factors (STATs) (Prior art literature 1 and 2). Specifically, JAK family dimers activate STATs; the activated STATs enter the cell nucleus and promote the production of new cytokines, thus inducing immune cell activity.

[0004] TYK2 is particularly activated by interleukin-12 (IL-12), interleukin-23 (IL-13), and type I and type III interferons, which are inflammatory cytokines that are major causes of various autoimmune diseases, including psoriasis (Prior Art Literature 3). Therefore, TYK2 activity is a pathogenic factor in many diseases. Several studies using TYK2-deficient mice support this view. For example, in IL-23-induced psoriasis experiments, TYK2-deficient mice showed reduced skin inflammation (Prior Art Literature 4). Furthermore, TYK2-deficient mice exhibited resistance in colitis and multiple sclerosis induction models (Prior Art Literature 5, 6). These results indicate that the TYK2 mechanism plays an important role in autoimmune diseases.

[0005] TYK2 is known to cause or exacerbate a variety of autoimmune diseases, including: plaque psoriasis, scalp psoriasis, nail psoriasis, palmoplantar pustulosis, psoriatic arthritis, various types of lupus (systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus), lupus nephritis, ulcerative colitis, Crohn's disease, alopecia areata, ankylosing spondylitis, multiple sclerosis, Sjögren's syndrome, type 1 diabetes, temporal arteritis, tendinitis, dermatomyositis, polymyositis, leukocyte adhesion deficiency, uveitis, celiac disease, adenomatous polyps, lichen planus, hidradenitis suppurativa, acute myeloid leukemia (AML), and COVID-19.

[0006] Therefore, the inventors completed this invention by studying novel compounds that can be used as TYK2 inhibitors and demonstrating their effectiveness in treating a variety of autoimmune diseases, inflammatory diseases, or cancer.

[0007] Existing technical documents

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

[0009] 2. Teng, MWL, Bowman, EP, McElwee, JJ, Smyth, MJ, Casanova, J.-L., Cooper, AM, & Cua, DJ (2015). IL-12 and IL-23cytokines: From discovery to targeted therapies for immune-mediated diseases. Nature Medicine, 21(7), 719-729.

[0010] 3. Garrido-Trigo, A., & Salas, A. Molecular Structure and Function ofJanus 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., & Müller, M., (2015). Intestinal Epithelial Cell TyrosineKinase 2 Transduces IL-22 Signals To Protect from Acute Colitis. Journal ofImmunology, 195(10), 5011-24。

[0013] 6. Oyamada, A., Ikebe, H., Itsumi, M., Saiwai, H., Okada, S.,Shimoda, K., Iwakura, Y., Nakayama, KI, Iwamoto, Y., Yoshikai, Y., &Yamada, H., (2009). Tyrosine kinase 2 plays critical roles in the pathogenicCD4 T cell responses for the development of experimental autoimmuneencephalomyelitis. Journal of Immunology, 183(11), 7539-7546.

[0014] 7. Lupardus, PJ, Ultsch, M., Wallweber, H., Bir Kohli, P.,Johnson, AR, & Eigenbrot, C. (2014). Structure of the pseudokinase-kinasedomains 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. Summary of the Invention

[0015] One object of this disclosure is to provide novel compounds having the following formula 1, their optical isomers, their stereoisomers, their solvates, their tautomers, or their pharmaceutically acceptable salts, said compounds being effective for the prevention, improvement, or treatment of TYK2-related diseases.

[0016] Another object of this disclosure is to provide a pharmaceutical composition for the prevention, improvement or treatment of TYK2-related diseases, said pharmaceutical composition comprising a compound of Formula 1, its optical isomer, its stereoisomer, its solvate, its tautomer or a pharmaceutically acceptable salt thereof as an active ingredient.

[0017] Another object of this disclosure is to provide the use of the compound in the preparation of medicaments for the prevention, improvement or treatment of TYK2-related diseases.

[0018] Another object of this disclosure is to provide a method for preventing, improving or treating TYK2-related diseases by administering the compound.

[0019] This disclosure will be described in detail below.

[0020] Unless otherwise defined, all technical terms used in this application have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless otherwise expressly stated, all numerical values ​​recorded herein include the meaning of "about". All publications and other references mentioned herein are incorporated herein by reference in their entirety.

[0021] The term "residue" as used in this specification is defined as follows. Furthermore, unless a separate definition is given for a residue, its meaning shall be used in accordance with the meaning commonly understood by those skilled in the art.

[0022] As used in this article, the term "independently" means that when more than one substituent is selected from a plurality of possible substituents, these substituents may be the same as or different from each other.

[0023] As used herein, the terms "optionally substituted" or "substituted" refer to the replacement of one or more hydrogen atoms with a monovalent or divalent group. Suitable substituents include, for example: deuterated, hydroxyl, nitro, amino, imino, cyano, halogenated, thio, sulfonyl, thioamide, amido, imino, oxaloamino, methoxyoxaloamino, amido, guanidinyl, sulfonamide, carboxyl, formyl, lower alkyl, halogenated lower alkyl, lower alkylamino, halogenated lower alkylamino, lower alkoxy, halogenated lower alkoxy, lower alkoxyalkyl, alkyl carbonyl, amino carbonyl, aryl carbonyl, aralkyl carbonyl, heteroaryl carbonyl, heteroaryl alkyl carbonyl, alkyl thio, aminoalkyl, cyanoalkyl, aryl, heteroaryl, heterocyclic, cycloalkyl, etc. When the substituent comprises a straight-chain group, substitution can occur intrachain (e.g., 2-hydroxypropyl, 2-aminobutyl, etc.) or terminally (e.g., 2-hydroxyethyl, 3-cyanopropyl, etc.). The substituent can be a straight-chain, branched, or cyclic configuration of a covalently bonded carbon or heteroatom. It should be understood that the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine groups, or a halogen atom substituted with another halogen atom). Such unacceptable substitution patterns are known to those skilled in the art.

[0024] As used in this article, the terms “halogenated,” “halogen,” and “halide” include fluorine, chlorine, bromine, and iodine.

[0025] As used herein, "alkyl" refers to an aliphatic hydrocarbon group, including straight-chain and branched hydrocarbon groups. For example, C1-C6 alkyl refers to an aliphatic hydrocarbon group having 1 to 6 carbon atoms, which 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 refers to C1- 10 Alkyl, preferably C 1-6 Alkyl and C 1-4 Alkyl, more preferably C 1-3 alkyl.

[0026] As used herein, the term "halogenated alkyl" refers to an alkyl group substituted with one or more (e.g., 1 to 3, 1 to 4) halogen atoms, and such alkyl group is as defined above. "Halogenated" means F, Cl, Br, or I, and this term is used interchangeably with the term "halogen." For example, halogenated alkyl means fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, etc.

[0027] As used herein, the term "alkenyl" refers to a hydrocarbon group derived from a saturated alkyl group and having at least one double bond. This alkenyl group can be either E-configured or Z-configured. For example, alkenyl means C... 2-10 Alkenyl, preferably C 2-6 alkenyl and C 2-4 alkenyl, more preferably C 2-3 Alkenyl group.

[0028] As used herein, the term "alkynyl" refers to a hydrocarbon group derived from a saturated alkyl group that has at least one triple bond. For example, alkynyl means C 2-10 Alkyne group, preferably C 2-6 alkynyl group and C 2-4 Alkyne group, more preferably C 2-3 Alkyne group.

[0029] As used herein, the term "alkoxy" refers to an -O-alkyl or alkyl-O- group, and the alkyl group is as defined above. For example, it can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy.

[0030] The term "hydroxyl group" as used in this article refers to -OH (used alone or in combination with other terms).

[0031] The term "amino" as used in this article refers to -NH2.

[0032] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group that may be substituted or unsubstituted, for example, C10. 3-20Cycloalkyl refers to a monovalent saturated hydrocarbon ring system having 3 to 20 carbon atoms. Cycloalkyl can be monocyclic or polycyclic. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Preferably, the cycloalkyl group can be C10-200-300 carbon atoms. 3-8 cycloalkyl or C 3-6 Cycloalkyl.

[0033] As used herein, the term "cycloalkenyl" refers to a cyclic olefinic group having a single double bond, derived from a saturated cycloalkyl group. Cycloalkenyl groups can be monocyclic or polycyclic. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Preferably, the cycloalkenyl group can be C10-20-3 ... 3-8 Cycloalkenyl or C 3-6 Cycloalkenyl.

[0034] As used in this article, the term "aryl" refers to a monovalent aromatic hydrocarbon, which, for example, has 6 to 20 carbon atoms (C6, C6, C7, C8, C9 ... 6-20 Aryl groups are derived by removing a hydrogen atom from a single carbon atom of a parent aromatic ring. An aryl group can include a bicyclic group containing an aromatic ring fused to a saturated or partially unsaturated ring. Exemplary aryl groups can include groups derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, tolyl, naphthalenyl, anthracene, indene, indanyl, etc. As a specific example, aryl means C 6-12 Aryl, preferably C 6-10 Aryl.

[0035] As used herein, "heterocycle" refers to an aromatic, saturated, or partially unsaturated monocyclic, bicyclic, or polycyclic system containing a specified number of ring atoms, comprising one or more heteroatoms selected from N, O, and S. As a ring member, the heterocycle can be linked to the base molecule via a ring atom (which can be C or N). Bicyclic systems can be linked by 1,1-fusion (helical connection), 1,2-fusion (co-fusion), or 1,2-fusion (bridging). Preferably, 1,1-fusion (helical connection) can be, but is not limited to, oxaspiro[3.3]heptyl, oxaspiro[3.4]octyl, azeosspiro[3.3]heptyl, azeosspiro[3.4]octyl, etc.

[0036] As used herein, "heteroaryl" refers to a monovalent or divalent substituent derived from mono- or poly-heterocyclic aromatic hydrocarbons, containing at least one, preferably one to four, one to three, or one to two heteroatoms selected from N, O, and S. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrroleyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxazolyl, 3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, indoleyl, etc. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiophene, benzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, furan-pyridyl, and similar groups. Unless otherwise defined, heteroaryl groups are 4-12-membered heteroaryl groups, preferably 4-10-membered heteroaryl groups, and more preferably 4-7-membered heteroaryl groups.

[0037] As used herein, "heterocyclic alkyl" refers to a monocyclic, bicyclic, tricyclic, or higher cyclic alkyl group having 3 to 10 cyclic carbon atoms and containing one or more (e.g., 1 to 4, 1 to 3, or 1 to 2) heteroatoms selected from N, O, and S. Furthermore, the heterocycles in this disclosure may also be fused or bridged heterocyclic alkyl groups. Examples of heterocyclic alkyl groups include azirrobutyl, oxacyclobutyl, tetrahydrofuranyl, pyrrolidinyl, imidazolinyl, oxazolinyl, oxazoalkyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiaranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyridinyl, tetrahydropyrazolopyridinyl, morpholinyl, dihydroindolyl, azirthiomorpholinyl, etc.

[0038] Heterocyclic alkyl substituents can be linked by carbon atoms or heteroatoms. Heterocyclic alkyl groups can optionally be substituted by one or more suitable groups via one or more of the aforementioned groups. Unless otherwise defined, heterocyclic alkyl refers to 4- to 12-membered heterocyclic alkyl groups, preferably 4- to 10-membered heterocyclic alkyl groups, and more preferably 4- to 7-membered heterocyclic alkyl groups.

[0039] Cyclic substituents (such as cycloalkyl, cycloalkenyl, aryl, heterocyclic, heteroaryl, heterocycloalkyl, etc.) can be unsubstituted or substituted.

[0040] compound

[0041] To address the aforementioned problems, this disclosure provides a compound represented by the following chemical formula 1, its optical isomer, its stereoisomer, its solvate, its tautomer, or a pharmaceutically acceptable salt thereof: [Formula 1]

[0042] In the above chemical formula, A1, A2, A3, A4, and A5 can each independently be C, CH, CH2, or N; R1 can be C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C8 cycloalkyl or 4- to 12-membered heterocyclic alkyl, wherein the C1-C 10 Alkyl, C1-C 10 The haloalkyl, C3-C8 cycloalkyl, or 4- to 12-membered heterocyclic alkyl group may be unsubstituted, or may be substituted by at least one, preferably one to four, substituents selected from the group consisting of: oxo (=O), halogen, C1-C 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Halogenated alkyl groups; R2 can be H, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C8 cycloalkyl, 4-12 membered heterocyclic alkyl, OR' or NR'R", wherein the C1-C 10 Alkyl, C1-C 10 The alkoxy or 4-12 membered heterocyclic alkyl group may be unsubstituted, or may be substituted by at least one, preferably one to four, substituents selected from the group consisting of: halogen, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkoxy C1-C 10 Alkyl, 4-12 membered heterocyclic alkyl, C6-C 10 Aryl and C3-C8 cycloalkyl groups; Where R' and R” can each independently be H, C1-C 10 Alkyl groups, and in this case, the C1-C 10 The alkyl group may be unsubstituted, or it may be substituted by one or more, preferably one to four, substituents selected from the group consisting of: halogen, cyano, 4-12 membered heterocyclic alkyl, C6-C 10 Aryl, C3-C8 cycloalkyl and C1-C 10 alkoxy; or R' and R” can form 4- to 12-membered heterocyclic alkyl groups together with N in NR'R”, wherein the 4- to 12-membered heterocyclic alkyl groups are unsubstituted or halogenated, C1-C 10 Alkoxy or C1-C 10 Alkoxy C1-C 10 Alkyl substitution; R3 can be H, C1-C 10 Alkyl, C1-C10 Deuterated alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, -C1-C 10 Alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 12-membered heterocyclic alkyl or -C1-C 10 Alkyl-4-12-membered heterocyclic alkyl, wherein the C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, -C1-C 10 Alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-12 membered heterocyclic alkyl or -C1-C 10 The alkyl-4-12-membered heterocyclic alkyl group may be unsubstituted or substituted with one or more, preferably one to four, substituents selected from the group consisting of: halogen, cyano, oxo, C1-C. 10 Alkyl, C2-C 10 Alkenyl, C1-C6 alkoxy, unsubstituted or substituted C3-C8 cycloalkyl and substituted 4-12 membered heterocyclic alkyl; R4 can be C1-C 10 Alkyl, C1-C 10 Deuterated alkyl or amino, wherein C1-C 10 Alkyl, C1-C 10 The deuterated alkyl or amino group may be unsubstituted, or may be selected from one or more, preferably one to four, hydroxyl and C1-C1 groups. 10 Alkyl substituents; R5 can be H, halogen, nitro, cyano, amino, hydroxyl, -C(=O)R"', -CO(=O)R"', -N(R"')2, -C(=O)NR"', -SO2R"', C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, 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 heterocyclic alkyl, 4-12 membered heterocyclic alkyl C1-C 10Alkyl, 4-12 heteroaryl or 4-12 heteroaryl C1-C 10 Alkyl, wherein the C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, 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 heterocyclic alkyl, 4-12 membered heterocyclic alkyl C1-C 10 Alkyl, 4-12 heteroaryl or 4-12 heteroaryl C1-C 10 The alkyl group is unsubstituted or substituted by one or more, preferably one to four, substituents selected from the group consisting of: halogen, cyano, nitro, amino, hydroxyl, C1-C. 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Alkoxy, C6-C 10 Aryl, 4-12 membered heterocyclic alkyl, 4-12 membered heteroaryl and C3-C8 cycloalkyl, R”' can be H, halogen, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, 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 heterocyclic alkyl, 4-12 membered heterocyclic alkyl C1-C 10 Alkyl, 4-12 heteroaryl or 4-12 heteroaryl C1-C 10 alkyl.

[0043] Furthermore, in one specific embodiment of this disclosure... R1 can be a C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 10-membered heterocyclic alkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 10-membered heterocyclic alkyl can be unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of: oxo, fluorine, chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

[0044] In a more specific embodiment, the C3-C6 cycloalkyl group of R1 may be cyclobutyl, cyclopentyl, or cyclohexyl, and the 4- to 10-membered heterocycloalkyl group of R1 may be oxacyclobutyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0045] In a more specific embodiment, the C1-C6 alkyl group of R1 can be methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.

[0046] R1's C1-C 10 Alkyl, C1-C 10 The haloalkyl, C3-C8 cycloalkyl or 4- to 12-membered heterocyclic alkyl may be unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: oxo, fluorine, methyl, ethyl, propyl, isopropyl, trifluoromethyl and methoxy.

[0047] In a more specific embodiment, R1 may be selected from the following groups: .

[0048] Furthermore, in one specific embodiment of this disclosure... R2 can be H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-10 heterocyclic alkyl, OR' or NR'R", and the C1-C6 alkyl, C1-C6 alkoxy, or 4-10 heterocyclic alkyl can be unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, 4-10 heterocyclic alkyl, C6-C 10 Aryl and C3-C6 cycloalkyl, and Wherein, R' and R" can each independently be H, or a C1-C6 alkyl group, and wherein the C1-C6 alkyl group can be unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, 4-10 membered heterocyclic alkyl, C6-C 10 Aryl, C3-C6 cycloalkyl and C1-C6 alkoxy.

[0049] Alternatively, R' and R” can be combined with the N of NR'R” to form a 4- to 10-membered heterocyclic alkyl group, wherein the 4- to 10-membered heterocyclic alkyl group can be unsubstituted or substituted with fluorine, chlorine, bromine, C1-C6 alkoxy or C1-C6 alkoxy-C1-C6 alkyl.

[0050] In a more specific embodiment, R2 may be selected from the following groups: .

[0051] Furthermore, in one specific embodiment of this disclosure... R3 can be H, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, -C1-C6 alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-10 heterocyclic alkyl, or -C1-C6 alkyl-4-10 heterocyclic alkyl, wherein the C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, -C1-C6 alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-10 heterocyclic alkyl, or -C1-C6 alkyl-4-10 heterocyclic alkyl can be unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, oxo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, unsubstituted or substituted with 1 to 3 halogens, C3-C8 cycloalkyl, and 4-10 heterocyclic alkyl.

[0052] In a more specific embodiment, R3 may be selected from the following groups: .

[0053] In one specific embodiment of this disclosure, R4 can be a C1-C6 alkyl, C1-C6 deuterated alkyl, or amino group, wherein the C1-C6 alkyl, C1-C6 deuterated alkyl, or amino group can be unsubstituted or substituted with one or two substituents selected from hydroxyl and C1-C6 alkyl groups.

[0054] In a more specific embodiment, R4 can be CH3, CD3, CH2OH, NH2, or NHCH3.

[0055] In one specific embodiment of this disclosure, R5 can be H, halogen, nitro, cyano, amino, hydroxyl, -C(=O)R"', -CO(=O)R"', -N(R"')2, -C(=O)NR"', -SO2R"', C1-C6 alkyl, C1-C6 deuterated alkyl, 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 Aryl C1-C6 alkyl, 4-10 heterocyclic alkyl, 4-10 heterocyclic alkyl C1-C6 alkyl, 4-10 heteroaryl, or 4-10 heteroaryl C1-C6 alkyl, wherein the C1-C6 alkyl, C1-C6 deuterated alkyl, 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 The aryl C1-C6 alkyl, 4-10 heterocyclic alkyl, 4-10 heterocyclic alkyl C1-C6 alkyl, 4-10 heteroaryl, or 4-10 heteroaryl C1-C6 alkyl may be unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of: halogen, cyano, nitro, amino, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C6-C 10 Aryl, 4-10 membered heterocyclic alkyl, 4-10 membered heteroaryl and C3-C6 cycloalkyl, and R”' can be H, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, 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 Aryl C1-C6 alkyl, 4-10 heterocyclic alkyl, 4-10 heterocyclic alkyl C1-C6 alkyl, 4-10 heteroaryl or 4-10 heteroaryl C1-C6 alkyl.

[0056] In one specific embodiment of this disclosure, the heterocyclic alkyl or heteroaryl group may include one or more, preferably one to four, more preferably one to three heteroatoms. The heteroatoms may be selected from N, O, and S.

[0057] In one specific embodiment, the compound of Formula 1 according to this disclosure may be selected from, but not limited to, one or more of the following compounds 1 to 117.

[0058] 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-methyloxetane-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-methoxyazacyclobutyl-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-methoxyazacyclobut-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-methoxyazacyclobutane-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-methoxyazacyclobut-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-methylpropyl-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-methoxyazacyclobut-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-methoxyazacyclobut-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)azacyclobutyl-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-(isopentoxy)-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-methoxyazacyclobut-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-methoxyazacyclobut-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-trifluoroprop-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-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 40: N-(3-(5-(3-methoxyazacyclobut-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-methoxyazacyclobutyl-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-methoxypyrrolidone-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-methoxypyrrolidone-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]oct-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]oct-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]hept-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-(oxecyclobutyl-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-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoropropyl-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]oct-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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]oct-6-yl)-1-(1,1,1-trifluoropropyl-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 59: N-(3-(1-(3,3-difluorobut-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 67: (S)-N-(3-(5-(3,3-difluoropyrrolidone-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 69: (S)-N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 75: (S)-N-(3-(5-(3-isopropoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-isopropoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-isopropoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-oxaspiro[3.3]hept-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 80: (S)-N-(1-(cyclopropylmethyl)-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-methoxyazacyclobutyl-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 83: (S)-N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 85: (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-((3-methyloxetane-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(oxetanebut-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-trifluoroprop-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]hept-2-yl)-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(7-oxaspiro[3.5]non-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 98: (S)-N-(1-(cyclopropylcarbonyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea.

[0059] Unless otherwise stated, the formulas or names given in the specification and claims cover tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and their racemates, as well as mixtures of enantiomers in different proportions, mixtures of diastereomers, or any of the above forms (including isomers and enantiomers), pharmaceutically acceptable salts (e.g. hydrates, including, for example, solvates and hydrates of free compounds, and solvates and hydrates or salts of such compounds).

[0060] In one embodiment, the compounds of this disclosure may be present in the form of pharmaceutically acceptable salts. As salts, acid addition salts formed from pharmaceutically acceptable free acids are useful. The term "pharmaceutically acceptable salt" in this disclosure refers to any organic or inorganic addition salt of the compound whose concentration is relatively non-toxic and harmless to the patient, and whose side effects do not diminish the beneficial efficacy of the compounds of this disclosure.

[0061] Acid addition salts can be prepared by conventional methods, such as dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent (such as methanol, ethanol, acetone, or acetonitrile). Alternatively, an acid or alcohol (e.g., ethylene glycol monomethyl ether) of the same molar amount as the compound can be heated with water, and the mixture can be evaporated to dryness, or the precipitated salt can be filtered.

[0062] In this case, organic and inorganic acids can be used as free acids; hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids; 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, glutamate, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc. can be used as organic acids, but are not limited to these.

[0063] In addition, alkalis can be used to prepare pharmaceutically acceptable metal salts. For example, an alkali metal salt or alkaline earth metal salt can be obtained by dissolving the compound in an excess solution of an alkali metal hydroxide or alkaline earth metal hydroxide, filtering out the undissolved compound salt, and then evaporating and drying the filtrate. In this case, it is particularly suitable to prepare sodium, potassium, or calcium salts as the metal salt, but not limited thereto. Furthermore, the corresponding silver salt can be obtained by reacting the alkali metal salt or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0064] Unless otherwise stated, pharmaceutically acceptable salts of the compounds disclosed herein include salts formed from acidic or basic groups that may be present in the compounds of Formula 1. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxyl groups; other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, mesylate, and tosylate, which can be prepared by salt-forming methods known in the art. In one specific embodiment, a pharmaceutically acceptable salt of the compounds disclosed herein may be a hydrochloride salt.

[0065] Salts of the compounds described in this disclosure 1 are pharmaceutically acceptable salts, and salts of any compound of formula 1 that exhibit pharmacological activity equivalent to that of the compound of formula 1 may be used without limitation.

[0066] Furthermore, the compounds of Formula 1 described in this disclosure include, but are not limited to, pharmaceutically acceptable salts thereof, solvates (e.g., hydrates) that can be prepared therefrom, and all possible stereoisomers. All stereoisomers of this disclosure, including enantiomeric and diastereomeric forms (e.g., isomers that may exist due to asymmetric carbons in various substituents), are covered within the scope of this disclosure. Individual stereoisomers of the compounds of this disclosure may, for example, be in a form substantially free of other isomers (e.g., as a pure or substantially pure optical isomer with specific activity), or may be in a form mixed with a racemic mixture, all other stereoisomers, or other selected stereoisomers. The chiral center of the compounds of this disclosure may have an S or R configuration as defined in IUPAC Recommendation 1974. The racemic form can be analyzed by physical methods, such as separation by chiral column chromatography, separation or crystallization of diastereomeric derivatives, or stepwise crystallization. Individual optical isomers may be obtained from the racemic mixture by any suitable method, including but not limited to crystallization after salting with an optically active acid.

[0067] Solvents and stereoisomers of the compound of formula 1 can be prepared from the compound using methods known in the art.

[0068] Furthermore, the compounds of Formula 1 according to this disclosure can be prepared in crystalline or amorphous form, and when prepared in crystalline form, they may optionally be in hydrate or solvate form. This disclosure may include compounds containing varying amounts of water, as well as stoichiometric hydrates of the compounds of Formula 1. Solvates of the compounds of Formula 1 according to this disclosure include stoichiometric solvates and non-stoichiometric solvates.

[0069] In one specific embodiment of this disclosure, the activity of the compound represented by Formula 1 of this disclosure against TYK2 JH2, JAK1 JH1, JAK2 JH1, JAK3 JH1, and TYK2 JH1 enzymes was evaluated, and its excellent activity and selectivity were confirmed. Furthermore, this compound exhibited excellent activity (IC50) in TYK2 / JAK1 cell activity. 50 < 50 nM).

[0070] Therefore, the compounds disclosed herein and their pharmaceutically acceptable salts are effective for the prevention, improvement or treatment of TYK2-related diseases, specifically autoimmune diseases, inflammatory diseases or cancer.

[0071] Preparation method

[0072] In another embodiment, this disclosure relates to a method for preparing the novel compound.

[0073] Compounds of Formula 1 can be synthesized via the synthetic routes described herein. In some embodiments, methods known in the chemical field or based on the methods disclosed herein may be employed. Typically, starting materials can be conveniently prepared using methods available from commercial sources or methods well known to those skilled in the art.

[0074] The compounds disclosed herein can be prepared from commercially available starting materials using the general methods illustrated herein. For illustration, reaction schemes 1 to 5 shown below provide pathways for the synthesis of the major intermediates and compounds of formula 1. More detailed descriptions of each reaction step can be found in the examples below. Those skilled in the art will understand that other synthetic pathways may also be employed. Although specific starting materials and reagents are shown in the reaction schemes and described below, other starting materials and reagents may be used instead to prepare various derivatives and / or to employ different reaction conditions. Furthermore, many compounds prepared using the methods described below can be further modified based on this disclosure using conventional chemicals known to those skilled in the art.

[0075] In one specific embodiment, the preparation method includes: Step 1: Prepare the compound represented by chemical formula 1 by boronizing the compound represented by formula 3 and then reacting it with the compound corresponding to chemical formula 2 via a Suzuki reaction or an Ullmann reaction.

[0076] As a specific example, in step 1, the compound represented by formula 3 is dissolved in a 1,4-dioxane ring, and bis(pinacol)diboron, potassium acetate, Pd(dba)2, and 0.6 M PCy3 in toluene are used as reaction reagents. After stirring at 90–110 °C for 1 hour to overnight, the mixture is filtered. Subsequently, the above reaction product and the compound represented by formula 2 are dissolved in 1,4-dioxane and water, and Pd(dppf)2Cl2 is used. . DCM and K3PO4 were used as reaction reagents. After stirring at 70-80°C for 1 hour to overnight, the compound of chemical formula 1 was obtained.

[0077] [Equation 2]

[0078] [Formula 3]

[0079] In the above formula, A1, A2, A3, A4, A5, R1, R2, R3, R4, and R5 are as defined in Chemical Formula 1. And X is a halogen, preferably fluorine, chlorine, bromine or iodine.

[0080] Specifically, the preparation method can be represented by the following reaction scheme 1.

[0081] [Reaction Scheme 1]

[0082] In the reaction scheme, A1, A2, A3, A4, A5, R1, R2, R3, R4, and R5 are as defined in Chemical Formula 1. Furthermore, X is a halogen, preferably fluorine, chlorine, bromine, or iodine.

[0083] Compounds of chemical formula 2 can be prepared by a method including the following steps: Step 2: Prepare the compound represented by the following chemical formula 5 by reacting the compound represented by formula 4 with NBS or NIS; Step 3: By subjecting the compound represented by the following chemical formula 5 to S N 2. The reaction or Chan-Lam reaction is used to prepare the compound represented by the following chemical formula 6; Step 4: Deacetylate the compound represented by the following chemical formula 6 by using an acid (e.g., hydrochloric acid), and then react it with an isocyanate or acetyl chloride to prepare the compound represented by chemical formula 2.

[0084] As a specific example, in step 2, the compound represented by chemical formula 4 is dissolved in a suitable solvent (e.g., N,N-dimethylformamide), and then NBS or NIS as a halogen donor is added dropwise, and the mixture is stirred overnight at room temperature.

[0085] As a specific example, in step 3, the compound represented by Formula 5 is dissolved in acetonitrile or N,N-dimethylformamide, then cesium carbonate is used as a base, and dimethyl sulfate or a haloalkyl compound or mesylate alcohol is used as a reaction reagent. The compound of Formula 6 is prepared by stirring overnight at room temperature or 80°C. The mesylate alcohol is prepared by dissolving the alcohol corresponding to R3 in dichloromethane, 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'-bipyridine, anhydrous copper(II) acetate, and sodium carbonate are used as reagents for the Chan-Lam reaction, and N,N-dimethylformamide is used as a solvent. The compound of Formula 6 is prepared by stirring overnight at 70°C.

[0086] As a specific example, in step 4, the compound represented by formula 6 is dissolved in methanol, and then 4N HCl in 1,4-dioxane is added dropwise, while stirring at 80°C for 5 hours. The reactants are concentrated and dissolved in dichloromethane, followed by the dropwise addition of N,N-diisopropylethylamine and 2,2,2-trichloroacetyl isocyanate at 0°C. The reactants are stirred at room temperature for 30 minutes, and then concentrated. After dissolving the reactants in methanol, a saturated aqueous solution of sodium bicarbonate is added dropwise. The compound represented by formula 2 is prepared by stirring at room temperature for 1 to 4 hours.

[0087] Specifically, the preparation method can be represented by the following reaction scheme 2.

[0088] [Reaction Scheme 2]

[0089] In the above reaction scheme, A2, A3, A4, A5, R3, and R4 are as defined in Chemical Formula 1. X is a halogen, preferably fluorine, chlorine, bromine or iodine.

[0090] As a specific example, compounds of formula 3—where R5 is H and R2 is a 4-12 membered heterocyclic alkyl group, OR', or NR'R"—can be prepared by a preparative method comprising the following steps: Step 5: Utilize the Mitsunobu reaction or S N 2. A reaction is performed to prepare the compound of formula 8 from the compound represented by formula 7 below; and Step 6: React the compound represented by Formula 8 below with NaHMDS (a disilicide) and an alcohol compound corresponding to R2 (e.g., HOR') or an amine compound corresponding to R2 (e.g., HNR'R" compound) to prepare the compound represented by Formula 3.

[0091] As a concrete example, in step five, the compound represented by formula 7 is dissolved in N,N-dimethylformamide, followed by the dropwise addition of cesium carbonate and a haloalkylide; the compound of formula 8 is prepared by stirring overnight at room temperature. Alternatively, the compound represented by formula 7 is dissolved in tetrahydrofuran, followed by the dropwise addition of R1OH, PhOPPh2 or PPh3, and DIAD or DEAD, and stirred overnight at room temperature to prepare the compound of formula 8.

[0092] As a concrete example, step 6 can be performed: dissolving the compound represented by formula 8 in 1,4-dioxane or tetrahydrofuran, and then adding dropwise 2N NaHMDS (2N NaHMDS in tetrahydrofuran) and an alcohol (HOR') or amine corresponding to R2 (HNR'R"). The compound of formula 3 is prepared by stirring at room temperature or 50°C for 1 to 4 hours.

[0093] As a concrete example, a compound of chemical formula 3—where R 5 "If H is H and R2 is a 4-12 membered heterocyclic alkyl group, OR' or NR'R" can be represented by the following reaction scheme 3.

[0094] [Reaction Scheme 3]

[0095] In the above reaction scheme, A1, R1, and R2 are as defined in chemical formula 1. X is a halogen, preferably fluorine, chlorine, bromine or iodine.

[0096] As a concrete example, a compound of chemical formula 3—where R5 is H, R2 is H, C1-C 10 Alkyl, C1-C 10 Alkoxy or C3-C8 cycloalkyl groups can be prepared by a method comprising the following steps: Step 7: By Mitsunobu reaction or S N 2. The compound represented by chemical formula 9 is used to prepare the compound represented by chemical formula 8.

[0097] As a specific example, in step seven, the compound represented by formula 9 is dissolved in N,N-dimethylformamide, followed by the dropwise addition of cesium carbonate and a haloalkylide. The compound represented by formula 8 is prepared by stirring overnight at room temperature. Alternatively, the compound represented by formula 9 is dissolved in tetrahydrofuran, followed by the dropwise addition of R1OH, PhOPPh2 or PPh3, and DIAD or DEAD, and stirred overnight at room temperature to prepare the compound represented by formula 8.

[0098] As a concrete example, a compound of chemical formula 3—where R5 is H, R2 is H, and C1-C 10 Alkyl, C1-C 10 The preparation method of alkoxy or C3-C8 cycloalkyl can be represented by the following reaction scheme 4.

[0099] [Reaction Scheme 4]

[0100] In the above reaction scheme, A1, R1, and R2 are as defined in chemical formula 1. X is a halogen, preferably fluorine, chlorine, bromine or iodine.

[0101] As a specific example, compounds of Formula 1 can also be prepared by a method comprising the following steps: Step 1': Boryl the compound of formula 3, and then react it with the compound of formula 6 via a Suzuki reaction or an Ullmann reaction to obtain the compound of formula 10; Step 2': Deacetylate the compound of formula 10 using an acid (e.g., hydrochloric acid), and then react it with acetoxyacetyl chloride or methylamine to obtain the compound of formula 1.

[0102] As a specific example, in step 1' above, the compound represented by formula 3 was dissolved in 1,4-dioxane, and 0.6 M PCy3 from bis(pinacol)diboron, potassium acetate, Pd(dba)2, and toluene were used as reaction reagents. After stirring at 90-110°C for 1 hour to overnight, the mixture was filtered. The reactants and the compound represented by formula 6 were dissolved in 1,4-dioxane and water, and Pd(dppf)2Cl2·DCM and K3PO4 were used as reaction reagents. After stirring at 70-80°C for 1 hour to overnight, the compound represented by formula 10 was obtained.

[0103] As a specific example, in step 2', the compound of formula 10 synthesized in step 1' 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 reactants are concentrated and dissolved in dichloromethane, and acetoxyacetyl chloride and pyridine are added dropwise. The mixture is stirred at room temperature for 3 hours and concentrated. The reactants are dissolved in methanol, and potassium carbonate is added dropwise. The mixture is stirred at room temperature for 15 minutes to obtain the compound of formula 1. Alternatively, the deacetylated reactants are concentrated and dissolved in tetrahydrofuran, triphosgene is added dropwise at 0°C, and the mixture is stirred for 1 hour. Methylamine is added dropwise to the reactants at room temperature, and the mixture is stirred to obtain the compound of formula 1.

[0104] Specifically, the manufacturing method mentioned above can be represented by the following reaction scheme 5.

[0105] [Reaction Scheme 5]

[0106] In the above reaction scheme, A1, A2, A3, A4, A5, R1, R2, R3, R4, and R5 are as defined in Chemical Formula 1 above, and X is a halogen, preferably fluorine, chlorine, bromine or iodine.

[0107] Pharmaceutical Compositions and Pharmaceutical Uses

[0108] Due to their biological properties, the compounds disclosed herein or their pharmaceutically acceptable salts may be suitable for the prevention, improvement or treatment of various diseases caused by TYK2 activity.

[0109] Therefore, in another embodiment, this disclosure relates to a pharmaceutical composition for the prevention, improvement or treatment of various diseases associated with TYK2, comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0110] TYK2-related diseases may include any disease, disorder, or condition that is directly or indirectly related to the expression or activity of TYK2, including overexpression and / or aberrant activity levels. Aberrant activity levels can be determined by comparing the activity levels in normal healthy tissues or cells with those in diseased cells. TYK2-mediated diseases may also include any disease, disorder, or condition that can be prevented, improved, inhibited, or cured by modulating TYK2 activity.

[0111] TYK2-mediated diseases that can be treated with the compounds disclosed herein can be autoimmune diseases, inflammatory diseases, cancers, or neurodegenerative diseases.

[0112] In one specific implementation, the autoimmune diseases and inflammatory diseases may be selected from one or more of the following groups: asthma, alopecia areata, ankylosing spondylitis, lupus, lupus nephritis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis (including plaque psoriasis, scalp psoriasis, and nail psoriasis), Sjögren's syndrome, multiple sclerosis, palmoplantar pustulosis, celiac disease, atopic dermatitis, contact dermatitis, delayed-type hypersensitivity reactions, treatment of eye diseases and conditions such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca and vernal keratoconjunctivitis, diseases involving the nose including allergic rhinitis, and intermittent... Pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyridine-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis, endometritis, leptospirosis, kidney disease, myocardial hypertrophy, muscle atrophy, catabolism disorders, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, pigment incontinence, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, allergic reactions, sinusitis Eye allergies, silica-induced diseases, chronic obstructive pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, COVID-19, cataracts, muscle inflammation with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 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, upper respiratory tract infection, etc. Condyleitis, epididymitis, fasciitis, fibrositis, gastritis, Henrönlein purpura, hepatitis, hidradenitis suppurativa, leukocyte adhesion deficiency, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis, but not limited to these.

[0113] In one specific implementation, the cancer may be selected from one or more of the following groups: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, urogenital cancer, seminoma, esophageal cancer, laryngeal cancer, gastric cancer, stomach cancer. Cancer, gastrointestinal cancer, skin cancer, keratoacanthoma, follicular carcinoma, melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, adenomatous polyps, colon cancer, pancreatic cancer, thyroid cancer, papillary carcinoma, bladder cancer, liver cancer, biliary tract cancer, kidney cancer, bone cancer, bone marrow diseases, lymphatic system diseases, pilomatricoma, oral and pharyngeal cancer (oral cavity), 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, cervical cancer, brain cancer, central nervous system cancer, peritoneal cancer, hepatocellular carcinoma, head cancer, neck cancer, Hopkins disease, and leukemia (acute myeloid leukemia), but not limited to these.

[0114] In one specific implementation, the neurodegenerative disease may be one or more diseases selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, but is not limited thereto.

[0115] All of the cancers described above, characterized by specific locations / organs in the body, are intended to include both primary tumors and metastatic tumors arising from them. All of these cancers can be further differentiated based on their histopathological classification.

[0116] The interchangeable terms “subject” or “patient” refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0117] The term “therapeutic effective amount” refers to an amount of an active compound or agent that elicits the biological or medical response sought by a researcher, veterinarian, physician or other clinician in a tissue, system, animal, subject or human.

[0118] The term “treatment” means one or more of the following: (1) suppressing a disease; for example, suppressing the disease, condition, or disorder in a subject who is experiencing or exhibiting pathological manifestations or symptoms of a disease, condition, or disorder (i.e., preventing the further development of the pathological manifestations and / or symptoms); and (2) improving a disease; for example, improving the disease, condition, or disorder in a subject who is experiencing or exhibiting pathological manifestations or symptoms of a disease, condition, or disorder (i.e., reversing the pathological manifestations and / or symptoms), such as reducing the severity of the disease. In one implementation, treatment includes preventing a disease or reducing the risk of developing a disease; for example, preventing a disease, condition, or disorder or reducing the risk of developing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but has not yet experienced or exhibited pathological manifestations or symptoms of the disease.

[0119] In one specific embodiment, the compounds according to this disclosure or their pharmaceutically acceptable salts and pharmaceutical compositions comprising them can be used in conjunction with non-pharmacological therapies known in the art for diseases associated with TYK2 activity. For example, they can be combined with radiotherapy and / or surgery and / or other compounds for the prevention, short-term treatment, or long-term treatment of the aforementioned diseases.

[0120] The pharmaceutical compositions disclosed herein can be administered to mammals, such as rats, mice, livestock, and humans, via various routes. In this disclosure, the routes of administration of the pharmaceutical compositions include, but are not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardiac, percutaneous, subcutaneous, intraperitoneal, intranasal, intraenteral, local, sublingual, or rectal routes.

[0121] Furthermore, oral and parenteral administration are preferred methods of administering the pharmaceutical composition. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrabursal, intrasternal, intradural, intralesional, and intracranial injection or infusion techniques.

[0122] The pharmaceutical compositions according to this disclosure may also contain one or more pharmaceutically acceptable carriers, one or more excipients, and / or diluents.

[0123] Non-limiting examples of pharmaceutically suitable carriers include solids and / or liquids, such as ethanol, glycerol, water, etc. The amount of carrier in a therapeutic composition may be from about 5% by weight to about 99% by weight, based on the total weight of the therapeutic composition or treatment combination. Non-limiting examples of suitable pharmaceutically acceptable excipients and diluents include non-toxic, compatible fillers, binders, disintegrants, buffers, preservatives, wetting agents, extenders, antioxidants, lubricants, flavoring agents, thickeners, colorants, surfactants, emulsifiers, suspensions, etc. Such excipients and diluents may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil, and it will be apparent to those skilled in the art that all other pharmaceutically acceptable carriers, excipients, and diluents may be used.

[0124] Compositions comprising compounds of Formula 1 or salts thereof disclosed herein can be formulated and used in conventional methods as oral preparations such as tablets, powders, granules, pills, capsules, suspensions, emulsions, solutions, emulsifiable concentrates, syrups, etc., as well as topical preparations, suppositories, or sterile injections.

[0125] The pharmaceutical compositions according to this disclosure may be in the form of sterile injectable formulations, such as sterile aqueous or oily suspensions for injection. The suspensions may be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents, according to techniques known in the art. Sterile injectable formulations may also be sterile injectable solutions or suspensions (e.g., solutions in 1,3-butanediol) in non-toxic and parenteral-acceptable diluents or solvents. Acceptable carriers and solvents include mannitol, water, Ringer's solution, or isotonic sodium chloride solution. Furthermore, sterile non-volatile oils are typically used as solvents or suspension media. For this purpose, any non-volatile oil with low irritation may be used, including synthetic monoglycerides or diglycerides. Natural oils (e.g., olive oil or castor oil) – wherein the fatty acids (e.g., oleic acid) and their glycerol derivatives are pharmaceutically acceptable, particularly their polyoxyethylene forms, and may be used in injectable formulations.

[0126] The pharmaceutical compositions according to this disclosure can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions and aqueous solutions.

[0127] The pharmaceutical compositions disclosed herein can also be used for rectal suppository administration. Such compositions can be prepared by mixing the disclosed compounds with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature. Such substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0128] Oral administration of the pharmaceutical compositions according to this disclosure is particularly useful when the desired treatment involves sites or organs easily accessible by topical application. When applied topically to the skin, the pharmaceutical composition should be formulated as a suitable ointment containing an active ingredient suspended or dissolved in a carrier. Carriers for topical application of the compounds of this disclosure include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing an 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-octyldodecanool, benzyl alcohol, and water. The pharmaceutical compositions of this disclosure can also be applied topically to the lower intestine as a suitable enema via rectal suppositories. This disclosure also includes transdermal patches for topical application.

[0129] The pharmaceutical compositions disclosed herein can be administered via nasal aerosol or inhalation. Such compositions can be prepared according to techniques known in the pharmaceutical field and can be prepared as saline solutions using benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, fluorocarbons, and / or other solubilizers or dispersants known in the art.

[0130] The pharmaceutical compositions disclosed herein contain the novel compound in a therapeutically effective amount or a preventatively effective amount. Preferred dosages of the compounds according to this disclosure may vary depending on the patient's condition and weight, disease severity, drug form, route of administration, and duration of administration, but may be appropriately selected by those skilled in the art. However, for optimal efficacy, the compounds of Formula 1 disclosed herein may be administered once or several times daily at a dose of 0.0001 to 1000 mg / kg, preferably 0.01 to 500 mg / kg.

[0131] Based on the total weight of the entire composition, the compounds of Formula 1 in the compositions disclosed herein may be blended in amounts from 0.0001 to 50% by weight.

[0132] In another embodiment, this disclosure relates to a method for preventing, improving or treating various diseases caused by the activity of TYK2, comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0133] In this case, the compound of Formula 1 of this disclosure or its pharmaceutically acceptable salt is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" in this disclosure means an amount sufficient to treat a disease with a reasonable benefit / risk ratio suitable for medical treatment and without causing side effects. The effective dose level can be determined based on factors including the patient's health status, the type and severity of the disease, the activity of the drug, sensitivity to the drug, the method of administration, the time of administration, the route of administration, the excretion rate, the duration of treatment, drugs mixed with or used concurrently, and other factors known in the medical field. The compositions of this disclosure can be administered as a single therapeutic agent or in combination with other therapeutic agents, sequentially or simultaneously with conventional therapeutic agents, and in a single dose or multiple doses. Importantly, taking all the above factors into account, the amount administered achieves the maximum effect with the minimum dosage and without side effects, which can be readily determined by those skilled in the art.

[0134] For example, since the dosage may be increased or decreased depending on the route of administration, disease severity, sex, weight, age, etc., the dosage does not limit the scope of this disclosure in any way.

[0135] Preferred doses of the compounds disclosed herein may vary depending on the patient’s condition and weight, disease severity, form of medicine, route of administration and duration of administration, but may be appropriately selected by those skilled in the art.

[0136] Combination therapy

[0137] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising them may be used alone or in combination with one or more adjunctive therapies (e.g., non-pharmacological treatments or therapeutic agents).

[0138] For example, combination therapy may combine two therapies, or three therapies (e.g., triple therapy with three therapeutic agents) or more. The dosage of one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) may be reduced compared to the standard dosage when administered alone.

[0139] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising them may be administered before, after, or concurrently with one or more such adjunctive therapies.

[0140] In one embodiment, the compound of Formula 1 may be used in combination with an adjunct therapeutic compound having anti-inflammatory or anti-proliferative properties or that can be used to treat autoimmune diseases, inflammatory diseases, or cancer. The adjunct therapeutic compound may be an NSAID or another anti-inflammatory agent. The adjunct therapeutic compound may be a chemotherapeutic agent.

[0141] In one specific embodiment, the compounds of this disclosure are administered in combination with any anti-IBD agent, including but not limited to: anti-inflammatory drugs, such as sulfasalazine, mesalazine; corticosteroids, such as budesonide, prednisone, cortisone, or hydrocortisone; immunosuppressants, such as azathioprine, mercaptopurine, infliximab, adalimumab, pegylated cetuzumab, methotrexate, cyclosporine, or natamizumab; antibiotics, such as metronidazole or ciprofloxacin; antidiarrheal agents, such as psyllium husk powder, loperamide, or methylcellulose; larzatibub; analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen; iron supplements, vitamin B supplements, vitamin D supplements, and any combination of the foregoing. In another instance, the compounds of this disclosure may be administered in combination with other anti-IBD treatments (e.g., surgery) (e.g., before, during, or after them).

[0142] In one specific embodiment, the compounds of this disclosure are administered in combination with any anti-psoriatic agent, including topical corticosteroids, vitamin D analogs such as calcipotriol or calcitriol, anthraquinone, topical retinoids such as tazarotene, calcineurin inhibitors such as tacrolimus or pimecrolimus, salicylic acid, coal tar, NSAIDs, moisturizing creams and ointments, oral or injectable retinoids such as acitretin, methotrexate, cyclosporine, hydroxyurea, immunomodulatory agents such as afacinate, etanercept, infliximab or ustekinumab, thioguanine, and any combination of the above-mentioned drugs, but not limited thereto. In another instance, the compounds of this disclosure may be administered in combination with another anti-psoriasis treatment, such as phototherapy, solar therapy, UVB therapy, narrowband UVB therapy, Gorkman therapy, photochemotherapy, such as psoralen combined with ultraviolet A (PUVA) therapy, excimer laser therapy, and pulsed dye laser therapy, or any combination of the anti-psoriasis agent and the anti-psoriasis treatment (e.g., before, during, or after).

[0143] In one specific embodiment, the compounds of this disclosure may be co-administered with any anti-asthmatic agent, including, but not limited to, β2-adrenergic receptor agonists, inhaled and oral corticosteroids, leukotriene receptor antagonists, and omalizumab. In another embodiment, the compounds of this disclosure may be co-administered with an anti-asthmatic agent selected from: NSAIDs, combinations of fluticasone and salmeterol, combinations of budesonide and formoterol, omalizumab, lebulizumab, and corticosteroids selected from fluticasone, budesonide, mometasone, flunisolone, and beclomethasone.

[0144] Compared with conventional TYK2 inhibitors, the compounds disclosed herein and their pharmaceutically acceptable salts have TYK2 inhibitory activity, and their cellular activity and enzyme selectivity are superior to those of compounds in the related art. Therefore, they can be effectively used to prevent, improve or treat TYK2-related diseases, specifically autoimmune diseases, inflammatory diseases, cancer or neurodegenerative diseases.

[0145] Detailed description of the implementation method

[0146] Preferred embodiments are given below to aid in understanding this disclosure. However, these embodiments are for illustrative purposes only and this disclosure is not intended to be limited to these embodiments.

[0147] Various synthetic methods are known for the starting materials used to synthesize the compounds disclosed herein, and when said starting materials are commercially available, they can be purchased from suppliers. Reagent suppliers include, but are not limited to, Sigma-Aldrich, TCI, an-gene, chemspace, chemscene, BLD, Alfa, combi-blocks, and Dae-Jung. Furthermore, unless otherwise stated, all commercially available materials are used directly without purification steps.

[0148] First, compounds for the synthesis in the following examples were prepared according to the following preparation examples. The following preparation examples are examples of compounds represented by Formula 1 of the aforementioned reaction formula 1, and may be appropriately modified according to the structure of the example to be prepared.

[0149] Preparation Example 1) Preparation 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 of Example 19)

[0150] Step 1) Preparation of 4-bromo-6-chloro-2-isopropylpyridazine-3(2H)-one

[0151] 500 mg (2.39 mmol) of 5-bromo-3-chloro-1H-pyridazin-6-one was dissolved in 10 mL of N,N-dimethylformamide, followed by the dropwise addition of 1556 mg (4.77 mmol) of cesium carbonate and 0.360 mL (3.58 mmol) of 2-iodopropane. After stirring at room temperature for 16 hours, 30 mL of water and 30 mL of ethyl acetate were added to allow for layer separation. The product was extracted with 200 mL of ethyl acetate. The organic layer was treated with anhydrous magnesium sulfate and then concentrated. The target compound (550 mg, 92%) was obtained by column chromatography.

[0152] LC-MS (ESI): Calculated value of C7H8BrClN2O: 249.95, Measured m / z: 250.62 [M+H] + .

[0153] Step 2) Preparation of 6-chloro-4-isobutoxy-2-isopropyl-pyridazin-3-one

[0154] 275 mg (1.09 mmol) of 4-bromo-6-chloro-2-isopropylpyridazine-3(2H)-one and 82 mg (1.09 mmol) of 2-methylprop-1-ol were dissolved in 5 mL of 1,4-dioxane, followed by the slow addition of (0.71 mL, 1.42 mmol) 2 M NaHMDS. After stirring at 50 °C for 1 hour, 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 then concentrated. The target compound (179 mg, 67%) was obtained by column chromatography.

[0155] LC-MS (ESI)C 11 H 17 Calculated value of ClN2O2: 244.10, measured m / z: 245.10 [M+H] + .

[0156] Step 3) Preparation of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0157] 10 g (54.23 mmol) of N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was dissolved in 50 mL of N,N-dimethylformamide, followed by the dropwise addition of 12.19 g (81.34 mmol) of NBS. 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 was extracted with 200 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and then concentrated. The resulting compound was used in subsequent reactions without further purification.

[0158] LC-MS (ESI) calculated value of C9H8BrN3O: 252.99, measured m / z: 254.27 [M+H] + .

[0159] 1H 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).

[0160] Step 4) Preparation of N-(3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0161] 7.4 g (29.13 mmol) of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was dissolved in 200 mL of acetonitrile, followed by the dropwise addition of 18.98 g (58.25 mmol) of cesium carbonate and 3.038 mL (32.04 mmol) of dimethyl sulfate. 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 was extracted with 200 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting compound was used in subsequent reactions without further purification. (7.74 g, 99%)

[0162] LC-MS (ESI) C 10 H 10 Calculated value of BrN3O: 267.00, measured m / z: 268.20 [M+H] + .

[0163] 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).

[0164] 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

[0165] 45 mg (0.18 mmol) of 6-chloro-4-isobutoxy-2-isopropyl-pyridazin-3-one, 93 mg (0.37 mmol) of bis(pinacol)diboron, 36 mg (0.37 mmol) of potassium acetate, 16 mg (0.028 mmol) of Pd(dba)2, and 0.092 mL (0.055 mmol) of toluene containing 0.6 M PCy3 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 through diatomaceous earth. Dissolve the mixture in 1 mL of 1,4-dioxane and 0.1 mL of water, then add dropwise 58 mg (0.18 mmol) of N-(3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide and 15 mg (0.018 mmol) of Pd(dppf)₂Cl₂. . DCM and 78 mg (0.37 mmol) of K3PO4 were stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was filtered using diatomaceous earth. The target compound (10.5 mg, 14%) was obtained by preparative HPLC separation.

[0166] LC-MS (ESI) C 21 H 27 Calculated value of N5O3: 397.21, measured m / z: 398.25 [M+H] + .

[0167] 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).

[0168] Preparation Example 2) Preparation of 1-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea (Compound of Example 37)

[0169] Step 1) Preparation of 4-bromo-6-chloro-2-(2,2,2-trifluoro-1-methyl-ethyl)pyridazin-3-one

[0170] 500 mg (2.39 mmol) of 5-bromo-3-chloro-1H-pyridazin-6-one, 409 mg (3.58 mmol) of 1,1,1-trifluoroprop-2-ol, and 1252 mg (4.77 mmol) of PPh3 were dissolved in 10 mL of tetrahydrofuran, and then 0.937 mL (4.77 mmol) of DIAD was slowly added dropwise at 0 °C. The temperature was raised to room temperature and stirred for 16 hours, followed by the addition of 20 mL of water and 20 mL of ethyl acetate. The organic layer was extracted with 100 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound (182 mg, 25%) was obtained by column chromatography.

[0171] Calculated value of C7H5BrClF3N2O by LC-MS (ESI): 303.92, measured m / z: 305.21 [M+H] + .

[0172] 1 H NMR (DMSO-d, 400 MHz) δ 8.31 (s, 1H), 5.73-5.80 (m, 1H), 1.54-1.56 (d, 3H).

[0173] Step 2) Preparation of 6-chloro-4-isobutoxy-2-(2,2,2-trifluoro-1-methyl-ethyl)pyridazin-3-one

[0174] The title compound was prepared by the same method as step 1 of Preparation Example 2.

[0175] LC-MS (ESI) C 11 H 14 Calculated value of ClF3N2O2: 298.07, measured m / z: 299.28 [M+H] + .

[0176] 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).

[0177] Step 3) Preparation of (3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)urea

[0178] 2500 mg (9.32 mmol) of N-(3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide was dissolved in 10 mL of methanol, and 11 mL (46.6 mmol) of 4N HCl 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 dichloromethane, and then 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 at 0 °C. The 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 then 10 mL of saturated sodium bicarbonate aqueous solution was added dropwise while stirring at room temperature for 4 hours. The precipitated solid was filtered and dried to obtain the target compound (2200 mg, 88%).

[0179] 1 H 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).

[0180] Step 4) Preparation of 1-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0181] 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(pinacol)diboron, 24 mg (0.25 mmol) of potassium acetate, 11 mg (0.019 mmol) of Pd(dba)2, and 0.062 mL (0.037 mmol) of 0.6 M PCy3 in 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 through diatomaceous earth. The mixture was dissolved in 1 mL of 1,4-dioxane and 0.1 mL of water, and then 33 mg (0.12 mmol) of (3-bromo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)urea and 10 mg (0.012 mmol) of Pd(dppf)₂Cl₂ were added dropwise.. DCM and 53 mg (0.25 mmol) of K3PO4 were stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was filtered using diatomaceous earth. The target compound (1.5 mg, 2.6%) was obtained by preparative HPLC.

[0182] Calculated value C of LC-MS (ESI) 20 H 23 F3N6O3: 452.18, measured m / z: 453.32 [M+H] + .

[0183] 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).

[0184] Preparation Example 3) Preparation of N-(1-cyclopropyl-3-(1-isopropyl-5-(3-methoxyazacyclobut-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (compound of Example 21)

[0185] Step 1) Preparation of 4-bromo-6-chloro-2-isopropylpyridazine-3(2H)-one

[0186] The title compound was obtained by the same method as in step 1 of Preparation Example 1.

[0187] Step 2) Preparation of 6-chloro-2-isopropyl-4-(3-methoxyazacyclobut-1-yl)pyridazin-3-one

[0188] 135 mg (1.09 mmol) of 3-methoxyazacyclobutane hydrochloride was dissolved in 5 mL of 1,4-dioxane, followed by the addition of 0.36 mL (2.19 mmol) of N,N-diisopropylethylamine and stirring at room temperature for 15 minutes. 275 mg (1.09 mmol) of 4-bromo-6-chloro-2-isopropylpyridazine-3(2H)-one and 0.71 mL (1.42 mmol) of 2M NaHMDS were added dropwise to the reaction mixture and 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 1N HCl aqueous solution. The organic layer was extracted with 100 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound (70 mg, 25%) was obtained by column chromatography.

[0189] LC-MS (ESI) C 11 H 16 Calculated value of ClN3O2: 257.09, measured m / z: 257.93 [M+H] + .

[0190] Step 3) Preparation of N-(3-bromo-1-cyclopropyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0191] 1430 mg (7.87 mmol) of anhydrous copper(II) acetate was dissolved in 12 mL of N,N-dimethylformamide, followed by the sequential addition of 1229 mg (7.87 mmol) of 2,2'-bipyridine, 962 mg (7.87 mmol) of sodium carbonate, 1392 mg (7.87 mmol) of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane, and 1000 mg (3.94 mmol) of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide. 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 was extracted with 200 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound was obtained by column chromatography. (951 mg, 82%)

[0192] LC-MS (ESI) C 12 H 12 Calculated value of BrN3O: 293.02, measured m / z: 294.30 [M+H] + .

[0193] Step 4) Preparation of N-(1-cyclopropyl-3-(1-isopropyl-5-(3-methoxyazacyclobut-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0194] 35 mg (0.14 mmol) of 6-chloro-2-isopropyl-4-(3-methoxyazacyclobut-1-yl)pyridazin-3-one, 69 mg (0.27 mmol) of bis(pinacol)diboron, 27 mg (0.27 mmol) of potassium acetate, 12 mg (0.020 mmol) of Pd(dba)2, and 0.068 mL (0.041 mmol) of toluene containing 0.6 M PCy3 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 through diatomaceous earth. Dissolve the mixture in 1 mL of 1,4-dioxane and 0.1 mL of water, then add dropwise 40 mg (0.14 mmol) of N-(3-bromo-1-cyclopropyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide and 11 mg (0.014 mmol) of Pd(dppf)₂Cl₂. . DCM and 58 mg (0.27 mmol) of K3PO4 were stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was filtered using diatomaceous earth. The target compound (2.4 mg, 4%) was obtained by preparative HPLC.

[0195] LC-MS (ESI) C 23 H 28 Calculated value of N6O3: 436.22, measured m / z: 437.32 [M+H] + .

[0196] 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).

[0197] Preparation Example 4) Preparation of N-(5-(5-(3-methoxyazacyclobutane-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide (Compound of Example 16)

[0198] Step 1) Preparation of 7-methylpyrrolo[1,2-c]pyrimidine-3-amine

[0199] 200 mg (0.81 mmol) of N-{7-methylpyrrolo[1,2-c]pyrimidin-3-yl}carbamate tert-butyl ester was dissolved in 2 mL of dichloromethane, followed by the addition of 0.1 mL of TFA. The mixture was stirred at room temperature until the reaction was complete, and the reaction mixture was concentrated under reduced pressure. The resulting compound was used in subsequent reactions without purification.

[0200] LC-MS (ESI) calculated value of C8H9N3: 147.08 m / z, measured value: 147.72 [M+H] + .

[0201] Step 2) Preparation of N-(7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide

[0202] 118 mg (0.80 mmol) of 7-methylpyrrolo[1,2-c]pyrimidine-3-amine was dissolved in 2 mL of tetrahydrofuran, followed by the dropwise addition of 0.091 mL (0.96 mmol) of acetic anhydride and 1.39 mL (8.00 mmol) of N,N-diisopropylethylamine. 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 was extracted with 100 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and then concentrated. The resulting compound was used in subsequent reactions without further purification.

[0203] LC-MS (ESI) C 10 H 11 Calculated N₃O: 189.09, Measured m / z: 190.13 [M+H] + .

[0204] Step 3) Preparation of N-(5-bromo-7-methyl-pyrrolo[1,2-c]pyrimidin-3-yl)acetamide

[0205] 60 mg (0.32 mmol) of N-(7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide was dissolved in 2 mL of dichloromethane, followed by the dropwise addition of 85 mg (0.48 mmol) of NBS. 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 was extracted with 100 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound (40 mg, 47%) was obtained by column chromatography.

[0206] LC-MS (ESI) C 10 H 10 Calculated value of BrN3O: 267.00, measured m / z: 268.01 [M+H] + .

[0207] Step 4) Preparation of N-[5-[5-(3-methoxyazacyclobut-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-pyridazin-3-yl]-7-methyl-pyrrolo[1,2-c]pyrimidin-3-yl]acetamide

[0208] 50 mg (0.17 mmol) of 6-chloro-4-(3-methoxyazacyclobut-1-yl)-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one, 86 mg (0.33 mmol) of bis(pinacol)diboron, 33 mg (0.33 mmol) of potassium acetate, 14 mg (0.025 mmol) of Pd(dba)2, and 0.083 mL (0.051 mmol) of toluene containing 0.6 M PCy3 were dissolved in 1 mL of 1,4-dioxane and stirred at 130 °C for 4 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth. Dissolve the mixture in 1 mL of 1,4-dioxane and 0.1 mL of water, then add dropwise 40 mg (0.15 mmol) of N-(5-bromo-7-methyl-pyrrolo[1,2-c]pyrimidin-3-yl)acetamide and 14 mg (0.017 mmol) of Pd(dppf)₂Cl₂. . DCM and 71 mg (0.33 mmol) of K3PO4 were stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth. The target compound (1 mg, 1%) was obtained by preparative HPLC.

[0209] LC-MS (ESI) C 23 H 28Calculated value of N6O4: 452.22, measured m / z: 453.45 [M+H] +

[0210] 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).

[0211] Preparation Example 5) 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 (Compound of Example 15)

[0212] Step 1) Preparation of 6-(6-chloro-3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one

[0213] 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, followed by dropwise addition of 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, and the mixture was stirred at 130 °C for 16 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth. The target compound (10 mg, 11%) was obtained using preparative HPLC.

[0214] LC-MS (ESI) C 17 H 17 Calculated value of ClN4O2: 344.10, measured m / z: 345.07 [M+H] + .

[0215] 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

[0216] 10 mg (0.029 mmol) of 6-(6-chloro-3-methyl-pyrrolo[3,2-c]pyridin-1-yl)-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one, 3.5 mg (0.058 mmol) of acetamide, 2.7 mg (0.0029 mmol) of Brettphos Pd(II) G3, and 28 mg (0.087 mmol) of cesium carbonate were dissolved in 2 mL of tert-butanol and stirred at 130 °C for 3 hours. After cooling to room temperature, the solution was filtered through diatomaceous earth. The target compound was obtained by preparative HPLC. (1.5 mg, 14%)

[0217] LC-MS (ESI) C 19 H 21 Calculated value of N5O3: 367.16, measured m / z: 368.26 [M+H] + .

[0218] 1 ¹H 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).

[0219] Preparation Example 6) 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 (compound of Example 5)

[0220] Step 1) Preparation of 6-chloro-4-methyl-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one

[0221] 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 and stirred for 16 hours, followed by the addition of 20 mL of water and 20 mL of ethyl acetate. The organic layer was extracted with 100 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound (30 mg, 19%) was obtained by column chromatography.

[0222] Calculated value C of LC-MS (ESI) 10 H 13 ClN2O2: 228.68, measured m / z: 229.13 [M+H] + .

[0223] Step 2) Preparation of N-(3-iodo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0224] 5 g (28.54 mmol) of N-(1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide was dissolved in 20 mL of N,N-dimethylformamide, followed by the dropwise addition of 7.7 g (34.25 mmol) of NIS. 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 was extracted with 200 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting compound was used in subsequent reactions without further purification.

[0225] LC-MS (ESI) calculated value of C9H8IN3O: 300.97, measured m / z: 301.67 [M+H] + .

[0226] Step 3) Preparation of N-(1-(3-cyanocyclobutyl)-3-iodo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0227] 631 mg (6.50 mmol) of 3-hydroxycyclobutyronitrile was dissolved in 7 mL of dichloromethane, and then 1.09 mL (7.80 mmol) of triethylamine and 0.550 mL (7.15 mmol) of methanesulfonyl chloride were slowly added dropwise at -10°C. 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 sodium bicarbonate aqueous solution. The organic layer was extracted with 200 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and then concentrated. The resulting compound was used in subsequent reactions without purification. 1505 mg (5.0 mmol) of N-(3-iodo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide and 3258 mg (10.0 mmol) of cesium carbonate were dissolved in 20 mL of N,N-dimethylformamide, and then 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 was extracted with 200 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and then concentrated. The target compound was obtained by column chromatography. (200 mg, 11%)

[0228] LC-MS (ESI) C 14 H 13 Calculated IN4O value: 380.01, measured m / z: 381.06 [M+H] + .

[0229] 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

[0230] 30 mg (0.13 mmol) of 6-chloro-4-methyl-2-(3-methyltetrahydrofuran-3-yl)pyridazin-3-one, 66 mg (0.26 mmol) of bis(pinacol)diboron, 26 mg (0.26 mmol) of potassium acetate and 11 mg (0.013 mmol) of Pd(dppf)2Cl2 were added. .DCM was dissolved in 1 mL of 1,4-dioxane and stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was filtered using diatomaceous earth. The mixture was then dissolved in 1 mL of 1,4-dioxane and 0.1 mL of water, followed by the dropwise addition of 49 mg (0.13 mmol) of N-[1-(3-cyanocyclobutyl)-3-iodopyrrolo[2,3-c]pyridin-5-yl]acetamide and 11 mg (0.013 mmol) of Pd(dppf)₂Cl₂. . DCM and 55 mg (0.26 mmol) of K3PO4 were stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was filtered using diatomaceous earth. The target compound (13 mg, 22%) was obtained by preparative HPLC.

[0231] LC-MS (ESI) C 24 H 26 Calculated value of N6O3: 446.21, measured m / z: 447.27 [M+H] + .

[0232] 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=9.3Hz), 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).

[0233] Preparation Example 7) Preparation of N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (compound of Example 39)

[0234] Step 1) Preparation of 4-bromo-6-chloro-2-(2,2,2-trifluoro-1-methyl-ethyl)pyridazin-3-one

[0235] The title compound was obtained by the same method as in step 1 of Preparation Example 2.

[0236] Step 2) Preparation of 6-chloro-4-(3-methoxyazacyclobutane-1-yl)-2-(1,1,1-trifluoroprop-2-yl)pyridazine-3(2H)-one

[0237] 97 mg (0.79 mmol) of 3-methoxyazacyclobutane hydrochloride was dissolved in 1 mL of 1,4-dioxane, followed by the addition of 0.22 mL (1.31 mmol) of N,N-diisopropylethylamine and stirring 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 2M NaHMDS were added dropwise to the reaction mixture and 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 was extracted with 100 mL of ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The target compound (56 mg, 27%) was obtained by column chromatography.

[0238] LC-MS (ESI) C 11 H 13 Calculated value of ClF3N3O2: 311.06, measured m / z: 311.95 [M+H] + .

[0239] Step 3) Preparation of N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0240] The following solutions were prepared: 62 mg (0.20 mmol) of 6-chloro-4-(3-methoxyazacyclobutan-1-yl)-2-(1,1,1-trifluoroprop-2-yl)pyridazine-3(2H)-one, 101 mg (0.40 mmol) of bis(pinacol)diboron, 39 mg (0.40 mmol) of potassium acetate, and 16 mg (0.020 mmol) of Pd(dppf)2Cl2. .DCM was dissolved in 1 mL of 1,4-dioxane and stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was filtered using diatomaceous earth. The mixture was then dissolved in 1 mL of 1,4-dioxane and 0.1 mL of water, followed by the dropwise addition of 63 mg (0.20 mmol) of N-(3-iodo-1-methyl-pyrrolo[2,3-c]pyridin-5-yl)acetamide and 16 mg (0.020 mmol) of Pd(dppf)₂Cl₂. . DCM and 84 mg (0.40 mmol) of K3PO4 were stirred overnight at 80 °C. After cooling to room temperature, the mixture was filtered using diatomaceous earth. The target compound (8 mg, 9%) was obtained by preparative HPLC.

[0241] LC-MS (ESI) C 21 H 23 Calculated value of F3N6O3: 464.18, Measured m / z: 465.54 [M+H] + .

[0242] 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).

[0243] Preparation Example 8) Preparation of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Compound of Example 115)

[0244] Step 1) Preparation of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0245] The title compound was obtained by the same method as in step 3 of Preparation Example 1.

[0246] Step 2) Preparation of 4-(2,2-difluoroethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-[(2S)-1,1,1-trifluoroprop-2-yl]pyridazin-3-one

[0247] 1000 mg (3.26 mmol) of 6-chloro-4-(2,2-difluoroethoxy)-2-[(2S)-1,1,1-trifluoroprop-2-yl]pyridazin-3-one, 1004 mg (3.91 mmol) of bis(pinacol)diboron, 14.6 mg (0.065 mmol) of Pd(OAc)2, 22.9 mg (0.065 mmol) of CyJohnPhos, and 384 mg (3.91 mmol) of potassium acetate were dissolved in ethylene glycol dimethyl ether and stirred at 60°C for 1 hour. 15 mL of ethyl acetate and 7 mL of water were added, the mixture was stirred, and filtered through diatomaceous earth. After drying with anhydrous magnesium sulfate and filtering, the mixture was concentrated, and 5 mL of diisopropyl ether was added dropwise while stirring overnight. The target compound was obtained by filtering the crystals. (800 mg, 62%)

[0248] 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).

[0249] Step 3) Preparation of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0250] 50 mg (0.20 mmol) of N-(3-bromo-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, 94 mg (0.24 mmol) of 4-(2,2-difluoroethoxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-[(2S)-1,1,1-trifluoroprop-2-yl]pyridazin-3-one, and 16 mg (0.020 mmol) of Pd(dppf)2Cl2 .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 mixture was filtered through diatomaceous earth. The target compound (11.8 mg, 13%) was obtained by preparative HPLC.

[0251] LC-MS (ESI) C 18 H 16 Calculated value of F5N5O3: 445.34, Measured m / z: 446.49 [M+H] + .

[0252] 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).

[0253] Preparation Example 9) Preparation of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetamide (Compound of Example 116)

[0254] 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-trifluoroprop-2-yl)pyridazine-3(2H)-one

[0255] 150 mg (0.32 mmol) of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide (Example 85) was dissolved in 1 mL of dichloromethane, followed by the addition of 0.3 mL of a 1,4-dioxane solution of 4N HCl, and the mixture was stirred overnight at 80 °C. After cooling to room temperature, the solution was concentrated and the target compound was obtained by preparative HPLC. (130 mg, 95%)

[0256] LC-MS (ESI) C 18 H 18 Calculated value of F5N5O2: 431.36, Measured m / z: 432.12 [M+H] + .

[0257] 1 H 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).

[0258] Step 2) Preparation of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetamide

[0259] 30 mg (0.0695 mmol) of (S)-6-(5-amino-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-(2,2-difluoroethoxy)-2-(1,1,1-trifluoroprop-2-yl)pyridazin-3(2H)-one was dissolved in 1 mL of dichloromethane, followed by the addition of 14.2 mg (0.104 mmol) of acetoxyacetyl chloride and 0.028 mL (0.348 mmol) of pyridine, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and dissolved in 1 mL of methanol, followed by the addition of 19.2 mg (0.139 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 15 minutes. After concentration under reduced pressure, the target compound was obtained by preparative HPLC. (10.7 mg, 31%)

[0260] LC-MS (ESI) C 20 H 20 Calculated value of F5N5O4: 489.40, measured m / z: 490.21 [M+H] + .

[0261] 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).

[0262] Preparation Example 10) Preparation of (S)-1-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea (Compound of Example 117)

[0263] 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-trifluoroprop-2-yl)pyridazine-3(2H)-one

[0264] The title compound was obtained by the same method as in step 1 of Preparation Example 9.

[0265] Step 2) Preparation of (S)-1-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea

[0266] 30 mg (0.0695 mmol) of (S)-6-(5-amino-1-ethyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-(2,2-difluoroethoxy)-2-(1,1,1-trifluoroprop-2-yl)pyridazin-3(2H)-one was dissolved in 1 mL of tetrahydrofuran, and then 21 mg (0.0695 mmol) of triphosgene was added dropwise at 0°C with stirring for 1 hour. After the temperature was raised to room temperature, 0.278 mL (0.556 mmol) of tetrahydrofuran containing 2M methylamine was added dropwise with stirring for 2 hours. After concentration under reduced pressure, the target compound was obtained by preparative HPLC. (7 mg, 21%)

[0267] 1H 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).

[0268] Referring to the preparation example above, the following examples were synthesized.

[0269] 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

[0270] The compound was obtained by the method of Preparation Example 7.

[0271] 1 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)

[0272] 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

[0273] The compound was obtained by the method of Preparation Example 6.

[0274] 1H 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)

[0275] Example 3: Synthesis of N-(1-methyl-3-(1-(3-methyloxetane-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0276] The compound was obtained by the method of Preparation Example 7.

[0277] 1 ¹H 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).

[0278] 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

[0279] The compound was obtained by the method of Preparation Example 2.

[0280] 1H 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).

[0281] 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

[0282] The compound was obtained by the method of Preparation Example 6.

[0283] 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=9.3Hz), 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).

[0284] 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

[0285] The compound was obtained by the method of Preparation Example 6.

[0286] 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).

[0287] 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

[0288] The compound was obtained by the method of Preparation Example 2.

[0289] 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).

[0290] 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

[0291] The compound was obtained by the method of Preparation Example 6.

[0292] 1H 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, 3H) 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).

[0293] 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

[0294] The compound was obtained by the method of Preparation Example 6.

[0295] 1 H NMR (400 MHz, methanol-d4) δ 8.84 - 8.89 (s, 1 H) 8.57 - 8.60 (s, 1H) 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, 1H) 2.21 - 2.23 (s, 3H) 1.71 - 1.74 (s, 3H) 1.52 - 1.58 (t, 3H).

[0296] Example 10: Synthesis of N-(1-(3-cyanocyclobutyl)-3-(5-(3-methoxyazacyclobutyl-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0297] The compound was obtained by the method of Preparation Example 6.

[0298] 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).

[0299] Example 11: Synthesis of 1-(3-(5-(3-methoxyazacyclobut-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

[0300] The compound was obtained by the method of Preparation Example 2.

[0301] 1 H NMR (DMSO-d6, 400 MHz) δ 8.89 (br s, 1H), 8.51 (s, 1H), 8.22 (brs, 1H), 8.14 (s, 1H), 6.38 (s, 1H), 4.38 (br s, 2H), 4.27 (br d, 2H, J=9.1Hz), 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).

[0302] 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

[0303] The compound was obtained by the method of Preparation Example 6.

[0304] 1 H 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, 2H) 2.96 - 3.05 (m, 2 H) 2.85 - 2.92 (m, 2 H) 2.21 - 2.28 (m, 1 H) 2.06 - 2.09 (s, 3 H) 1.10 - 1.14 (m, 2 H) 1.00 - 1.04 (m, 2 H).

[0305] 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

[0306] The compound was obtained by the method of Preparation Example 6.

[0307] 1H 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=8.5Hz), 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).

[0308] 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

[0309] The compound was obtained by the method of Preparation Example 2.

[0310] 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).

[0311] 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

[0312] The compound was obtained by the method of Preparation Example 5.

[0313] 1¹H 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).

[0314] Example 16: Synthesis of N-(5-(5-(3-methoxyazacyclobutane-1-yl)-1-(3-methyltetrahydrofuran-3-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-7-methylpyrrolo[1,2-c]pyrimidin-3-yl)acetamide

[0315] The compound was obtained by the method of Preparation Example 4.

[0316] 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).

[0317] Example 17: Synthesis of N-(3-(5-(3-methoxyazacyclobut-1-yl)-1-(2-methoxyethyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0318] The compound was obtained by the method of Preparation Example 1.

[0319] 1H NMR (400 MHz, methanol-d4) δ 8.54 (s, 1 H) 8.85 (s, 1 H) 6.37 (s, 1H) 7.96 (s, 1 H) 4.45 - 4.52 (m, 2 H) 4.37 - 4.42 (t, 2 H) 4.32 - 4.37 (m, 1H) 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).

[0320] Example 18: Synthesis of N-(3-(1-(1-methoxy-2-methylpropyl-2-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0321] The compound was obtained by the method of Preparation Example 1.

[0322] 1 ¹H 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).

[0323] 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

[0324] The compound was obtained by the method of Preparation Example 1.

[0325] 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).

[0326] Example 20: Synthesis of N-(3-(1-isopropyl-5-(3-methoxyazacyclobut-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0327] The compound was obtained by the method of Preparation Example 1.

[0328] 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).

[0329] Example 21: Synthesis of N-(1-cyclopropyl-3-(1-isopropyl-5-(3-methoxyazacyclobut-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0330] The compound was obtained by the method of Preparation Example 3.

[0331] 1H 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).

[0332] 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

[0333] The compound was obtained by the method of Preparation Example 6.

[0334] 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=6.6Hz), 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).

[0335] 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

[0336] The compound was obtained by the method of Preparation Example 7.

[0337] 1H 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).

[0338] Example 24: Synthesis of N-(3-(1-cyclobutyl-5-(3-(methoxymethyl)azacyclobutyl-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0339] The compound was obtained by the method of Preparation Example 7.

[0340] 1 H 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 (brs, 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).

[0341] Example 25: Synthesis of N-(3-(5-(isopentoxy)-1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0342] The compound was obtained by the method of Preparation Example 1.

[0343] 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).

[0344] 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

[0345] The compound was obtained by the method of Preparation Example 1.

[0346] 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).

[0347] 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

[0348] The compound was obtained by the method of Preparation Example 1.

[0349] 1H 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).

[0350] 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

[0351] The compound was obtained by the method of Preparation Example 7.

[0352] 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).

[0353] Example 29: Synthesis of N-(3-(1-(tert-butyl)-5-(3-methoxyazacyclobut-1-yl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0354] The compound was obtained by the method of Preparation Example 7.

[0355] 1H 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).

[0356] 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

[0357] The compound was obtained by the method of Preparation Example 7.

[0358] 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).

[0359] Example 31: Synthesis of N-(3-(5-(3-methoxyazacyclobut-1-yl)-1-(1-methylcyclopentyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0360] The compound was obtained by the method of Preparation Example 7.

[0361] 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).

[0362] 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

[0363] The compound was obtained by the method of Preparation Example 7.

[0364] 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).

[0365] 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

[0366] The compound was obtained by the method of Preparation Example 1.

[0367] 1H 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)

[0368] 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

[0369] The compound was obtained by the method of Preparation Example 2.

[0370] 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).

[0371] 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

[0372] The compound was obtained by the method of Preparation Example 2.

[0373] 1H 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).

[0374] Example 36: Synthesis of N-(1-cyclobutyl-3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0375] The compound was obtained by the method of Preparation Example 7.

[0376] 1 H 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).

[0377] Example 37: Synthesis of 1-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)urea

[0378] The compound was obtained by the method of Preparation Example 2.

[0379] 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).

[0380] 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

[0381] The compound was obtained by the method of Preparation Example 2.

[0382] 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).

[0383] Example 39: Synthesis of N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0384] The compound was obtained by the method of Preparation Example 7.

[0385] 1H 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).

[0386] Example 40: Synthesis of N-(3-(5-(3-methoxyazacyclobut-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0387] The compound was obtained by the method of Preparation Example 7.

[0388] 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).

[0389] Example 41: Synthesis of N-(1-cyclobutyl-3-(5-(3-methoxyazacyclobutyl-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0390] The compound was obtained by the method of Preparation Example 7.

[0391] 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).

[0392] 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

[0393] The compound was obtained by the method of Preparation Example 7.

[0394] 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).

[0395] Example 43: Synthesis of (S)-N-(1-cyclobutyl-3-(5-(3-methoxypyrrolidone-1-yl)-1-(1-methylcyclobutyl)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0396] The compound was obtained by the method of Preparation Example 7.

[0397] 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).

[0398] Example 44: Synthesis of N-(1-cyclobutyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]oct-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0399] The compound was obtained by the method of Preparation Example 7.

[0400] 1 H 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).

[0401] Example 45: Synthesis of N-(1-methyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]oct-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0402] The compound was obtained by the method of Preparation Example 7.

[0403] 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=10.5Hz), 1.84 (br d, 1H, J=10.5 Hz), 1.73 (s, 3H), 1.28 (s, 1H).

[0404] Example 46: Synthesis of N-(1-methyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0405] The compound was obtained by the method of Preparation Example 7.

[0406] 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).

[0407] 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

[0408] The compound was obtained by the method of Preparation Example 7.

[0409] 1 H 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).

[0410] Example 48: Synthesis of N-(1-methyl-3-(1-(1-methylcyclobutyl)-5-(oxecyclobutyl-3-ylmethoxy)-6-oxo-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0411] The compound was obtained by the method of Preparation Example 7.

[0412] 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, 2H) 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).

[0413] Example 49: Synthesis of N-(1-cyclopropyl-3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoropropyl-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0414] The compound was obtained by the method of Preparation Example 3.

[0415] 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).

[0416] Example 50: Synthesis of (R)-N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0417] The compound was obtained by the method of Preparation Example 7.

[0418] 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).

[0419] Example 51: Synthesis of N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0420] The compound was obtained by the method of Preparation Example 7.

[0421] 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).

[0422] Example 52: Synthesis of N-(1-cyclopropyl-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoropropyl-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0423] The compound was obtained by the method of Preparation Example 3.

[0424] 1 H 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).

[0425] Example 53: Synthesis of N-(1-cyclopropyl-3-(1-(1-methylcyclobutyl)-6-oxo-5-(2-oxa-6-azaspiro[3.4]oct-6-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0426] The compound was obtained by the method of Preparation Example 3.

[0427] 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=6.1Hz), 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).

[0428] Example 54: Synthesis of (S)-N-(3-(5-isobutoxy-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0429] The compound was obtained by the method of Preparation Example 7.

[0430] 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).

[0431] Example 55: Synthesis of N-(3-(5-(cyclobutylmethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0432] The compound was obtained by the method of Preparation Example 7.

[0433] 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).

[0434] Example 56: Synthesis of N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0435] The compound was obtained by the method of Preparation Example 7.

[0436] 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).

[0437] 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

[0438] The compound was obtained by the method of Preparation Example 7.

[0439] 1 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).

[0440] Example 58: Synthesis of (S)-N-(1-cyclopropyl-3-(6-oxo-5-(2-oxa-6-azaspiro[3.4]oct-6-yl)-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0441] The compound was obtained by the method of Preparation Example 3.

[0442] 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)

[0443] Example 59: Synthesis of N-(3-(1-(3,3-difluorobut-2-yl)-5-isobutoxy-6-oxo-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0444] The compound was obtained by the method of Preparation Example 7.

[0445] 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).

[0446] 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

[0447] The compound was obtained by the method of Preparation Example 7.

[0448] 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).

[0449] Example 61: Synthesis of (S)-N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0450] The compound was obtained by the method of Preparation Example 7.

[0451] 1H 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).

[0452] Example 62: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0453] The compound was obtained by the method of Preparation Example 7.

[0454] 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=12.3Hz), 3.94 (s, 3H), 2.10 (s, 3H), 1.7-1.9 (m, 6H).

[0455] Example 63: Synthesis of N-(1-((1S,3R)-3-cyanocyclobutyl)-3-(5-isobutoxy-6-oxo-1-((S)-1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0456] The compound was obtained by the method of Preparation Example 6.

[0457] 1H 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).

[0458] Example 64: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoropropyl-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0459] The compound was obtained by the method of Preparation Example 3.

[0460] 1 H 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).

[0461] Example 65: Synthesis of N-(1-cyclopropyl-3-(5-((R)-2-methoxypropoxy)-6-oxo-1-((S)-1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0462] The compound was obtained by the method of Preparation Example 3.

[0463] 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, 9.7Hz), 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).

[0464] Example 66: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(2-methoxyethoxy)-6-oxo-1-(1,1,1-trifluoropropyl-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0465] The compound was obtained by the method of Preparation Example 3.

[0466] 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).

[0467] Example 67: Synthesis of (S)-N-(3-(5-(3,3-difluoropyrrolidin-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0468] The compound was obtained by the method of Preparation Example 7.

[0469] 1 H 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).

[0470] Example 68: Synthesis of N-(1-((1S,3R)-3-cyanocyclobutyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0471] The compound was obtained by the method of Preparation Example 6.

[0472] 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).

[0473] Example 69: Synthesis of (S)-N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3

[0474] The compound was obtained by the method of Preparation Example 7.

[0475] 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).

[0476] Example 70: Synthesis of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0477] The compound was obtained by the method of Preparation Example 7.

[0478] 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).

[0479] Example 71: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0480] The compound was obtained by the method of Preparation Example 3.

[0481] 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).

[0482] Example 72: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide-2,2,2-d3

[0483] The compound was obtained by the method of Preparation Example 7.

[0484] 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).

[0485] Example 73: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(methyl-d3)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0486] The compound was obtained by the method of Preparation Example 7.

[0487] 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=12.3Hz), 2.10 (s, 3H), 1.7-1.9 (m, 6H).

[0488] Example 74: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0489] The compound was obtained by the method of Preparation Example 3.

[0490] 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), 7.47 (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).

[0491] Example 75: Synthesis of (S)-N-(3-(5-(3-isopropoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0492] The compound was obtained by the method of Preparation Example 7.

[0493] 1H 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).

[0494] Example 76: Synthesis of (S)-N-(1-ethyl-3-(5-(3-isopropoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0495] The compound was obtained by the method of Preparation Example 7.

[0496] 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).

[0497] Example 77: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(3-isopropoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0498] The compound was obtained by the method of Preparation Example 3.

[0499] 1H 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).

[0500] Example 78: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0501] The compound was obtained by the method of Preparation Example 7.

[0502] 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).

[0503] Example 79: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-oxaspiro[3.3]hept-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0504] The compound was obtained by the method of Preparation Example 7.

[0505] 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).

[0506] Example 80: Synthesis of (S)-N-(1-(cyclopropylmethyl)-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoropropyl-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0507] The compound was obtained by the method of Preparation Example 7.

[0508] 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).

[0509] Example 81: Synthesis of (S)-N-(1-((3,3-difluorocyclobutyl)methyl)-3-(5-(3-methoxyazacyclobutyl-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0510] The compound was obtained by the method of Preparation Example 7.

[0511] 1 ¹H 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).

[0512] Example 82: Synthesis of (S)-N-(1-(2-fluoro-2-methylpropyl)-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoropropyl-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0513] The compound was obtained by the method of Preparation Example 7.

[0514] 1 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).

[0515] Example 83: Synthesis of (S)-N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-methylallyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0516] The compound was obtained by the method of Preparation Example 7.

[0517] 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=7.0Hz), 1.7-1.8 (m, 3H).

[0518] Example 84: Synthesis of (S)-N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0519] The compound was obtained by the method of Preparation Example 7.

[0520] 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)

[0521] Example 85: Synthesis of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide.

[0522]

[0523] The compound was obtained by the method of Preparation Example 7.

[0524] 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), 7.44 (s, 1H), 6.4-6.7 (m, 1H), 5.86 (quin, 1H, J=7.3Hz), 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).

[0525] Example 86: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0526] The compound was obtained by the method of Preparation Example 7.

[0527] 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).

[0528] Example 87: Synthesis of (S)-N-(1-(2-cyanoethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0529] The compound was obtained by the method of Preparation Example 7.

[0530] 1H 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).

[0531] Example 88: Synthesis of (S)-N-(1-(3-cyanopropyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0532] The compound was obtained by the method of Preparation Example 7.

[0533] 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).

[0534] Example 89: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3-oxocyclobutyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0535] The compound was obtained by the method of Preparation Example 7.

[0536] 1H 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).

[0537] Example 90: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-((3-methyloxetane-3-yl)methyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0538] The compound was obtained by the method of Preparation Example 7.

[0539] 1 H 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).

[0540] Example 91: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-morpholinoethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0541] The compound was obtained by the method of Preparation Example 7.

[0542] 1H 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).

[0543] Example 92: Synthesis of (S)-N-(1-(cyclopropylmethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0544] The compound was obtained by the method of Preparation Example 7.

[0545] 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).

[0546] Example 93: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(oxetanebut-3-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0547] The compound was obtained by the method of Preparation Example 7.

[0548] 1H 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).

[0549] Example 94: Synthesis of N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-((R)-tetrahydrofuran-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0550] The compound was obtained by the method of Preparation Example 7.

[0551] 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).

[0552] Example 95: Synthesis of (S)-N-(1-(6,6-difluorospiro[3.3]hept-2-yl)-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0553] The compound was obtained by the method of Preparation Example 7.

[0554] 1 H 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).

[0555] Example 96: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

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

[0557] 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).

[0558] Example 97: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(7-oxaspiro[3.5]non-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0559] The compound was obtained by the method of Preparation Example 7.

[0560] 1H 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).

[0561] Example 98: Synthesis of (S)-N-(1-(cyclopropylcarbonyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0562] The compound was obtained by the method of Preparation Example 7.

[0563] 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).

[0564] Example 99: Synthesis of (S)-N-(1-(2,2-difluoroethyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0565] The compound was obtained by the method of Preparation Example 7.

[0566] 1¹H 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).

[0567] Example 100: Synthesis of N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-((S)-1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(3-fluorocyclobut-2-en-1-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0568] The compound was obtained by the method of Preparation Example 7.

[0569] 1 H 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).

[0570] Example 101: Synthesis of (S)-N-(3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0571] The compound was obtained by the method of Preparation Example 7.

[0572] 1H 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).

[0573] Example 102: Synthesis of (S)-N-(1-ethyl-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0574] The compound was obtained by the method of Preparation Example 7.

[0575] 1 ¹H 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).

[0576] Example 103: Synthesis of (S)-N-(3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0577] The compound was obtained by the method of Preparation Example 7.

[0578] 1H NMR (chloroform-d, 400 MHz) δ 8.96 (br s, 1H), 8.45 (br s, 1H), 7.94 (brs, 1H), 7.55 (s, 1H), 6.89 (s, 1H), 5.8-6.0 (m, 1H), 4.16 (br d, 2H, J=16.6Hz), 3.94 (s, 3H), 2.25 (s, 3H), 1.8-2.0 (m, 3H), 1.5-1.6 (m, 6H).

[0579] Example 104: Synthesis of (S)-N-(1-methyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0580] The compound was obtained by the method of Preparation Example 7.

[0581] 1 H NMR (chloroform-d, 400 MHz) δ 8.95 (br s, 1H), 8.46 (br s, 1H), 8.00 (brs, 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).

[0582] Example 105: Synthesis of (S)-N-(1-ethyl-3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0583] The compound was obtained by the method of Preparation Example 7.

[0584] 1H NMR (chloroform-d, 400 MHz) δ 8.97 (br s, 1H), 8.47 (br s, 1H), 8.00 (brs, 1H), 7.61 (s, 1H), 6.89 (s, 1H), 5.9-6.0 (m, 1H), 4.30 (br d, 2H, J=6.9Hz), 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).

[0585] Example 106: Synthesis of (S)-N-(1-ethyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0586] The compound was obtained by the method of Preparation Example 7.

[0587] 1 H NMR (chloroform-d, 400 MHz) δ 8.96 (br s, 1H), 8.49 (br s, 1H), 7.97 (brs, 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).

[0588] Example 107: Synthesis of (S)-N-(1-cyclopropyl-3-(6-oxo-5-(2,2,2-trifluoroethoxy)-1-(1,1,1-trifluoropropyl-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0589] The compound was obtained by the method of Preparation Example 3.

[0590] 1H NMR (chloroform-d, 400 MHz) δ 8.94 (br s, 1H), 8.66 (br s, 1H), 7.95 (brs, 1H), 7.61 (s, 1H), 7.03 (s, 1H), 5.8-6.0 (m, 1H), 4.76 (br d, 2H, J=7.9Hz), 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).

[0591] Example 108: Synthesis of (S)-N-(1-ethyl-3-(5-(3-fluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0592] The compound was obtained by the method of Preparation Example 7.

[0593] 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).

[0594] Example 109: Synthesis of (S)-N-(3-(5-(3-fluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0595] The compound was obtained by the method of Preparation Example 7.

[0596] 1H 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, 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=7.1Hz).

[0597] Example 110: Synthesis of (S)-N-(1-cyclopropyl-3-(5-(2-fluoro-2-methylpropoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0598] The compound was obtained by the method of Preparation Example 3.

[0599] 1 H 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 (brs, 1H), 1.6 (s, 3H), 1.5 (s, 3H), 1.2-1.3 (m, 4H), 1.13 (br s, 2H).

[0600] Example 111: Synthesis of N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0601] The compound was obtained by the method of Preparation Example 7.

[0602] 1 H NMR (chloroform-d, 400 MHz) δ 8.95 (br s, 1H), 8.49 (br s, 1H), 8.00 (brs, 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).

[0603] Example 112: Synthesis of N-(1-cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0604] The compound was obtained by the method of Preparation Example 3.

[0605] 1 H NMR (chloroform-d, 400 MHz) δ 8.94 (br s, 1H), 8.66 (br s, 1H), 7.95 (brs, 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).

[0606] Example 113: Synthesis of (R)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0607] The compound was obtained by the method of Preparation Example 7.

[0608] 1 H 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=7.3Hz), 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).

[0609] Example 114: Synthesis of (R)-N-(1-cyclopropyl-3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0610] The compound was obtained by the method of Preparation Example 3.

[0611] 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).

[0612] Example 115: Synthesis of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide

[0613] The compound was obtained by the method described in Example 8.

[0614] 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).

[0615] Example 116: Synthesis of (S)-N-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetamide

[0616] The compound was obtained by the method of Preparation Example 9.

[0617] 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).

[0618] Example 117: Synthesis of (S)-1-(3-(5-(2,2-difluoroethoxy)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea

[0619] The compound was obtained by the method of Preparation Example 10.

[0620] 1H 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).

[0621] TYK2 pseudokinase ligand

[0622] Like other Janus kinase family proteins, TYK2 consists of four domains (FERM, SH2, JH2, and JH1 domains) (Prior Art Document 7). The JH1 domain is the active kinase domain that actually transmits intracellular signals, while the JH2 domain is a pseudokinase domain with regulatory function, inhibiting the activation of the JH1 domain before receiving external stimuli (Prior Art Document 7). That is, the TYK2 pseudokinase domain stabilizes the structurally inactive state of the kinase domain. Therefore, small molecule pseudokinase ligands can inhibit TYK2 activity by stabilizing this inactive structure.

[0623] Experimental Examples

[0624] The following experiments were conducted on the compounds prepared in the examples as described above.

[0625] Experimental Example 1: Affinity Analysis of Binding Domain to TYK2 Pseudokinase

[0626] To analyze the binding affinity of the test compounds to the TYK2 pseudokinase domain, a polarized fluorescence-based TYK2 JH2 pseudokinase domain inhibitor screening assay kit (BPS Bioscience) was used. The compounds were evaluated according to the manufacturer's operating procedures, as follows: The test compound or control compound (Deucravacitnib) was serially diluted in DMSO and then diluted to 1 / 10 with distilled water to prepare a 10× compound solution. This compound solution was mixed with probe 1 prepared using binding reaction buffer (JH2 binding buffer) and reacted at 25°C for 10 min. The reaction was then initiated by adding a TYK2 pseudokinase domain enzyme prepared using binding reaction buffer. The reaction was incubated in black 384-well plates at 25°C for 1 h. Polarized fluorescence was measured using a Synergy Neo (BioTek Instruments). The enzyme-free reaction mixture served as a negative control, and the mixture containing no compound served as a positive control.

[0627] Experimental Example 2: JAK Kinase Domain Activity Analysis

[0628] The activity of JAK family kinase domains was analyzed using the ADP-Glo ​​kinase assay kit (Promega). Compounds were evaluated according to the manufacturer's operating procedures, as follows: The 10 mM test compound was diluted to 0.5 mM in DMSO in a 96-well plate, followed by a 5-fold serial dilution in DMSO. The diluted compound was then diluted to 1 / 10 with 1× reaction buffer (composition) to prepare 5× compound solutions. 5 μL of the 5× compound solution was mixed with 10 μL of a substrate and ATP mixture prepared using reaction buffer (40 mM Tris, 20 mM MgCl2, 0.1 mg / ml BSA, 0.05 mM MTT, pH 7.5). The enzyme reaction was then initiated by adding 10 μL of JAK family enzyme prepared in the reaction buffer. A short centrifugation was performed to allow all solutions to settle to the bottom of the plate. The final concentrations of the test compound in the reaction mixture were 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, and 3.2 nM. The concentration of the control compound (Brepocitinib or Tofacitinib) was 10-fold lower. The enzyme reaction was carried out at 25°C for 1 hour. 25 μL of ADP-Glo ​​reagent was added, and the reaction was continued at 25°C for 1 hour. 50 μL of kinase assay reagent was mixed and the reaction was terminated. The luminescence signal was measured using a Synergy Neo (BioTek Instruments). The reaction mixture without the enzyme served as a negative control, and the mixture without any 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.

[0629] [Table 1]

[0630] [Table 2] Confirmation results of TYK2 pseudokinase and JAK kinase domain activity

[0631] ND: Not measured

[0632] Experimental Example 3: Analysis of TYK2 / JAK1 cell viability by IFNα2B stimulation

[0633] The inhibitory effect of the test compounds on TYK2 / JAK1 activity was analyzed using the HEK-Blue IFNα / β cell line (InvivoGen), which secretes SEAP (secretory embryonic alkaline phosphatase) according to the degree of cell stimulation. Cell culture and evaluation were performed according to the manufacturer's recommendations as follows: Cells cultured in growth medium (Dulbecco modified Eagle medium, 10% fetal bovine serum, 1% penicillin-streptomycin, 100 μg / mL Normocin, 10 mg / mL blastcin, 100 mg / mL Zeocin) were collected and resuspended in test medium (DMEM, 10% FBS, 1% penicillin-streptomycin), and dispensed into each well of a 96-well plate with 3.5 × 10⁶ cells. 4 160 μL of cells were cultured in a CO2 incubator at 37°C for 24 hours. Then, 20 μL of the test compound or control compound (deuterium celexitinib) diluted in test medium was added, followed by incubation at 37°C for 1 hour and 30 minutes. Next, 20 μL of recombinant human IFNα2B protein prepared using test medium (PBL assay science) (final concentration 1 U / mL) was added to each well, followed by incubation at 37°C for 24 hours. 20 μL and 180 μL of cell culture 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 a Synergy Neo (BioTek Instruments). The reaction mixture without IFNα2B served as a negative control, and the mixture without any compound served as a positive control. The experimental results are shown in Table 3.

[0634] [Table 3] Results of TYK2 / JAK1 cell viability in IFNα2B stimulation assay

[0635] A: IC 50 A: IC50 >50 nM and < 500 nM; B: IC50 >50 nM and < 500 nM; C: IC 50> 500nM

[0636] ND: Not measured

Claims

1. A compound represented by the following chemical formula 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: [Formula 1] In the above chemical formula, A1, A2, A3, A4 and A5 are each independently C, CH, CH2 or N; R1 is C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C3-C8 cycloalkyl or 4- to 12-membered heterocyclic alkyl, wherein the C1-C 10 Alkyl, C1-C 10 The haloalkyl, C3-C8 cycloalkyl, or 4- to 12-membered heterocyclic alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: oxo, halogen, C1-C. 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Halogenated alkyl groups; R2 is H, C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C8 cycloalkyl, 4-12 membered heterocyclic alkyl, OR' or NR'R", wherein the C1-C 10 Alkyl, C1-C 10 The alkoxy or 4-12 membered heterocyclic alkyl group is unsubstituted or substituted with one or more, preferably one to four, substituents selected from the group consisting of: halogen, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkoxy C1-C 10 Alkyl, 4-12 membered heterocyclic alkyl, C6-C 10 Aryl and C3-C8 cycloalkyl, Where R' and R" are each independently H or Cl-C 10 Alkyl, wherein the C1-C 10 The alkyl group is either unsubstituted or substituted with one or more substituents selected from the group consisting of: halogens, cyano groups, 4-12 membered heterocyclic alkyl groups, and C6-C groups. 10 Aryl, C3-C8 cycloalkyl and C1-C 10 alkoxy, or R' and R” can form 4- to 12-membered heterocyclic alkyl groups together with N in NR'R”, wherein the 4- to 12-membered heterocyclic alkyl groups are unsubstituted or halogenated, C1-C substituted. 10 Alkoxy or C1-C 10 Alkoxy C1-C 10 Alkyl substitution; R3 is H, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, -C1-C 10 Alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 12-membered heterocyclic alkyl, or -C1-C 10 Alkyl-4-12-membered heterocyclic alkyl, wherein the C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C3-C8 cycloalkyl, -C1-C 10 Alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-12 membered heterocyclic alkyl, or -C1-C 10 The alkyl-4-12-membered heterocyclic alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of: halogen, cyano, oxo, C1-C. 10 Alkyl, C2-C 10 Alkenyl, C1-C6 alkoxy, unsubstituted or substituted with 1 to 3 halogens, C3-C8 cycloalkyl and 4-12 membered heterocyclic alkyl; R4 is C1-C 10 Alkyl, C1-C 10 Deuterated alkyl or amino, wherein C1-C 10 Alkyl, C1-C 10 The deuterated alkyl or amino group is unsubstituted or is composed of one or more, preferably one to four, selected from hydroxyl and C1-C1 groups. 10 Alkyl substituents; R5 represents H, halogen, nitro, cyano, amino, hydroxyl, -C(=O)R"', -CO(=O)R"', -N(R"')2, -C(=O)NR"', -SO2R"', C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, 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 heterocyclic alkyl, 4-12 membered heterocyclic alkyl C1-C 10 Alkyl, 4-12 heteroaryl or 4-12 heteroaryl C1-C 10 Alkyl, wherein the C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, 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 heterocyclic alkyl, 4-12 membered heterocyclic alkyl C1-C 10 Alkyl, 4-12 heteroaryl or 4-12 heteroaryl C1-C 10 The alkyl group is unsubstituted and substituted by one or more substituents selected from the group consisting of: halogen, cyano, nitro, amino, hydroxyl, C1-C. 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Alkoxy, C6-C 10 Aryl, 4-12 membered heterocyclic alkyl, 4-12 membered heteroaryl and C3-C8 cycloalkyl, and R”' is H, halogen, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, 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 heterocyclic alkyl, 4-12 membered heterocyclic alkyl C1-C 10 Alkyl, 4-12 heteroaryl or 4-12 heteroaryl C1-C 10 alkyl.

2. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R1 is a C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or a 4- to 10-membered heterocyclic alkyl, wherein... The C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 10-membered heterocyclic alkyl group is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of oxo, fluorine, chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl.

3. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, The C3-C6 cycloalkyl group of R1 is cyclobutyl, cyclopentyl, or cyclohexyl.

4. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, The 4- to 10-membered heterocyclic alkyl group of R1 is oxoheterobutyl, tetrahydrofuranyl, or tetrahydropyranyl.

5. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R1's C1-C 10 Alkyl, C1-C 10 The haloalkyl, C3-C8 cycloalkyl or 4- to 12-membered heterocyclic alkyl group is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of: oxo, fluorine, methyl, ethyl, propyl, isopropyl, trifluoromethyl and methoxy.

6. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from the following groups: 。 7. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, in, The R2 is H, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-10 membered heterocyclic alkyl, OR' or NR'R', and the C1-C6 alkyl, C1-C6 alkoxy or 4-10 membered heterocyclic alkyl is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, 4-10 membered heterocyclic alkyl, C6-C 10 Aryl and C3-C6 cycloalkyl, Wherein, R' and R" are each independently H or C1-C6 alkyl, and wherein the C1-C6 alkyl is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, 4-10 membered heterocyclic alkyl, C6-C 10 aryl, C3-C6 cycloalkyl and C1-C6 alkoxy, or R' and R" may be combined with N in NR'R" to form 4 to 10-membered heterocyclic alkyl groups, wherein the 4 to 10-membered heterocyclic alkyl groups are unsubstituted or substituted with fluorine, chlorine, bromine, C1-C6 alkoxy or C1-C6 alkoxy-C1-C6 alkyl.

8. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, The R2 is selected from the following groups: 。 9. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R3 is H, C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, -C1-C6 alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-10 heterocyclic alkyl, or -C1-C6 alkyl-4-10 heterocyclic alkyl, and wherein, The C1-C6 alkyl, C1-C6 deuterated alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, -C1-C6 alkyl-C3-C8 cycloalkyl, -C(=O)-C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4-10 heterocyclic alkyl or -C1-C6 alkyl-4-10 heterocyclic alkyl are unsubstituted or substituted with 1 to 4 substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, oxo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, unsubstituted or substituted with 1 to 3 halogens, and 4-10 heterocyclic alkyl.

10. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R3 is selected from the following groups: 。 11. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R4 is a C1-C6 alkyl, C1-C6 deuterated alkyl, or amino group, and the C1-C6 alkyl, C1-C6 deuterated alkyl, or amino group is unsubstituted or substituted with one or two substituents selected from hydroxyl and C1-C6 alkyl groups.

12. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R4 is CH3, CD3, CH2OH, NH2, or NHCH3.

13. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, in, R5 represents H, halogen, nitro, cyano, amino, hydroxyl, -C(=O)R"', -CO(=O)R"', -N(R"')2, -C(=O)NR"', -SO2R"', C1-C6 alkyl, C1-C6 deuterated alkyl, 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 Aryl C1-C6 alkyl, 4-10 heterocyclic alkyl, 4-10 heterocyclic alkyl C1-C6 alkyl, 4-10 heteroaryl, or 4-10 heteroaryl C1-C6 alkyl, wherein the C1-C6 alkyl, C1-C6 deuterated alkyl, 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 The aryl C1-C6 alkyl, 4-10 heterocyclic alkyl, 4-10 heterocyclic alkyl C1-C6 alkyl, 4-10 heteroaryl, or 4-10 heteroaryl C1-C6 alkyl is unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of: halogen, cyano, nitro, amino, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C6-C 10 Aryl, 4-10 membered heterocyclic alkyl, 4-10 membered heteroaryl and C3-C6 cycloalkyl, and Wherein, R”' is H, halogen, C1-C6 alkyl, C1-C6 deuterated alkyl, 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 Aryl C1-C6 alkyl, 4-10 heterocyclic alkyl, 4-10 heterocyclic alkyl C1-C6 alkyl, 4-10 heteroaryl or 4-10 heteroaryl C1-C6 alkyl.

14. The compound of claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, in, The compound is selected from compounds 1 to 117 below: 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-methyloxetane-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-methoxyazacyclobutyl-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-methoxyazacyclobut-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-methoxyazacyclobutane-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-methoxyazacyclobut-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-methylpropyl-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-methoxyazacyclobut-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-methoxyazacyclobut-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)azacyclobutyl-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-(isopentoxy)-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-methoxyazacyclobut-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-methoxyazacyclobut-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-trifluoroprop-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-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 40: N-(3-(5-(3-methoxyazacyclobut-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-methoxyazacyclobutyl-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-methoxypyrrolidone-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-methoxypyrrolidone-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]oct-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]oct-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]hept-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-(oxecyclobutyl-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-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoropropyl-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]oct-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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]oct-6-yl)-1-(1,1,1-trifluoropropyl-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 59: N-(3-(1-(3,3-difluorobut-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 67: (S)-N-(3-(5-(3,3-difluoropyrrolidone-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 69: (S)-N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 75: (S)-N-(3-(5-(3-isopropoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-isopropoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-isopropoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(2-oxaspiro[3.3]hept-6-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 80: (S)-N-(1-(cyclopropylmethyl)-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-methoxyazacyclobutyl-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 83: (S)-N-(3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-((3-methyloxetane-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(oxetanebut-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-trifluoroprop-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]hept-2-yl)-3-(5-(3-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-(7-oxaspiro[3.5]non-2-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)acetamide, Compound 98: (S)-N-(1-(cyclopropylcarbonyl)-3-(5-(2,2-difluoropropoxy)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-methoxyazacyclobut-1-yl)-6-oxo-1-(1,1,1-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoropropyl-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-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-trifluoroprop-2-yl)-1,6-dihydropyridazin-3-yl)-1-ethyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-3-methylurea.

15. A pharmaceutical composition for the prevention, improvement or treatment of TYK2-related diseases, comprising a TYK2 inhibitor compound as claimed in any one of claims 1 to 14, its stereoisomer or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 15, wherein, The TYK-related diseases mentioned are autoimmune diseases, inflammatory diseases, cancer, or neurodegenerative diseases.

17. The pharmaceutical composition of claim 16, wherein, Autoimmune and inflammatory diseases are selected from one or more of the following groups: asthma, autoimmune inflammatory bowel disease, alopecia areata, ankylosing spondylitis, lupus, lupus nephritis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis (including plaque psoriasis, scalp psoriasis, and nail psoriasis), Sjögren's syndrome, multiple sclerosis, palmoplantar pustulosis, celiac disease, atopic dermatitis, contact dermatitis, delayed-type hypersensitivity reactions, treatment of eye diseases and conditions such as eye allergies, conjunctivitis, keratoconjunctivitis sicca and vernal keratoconjunctivitis, diseases involving the nose including allergic rhinitis, interstitial lung fibrosis. Vitiligo, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyridine-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis, endometritis, leptospirosis, kidney disease, myocardial hypertrophy, muscle atrophy, catabolism disorders, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, pigment incontinence, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity reactions, allergic reactions, sinusitis, ocular allergies, etc. Diseases induced by silica, chronic obstructive pulmonary disease (COPD), cystic fibrosis, acid-induced lung injury, pulmonary hypertension, COVID-19, cataracts, muscle inflammation with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, temporal arteritis, tendinitis, dermatomyositis, appendicitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis. Epididymitis, epididymitis, fasciitis, fibrositis, gastritis, Henrönlein purpura, hepatitis, hidradenitis suppurativa, leukocyte adhesion deficiency, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, and vulvitis.

18. The pharmaceutical composition of claim 16, wherein, The cancer is selected from one or more of the following groups: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, genitourinary cancer, seminoma, esophageal cancer, laryngeal cancer, gastric cancer, stomach cancer, gastrointestinal cancer, skin cancer, keratoacanthoma, follicular carcinoma, melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, adenomatous polyps, colon cancer, pancreatic cancer, thyroid cancer, papillary carcinoma, bladder cancer. Liver cancer, bile duct cancer, kidney cancer, bone cancer, bone marrow diseases, lymphatic system diseases, pilomatricoma, oral and pharyngeal cancer (oral cavity), 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, cervical cancer, brain cancer, central nervous system cancer, peritoneal cancer, hepatocellular carcinoma, head cancer, neck cancer, Hopkins disease, and leukemia (acute myeloid leukemia).

19. The pharmaceutical composition of claim 16, wherein, The neurodegenerative disease is selected from one or more of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

20. A method for preparing chemical formula 1 as described in claim 1, the method comprising: Borylation of the compound represented by the following chemical formula 3, followed by a Suzuki or Ullmann reaction with the compound corresponding to chemical formula 2, yields the compound represented by chemical formula 1: [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] In the above formula, A1, A2, A3, A4, A5, R1, R2, R3, R4, and R5 are as defined in claim 1, and X is a halogen.

21. The preparation method according to claim 20, wherein, The compound of chemical formula 2 is prepared by a preparation method comprising the following steps: The compound represented by chemical formula 4 below is prepared by reacting the compound represented by chemical formula 4 below with NBS or NIS; By subjecting the compound represented by the following chemical formula 5 to S N 2. The reaction or Chan-Lam reaction is used to prepare the compound represented by the following chemical formula 6; as well as The compound represented by chemical formula 2 was prepared by deacetylation of the compound represented by chemical formula 6 with an acid, followed by reaction with an isocyanate or acetyl chloride. in: [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] In the above formula, A2, A3, A4, A5, R3, and R4 are defined as in Equation 1, and X is a halogen.

22. The preparation method according to claim 20, wherein, The compound of chemical formula 3 is prepared by a preparation method comprising the following steps: via the Mitsunobu reaction or S N 2. A reaction is performed to prepare a compound represented by chemical formula 8 from a compound represented by chemical formula 7; and Compounds represented by chemical formula 3 are prepared by reacting the compound represented by chemical formula 8 with HOR' or HNR'R": in: [Chemical Formula 7] [Chemical Formula 8] In the above formula, A1 and R1 are defined as in Equation 1, and X is a halogen.

23. The preparation method according to claim 20, wherein, The compound of chemical formula 3 is prepared by a preparation method comprising the following steps: via the Mitsunobu reaction or S N 2. The compound represented by chemical formula 9 is used to prepare the compound represented by chemical formula 8 from the compound represented by chemical formula 9 below; [Chemical Formula 9] In the above formula, A1 and R1 are defined as in Equation 1, and X is a halogen.

24. A method for preparing chemical formula 1 as described in claim 1, the method comprising: The compound of chemical formula 3 is boronized and then reacted with the compound of chemical formula 6 by a Suzuki reaction or a Ullmann reaction to obtain the compound of chemical formula 10. as well as The steps of deacetylation of the compound of formula 10 with an acid, followed by reaction with acetoxyacetyl chloride or methylamine to obtain the compound of formula 1: [Chemical Formula 1] [Chemical Formula 3] [Chemical Formula 10] In the above formula, A1, A2, A3, A4, A5, R1, R2, R3, R4, and R5 are as defined in claim 1, and X is a halogen.

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