TYK-2 inhibitors

Abstract

Disclosed herein is a compound having formula (I) for inhibiting TYK2 and treating a disease associated with undesirable TYK-2 activity (TYK-2-related disease), a method of using the compound disclosed herein to treat an inflammatory disease or an autoimmune disease, and a pharmaceutical composition comprising the compound.

Description

Technical Field

[0001] Disclosed herein are compounds having formula (I) for inhibiting TYK2 and treating diseases associated with undesired TYK-2 activity (TYK-2-related diseases), methods of using the compounds disclosed herein to treat inflammatory diseases or autoimmune diseases, and pharmaceutical compositions comprising the compounds. Background Art

[0002] The Janus kinase family includes JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2), and is a non-receptor tyrosine kinase that binds to the intracellular portion of cell surface cytokine receptors. In response to stimulation of these receptors, Janus kinases phosphorylate signal transducer and activator of transcription (STAT) proteins, which then dimerize, translocate to the nucleus, and activate gene transcription. Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been shown to regulate mouse (Ishizaki, M. et al., “Involvement of Tyrosine Kinase-2in Both theIL-12 / TH1 and IL-23 / TH17 Axes in vivo”, J. Immunol., 187:181-189 (2011); Prachal-Murphyl, M. et al., “TYK2 kinase activity is required for functional type I interferon responses in vivo”, PloS one, 7:e39141 (2012)) and human (Minegishi, Y. et al., “Human tyrosine kinase Tyk2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate acquired immunity”, Immunity, 25:745-755 (2006). Tyk2 mediates receptor-induced phosphorylation of members of the STAT family of transcription factors, an essential signal leading to STAT protein dimerization and STAT-dependent proinflammatory gene transcription.Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, demonstrating the importance of Tyk2-mediated signaling in autoimmunity and related disorders (Ishizaki, M. et al., “Involvement of Tyrosine Kinase-2 in Both the IL-12 / TH1 and IL-23 / TH17 Axes in vivo,” J. Immunol., 187:181-189 (2011); Oyamada, A. et al., “Tyrosine kinase 2plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis.” T cell response plays a key role]", J. Immunol. [Journal of Immunology], 2009, 183, 7539-7546).

[0003] To date, most of the known small molecule JAK inhibitors that have entered the development stage are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein (also known as JH1 or "Janus homology 1" domain), thereby hindering the catalytic activity of the kinase by blocking ATP, downstream phosphorylation and resulting pathway signaling (Bryan, M. et al., "Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances", J. Med. Chem. 2018, 61, 9030-9058).It is well known that JAK2 is involved in hematopoiesis (Neubauer, H. et al., "JAK2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis", Cell 1998, 93, 397-409), and inhibition of JAK2 can cause side effects such as anemia, neutropenia, and increased risk of infection and dyslipidemia (Wollenhaupt, J. et al., "Safety and efficacy of tofacitinib, an oral Janus Kinase Inhibitor, for the treatment of rheumatoid arthritis in open-label. J. Rheumatol. 2014, 41, 837-852; He, Y. et al., Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis arthritis: a systematic review and meta-analysis. [Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis] BMC Musculoskelet. Disord. [BMC musculoskeletal disorders] 2013, 14, 298; Zerbini, CA et al., Tofacitinib for the treatment of rheumatoid arthritis. [Tofacitinib is used to treat rheumatoid arthritis] Expert Rev. Clin. Immunol. [Clinical Immunology Expert Review] 2012, 8, 319-331).

[0004] Small molecule inhibitors of the TYK2-JH2 domain are being developed for the treatment of autoimmune diseases. BMS986165 (WO 2014074661 A1, WO 2018183649 A1, WO 2018183656 A1, and WO 2019232138A1) is the first TYK2-JH2 inhibitor, and multiple clinical trials are currently underway for psoriasis, ulcerative colitis (UC), lupus, and systemic lupus erythematosus. Other TYK2-JH2 inhibitors entering clinical trials are ABBV-712 (see, e.g., WO2019178079 A1, WO 2019178079 A9, JP 6557436 B1, and US 2019276450 A1), which is in clinical trials for psoriasis.

[0005] In this patent, the compounds bind to the pseudokinase (JH2) domain of TYK2 and inhibit its function through an allosteric mechanism. At the same time, these compounds greatly improve the selectivity compared to other JAK family members (JAK1, JAK2 and JAK3). Summary of the invention

[0006] Disclosed herein is a series of compounds that inhibit the pseudokinase (JH2) domain of TYK2. These compounds show picomolar to nanomolar biochemical activity in TYK2-JH2 binding assays and also show nanomolar activity in cell assays. At the same time, these compounds show excellent selectivity in TYK2 biochemical / cell assays for JAK1.

[0007] In a first aspect, disclosed herein is a compound having the following formula (I):

[0008]

[0009] or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

[0010] R 1 It is hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein the C 1-6 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted with 0-7 R 1a replace;

[0011] R 1a is independently at each occurrence hydrogen, deuterium, halogen, -CN or -OMe;

[0012] R 2 Yes-C(O)R 2aor a 4-10 membered heterocyclic group containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the 4-10 membered heterocyclic group is optionally substituted by 0-4 R 2b replace;

[0013] R 2a Independently C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0014] R 2b is independently at each occurrence hydrogen, =O, halogen, -CN, -(CH2) r -C 3-6 Cycloalkyl, or -(CH2) containing carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur r -3-10 membered heterocyclic group, wherein said -(CH2) r -C 3-6 Cycloalkyl and -(CH2) r -3-10 membered heterocyclic group each optionally substituted with 0-2 R 2c replace;

[0015] R 2c is independently at each occurrence hydrogen, -haloC 1-3 Alkyl or -C 1-3 alkyl;

[0016] R 3 yes wherein n is an integer selected from 0, 1, 2, 3 and 4; and

[0017] R 3a is independently at each occurrence hydrogen, halogen, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -P(O)R 3d R 3e 、-(L 1 ) r -CyA; or CyA, wherein the -C 1-6 Alkyl and -C 1-6 Each alkoxy group is optionally substituted with 0-3 R 3d replace;

[0018] L 1 is independently at each occurrence -O-, -S-, -C(O)-, -NH-, -CH2-, or -NHC(O)-;

[0019] CyA is C 3-10cycloalkyl, a 3-10 membered heterocyclyl containing carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen or sulfur, a 6-10 membered aryl, or a 4-10 membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein said C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 4-10 membered heteroaryl are each substituted with 0-3 R 3b replace;

[0020] R 3b is independently at each occurrence hydrogen, halogen, -C 1-6 Alkyl, -oxo-, -OR 3c 、-C(O)R 3d 、-S(O)2R 3d 、-NR 3d R 3e , C 3-10 cycloalkyl, 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from nitrogen, oxygen or sulfur, 6-10 membered aryl, or 4-10 membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen or sulfur; wherein the -C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 4-10 membered heteroaryl are each optionally substituted by 0-3 -R 3d replace;

[0021] R 3c and R 3d is independently at each occurrence hydrogen, halogen, -CN, hydroxy, -C 1-6 Alkyl, -C 1-6 an alkoxyl group, a 5-6 membered aryl group, a 3-6 membered heterocyclic group containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, or a 5-6 membered heteroaryl group containing carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the -C 1-6 Alkyl, -C 1-6 Alkoxy, 5-6 membered aryl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl are optionally substituted with -halogen, -CN, hydroxyl, -C 1-6 Alkyl, -C 1-6 Alkoxy, C 1-6 Alkylamino, di-C 1-6 Alkylamino, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0022] R 3e is independently selected at each occurrence from -H, -C 1-6 Alkyl, -S(O)2R 3f or -C(O)R 3f , where R 3f Independently C 1-6 Alkyl or C3-6 cycloalkyl; and

[0023] r is an integer of 0, 1 or 2.

[0024] In one embodiment, R 2 is oxetane, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or quinolyl, each of which is substituted by 0 to 3 R 2b replace.

[0025] In one embodiment, R 2 Yes-C(O)R 2a .

[0026] In one embodiment, R2 is selected from

[0027] In one embodiment, R 1 is methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted by 0 to 3 R 1a replace.

[0028] In one embodiment, R 1 is a methyl group, or -CD3.

[0029] In one embodiment, R 3 yes And R 3a and n are as defined above.

[0030] In one embodiment, R 3a It is hydrogen, halogen, -CN, -C 1-6 Alkyl, -P(O)R 3d R 3e 、-(L 1 ) 0-2 -CyA or CyA, wherein CyA is a 3-6 membered heterocyclyl or heteroaryl group comprising carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen or sulfur, and is optionally substituted by 0-3 R 3d replace.

[0031] In one embodiment, L 1 is independently at each occurrence -O-, -S-, -C(O)-, -NH-, -CH2-, or -NHC(O)-.

[0032] In one embodiment, R 3a is a 3-6 membered heterocyclic or heteroaryl group containing carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen or sulfur.

[0033] In one embodiment, CyA is a 5-6 membered heterocyclic group comprising carbon atoms and 1-4 heteroatoms selected from nitrogen or oxygen.

[0034] In one embodiment, CyA is azetidinyl, piperidinyl and piperazinyl, each of which is replaced by 0-3 R 3b replace.

[0035] In one embodiment, CyA is a 7-10 membered bridged heterocyclic group comprising carbon atoms and 1-2 heteroatoms selected from N and O, surrounded by 0-3 R 3b replace.

[0036] In one embodiment, CyA is

[0037] In one embodiment, the N heteroatom on CyA is attached to R 3 .

[0038] In one embodiment, R 3b It is hydrogen, halogen, -C 1-3 Alkyl, -OR 3c 、-C(O)R 3d NR 3d R 3e , C 3-10 Cycloalkyl, wherein the -C 1-3 Alkyl and C 3-10 The cycloalkyl group is optionally substituted with 0-3 -R 3d replace.

[0039] In one embodiment, R 3c and R 3d is independently selected at each occurrence from hydrogen, halogen, -CN, hydroxy, -C 1-3 Alkyl, -C 1-3 alkoxy, phenyl, a 3-6 membered heterocyclic group containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, a 5-6 membered heteroaryl group containing carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the -C 1-6 Alkyl, -C 1-6 Alkoxy, phenyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl are optionally substituted with -halogen, -CN, hydroxyl, -C 1-3 Alkyl, -C 1-3 Alkoxy, C 1-3 Alkylamino, di-C 1-6 The amino group may be substituted with an alkylamino group, a 3-6 membered heterocyclyl group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group.

[0040] In one embodiment, R 3bis hydrogen, halogen, methyl, ethyl, propyl, isopropyl, isobutyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -OR 3c NR 3d R 3e , C 3-10 Cycloalkyl, wherein the -C 1-3 Alkyl and C 3-10 The cycloalkyl group is optionally substituted with 0-3 -R 3d replace.

[0041] In one embodiment, R 3 yes

[0042]

[0043]

[0044] In one embodiment, the compound is selected from the compounds exemplified in Example A4, A5, C1, C2, C3, C4, C5, D1, E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, F1, G1, H1, J1, J2, K1, L1, L2, L3, L4, L5, M1, N2, N3, O1, P1 or Q1.

[0045] In a second aspect, disclosed herein is a pharmaceutical composition comprising one or more compounds disclosed herein, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

[0046] In a third aspect, disclosed herein is a method for treating a disease associated with undesired TYK2 activity (TYK2-related disease), the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the disease is an inflammatory disease or an autoimmune disease. DETAILED DESCRIPTION

[0048] definition

[0049] The following terms have the indicated meanings throughout this specification:

[0050] As used herein, including the appended claims, singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0051] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or".

[0052] The term "alkyl" refers to a hydrocarbon group selected from straight and branched saturated hydrocarbon groups containing from 1 to 18 (such as from 1 to 12, further such as from 1 to 10, further such as from 1 to 8, or from 1 to 6, or from 1 to 4) carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2- The alkyl groups may be optionally enriched with deuterium, for example, -CD3, -CD2CD3, etc.

[0053] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0054] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, and iodine). Examples of haloalkyl groups include halo C 1-8 Alkyl, halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl, but not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3 and the like.

[0055] The term "alkyloxy" or "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. 1-6 Alkyloxy or C 1-4 Examples of alkyloxy) include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0056] The term "alkoxy-alkyl-" refers to an alkyl group as defined above which is further substituted by an alkoxy group as defined above. 1-8 Alkoxy-C 1-8 Alkyl- or C1-6 Alkoxy-C 1-6 Examples of alkyl- include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl, or propoxymethyl and the like.

[0057] The term "amino" refers to -NH2. The term "alkylamino" refers to -NH(alkyl). The term "dialkylamino" refers to -N(alkyl)2.

[0058] The term "alkenyl" herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and from 2 to 18 (such as from 2 to 8, further such as from 2 to 6) carbon atoms. Examples of alkenyl groups (e.g., C2-6 alkenyl) include, but are not limited to, vinyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, butane-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.

[0059] The term "alkynyl" herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and from 2 to 18 (such as from 2 to 8, further such as from 2 to 6) carbon atoms. Examples of alkynyl groups (e.g., C2-6 alkynyl) include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0060] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl groups.

[0061] For example, the cycloalkyl group can include from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4 carbon atoms.Even further for example, the cycloalkyl group can be selected from and include from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms of the monocyclic group.The example of monocyclic cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl groups.Especially, saturated monocyclic cycloalkyl groups (such as C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl groups are monocyclic rings (abbreviated as C 3-6Cycloalkyl) includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms, having a fused bicyclic arrangement selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or having a bridged bicyclic arrangement selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Additional examples of bicyclic cycloalkyl groups include those having a bicyclic arrangement selected from [5,6] and [6,6] ring systems.

[0062] The term "cycloalkenyl" refers to a non-aromatic cycloalkyl group of from 3 to 10 carbon atoms having a single ring or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds. In one embodiment, the cycloalkenyl is a cyclopentenyl or cyclohexenyl, preferably a cyclohexenyl.

[0063] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having a single ring or multiple rings and having at least one triple bond.

[0064] The term "deuterated" is used herein to modify a chemical structure or organic group (group or radical) in which one or more carbon-bonded hydrogens are replaced by one or more deuteriums, such as "deuterated alkyl", "deuterated cycloalkyl", "deuterated heterocycloalkyl", "deuterated-aryl", "deuterated morpholinyl", etc. For example, the term "deuterated alkyl" defined above refers to an alkyl group as defined herein in which at least one carbon-bonded hydrogen atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium; and a carbon atom may be bonded to at most one deuterium; more than one carbon atom in an alkyl group may also be bonded to deuterium.

[0065] The term "aryl", used alone or in combination with other terms, refers to a group selected from:

[0066] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0067] - bicyclic ring systems (such as 7- to 12-membered bicyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0068] - a tricyclic ring system (eg a 10- to 15-membered tricyclic ring system) in which at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0069] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0070] The term "heteroaryl" as used herein refers to a group selected from:

[0071] - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments from 1 to 3, in some embodiments from 1 to 2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), wherein the remaining ring atoms are carbon;

[0072] - a 7- to 12-membered bicyclic ring containing as a ring member at least one heteroatom (e.g. from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms) selected from nitrogen, oxygen or optionally oxidized sulfur, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0073] - an 11- to 14-membered tricyclic ring comprising as a ring member at least one heteroatom (e.g. from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms) selected from nitrogen, oxygen or optionally oxidized sulfur, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0074] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When the heteroaryl group contains more than one heteroatom ring member, these heteroatoms can be the same or different. The nitrogen atoms in one or more rings of the heteroaryl group can be oxidized to form N-oxides.

[0075] As used herein, the term "optionally oxidized sulfur" refers to S, SO or SO2.

[0076] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure herein. In some embodiments, monocyclic or bicyclic aromatic heterocycles have 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, monocyclic or bicyclic aromatic heterocycles are monocyclic or bicyclic rings comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, monocyclic or bicyclic aromatic heterocycles are 5 to 6 heteroaryl rings, which are monocyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, monocyclic or bicyclic aromatic heterocycles are 8 to 10 heteroaryl rings, which are bicyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

[0077] Examples of heteroaryl groups, or monocyclic or bicyclic aromatic heterocycles, include, but are not limited to, (numbering from the attachment position designated as priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4 ...3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4- 4-triazolyl), quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thiazolyl -2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzophenylthio, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, fluoropyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0078] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon, including monocyclic, fused, bridged, and spiro rings, i.e., containing monocyclic heterocyclyls, bridged heterocyclyls, spiro heterocyclyls, and fused heterocyclic groups.

[0079] The term "monocyclic heterocyclyl" refers to a monocyclic group wherein at least one ring member is a heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0080] Exemplary monocyclic 4 to 9 membered heterocyclyl groups include, but are not limited to, (numbered starting from the attachment position designated as priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidinon-2-yl, imidazolidinon-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridine-1-yl, aziridine-2-yl, aziridine-3-yl, aziridine-4-yl, aziridine-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, azetidin-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, azetidin-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, azetidin-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, azetidin-4-yl, azetidin-5-yl 1,4-oxathiolanyl, 1,4-dioxepanyl, 1,4-oxathiolanyl, 1,4-dithiolanyl, 1,4-thiazepan ... Base, diazepine Thiazepine 1,1-dioxanyl, 1,3-dioxolanyl, pyrazolyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, or 1,1-dioxo-thiomorpholinyl.

[0081] The term "spiro heterocyclic group" refers to a 5 to 20-membered polycyclic heterocyclic group having a ring connected by a shared carbon atom (referred to as a spiral atom), which includes one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of a spiral heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the spiral heterocyclic group is 6 to 14 yuan and more preferably 7 to 12 yuan. According to the shared spiral atom number, the spiral heterocyclic group is divided into a monospiro heterocyclic group, a di-spiro heterocyclic group or a polyspiro heterocyclic group, and preferably refers to a monospiro heterocyclic group or a di-spiro heterocyclic group, and more preferably 4 yuan / 4 yuan, 3 yuan / 5 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group.

[0082] The term "fused heterocyclic group" refers to a 5 to 20-membered polycyclic heterocyclic radical group (wherein each ring in the system shares adjacent pairs of atoms (carbon and carbon atoms, or carbon and nitrogen atoms) with another ring), which contains one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the fused heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the fused heterocyclic group is 6 to 14 yuan and more preferably 7 to 10 yuan. According to the number of member rings, the fused heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, and more preferably a 5 yuan / 5 yuan or 5 yuan / 6 yuan bicyclic fused heterocyclic group. Representative examples of fused heterocycles include, but are not limited to, the following: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolyl (e.g., isoindolyl-2-yl), octahydro-benzo[b][1,4]dioxin.

[0083] The term "bridged heterocyclic group" refers to a 5-14-membered polycyclic heterocycloalkyl group (wherein each two rings in the system share two discontinuous atoms), which contains one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, wherein the remaining ring members are carbon. One or more rings of the bridged heterocyclic group may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, the bridged heterocyclic group is 6 to 14 yuan and more preferably 7 to 10 yuan. According to the number of member rings, the bridged heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, and more preferably a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclic groups include, but are not limited to, the following: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0084] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound, which are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a wider class of stereoisomers. It is intended to include all possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, a reference to an isomer is applicable to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0085] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, even further such as no more than 20% of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, such as no more than 5%, such as no more than 1% of any one or more other stereoisomers.

[0086] When the compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0087] When the compounds disclosed herein contain disubstituted cyclohexyl or cyclobutyl groups, the substituents found on the cyclohexyl or cyclobutyl ring can adopt cis and trans formations. The cis formation means that both substituents are located on the upper side of the 2 substituent positions on the carbon, while the trans form means that they are located on the opposite side.

[0088] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter referred to as separation) to the desired uniformity by ordinary techniques in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example: reverse phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art will apply the technology most likely to achieve the desired separation.

[0089] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of each other. Diastereoisomer mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art (e.g., by chromatography and / or fractional crystallization). Enantiomers can be separated as follows: by reacting an enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher'sacid chloride), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0090] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolution of racemic mixtures using an optically active resolving agent to form diastereomers (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective [Chromatographic resolution of enantiomers: a selective review]" J. Chromatogr. [Journal of Chromatography], 113(3) (1975): pp. 283-302]. Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including: (1) forming ionic diastereomeric salts with chiral compounds and separating them by fractional crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating these diastereomers and converting them to pure stereoisomers; and (3) separating substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., ed. Drug Stereochemistry: Analytical Methods and Pharmacology. [Drug Stereochemistry: Analytical Methods and Pharmacology] New York: Marcel Dekker, Inc. [New York: Marcel Dekker Company], 1993.

[0091] The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or separately by reacting an acidic group with a suitable base.

[0092] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (such as a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0093] As defined herein, "pharmaceutically acceptable salts thereof" include at least one salt of a compound having formula (I), and salts of stereoisomers of a compound having formula (I), such as salts of enantiomers, and / or salts of diastereomers.

[0094] The terms "administration / administering" and "treating / treatment" herein, when applied to an animal, a human, an experimental subject, a cell, a tissue, an organ, or a biological fluid, mean contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses contact of an agent with a cell and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administration" and "treatment" also mean in vitro and ex vivo treatment of a cell, such as by an agent, a diagnostic agent, a binding compound, or another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0095] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (such as a compound) sufficient to affect the treatment of a disease, disorder or symptom when administered to a subject to treat a disease, or at least one clinical symptom of a disease or disorder. The "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art, or may be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one of its stereoisomers, and / or at least one of its pharmaceutically acceptable salts as defined above that is effective in treating a disease or disorder in a subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of a combination object used to effectively treat a disease, disorder or condition.

[0096] The pharmaceutical composition comprising the compounds disclosed herein can be administered orally, by inhalation, rectally, parenterally or topically to a subject in need. For oral administration, the pharmaceutical composition can be a conventional solid formulation, such as a tablet, powder, granule, capsule, etc.; a liquid formulation, such as water or oil suspension; or other liquid formulations, such as syrups, solutions, suspensions, etc.; for parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oil suspension concentrate, a lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays or injections, more preferably tablets or capsules. The pharmaceutical composition can be a single unit administration with a precise dose. In addition, the pharmaceutical composition may further comprise other active ingredients.

[0097] All formulations of the pharmaceutical composition disclosed herein can be produced by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients and then made into the desired formulation. "Pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as: diluents, vehicles (such as water, various organic solvents, etc.), fillers (such as starch, sucrose, etc.), adhesives (such as cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone (PVP)); wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as hexadecanol; absorption carriers, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition also includes other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners and dyes.

[0098] The term "disease" refers to any illness, ailment, disease, symptom, or indication, and is interchangeable with the terms "disorder" or "condition."

[0099] Throughout this specification and the appended claims, unless the context requires otherwise, the term "comprising" and variations such as "including" and "containing" are intended to specify the presence of the following features, but not to exclude the presence or addition of one or more other features. When used herein, the term "comprising" may be replaced with the terms "containing" or "including", or sometimes with "having".

[0100] Throughout this specification and the appended claims, the term "Cn-m" indicates a range including endpoints, where n and m are integers and indicate the number of carbons. Examples include C1-8, C1-6, etc.

[0101] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0102] Examples

[0103] The following examples are intended to be purely exemplary and should not be considered to be limiting in any way. Although efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should be considered. Unless otherwise stated, temperatures are expressed in degrees Celsius. Reagents are purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and, unless otherwise stated, can be used without further purification.

[0104] Unless otherwise noted, the reactions described below were performed under a positive pressure of nitrogen or argon or in anhydrous solvents with a drying tube; reaction flasks were equipped with rubber septa for introduction of substrates and reagents via syringe; and glassware was oven-dried and / or heat-dried.

[0105] Unless otherwise noted, the reactions described below were performed under a positive pressure of nitrogen or argon or in anhydrous solvents with a drying tube; reaction flasks were equipped with rubber septa for introduction of substrates and reagents via syringe; and glassware was oven-dried and / or heat-dried.

[0106] Unless otherwise stated, column chromatography purifications were performed on a Biotage system (manufacturer: Dyax Corporation) with silica columns or on silica SepPak columns (Waters), or on a Teledyne Isco Combiflash purification system using pre-packed silica columns.

[0107] Recorded on a Varian instrument operating at 400 MHz 1 H NMR spectra. Obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)2CO: 2.05) as reference standards 1 H-NMR spectra. When reporting the number of multiplets, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (double of doublets), dt (double of triplets). If coupling constants are given, they are reported in Hertz (Hz). Compound names other than reagents were generated by ChemDraw version 12.0.

[0108] abbreviation:

[0109] AcOH Acetic acid

[0110] Aq water based

[0111] Brine Saturated Aqueous Sodium Chloride Solution

[0112] Bn Benzyl

[0113] BnBr Benzyl bromide

[0114] (Boc)2O Di-tert-butyl dicarbonate

[0115] DMF N,N-Dimethylformamide

[0116] Dppf 1,1"-Bis(diphenylphosphino)ferrocene

[0117] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0118] DIEA or DIPEA N-ethyl-N-isopropylpropane-2-amine

[0119] DMAP 4-N,N-dimethylaminopyridine

[0120] DMF N,N-Dimethylformamide

[0121] DMSO Dimethyl sulfoxide

[0122] EtOAc Ethyl acetate

[0123] EtOH

[0124] Et2O or diethyl ether

[0125] Et3N Triethylamine

[0126] HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0127] HPLC High Performance Liquid Chromatography

[0128] IPA 2-Propanol

[0129] i-PrOH Isopropyl alcohol

[0130] ms or MS mass spectrometry

[0131] NaHMDS Sodium hexamethylenedisilazane

[0132] PE Petroleum Ether

[0133] PPA Polyphosphoric acid

[0134] p-TSA p-Toluenesulfonic acid

[0135] Rt retention time

[0136] Rt or rt Room temperature

[0137] TBAF Tetrabutylammonium fluoride

[0138] TBSCl tert-Butyldimethylsilyl chloride

[0139] TFA Trifluoroacetic acid

[0140] THF Tetrahydrofuran

[0141] TLC Thin layer chromatography

[0142] Example A

[0143] Example A1: Synthesis of 4-(benzo[d]oxazol-2-ylamino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (Compound 1)

[0144]

[0145] Step 1: 4-(Benzo[d]oxazol-2-ylamino)-6-chloro-N-methylpyridazine-3-carboxamide

[0146]

[0147] To a solution of benzo[d]oxazole-2-amine (134 mg, 1 mmol) and 4,6-dichloro-N-methylpyridazine-3-carboxamide (410 mg, 2 mmol) in 10 mL of THF was added KHMDS (4 mL, 1 M in THF) at room temperature, and the resulting solution was stirred at this temperature for 2 hours. After the reaction was complete, 1N HCl was added to adjust pH=7. The solution was concentrated in vacuo, and the residue was purified by CombiFlash (MeOH / DCM=1%-10%) to give the product as a yellow solid (60 mg, 19%). MS (ESI) m / e[M+1] + =303.9.

[0148] Step 2: 4-(Benzo[d]oxazol-2-ylamino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (Compound 1)

[0149]

[0150] A mixture of 4-(benzo[d]oxazol-2-ylamino)-6-chloro-N-methylpyridazine-3-carboxamide (30 mg, 0.1 mmol), cyclopropanecarboxamide (34 mg, 0.4 mmol), dimethylxanthene (xantPhos)-Pd-G3 (5 mg, 0.005 mmol), dimethylxanthene (3 mg, 0.005 mmol) and Cs2CO3 (163 mg, 0.5 mmol) in 3 mL of dioxane was heated in a sealed tube at 130° C. for 4 hours under N2. After cooling to room temperature, the solution was concentrated under vacuum, and the residue was purified by preparative TLC (MeOH / DCM=10:1) to give the product (3 mg, 9%). 1H NMR (400MHz, DMSO-d6) δ12.03(s,1H),10.45(s,1H),7.57(t,J=7.9Hz,1H),7.47(s,1H),7.34(d,J=6.5Hz,1H),7.20(d ,J=8.3Hz,1H),7.13(t,J=7.7Hz,1H),3.55(s,3H),2.05(d,J=4.4Hz,1H),0.84(d,J=7.6Hz,2H),0.78(d,J=3.8Hz,2H). MS(ESI)m / e[M+1]+=352.9.

[0151] The following compounds 2-5 were synthesized according to a similar procedure as described for compound 1 starting from the corresponding starting materials.

[0152]

[0153] Example B

[0154] Example B1: Synthesis of 4-((6-(azetidin-1-yl)-7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (Compound 6)

[0155]

[0156] Step 1: 6-Bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine

[0157]

[0158] The solution of 5-bromo-4-methoxypyridine-2-amine (950mg, 5mmol) and O-carbon isothiocyanate (606mg, 3mmol) in 10mL dioxanes was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed in a vacuum, and the residue was redissolved with 10mL ethanol, then hydroxylamine hydrochloride (1g, 15mmol) and DIPEA (1.16g, 9mmol) were added, and the mixture was stirred at 70 ℃ for 24 hours. After cooling to room temperature, the solution was concentrated, and 50mL water was added. The precipitated solid was collected and dried to give the product (500g, 69%) as a white solid. MS (ESI) m / e [M+1] + =242.9.

[0159] Step 2: 6-(azetidin-1-yl)-7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine

[0160]

[0161] Under N2 atmosphere, a mixture of 6-bromo-7-methoxy-[1,2,4]triazolo[1,5-a]pyridine-2-amine (570 mg, 2.35 mmol), azetidine hydrochloride (441 mg, 4.7 mmol), Pd2(dba)3 (1.1 g, 1.18 mmol), dimethylxanthene (683 mg, 1.18 mmol) and Cs2CO3 (3.06 g, 9.4 mmol) in 20 mL of dioxane was heated at 130°C in a sealed tube for 4 hours. After cooling to room temperature, the solution was removed in vacuo, and the residue was purified by Combiflash (MeOH / DCM=1%-15%) to give the product as a white solid (300 mg, 58%). MS (ESI) m / e[M+1] + =220.

[0162] Step 3: 4-((6-(azetidin-1-yl)-7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl) (amino)-6-chloro-N-methylpyridazine-3-carboxamide

[0163]

[0164] The desired compound was prepared from 6-(azetidin-1-yl)-7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine and 4,6-dichloro-N-methylpyridazine-3-carboxamide according to a procedure similar to compound 1, step 1, to give the product as a brown solid (140 mg, 56%). MS (ESI) m / e [M+1] + =388.9.

[0165] Step 4: 4-((6-(azetidin-1-yl)-7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl) Amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (Compound 6)

[0166]

[0167] The desired compound was prepared from 4-((6-(azetidin-1-yl)-7-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide according to a procedure similar to compound 1 in step 2 of Example A1 to give the product (10 mg, 91%). MS (ESI) m / e [M+1] + =438. 1 H NMR(400MHz,DMSO-d6)δ11.90(s,1H),11.35(s,1H),9.28(s,2H),7.71(s,1H),7.01(s,1H),3.91(s,3H ), 3.84 (t, J = 6.7Hz, 4H), 2.86 (d, J = 3.7Hz, 3H), 2.30-2.19 (m, 2H), 2.14 (s, 1H), 0.89 (d, J = 8.3Hz, 4H). (s,4H).

[0168] Example C

[0169] Examples C1, C2 and C3: tert-butyl 3-((2-((6-(cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)azetidine-1-carboxylate (Compound 7), 4-((6-(azetidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)azetidine-1-carboxylate Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-4-((6-((1-(methylsulfonyl)azetidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 9)

[0170]

[0171] Step 1: 2-Amino-[1,2,4]triazolo[1,5-a]pyridin-6-ol

[0172]

[0173] 6-methoxy-[1,2,4]triazolo[1,5-a]pyridine-2-amine (800mg, 4.88mmol) was added to a slurry of aluminum chloride (1.29g, 9.76mmol) in DCM (50mL), and the resulting mixture was stirred at room temperature overnight. After the reaction was complete, water was added, and the resulting solution was extracted with DCM. The combined organic layers were concentrated, and the residue was purified by flash chromatography (MeOH:DCM=15:85) to give a product (600mg, 73%) as a yellow oil. MS (ESI) m / e[M+H] + =151.

[0174] Step 2: 3-((2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)azetidine-1-carboxylic acid Tert-butyl ester

[0175]

[0176] A mixture of 2-amino-[1,2,4]triazolo[1,5-a]pyridine-6-ol (300 mg, 2.00 mmol), 3-bromoazetidine-1-carboxylic acid tert-butyl ester (517 mg, 2.20 mmol) and Cs2CO3 (1.30 g, 4.00 mmol) in DMF (20 mL) was stirred overnight at 60 ° C. After cooling to room temperature, the solution was removed in vacuo, and the residue was dissolved in MeOH / DCM (5 mL / 25 mL), the solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH: DCM = 6: 94) to give the product as a white solid (600 mg, 73%). MS (ESI) m / e [M+H] + =306.

[0177] Step 3: 3-((2-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo[1, tert-Butyl 5-a]pyridin-6-yl)oxy)azetidine-1-carboxylate

[0178] At 70 ° C, to tert-butyl 3-((2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)azetidine-1-carboxylate (133 mg, 0.44 mmol) and 4,6-dichloro-N-methylpyridazine-3-carboxamide (133 mg, 0.65 mmol) in THF (10 mL) was added NaHMDS (1M in THF, 1.95 mL) at one time, and the resulting mixture was stirred at this temperature for 10 minutes. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (MeOH: DCM = 7: 93) to give the product as a yellow solid (120 mg, 39%). MS (ESI) m / e [M + H] + =475.

[0179] Step 4: 3-((2-((6-(cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)- [1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)azetidine-1-carboxylic acid tert-butyl ester (Compound 7)

[0180]

[0181] The desired compound was prepared from tert-butyl 3-((2-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)azetidine-1-carboxylate according to a procedure similar to compound 1 in Step 2 of Example A1 to give the product (66 mg, 55%). 1H NMR(400MHz, DMSO-d6)12.09(s,1H),11.40(s,1H),9.31-9.34(m,2H),8.44(d,J=2.2Hz,1H),7.67(d,J=9.7Hz,1H),7.46(dd,J=9.6,2.3H z,1H),5.12-5.13(m,1H),4.34-4.35(m,2H),3.86-3.88(m,2H),2.87(d,J=4.8Hz,3H),2.14-2.15(m,1H),1.42(s,9H),0.88-0.92(m,4H). MS(ESI)m / e[M+H] + =524.

[0182] Step 5: 4-((6-(azetidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino yl)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (Compound 8)

[0183]

[0184] To a solution of tert-butyl 3-((2-((6-(cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy)azetidine-1-carboxylate (60 mg, 0.11 mmol) in DCM (10 mL) was added TFA (1 mL) and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed in vacuo and the residue was lyophilized with 0.5 M HCl to give the product (30 mg, 48%). 1 H NMR (400MHz, DMSO-d6)12.12(s,1H),11.43(s,1H),9.20-9.35(m,4H),8.55(s,1H),7.71(d,J=9.6Hz,1H),7.49(d,J=9.6Hz ,1H),5.19-5.20(m,1H),4.47-4.48(m,2H),4.06-4.07(m,2H),2.87(d,J=4.7Hz,3H),2.15-2.17(m,1H),0.89-0.91(m,4H). MS(ESI)m / e[M+H] + =424.

[0185] Step 6: 6-(Cyclopropanecarboxamido)-N-methyl-4-((6-((1-(methylsulfonyl)azetidin-3-yl) Oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 9)

[0186]

[0187] TowardsTo a solution of 4-((6-(azetidine-3-yloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (7 mg, 0.017 mmol) in THF (2 mL) was added methanesulfonyl chloride (4 mg, 0.034 mmol) and TEA (5 mg, 0.051 mmol). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed in vacuo, and the residue was purified by preparative TLC (MeOH:DCM=1:20) to give the product (2.13 mg, 30%). 1 H NMR(400MHz, DMSO-d6)12.10(s,1H),11.40(s,1H),9.30-9.33(m,2H),8.52(s,1H),7.69(d,J=9.5Hz,1H),7.48(d,J=12.0Hz,1H), 5.16-5.17(m,1H),4.34-4.35(m,2H),3.98-4.00(m,2H),3.09(s,3H),2.87(d,J=4.8Hz,3H),2.15-2.16(m,1H),0.88-0.90(m,4H). MS(ESI)m / e[M+H] + =502.

[0188] Compounds 10 and 51 were synthesized according to a similar procedure as described for compound 9 starting from the corresponding starting materials.

[0189]

[0190]

[0191] Example D

[0192] Example D1: Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-4-((6-((1-(tetrahydrofuran-3-yl)azetidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 52)

[0193]

[0194] To a solution of 4-((6-(azetidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (7 mg, 0.017 mmol) and dihydrofuran-3(2H)-one (7 mg, 0.085 mmol) in DMF (2 mL) was added NaBH(OAc) (35 mg, 0.17 mmol), and the resulting mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was removed in vacuo, and the residue was purified by preparative TLC (MeOH:DCM=1:20) to give the product (2.23 mg, 31%). 1 H NMR(400MHz, DMSO-d6)12.09(s,1H),11.40(s,1H),9.30-9.34(m,2H),8.42(s,1H),7.66(d,J=9.3Hz,1H),7.45(d,J=9.3Hz,1H),4.9 6-4.97(m,1H),3.40-3.74(m,7H),3.07-3.10(m,2H),2.87(d,J=3.9Hz,3H),2.15-2.16(m,1H),1.67-1.83(m,2H),0.88-0.90(m,4H). MS(ESI)m / e[M+H] + =494.

[0195] Example E

[0196] Example E1: Synthesis of 4-((6-(azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (Compound 11)

[0197]

[0198] step 1: 5-(azetidin-1-yl)-2-nitropyridine

[0199]

[0200] At room temperature, azetidine hydrochloride (1.38g, 14.8mmol) and N-ethyl-N-isopropylpropane-2-amine (7.64g, 59.1mmol) were added to a solution of 5-bromo-2-nitropyridine (3.0g, 14.8mmol) in EtOH (30mL). The mixture was heated until 60°C and stirred at this temperature for 16 hours under N2. After cooling to room temperature, the solution was removed in vacuo, and the residue was redissolved with water (5mL). The resulting solution was extracted with EA / THF (v:v=2:1, 20mL, 10mL). The combined organic layer was washed with brine (10mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EA=50:1, to 0:1) to give a product (1.2g, 45.3%) as a yellow solid. MS (ESI) m / e[M+1] + 180.3.

[0201] step 2: 5-(azetidin-1-yl)pyridin-2-amine.

[0202]

[0203] At room temperature, 5-(azetidine-1-yl)-2-nitropyridine (1.2 g, 6.7 mmol) was added to a solution of MeOH / H2O (v:v=10:1, 11 mL)NH4Cl (716.5 mg, 13.4 mmol) and iron powder (1.12 g, 20 mmol). Under N2 atmosphere, the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the solid was filtered, and the filtrate was concentrated in vacuo to give a product as a light yellow solid (650 mg, 65%), which was used in the next step without further purification.

[0204] step 3: Ethyl N-([5-(azetidin-1-yl)pyridin-2-yl]thiocarbamoyl)carbamate

[0205]

[0206] To a solution of 5-(azetidine-1-yl)pyridine-2-amine (650 mg, 4.4 mmol) in 1,4-dioxane (3 mL) was added O-carbon isothiocyanate (685.7 mg, 5.2 mmol), and the resulting mixture was stirred at room temperature for 3 hours under an N2 atmosphere. After the reaction was complete, the solvent was removed in vacuo to give a brown solid product (1.3 g, crude product), which was used in the next step without further purification.

[0207] Step 4: 6-(Azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine.

[0208]

[0209] At room temperature, DIPEA (1.2 g, 9.3 mmol) and NHOH HCl (966.7 mg, 13.9 mmol) were added to a solution of ethyl N-([5-(azetidin-1-yl)pyridin-2-yl]thiocarbamoyl)carbamate (1.3 g, 4.6 mmol) in MeOH / EtOH (v:v=1:1, 15 mL). The resulting mixture was stirred at 60 ° C for 15 hours. After cooling to room temperature, the solution was removed in vacuo, and the residue was redissolved with water (15 mL). The resulting solution was extracted with DCM / MeOH (v:v=5:1, 30 mL x 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH, 100:1 to 1:1) to give a product (240 mg, 27.3%) as an off-white solid. 1 H NMR (DMSO-d6) δ7.65 (s, 1H), 7.21-7.18 (d, J = 9.2Hz, 1H), 6.84-6.81 (m, 1H), 5.67 (s, 2H), 3.76-3.72 (t, J = 7Hz, 4H), 2.3-2.24 (m, 2H). MS(ESI)m / e[M+1] + 190.1.

[0210] Step 5: 4-((6-(azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6- Chloro-N-methylpyridazine-3-carboxamide

[0211]

[0212] At 70 ° C, 4,6-dichloro-N-methylpyridazine-3-carboxamide (54 mg, 0.26 mmol) and 6- (azetidin-1-yl) -[1,2,4] triazolo [1,5-a] pyridine-2-amine (50 mg, 0.26 mmol) were added to a suspension of THF (10 mL) at once. NaHMDS (0.5 mL, 1 M in THF) was added, and the resulting mixture was stirred at this temperature for 2 hours. After cooling to room temperature, the solution was removed in vacuo, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0% -10%) to give the product as a brown solid (32 mg, 31%). MS (ESI) m / e [M + 1] + 358.9.

[0213] Step 6: 4-((6-(azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6- (Cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (Compound 11)

[0214]

[0215] Under N2 atmosphere, a mixture of 4-((6-(azetidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (32 mg, 0.09 mmol), cyclopropanecarboxamide (50 mg, 0.59 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), dimethylxanthene (30 mg, 0.05 mmol) and Cs2CO3 (100 mg, 0.31 mmol) in 1,4-dioxane (4 mL) and DMA (1 mL) was heated at 130°C in a sealed tube for 4 hours. After cooling to room temperature, DCM (10 mL) and MeOH (5 mL) were added, and the resulting solution was filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative TLC (DCM:MeOH=15:1) to give the product as a white solid (2.02 mg, 5.8%). 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),11.38(s,1H),9.35(s,1H),9.30(d,J=4.7Hz,1H),7.87(d,J=1.9Hz,1H),7.56(d,J=9.4Hz, 1H),7.09(dd,J=9.4,2.1Hz,1H),3.86(t,J=7.2Hz,4H),2.87(d,J=4.8Hz,3H),2.39-2.26(m,2H),2.14(m,1H),1.04-0.76(m,4H). MS(ESI)m / e[M+1] + 407.9.

[0216] Example E2: Synthesis of 6-(cyclopropanecarboxamido)-4-((6-(3-methoxyazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (Compound 12)

[0217]

[0218] step 1: 5-(3-methoxyazetidin-1-yl)-2-nitropyridine

[0219]

[0220] A mixture of 5-fluoro-2-nitropyridine (1 g, 7.0 mmol), 3-azetidine hydrochloride (1.13 g, 9.1 mmol) and DIEA (2.73 g, 21.2 mmol) in dioxane (10 mL) was stirred at 100 ° C for 3 hours. The mixture was concentrated, and the residue was redissolved in EA (20 mL). The organic phase was washed with saturated NH4Cl (20 mL x 2) and brine (10 mL), dried over Na2SO4, filtered and concentrated to obtain the product (1 g, 68.3%) as a yellow solid. 1 H NMR(DMSO-d6)δ8.15(d,J=9.0Hz,1H),7.71(d,J=2.8Hz,1H),6.94(d,J=9.0,3. 0Hz,1H),4.36-4.43(m,1H),4.26-4.34(m,2H),3.90-3.97(m,2H),3.25(s,3H).

[0221] step 2: 5-(3-methoxyazetidin-1-yl)pyridin-2-amine

[0222]

[0223] Under H2(15Psi) atmosphere, a mixture of 5-(3-methoxyazetidine-1-yl)-2-nitropyridine (500mg, 2.39mmol) and Raney Ni (Raney Ni) (wet, 500mg) in THF (20mL) was stirred at 25°C for 3 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated to obtain a product (500mg, crude product) as a brown solid. It was used directly in the next step without further purification.

[0224] step 3: N-([5-(3-methoxyazetidin-1-yl)pyridin-2-yl]thiocarbamoyl)amino Ethyl acetate

[0225]

[0226] A mixture of 5-(3-methoxyazetidin-1-yl)pyridin-2-amine (500 mg, 2.79 mmol) and ethyl O-isothiocyanate (549 mg, 4.19 mmol) in dioxane (10 mL) was stirred at 25° C. for 3 hours. The solvent was removed to give the product as a brown solid (1 g, crude product). It was used directly in the next step without further purification.

[0227] step 4: 6-(3-methoxyazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

[0228]

[0229] By N-([5-(3-methoxyazetidine-1-yl)pyridin-2-yl]thiocarbamoyl)-carbamic acid ethyl ester (1g, 2.7mmol), NH2OH.HCl (562.8mg, 8.1mmol) and DIEA (1.05g, 8.1mmol) in MeOH (5mL) / EtOH (5mL) mixture was stirred at 60°C for 10 hours. The mixture was concentrated, and the residue was redissolved with EA (20mL). The organic layer was washed with saturated NH4Cl (20mL x 2) and brine (10mL), dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE:EA=2:1) ​​to obtain the product (300mg, 50.6%) as a yellow solid. 1 H NMR(DMSO-d6)δ7.72(d,J=2.0Hz,1H),7.23(d,J=9.2Hz,1H),6.87(d,J=9.3,2.2Hz,1H),5.63 -5.73(m,2H),4.26-4.33(m,1H),3.98-4.07(m,2H),3.56(d,J=8.3,4.5Hz,2H),3.21(s,3H). MS(ESI)m / e[M+1] + 220.2.

[0230] Step 5: 6-chloro-4-((6-(3-methoxyazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine- 2-amino)-N-methylpyridazine-3-carboxamide

[0231]

[0232] Under nitrogen atmosphere, 4,6-dichloro-N-methylpyridazine-3-carboxamide (1.88 g, 9.12 mmol) was added to a solution of 6-(3-methoxyazetidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine (1.0 g, 4.56 mmol) in THF (30 mL) at 25 ° C. The resulting mixture was heated until 70 ° C., and KHMDS (18.2 mL, 1.0 M) was added thereto at one time. Under nitrogen atmosphere, the resulting mixture was stirred at this temperature for 1 hour. After cooling to room temperature, the mixture was poured into water (500 mL) and extracted with EA (300 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (PE:EA=1:1) to give the product as a light yellow solid (2.1 g, 20%). 1H NMR (CDCl3) δ: 11.89 (s, 1H), 8.76 (s, 1H), 8.2 (d, J = 4.4Hz, 1H), 7.58 (s, 1H), 7.40 (d, J = 9.2Hz, 1H), 6.87 (t,J=5.8Hz,1H),4.31-4.34(m,1H),4.09(t,J=6.8Hz,2H),3.66-3.69(m,2H),3.29(s,3H),3.00(s,3H). MS(ESI)m / e[M+1] + 389.1.

[0233] Step 6: 6-(Cyclopropanecarboxamido)-4-((6-(3-methoxyazetidin-1-yl)-[1,2,4]triazole (1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0234]

[0235] In a sealed tube, cyclopropanecarboxamide (438 mg, 5.14 mmol), dimethylxanthene (149 mg, 257 umol), Pd2(dba)3 (235 mg, 257 umol) and Cs2CO3 (1.68 g, 5.14 mmol) were added to a solution of 6-chloro-4-((6-(3-methoxyazetidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (500 mg, 1.29 mmol) in DMA (5 mL). The reaction mixture was heated until 120 ° C and stirred at this temperature for 15 hours under a nitrogen atmosphere. After cooling to room temperature, the solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX; phases: A-H2O (10 mM NH4HCO3); B-acetonitrile, B%: 13%-43% in 20 min) to give the product as a light yellow solid (290 mg, 12%). 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),11.38(s,1H),9.37-9.24(m,2H),7.92(d,J=1.9Hz,1H),7.58(d,J=9.3Hz,1H),7.12(d,J=9.4Hz,1 H), 4.33 (d, J = 6.2Hz, 1H), 4.14-4.09 (m, 2H), 3.68 (d, J = 8.3Hz, 2H), 3.25 (s, 3H), 2.87 (d, J = 4.8Hz, 3H), 2.14 (s, 1H), 0.93-0.86 (m, 4H). MS(ESI)m / e[M+1] + =437.9.

[0236] The following compounds 13-15, 17, 19-25, 29-31, 33, 35, 54-55 were synthesized according to a similar procedure as described for compound 11 starting from the corresponding starting materials.

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] Example F

[0245] Example F1: Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-4-((6-(3-(N-methylmethylsulfonylamino)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 16)

[0246]

[0247] Step 1: tert-Butyl 3-(N-methylmethylsulfonylamino)azetidine-1-carboxylate

[0248]

[0249] To 3-(methylamino)azetidine-1-carboxylic acid tert-butyl ester (930mg, 5mmol) and KCO (1380mg, 10mmol) in CHCN (20mL) mixture, add methanesulfonyl chloride (575mg, 5mmol), and the resulting mixture is stirred at room temperature for 4 hours. After the reaction is complete, the solid is removed by filtration, and the filtrate is concentrated in vacuo to give a crude product as a white solid. It is used directly in the next step without further purification. MS (ESI) m / e [M+1] + =208.9.

[0250] Step 2: N-(azetidin-3-yl)-N-methylmethanesulfonamide

[0251]

[0252] To a solution of tert-butyl 3-(N-methylsulfonylamino)azetidine-1-formate (2.3 g, 8.5 mmol) in DCM (40 mL) was added TFA (4 mL), and the resulting solution was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was removed in vacuo, and the residue was dissolved in DCM (50 mL), then K2CO3 (1 g) was added, and the resulting slurry was stirred at room temperature for 30 minutes, filtered and concentrated to give a product as a yellow oil. (1.18 g, crude product). MS (ESI) m / e [M+1] + =164.9.

[0253] Step 3: N-(1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)azetidin-3-yl)-N- Methyl sulfonamide

[0254]

[0255] The desired compound was prepared from 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine and N-(azetidin-3-yl)-N-methylmethylsulfonamide according to a procedure similar to compound 1, step 2, to give the product as a yellow solid (yield: 193 mg, 71.4%). MS (ESI) m / e [M+1] + =296.9.

[0256] Step 4: 6-chloro-N-methyl-4-((6-(3-(N-methylmethylsulfonylamino)azetidin-1-yl)-[1,2, 4]Triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide

[0257]

[0258] The desired compound was prepared from N-(1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)azetidin-3-yl)-N-methylmethylsulfonamide and 4,6-dichloro-N-methylpyridazine-3-carboxamide according to a procedure similar to that of compound 7, step 3, to give the product as a yellow solid (15 mg, 13.1%). MS (ESI) m / e [M+1] + =465.8.

[0259] Step 5: 6-(cyclopropanecarboxamido)-4-((6-(3-(N-ethylmethylsulfonylamino)azetidine-1-yl)- 1-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (Compound 16 )

[0260]

[0261] The desired compound was prepared from 6-chloro-N-methyl-4-((6-(3-(N-methylmethylsulfonylamino)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide according to a procedure similar to compound 1, step 2, to give the product (yield: 3 mg, 6.8%). MS (ESI) m / e [M+1] + =514.9.

[0262] Example G

[0263] Example G1: Synthesis of 6-(cyclopropanecarboxamido)-4-((6-(3-(1-hydroxyethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (Compound 26)

[0264]

[0265] Step 1: 4-((6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)azetidin-1-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

[0266]

[0267] At room temperature, to 6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)azetidine-1-yl)-[1,2,4]triazol [1,5-a]pyridine-2-amine (173mg, 0.5mmol) and 4,6-dichloro-N-methylpyridazine-3-carboxamide (205mg, 1mmol) in 5mL THF solution, add KHMDS (2mL, 1M in THF), the resulting solution is stirred at room temperature for 2 hours. After the reaction is complete, the solution is poured into 30mL water, and the resulting mixture is extracted with DCM (10mL x 3). The combined organic layer is washed with 50mL water, dried over Na2SO4, and concentrated in vacuo. The crude product is washed with 10mL MeOH to give the product (100mg, 39%) as a brown solid.

[0268] Step 2: 4-((6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)azetidin-1-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide

[0269]

[0270] The desired compound was prepared from 4-((6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide according to a procedure similar to compound 1, step 2, to give the product as a white solid (40 mg, 75%). MS (ESI) m / e [M+1] + =565.9.

[0271] Step 3: 6-(Cyclopropanecarboxamido)-4-((6-(3-(1-hydroxyethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0272]

[0273] To a solution of 4-((6-(3-(1-((tert-butyldimethylsilyl)oxy)ethyl)azetidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (30 mg, 0.05 mmol) in 3 mL of THF was added 1 mL of tetrabutylammonium fluoride, and the resulting solution was stirred at room temperature for 24 hours. After the reaction was complete, the solvent was removed in vacuo, and the residue was purified by preparative TLC (MeOH:DCM=1:7) to give the product as a white solid (10 mg, 44%). MS (ESI) m / e[M+1] + =451.9. 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),11.37(s,1H),9.39-9.24(m,2H),7.85(s,1 H),7.56(d,J=9.4Hz,1H),7.09(d,J=9.4Hz,1H),4.73(d,J=4.9Hz,1H),3.92-3.8 4(m,2H),3.74(dd,J=19.7,6.1Hz,2H),3.58(s,1H),2.86(d,J=4.7Hz,3H),2.69- 2.61 (m, 1H), 2.14 (d, J = 4.6 Hz, 1H), 1.04 (d, J = 6.1 Hz, 3H), 0.90 (d, J = 9.9 Hz, 4H).

[0274] Example H

[0275] Example H1: Synthesis of 6-(cyclopropanecarboxamido)-4-((6-(3-hydroxyazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (Compound 27)

[0276]

[0277] Step 1: 1-(6-nitropyridin-3-yl)azetidin-3-ol

[0278]

[0279] By 5- bromo-2-nitropyridine (5g, 24.6mmol), azetidine-3-ol hydrochloride (4g, 39.9mmol) and K2CO3 (5g, 36.9mmol) in DMSO (100mL) mixture was stirred at 100 ℃ for 4 hours.After the reaction is complete, the mixture is poured into H2O (400mL), and the resulting solution is extracted with EA (50mL x 3).The combined organic layer is dried over Na2SO4, filtered and concentrated to give a residue, which is purified by silica gel column chromatography (petroleum ether / EA=50:1 to 1:1) to give the product (2.3g, 25.8%) as a yellow solid.

[0280] Step 2: 5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-nitropyridine

[0281]

[0282] To a solution of 1-(6-nitropyridine-3-yl)azetidine-3-ol (2.3 g, 11.8 mmol) and imidazole (3.21 g, 47.1 mmol) in DMF (20 mL), TBSCl (3.55 g, 23.6 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, H2O (30 mL) was added, and the resulting mixture was extracted with EA (50 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether / EA=50:1 to 3:1) to give a product (2.8 g, 76.8%) as a yellow solid.

[0283] Step 3: 5-(3-((tert-Butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-2-amine

[0284]

[0285] To a solution of 5-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-yl)-2-nitro-pyridine (2.8 g, 9.1 mmol) in THF (300 mL), Raney nickel (1 g, wet) was added, and the suspension was degassed under vacuum and purged several times with H. The mixture was stirred at room temperature for 4 hours under an atmosphere of H (15 psi). After the reaction was complete, the catalyst was filtered out, and the filtrate was concentrated to give a product (2.5 g, crude product) as a yellow solid, which was used in the next step without further purification.

[0286] Step 4: N-[(5-(3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl)pyridin-2-yl) [thiocarbamoyl]ethyl carbamate

[0287]

[0288] A solution of 5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyridin-2-amine (2.5 g, crude) and ethyl O-carboisothiocyanate (1.4 g, 10.7 mmol) in dioxane (50 mL) was stirred at 60° C. for 12 hours. After cooling to room temperature, the solution was removed in vacuo to give the product as a red oil (3.67 g, crude).

[0289] Step 5: 6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-[1,2,4]triazol [1,5-a]pyridin-2-amine

[0290]

[0291] The desired compound was prepared from ethyl N-[(5-(3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl)pyridin-2-yl)carbamothioyl]carbamate according to a procedure similar to step 4 of compound 11 to give the product as an off-white solid (1.5 g, 52.4% yield). 1 H NMR(400MHz,DMSO-d6)δppm 0.07(s,6H),0.87(s,9H)3.46(d,J=7.63,5.25Hz,2H)4.10(t,J=7.07Hz,2H)4.73(q,J =5.57Hz, 1H), 5.68 (s, 2H) 6.87 (dd, J = 9.32Hz, 1H) 7.21 (d, J = 9.26Hz, 1H) 7.73 (s, 1H). MS(ESI)m / e[M+1] + =320.2.

[0292] Step 6: 4-((6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-[1,2,4]triazine oxazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

[0293]

[0294] The desired compound was prepared from 4,6-dichloro-N-methylpyridazine-3-carboxamide and 6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine according to a procedure similar to compound 1, step 1, to give the product as an off-white solid (50 mg, 32%). MS (ESI) m / e [M+1] + =488.9.

[0295] Step 7: 6-(Cyclopropanecarboxamido)-4-((6-(3-hydroxyazetidin-1-yl)-[1,2,4]triazolo [1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide

[0296]

[0297] The desired compound was prepared from 4-((6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide according to a procedure similar to compound 1, step 2 to give the product (6 mg, 13.8%). 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),11.37(s,1H),9.34(s,1H),9.29(m,1H),7.91(d,J=1.9Hz,1H),7.56(d,J=9.4Hz,1H),7.11(dd,J=9.5,2.0Hz ,1H),5.68(d,J=6.5Hz,1H),4.58(m,1H),4.13(t,J=7.1Hz,2H),3.56(dd, J=7.6,5.2Hz,2H),2.87(d,J=4.7Hz,3H),2.14(m,1H),1.01-0.81(m,4H). MS(ESI)m / e[M+1] + =424.4.

[0298] Example J

[0299] Example J1: Synthesis of 6-(cyclopropanecarboxamido)-4-((6-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (Compound 32)

[0300]

[0301] Step 1: (3-Fluoro-1-(6-nitropyridin-3-yl)azetidin-3-yl)methanol

[0302]

[0303] At room temperature, DIEA (2.48 g, 19.2 mmol) and 5-fluoro-2-nitropyridine (682 mg, 19.2 mmol) were added to a solution of (3-fluoroazetidine-3-yl)methanol hydrochloride (680 mg, 4.8 mmol) in 1,4-dioxane (5 mL). Under N2, the resulting mixture was stirred at 80 ° C for 15 hours. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether: EA = 1: 1) to give a product as a yellow solid (700 mg, 64% yield). 1 H NMR (DMSO-d6) δ 8.17-8.19 (d, J = 8Hz, 1H) 7.79-7.80 (d, J = 4Hz, 1H) 7.03-7.06 (m, 1H) 5.37-5.40 (t, J = 12Hz, 1H) 4.16-4.27 (m, 4H) 3.33-3.78 (m, 2H).

[0304] Step 2: 5-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidin-1-yl)-2- Nitropyridine

[0305]

[0306] The desired compound was prepared from (3-fluoro-1-(6-nitropyridin-3-yl)azetidin-3-yl)methanol according to a procedure similar to compound 27 step 2 to give the product as a yellow solid (750 mg, 71.3%). 1 HNMR(CDCl3)δ8.15-8.17(d,J=8Hz,1H),7.68-7.69(d,J=2.8Hz,1H),6.76-6. 79(m,1H),4.14-4.26(m,4H),3.87-3.91(m,4H),0.855(s,9H),0.088(s,6H).

[0307] Step 3: 5-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidin-1-yl)pyrrolidone Pyridin-2-amine

[0308]

[0309] The desired compound was prepared from 5-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidin-1-yl)-2-nitropyridine according to a procedure similar to that of compound 27, step 3, to give the product as a grey solid (600 mg, crude), which was used in the next step without further purification.

[0310] Step 4: N-([5-(3-([(tert-butyldimethylsilyl)oxy]methyl)-3-fluoroazetidine-1-yl)- [(2-[( ...

[0311]

[0312] The desired compound was prepared from 5-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidin-1-yl)pyridin-2-amine according to a procedure similar to compound 6 in Example B1, Step 1, to give the product as a brown solid (800 mg, crude), which was used in the next step without further purification.

[0313] Step 5: 6-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidin-1-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-amine

[0314]

[0315] To a solution of ethyl N-([5-(3-([(tert-butyldimethylsilyl)oxy]methyl)-3-fluoro-azetidin-1-yl)pyridin-2-yl]carbamothioyl)carbamate (800 mg, 2.28 mmol) in MeOH / EtOH (v:v=1:1, 8 mL) was added DIEA (882 mg, 6.83 mmol) and NH2OH HCl (790 mg, 11.38 mmol) at room temperature. The resulting mixture was stirred at 80°C for 15 hours under N2 atmosphere. After cooling to room temperature, water (5 mL) was added, and the resulting solution was extracted with DCM / MeOH (v:v=3:1, 16 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EA:THF=1:1) to give the product as a light red solid (360 mg, 66.7%). 1 H NMR(DMSO-d6)δ7.77(s,1H),7.15-7.17(d,J=9.2Hz,1H),6.85-6.87(m,1H),5 .64(s,2H),3.82-3.92(m,4H),3.71-3.78(m,2H),0.783(s,9H),0.00(s,6H). MS(ESI)m / e[M+1] + =352.2.

[0316] Step 6: 4-((6-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidine-1- 1-(2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide

[0317]

[0318] The desired compound was prepared from 4,6-dichloro-N-methylpyridazine-3-carboxamide and 6-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine according to a procedure similar to that of compound 7, step 3, to give the product as a yellow solid (56 mg, 37%). MS (ESI) m / e [M+1] + =520.8.

[0319] Step 7: 4-((6-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidine-1- 1-(4-(4-(2-(4-nitro-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxylic acid amine

[0320]

[0321] The desired compound was prepared from 4-((6-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide and cyclopropanecarboxamide according to a procedure similar to compound 1, step 2 to give the product as a yellow solid (47 mg, 74%). 1 HNMR(DMSO-d6)δ12.01(s,1H),11.38(s,1H),9.42-9.24(m,2H),8.07(s,1H),7.59(d,J=9.4Hz,1H),7.19 (d,J=7.7Hz,1H),4.08-3.90(m,6H),2.87(d,J=4.6Hz,3H),2.14(s,1H),1.23(s,6H),0.9-0.84(m,13H). MS(ESI)m / e[M+1] + =570.6.

[0322] Step 8: 6-(Cyclopropanecarboxamido)-4-((6-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)-[1, 2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpyridazine-3-carboxamide (Compound 32)

[0323]

[0324] To a solution of 4-((6-(3-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoroazetidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (47 mg, 0.082 mmol) in DCM (200 mL) was added TBAF (2 mL, 1 mol / L), and the resulting solution was stirred at room temperature overnight. After the reaction was complete, the solvent was removed in vacuo, and the residue was purified by preparative TLC (MeOH:DCM=1:20) to give the desired product (5 mg, 13%). 1 H NMR(DMSO-d6)δ12.01(s,1H),11.37(s,1H),9.38-9.21(m,2H),8.04(s,1H),7.60(d,J=9.4Hz,1H),7.18(dd,J=9.4,1.7Hz,1H) ,4.09-4.02(m,2H),3.95-.3.88(m,2H),3.76(s,1H),3.70(s,1H),2.87(d,J=4.6Hz,3H),2.17-2.11(m,1H),0.96-0.82(m,4H).

[0325]

[0326] Example K

[0327] Example K1: Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-4-((6-(2-oxo-4-phenylazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 38)

[0328]

[0329] Step 1: 4-((6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-yl Formamide

[0330]

[0331] existAt room temperature, to a solution of 4,6-dichloro-N-methylpyridazine-3-carboxamide (1.16 g, 5.6 mmol) and 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (1 g, 4.7 mmol) in THF (20 mL) was added LiHMDS (1 M in THF, 11.75 mL, 11.75 mmol), and the resulting mixture was stirred at this temperature for 1 hour. After the reaction was complete, water was added, and the resulting solution was extracted with EA (10 mL x 3). The combined organic layers were concentrated in vacuo, and the residue was recrystallized in MeOH to give the product as a white solid (820 mg, 45.6%). MS (ESI) m / e [M+1] + =381.8.

[0332] Step 2: 6-Chloro-N-methyl-4-((6-(2-oxo-4-phenylazetidin-1-yl)-[1,2,4]triazol [1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide

[0333]

[0334] Under N2 atmosphere, a mixture of 4-((6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (380 mg, 1 mmol), 4-phenylazetidine-2-one (294 mg, 2 mmol), Pd2(dba)3 (274.5 mg, 0.3 mmol), dimethylxanthene (346.8 mg, 0.6 mmol) and Cs2CO3 (652 mg, 2 mmol) in dioxane (10 mL) was stirred at 100 ° C for 2 hours. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH=15:1) to give the desired product (270 mg, 60% purity) as a brown solid. MS (ESI) m / e[M+1] + =448.9.

[0335] Step 3: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-(2-oxo-4-phenylazetidin-1-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 38)

[0336]

[0337] Under N2 atmosphere, a mixture of 6-chloro-N-methyl-4-((6-(2-oxo-4-phenylazetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (200 mg, 0.45 mmol), cyclopropanecarboxamide (189.4 mg, 2.23 mmol), Pd2(dba)3 (128.1 mg, 0.14 mmol), dimethylxanthene (161.8 mg, 0.28 mmol) and Cs2CO3 (368.4 mg, 1.13 mmol) in dioxane (7 mL) was stirred at 140°C for 4 hours. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC (DCM:MeOH=10:1) to give the desired product (17.57 mg, 7.85%). 1 H NMR (400MHz, DMSO-d6) δ12.12(s,1H),11.41(s,1H),9.37(s,1H),9.32(d,J=4. 7Hz,1H),8.64(s,1H),7.67(d,J=18.1Hz,2H),7.52(d,J=7.3Hz,2H),7.46-7.2 6(m,3H),5.40(d,J=3.0Hz,1H),3.70(d,J=15.3,5.6Hz,1H),3.05(s,2H),2.86 (d,J=4.6Hz,3H),2.14(d,J=4.7Hz,1H),0.99-0.80(m,4H)..MS(ESI)m / e[M+1] + =498.5.

[0338] Example L

[0339] Example L1: Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-4-((6-(1-(methylsulfonyl)azetidin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 39)

[0340]

[0341] Step 1: tert-Butyl 3-(6-aminopyridin-3-yl)azetidine-1-carboxylate

[0342]

[0343] By 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyridine-2-amine (7g, 31.80mmol), 3-iodoazetidine-1-tert-butyl formate (7.21g, 25.40mmol), Pd(PPh3)4(1.83g, 1.54mmol), K3PO4(13.3g, 63.56mmol) in DMF (105mL) and H2O (7mL) mixture was stirred at 60 DEG C for 12 hours.After cooling to room temperature, the mixture was poured into H2O (200mL), and the resulting solution was extracted with EA (50mL x 2).The combined organic layer was washed with brine, through Na2SO4, dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:EA=5:1-1:2) to give the product (4.5 g, 71%) as a yellow solid.

[0344] Step 2: tert-Butyl 3-(6-(3-(ethoxycarbonyl)thioureido)pyridin-3-yl)azetidine-1-carboxylate

[0345]

[0346] The desired compound was prepared from tert-butyl 3-(6-aminopyridin-3-yl)azetidine-1-carboxylate according to a procedure similar to compound 6, step 1, to give the product as a brown solid (6.9 g, crude).

[0347] Step 3: tert-Butyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)azetidine-1-carboxylate

[0348]

[0349] The desired compound was prepared from tert-butyl 3-(6-(3-(ethoxycarbonyl)thioureido)pyridin-3-yl)azetidine-1-carboxylate according to a procedure similar to step 4 of compound 11 to give the product as a white solid (4.2 g, 14.5 mmol, 80%). 1 H NMR (DMSO-d6) δ 8.52 (s, 1H), 7.48 (d, J = 9.01Hz, 1H), 7.36 (d, J = 9.38Hz, 1H) 5.94 (s, 2H) 4.23 (t, J = 6.94Hz, 2H) 3.80-3.93 (m, 3H) 1.41 (s, 9H). MS(ESI)m / e[M+1] + =290.2.

[0350] Step 3: 3-(2-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo[1, tert-Butyl 5-a]pyridin-6-yl)azetidine-1-carboxylate

[0351]

[0352] The desired compound was prepared from tert-butyl 3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)azetidine-1-carboxylate and 2,4-dichloro-N-methylbenzamide according to a procedure similar to compound 7, step 3, to give the product as a yellow solid (260 mg, 26%). MS (ESI) m / e [M+H] + =459.

[0353] Step 4: 3-(2-((6-(cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1, tert-Butyl 2,4-triazolo[1,5-a]pyridin-6-yl)azetidine-1-carboxylate

[0354]

[0355] The desired compound was prepared from tert-butyl 3-(2-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)azetidine-1-carboxylate according to a procedure similar to Example A1, Compound 1, Step 2 to give the product as a yellow solid (110 mg, 42%). 1 H NMR(400MHz,DMSO-d6)12.12(s,1H),11.41(s,1H),9.41(s,1H),9.33(d,1H),8.82(s,1H),7.71-7.77(m,2 H),4.26-4.27(m,2H),3.95-3.96(m,3H),2.87(d,3H),2.15-2.16(m,1H),1.42(s,9H),0.89-0.91(m,4H). MS(ESI)m / e[M+H] + =508.

[0356] Step 5: 4-((6-(azetidin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6- (Cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide Hydrochloride

[0357]

[0358] To a solution of tert-butyl 3-(2-((6-(cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)azetidine-1-carboxylate (14 mg, 0.02 mmol) in DCM (2 mL) was added TFA (0.2 mL) and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed in vacuo and the residue was lyophilized with a few drops of 0.5 M HCl to give the product as a yellow semisolid (12 mg, 99%). 1H NMR(400MHz,DMSO-d6)12.17(s,1H),11.45(s,1H),8.95-9.40(m,5H),7.77-7.86(m,2H) ,4.18-4.27(m,5H),2.87(d,3H),2.14-2.17(m,1H),0.89-0.91(m,4H).MS(ESI)m / e[M+H] + =408.

[0359] Step 6: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-(1-(methylsulfonyl)azetidin-3-yl)- [1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 39)

[0360]

[0361] The desired compound was prepared from 4-((6-(azetidin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide hydrochloride according to a procedure similar to step 5 of compound 7 to give the product (2.22 mg, 31%). 1 H NMR(400MHz,DMSO-d6)12.15(s,1H),11.43(s,1H),9.40(s,1H),9.33(d,1H),8.85(s,1H),7.74-7.80(m,2 H),4.23-4.24(m,2H),4.40-4.45(m,3H),3.11(s,3H),2.87(d,3H),2.15-2.16(m,1H),0.89-0.92(m,4H). MS(ESI)m / e[M+H] + =486.

[0362] The following compounds 42-43, 48-50 were synthesized according to a similar procedure as described for compound 39 starting from the corresponding starting materials.

[0363]

[0364]

[0365]

[0366] Example M

[0367] Example M1: Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-4-((6-(1-methylazetidin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 41)

[0368]

[0369] To a solution of 4-((6-(azetidine-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (200 mg, 0.49 mmol) in MeOH (200 mL) was added formaldehyde (500 mg, 4.9 mmol) and NaBH(OAc)3 (1.04 g, 4.9 mmol) in water. The resulting mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was removed in vacuo, and the residue was purified by reverse phase C18 column chromatography (ACN / H2O=20%-60%) to give the product (70 mg, 34%). 1 H NMR(400MHz, DMSO-d6)12.15(s,1H),11.43(s,1H),9.40(s,1H),9.34(d,J=4.4Hz,1H),8.88(s,1H),7.83(d,J=9.1Hz,1H),7.73( d,J=9.3Hz,1H),4.02-4.05(m,3H),3.80-3.81(m,2H),2.87(d,J=4.6Hz,3H),2.64(s,3H),2.16-2.17(m,1H),0.89-0.91(m,4H). MS(ESI)m / e[M+H] + =422.

[0370] Example N

[0371] Example N1: Synthesis of 4-((6-(azetidin-1-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (Compound 44)

[0372]

[0373] step 1: tert-butyl (5-bromo-3-methoxypyridin-2-yl)(tert-butoxycarbonyl)carbamate

[0374]

[0375] To 5-bromo-3-methoxypyridine-2-amine (3.57g, 17.7mmol), di-tert-butyl carbonate (7.7g, 35.4mmol) and TEA (3575mg, 35.4mmol) in 30mL DMF solution, add DMAP (2116mg, 17.7mmol), and the resulting solution is stirred at room temperature for 48 hours. After the reaction is complete, the solvent is removed in a vacuum, and the residue is purified by silica gel column chromatography (petroleum ether: EA=1:1) to give the product (5g, 70%) as a colorless oil. MS (ESI) m / e[M+1] + =402.8.

[0376] step 2: (5-(azetidin-1-yl)-3-methoxypyridin-2-yl)(tert-butoxycarbonyl)carbamic acid tert- Butyl Ester

[0377]

[0378] The desired compound was prepared from tert-butyl (5-bromo-3-methoxypyridin-2-yl)(tert-butoxycarbonyl)carbamate according to a procedure similar to compound 38, step 2, to give the product as a brown solid (500 mg, 52%). MS (ESI) m / e [M+1] + =379.9.

[0379] Step 3: 5-(azetidin-1-yl)-3-methoxypyridin-2-amine

[0380]

[0381] A solution of tert-butyl (5-(azetidin-1-yl)-3-methoxypyridin-2-yl)(tert-butoxycarbonyl)carbamate (500 mg, 1.32 mmol) in 6 mL of DCM / TFA (v:v=3:1) was stirred at room temperature overnight. After the reaction was complete, the solvent was removed in vacuo to give the product 500 mg (crude product) as a brown oil. MS (ESI) m / e [M+1] + =180.

[0382] Step 4: N-([5-(azetidin-1-yl)pyridin-2-yl]-2-methoxy-thiocarbamoyl)amino Ethyl formate

[0383]

[0384] The desired compound was prepared from 5-(azetidin-1-yl)-3-methoxypyridin-2-amine according to a procedure similar to compound 2, step 1, to give the product as a brown solid (310 mg, 100%). MS (ESI) m / e [M+1] + =310.9.

[0385] Step 5: 6-(azetidin-1-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine

[0386]

[0387] The desired compound was prepared from ethyl N-([5-(azetidin-1-yl)pyridin-2-yl]-2-methoxy-carbamothioyl)carbamate according to a procedure similar to step 4 of compound 11 to give the product as a white solid (75 mg, 91%).

[0388] Step 6: 4-((6-(azetidin-1-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl) (amino)-6-chloro-N-methylpyridazine-3-carboxamide

[0389]

[0390] The desired compound was prepared from 6-(azetidin-1-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine according to a procedure similar to compound 1, step 1, to give the product as a brown solid (75 mg, 60%). MS (ESI) m / e [M+1] + =388.9.

[0391] Step 7: 4-((6-(azetidin-1-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl) Amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide

[0392]

[0393] The desired compound was prepared from 4-((6-(azetidin-1-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide according to a procedure similar to compound 1, step 2 to give the product as a white solid (2 mg, 2.5%). 1 H NMR(400MHz,DMSO-d6)δ11.95(s,1H),11.36(s,1H),9.34-9.15(m,2H),7.45(s,1H),6.51(s,1H),3.99(s ,3H),3.86(t,J=7.1Hz,4H),2.86(d,J=4.6Hz,3H),2.35-2.30(m,2H),2.14(s,1H),0.88(d,J=8.0Hz,4H). MS(ESI)m / e[M+1] + =437.9.

[0394] The following compounds 45 and 46 were synthesized according to a similar procedure as described for compound 11 starting from the corresponding starting materials.

[0395]

[0396]

[0397] Example O

[0398] Example O1: Synthesis of 4-((6-(azetidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (Compound 48)

[0399]

[0400] Step 1: 2-Amino-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid

[0401]

[0402] To a solution of 2-amino-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester (2g, 10.4mmol) in MeOH / THF (10mL / 10mL) was added LiOH H2O (1.3g, 31.3mmol) in H2O (10mL). The resulting mixture was stirred at rt for 12 hours. After the reaction was complete, the organic solvent was removed in vacuo, and the remaining aqueous solution was acidified with 1N HCl to adjust pH=3. The precipitated solid was collected by filtration, and the filter cake was washed with water (5mL), dried in air to give the product as a light yellow solid (700mg, yield 37.8%). 1 H NMR (DMSO-d6) δ13.23 (s, 1H), 8.96 (s, 1H), 7.83 (dd, J = 9.3Hz, 1.4Hz, 1H), 7.39 (d, J = 9.1Hz, 1H), 6.34 (s, 2H). MS(ESI)m / e[M+1] + =179.3.

[0403] Step 2: (2-Amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)(azetidin-1-yl)methanone.

[0404]

[0405] HATU (768 mg, 2.0 mmol) was added to a solution of 2-amino-[1,2,4]triazol[1,5-a]pyridine-6-carboxylic acid (300 mg, 1.7 mmol) and TEA (511 mg, 5.1 mmol) in DCM (5 mL) and DMF (15 mL). The resulting mixture was stirred at rt for 30 minutes. Azetidine hydrochloride (189 mg, 2.0 mmol) was then added, and the mixture was stirred at room temperature for another 12 hours. After the reaction was complete, the precipitated solid was collected by filtration, and the filter cake was washed with DCM (10 mL), dried in air to give a product as an off-white solid (220 mg, 60.1% yield). 1 H NMR(DMSO-d6)δ8.76(s,1H),7.63(d,J=9.1Hz,1H),7.37(d,J=9.0Hz,1H),6.21(s,2H),4.41(s,2H),4.06(s,2H),2.34-2.21(m,2H). MS(ESI)m / e[M+1] + =218.3.

[0406] Step 3: 4-((6-(azetidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)- 6-Chloro-N-methylpyridazine-3-carboxamide

[0407]

[0408] To a suspension of 4,6-dichloro-N-methylpyridazine-3-carboxamide (100 mg, 0.49 mmol) and (2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)(azetidin-1-yl)methanone (100 mg, 0.46 mmol) in THF (100 mL) was added NaHMDS (2 mL, 2 mmol, 1 M in THF) at 70 °C, and the mixture was stirred at this temperature for 5 minutes. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by combi-flash (MeOH / DCM=0%-10%) to give the product as a brown solid (100 mg, 53% yield). MS (ESI) m / e[M+1] + =386.9.

[0409] Step 4: 4-((6-(azetidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)- 6-(Cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide (Compound 48)

[0410]

[0411] The desired compound was prepared from 4-((6-(azetidine-1-carbonyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-chloro-N-methylpyridazine-3-carboxamide according to a procedure similar to compound 6, step 2, to give the product (3 mg, 5.3%). 1 H NMR (400MHz, DMSO-d6) δ12.24(s,1H),11.45(s,1H),9.43(s,1H),9.36(m,1H),9.01(s,1H),7.86(d,J=9.3Hz,1H),7.74(d ,J=9.3Hz,1H),4.45(s,2H),4.09(s,2H),2.88(d,J=4.8Hz,3H),2.35-2.23(m,2H),2.18-2.12(m,1H),0.97-0.85(m,4H). MS(ESI)m / e[M+1] + =435.9.

[0412] Example P

[0413] Example P1: Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-4-((6-(4-(1-methylazetidin-3-yl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 55)

[0414]

[0415] Step 1: tert-Butyl 3-(pyridin-4-yl)azetidine-1-carboxylate

[0416]

[0417] By pyridine-4-ylboronic acid (1g, 8.13mmol), 3-iodoazetidine-1-carboxylic acid tert-butyl ester (1.84g, 6.50mmol), Pd(PPh3)4(469.7mg, 406.50umol) and K3PO4(3.4g, 16.20mmol) in DMF (15mL) and H2O (1mL) mixture was stirred at 60 DEG C for 12 hours.After cooling to room temperature, H2O (50mL) was added, and the resulting solution was extracted with EA (30mL x 3).The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated.The residue was purified by silica gel column chromatography (petroleum ether: EA=20:1 to 1:1), to obtain the product (240mg, 12% yield) as brown oil. 1H NMR (CDCl3) δ8.59 (d, J = 5.04Hz, 2H), 7.25 (d, J = 6.00Hz, 2H), 4.36 (t, J = 8.69Hz, 2H), 3.71 (t, J = 8.61Hz, 1H), 1.47 (s, 9H).

[0418] Step 2: tert-Butyl 3-(piperidin-4-yl)azetidine-1-carboxylate

[0419]

[0420] Under H2(30Psi) atmosphere, by 3-(pyridine-4-yl)azetidine-1-t-butyl formates (570mg, 2.43mmol) and PtO2(300mg) in AcOH(10mL) and MeOH(10mL) mixture is stirred at room temperature for 12 hours.After the reaction is completed, catalyst is removed by filtration, and filtrate is concentrated in a vacuum to give the product (500mg, crude product) of brown oil. It is directly used in the next step without further purification.

[0421] Step 3: tert-Butyl 3-(1-(6-nitropyridin-3-yl)piperidin-4-yl)azetidine-1-carboxylate

[0422]

[0423] The mixture of 5-fluoro-2-nitropyridine (300mg, 2.08mmol), 3-(piperidin-4-yl)azetidine-1-formic acid tert-butyl ester (500mg, 2.12mmol) and DIEA (1.6g, 12.48mmol) in dioxane (30mL) was stirred at 100 DEG C for 12 hours. After cooling to room temperature, the solution was removed in a vacuum, and the residue was redissolved with H2O (30mL). The resulting solution was extracted with EA (20mL x 3), and the combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: EA=1:1) to obtain the product (410mg, 1.13mmol, 54% yield) as a yellow solid.

[0424] Step 4: tert-Butyl 3-(1-(6-aminopyridin-3-yl)piperidin-4-yl)azetidine-1-carboxylate

[0425]

[0426] Under H2 (15Psi) atmosphere, a mixture of tert-butyl 3-(1-(6-nitropyridine-3-yl)piperidin-4-yl)azetidine-1-formate (410mg, 1.13mmol) and Pd / C (10%, 200mg) in THF (10mL) was stirred at room temperature for 3 hours. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give a product (450mg, crude product) as a brown oil. It was used directly in the next step without further purification.

[0427] Step 5: 3-(1-(6-(3-(ethoxycarbonyl)thioureido)pyridin-3-yl)piperidin-4-yl)azetidine-1-yl Tert-Butyl Formate

[0428]

[0429] The desired compound was prepared from tert-butyl 3-(1-(6-aminopyridin-3-yl)piperidin-4-yl)azetidine-1-carboxylate according to a procedure similar to that of compound 11, step 3, to give the product as a brown oil (625 mg, crude product). It was used directly in the next step without further purification.

[0430] Step 6: 3-(1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-4-yl)azetidine tert-Butyl 1-oxanecarboxylate

[0431]

[0432] The desired compound was prepared from tert-butyl 3-(1-(6-(3-(ethoxycarbonyl)thioureido)pyridin-3-yl)piperidin-4-yl)azetidine-1-carboxylate according to a procedure similar to step 4 of compound 11 to give the product as an off-white solid (202 mg, 42% yield). 1 H NMR(DMSO-d6)δ7.96(d,J=1.75Hz,1H),7.35(dd,J=9.57,2.06Hz,1H),7.21(d,J=9.51Hz,1H),5.71(s,2H),3.87(brs,2H),3.59(brs,2H), 3.46-3.54(m,2H),2.53-2.60(m,2H),2.23-2.35(m,1H),1.71(d,J=12.13Hz,2H),1.52(d,J=9.76Hz,1H),1.37(s,9H),1.10-1.23(m,2H). MS(ESI)m / e[M+1] + =373.3.

[0433] Step 7: 3-(1-(2-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo tert-Butyl [1,5-a]pyridin-6-yl)piperidin-4-yl)azetidine-1-carboxylate

[0434]

[0435] The desired compound was prepared from tert-butyl 3-(1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-4-yl)azetidine-1-carboxylate according to a procedure similar to that of compound 26, step 1, to give the product as a brown solid (150 mg, 43%). MS (ESI) m / e [M+1] + =542.

[0436] Step 8: 3-(1-(2-((6-(cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)- tert-Butyl [1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-4-yl)azetidine-1-carboxylate

[0437]

[0438] The desired compound was prepared from tert-butyl 3-(1-(2-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-4-yl)azetidine-1-carboxylate according to a procedure similar to compound 1, step 2, to give the product as a yellow solid (100 mg, 62%). MS (ESI) m / e [M+1] + =590.9.

[0439] Step 9: 4-((6-(4-(azetidin-3-yl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine- 2-amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide

[0440]

[0441] A solution of tert-butyl 3-(1-(2-((6-(cyclopropanecarboxamido)-3-(methylcarbamoyl)pyridazin-4-yl)amino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl)piperidin-4-yl)azetidine-1-carboxylate (100 mg, 0.17 mmol) in 2 mL of DCM / TFA (v:v=3:1) was stirred at room temperature for 2 hours. After the reaction was complete, the solution was removed in vacuo, and the residue was purified by preparative TLC (MeOH / DCM=10%) to give the product as a brown solid (80 mg, 96%). MS (ESI) m / e[M+1] + =490.9.

[0442] Step 10: 6-(Cyclopropanecarboxamido)-N-methyl-4-((6-(4-(1-methylazetidin-3-yl)piperidin-4-yl)- pyridin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 55)

[0443]

[0444] The desired compound was prepared from 4-((6-(4-(azetidin-3-yl)piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-6-(cyclopropanecarboxamido)-N-methylpyridazine-3-carboxamide according to a procedure similar to compound 41 to give the product (10 mg, 13%). 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),11.39(s,1H),9.32(d,J=17.9Hz,2H),8.18(s,1H),7.64(d ,J=9.6Hz,1H),7.57(d,J=9.5Hz,1H),4.15(s,1H),4.02(s,1H),3.91(s,1H),3.77(d,J=7.6Hz,1 H),3.64(d,J=10.9Hz,2H),2.87(d,J=4.3Hz,3H),2.82(d,J=4.9Hz,1H),2.76(d,J=4.8Hz,2H),2 .68-2.59(m,2H),2.15(s,1H),1.72(dd,J=34.1,12.1Hz,3H),1.23(s,3H),0.89(d,J=8.1Hz,4H). MS(ESI)m / e[M+1] + =505.1.

[0445] Example Q

[0446] Example Q1: Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-4-((6-(3-(thiazolidine-3-carbonyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 56)

[0447]

[0448] Step 1: tert-Butyl 3-(thiazolidine-3-carbonyl)azetidine-1-carboxylate

[0449]

[0450] At room temperature, HOBt (795mg, 5.9mmol), EDCI (1.4g, 7.4mmol) and DIPEA (2.5g, 19.6mmol) were added to a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (1g, 4.9mmol) and thiazolidine (885mg, 9.9mmol) in DCM (30mL), and the resulting mixture was stirred at this temperature for 12 hours. After the reaction was complete, the solvent was removed in vacuo, and the residue was redissolved with water (100mL). The resulting solution was extracted with DCM (50mL x3), and the combined organic layer was washed with brine (30mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EA=10:1) to give a product (1.2g, 89%) as a yellow oil. MS (ESI) m / e [M+1] + =273.1.

[0451] Step 2: Azetidin-3-yl(thiazolidin-3-yl)methanone

[0452]

[0453] To the solution of 3- (thiazolidine -3- carbonyl) azetidine -1- tert-butyl formate (1.2g, 4.4mmol) in DCM (10mL), TFA (10mL) is added, and the reaction mixture is stirred at room temperature for 1 hour. After the reaction is completed, saturated Na is added CO to adjust the pH value to 9-10, then DCM (30mL x 3) is extracted. The organic layer merged is washed with brine (10mL), through Na SO dried, filtered and concentrated to give the product (0.75g, crude product) as a yellow solid. MS (ESI) m / e [M+1] + =173.1.

[0454] Step 3: (1-(6-nitropyridin-3-yl)azetidin-3-yl)(thiazolidin-3-yl)methanone

[0455]

[0456] At room temperature, DIPEA (1.69 g, 13.08 mmol) and 5-fluoro-2-nitropyridine (619 mg, 4.36 mmol) were added to a solution of azetidine-3-yl (thiazolidine-3-yl) ketone (750 mg, 4.36 mmol) in 1,4-dioxane (20 mL), and the resulting mixture was stirred at 100 ° C for 12 hours. After cooling to room temperature, the solvent was removed in a vacuum, and the residue was redissolved with water (50 mL). The resulting solution was extracted with EA (40 mL x 3), and the combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EA=10:1) to give a product (1 g, 78%) as a yellow solid.

[0457] Step 4: (1-(6-aminopyridin-3-yl)azetidin-3-yl)(thiazolidin-3-yl)methanone

[0458]

[0459] To a solution of (1-(6-nitropyridin-3-yl)azetidin-3-yl)(thiazolidin-3-yl)methanone (1 g, 3.4 mmol) in THF (20 mL) was added Pd / C (10%, 100 mg), and the mixture was stirred at room temperature for 2 hours under H2 (15 psi) atmosphere. After the reaction was complete, the catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the product as a yellow oil (800 mg, crude), which was used in the next step without further purification. MS (ESI) m / e [M+1] + =265.1.

[0460] Step 5: N-((5-[3-(1,3-thiazolidine-3-carbonyl)azetidin-1-yl]pyridin-2-yl)thioamino ethyl carbamate

[0461]

[0462] The desired compound was prepared from (1-(6-aminopyridin-3-yl)azetidin-3-yl)(thiazolidin-3-yl)methanone according to a procedure similar to step 3 of compound 11 to give the product as a yellow oil (1 g, crude), which was used in the next step without further purification.

[0463] Step 6: (1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)azetidin-3-yl)(thiazole 3-Alkyl)methanone

[0464]

[0465] The desired compound was prepared from ethyl N-((5-[3-(1,3-thiazolidine-3-carbonyl)azetidin-1-yl]pyridin-2-yl)carbamothioyl)carbamate according to a procedure similar to step 4 of compound 11 to give the product as a yellow solid

[0466] (416 mg, 54%). 1 H NMR(DMSO-d6)δ: 7.75(s,1H),7.23(d,J=9.3Hz,1H),6.88(d,J=9.1Hz,1H),5.69(s,2H),4.47(s,2H),3. 97-4.07(m,2H),3.76-3.91(m,3H),3.65(d,J=12.6Hz,2H),3.08(t,J=6.2Hz,1H),3.00(t,J=6.3Hz,1H). MS(ESI)m / e[M+1] + =305.1.

[0467] Step 7: 6-Chloro-N-methyl-4-((6-(3-(thiazolidine-3-carbonyl)azetidin-1-yl)-[1,2,4]triazolidine-1-yl)- oxazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide

[0468]

[0469] The desired compound was prepared from (1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)azetidin-3-yl)(thiazolidin-3-yl)methanone according to a procedure similar to compound 26, step 1, to give the product as a brown solid (50 mg, 13%). MS (ESI) m / e [M+1] + =474.

[0470] Step 8: 6-(cyclopropanecarboxamido)-N-methyl-4-((6-(3-(thiazolidine-3-carbonyl)azetidine-1-yl)- 1-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide (Compound 56)

[0471]

[0472] The desired compound was prepared from 6-chloro-N-methyl-4-((6-(3-(thiazolidine-3-carbonyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)pyridazine-3-carboxamide according to a procedure similar to compound 1, step 2 to give the product (5 mg, 11%). 1H NMR (400MHz, DMSO-d6) δ12.01(s,1H),11.37(s,1H),9.32(d,J=23.3Hz,2H),7.96(s,1H),7.58(d,J=9.7Hz,1H),7.15(s,1H),4.49( s,2H),4.11(s,2H),3.96(s,2H),3.65(s,2H),3.10(s,1H),3.01(s,2H),2.87(d,J=4.5Hz,3H),2.14(s,1H),0.89(d,J=8.2Hz,4H). MS(ESI)m / e[M+1] + =522.9.

[0473] Assay A: TYK2-JH2 biochemical assay

[0474] In a homogeneous time-resolved fluorescence-based assay, the compounds disclosed herein were tested for blocking of TYK2-JH2 (aa575-869, internal) protein and its probe. Compound dilutions were performed according to the following scheme: (1) 500× compound solutions were prepared from 500uM in DMSO by 5-fold dilutions, including a total of 10 doses; (2) 10× compound solutions were prepared in assay buffer containing 20mM HEPES (pH 7.5), 10mM MgCl2, 0.005% BSA, 2mM DTT, 0.015% Brij-35 by transferring 1μl of the serial 500× stock solution to 49μl of assay buffer. 4μl of 0.2nM recombinant TYK2-JH2 protein was pre-incubated with 1μl of the 10× serially diluted compounds at room temperature for 0.5 hours. Then 5 μl of 10 nM internal probe 1 (6-((3,5-dimethylphenyl)amino)-8-((4,26-dioxo-30-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-7,10,13,16,19,22-hexaoxa-3,25-diazatriacontanoyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide, KD=10 nM), 5 μl of Mab Anti-6His Tb cryptate Gold (Catalog: 61HI2TLB, Cisbio Bioassays) and Streptavidin-XL665 (Catalog: 610SAXLB, Cisbio Bioassays) mixture were added to the plate and further incubated for 1 hour at room temperature. HTRF signals (ex337 nm, em620 nm / 665 nm) were read on a BMG PHERAstar FS instrument. Based on the fluorescence ratio at 615 nm to 665 nm, the percentage inhibition of the interaction between TYK2 and its probe was calculated at increasing compound concentrations. The data were fitted to a four-parameter logistic equation by Dotmatics to derive the IC50 of each compound.

[0475] Assay B: JAK1-JH2 biochemical assay

[0476] In a homogeneous time-resolved fluorescence-based assay, the compounds disclosed herein (aa 561-860, internal) were tested for blocking of JAK1-JH2 protein and its probe. Compound dilutions were performed according to the following protocol: (1) 500× compound solution was prepared from 500uM in DMSO by 5-fold dilution, including a total of 10 doses; (2) 10× compound solution was prepared in an assay buffer containing 20mM HEPES (pH 7.5), 10mM MgCl2, 0.005% BSA, 2mM DTT, 0.015% Brij-35 by transferring 1μl of a continuous 500× stock solution to 49μl of assay buffer. 4μl of 1.17nM recombinant JAK1-JH2 protein was pre-incubated with 1μl of 10× serially diluted compounds at room temperature for 0.5 hours. Then 5 μL of 2.9 nM internal probe 2 (N-(2-(4-(2-(methyl(4-((((Z)-2-oxoindolin-3-ylidene)(phenyl)methyl)amino)phenyl)amino)-2-oxoethyl)piperazin-1-yl)ethyl)-1-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12,15,18-hexaoxaheneicosane-21-amide, KD=2.9 nM), 5 μL of Mab Anti-6His Tb cryptate Gold (Catalog: 61HI2TLB, Cisbio Bioassays) and Streptavidin-XL665 (Catalog: 610SAXLB, Cisobio Bioassays) mixture were added to the plate and further incubated at room temperature for 1 hour. HTRF signals (ex337 nm, em620 nm / 665 nm) were read on a BMG PHERAstar FS instrument. Based on the fluorescence ratio at 615 nm to 665 nm, the percentage inhibition of the interaction between JAK1 and its probe was calculated at increasing compound concentrations. The data were fitted to a four-parameter logistic equation by Dotmatics to derive the IC50 of each compound.

[0477] Assay C: IL-12-JAK2, TYK2 / p-STAT4 (Tyr693) inhibition IC50 cell assay

[0478] To evaluate the inhibitory effect of the compounds disclosed herein on JAK2, TYK2 / p-STAT4 (Tyr693) activated by IL-12 in the NK-92 cell line, NK-92 cells were collected and washed three times with DPBS and resuspended in MEM-α (Gibco, catalog number 12561056) containing 10% FBS (Gibco, catalog number 10099, lot number 1891605), without IL-2 (R&D systems, catalog number 202-IL), and starved overnight. The cells were collected and resuspended in 1640 medium (without phenol red, Gibco, catalog number 11835-030) containing 0.1% BSA, and 12.5 μl / 5×10 4 / well cell suspension was inoculated into 96-well plates (Corning, catalog number 3799). The cells were then treated with compounds diluted in 0.2% DMSO 1640 medium for 1 hour at 37°C. Dilutions were performed according to the following scheme: (1) 500x compound solutions were prepared from 5 mM in DMSO by 4-fold dilutions, including a total of 8 doses; (3) 2x compound solutions in assay medium were prepared by transferring 0.5 μl of the continuous 500x stock solution to 125 μl of assay medium; (4) 15 μl of the 2x continuous solution was added to the cells and incubated at 37°C for 1 hour, with final compound concentrations of 10000 nM, 2500 nM, 625 nM, 156.25 nM, 39 nM, 9.8 nM, 2.4 nM and 0.61 nM, respectively. After 1 hour, cells were treated with 2.5 μl culture medium containing IL-12 at 37 ° C (R&D Systems, catalog number 219-IL-005, final concentration 40 ng / ml) for 30 minutes. Subsequently, cells were lysed for 1 hour at RT with 7.5 μl lysis buffer accompanied by shaking on a shaker. 10 μL cell lysates were transferred to PE 384-well Proxiplate detection plates, and 5 μL pre-mixed Alphascreen beads were added to each well. Cover the plate with a plate sealer, rotate at 1000 rpm for 1 minute, mix, and incubate overnight at room temperature. Read on BMG PheraStar with Alphascreen scheme. IC 50 values ​​were calculated by fitting the dependent data to a four-parameter logistic model using dotmatics software. Measured by using AlphaLISA SureFire Ultra p-STAT4 (Tyr693) assay kit-large capacity (PE, catalog number ALSU-PST4-A-HV).

[0479] Assay D: IL-6-JAK1 / p-STAT3 (Tyr705) inhibition IC50 cell assay

[0480] To evaluate the inhibitory effect of the compounds disclosed herein on JAK1 / p-STAT3 (Tyr705) activated by IL-6 in the TF-1 cell line, TF-1 cells were collected and washed three times with DPBS and resuspended in RPMI-1640 (without phenol red, Gibco, catalog number 11835-030) containing 0.1% FBS (Gibco, catalog number 10099, lot number 1891605) and without GM-CSF (R&D Systems, catalog number 215-GM-050) and starved overnight. The cells were collected and resuspended in 1640 medium (without phenol red, Gibco, catalog number 11835-030) containing 0.1% BSA, and 12.5 μl / 10×10 4 / well cell suspension was inoculated into 96-well plates (Corning, catalog number 3799). The cells were then treated with compounds diluted in 0.2% DMSO1640 medium at 37°C for 1 hour. Dilutions were performed according to the following scheme: (1) 500x compound solutions were prepared from 5 mM in DMSO by 4-fold dilution, including a total of 8 doses; (3) 2x compound solutions in assay medium were prepared by transferring 0.5 μl of continuous 500x stock solution to 125 μl assay medium; (4) 15 μl of 2x solution was added to the cells and incubated at 37°C for 1 hour, with final compound concentrations of 10000 nM, 2500 nM, 625 nM, 156.25 nM, 39 nM, 9.8 nM, 2.4 nM and 0.61 nM, respectively. After 1 hour, the cells were treated with 2.5 μl culture medium containing IL-6 at 37 ° C (R&D Systems, catalog number 206-IL-010, final concentration 50 ng / ml) for 30 minutes. The cells were then lysed for 1 hour at RT with 10 μl lysis buffer accompanied by shaking on a shaker. 16 μL of cell lysate was transferred to a PE 384-well HTRF detection plate, and 4 μL of premixed HTRF antibodies were added to each well. The plate was covered with a plate sealer, rotated at 1000 rpm for 1 minute, mixed, and incubated overnight at room temperature. Reading (337 nm–665 nm–620 nm) was performed on a BMG PheraStar with an HTRF scheme. IC 50 values ​​were calculated by fitting the dependency data to a four-parameter logistic model using dotmatics software. Measured by using HTRF Phospho-STAT3 (Tyr705) cell assay kit (Cisbio, catalog number 62AT3PEG).

[0481] The compounds disclosed herein show picomolar to nanomolar biochemical activity in TYK2-JH2 binding assays and nanomolar activity in cell assays. At the same time, these compounds show excellent selectivity in TYK2 biochemical / cell assays for JAK1. See Table 1.

[0482] Table 1:

[0483]

[0484]

[0485]

[0486]

[0487] It will be appreciated that, even if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

[0488] In the following claims and the foregoing embodiments of the present invention, unless the context requires otherwise due to expressive language or necessary meaning, the word "comprise" or variations such as "comprises" or "comprising" are used in an inclusive sense, that is, specifying the presence of the features described, but not excluding the presence or addition of other features in various embodiments of the present invention.

[0489] The disclosures of all publications, patents, patent applications, and published patent applications cited herein by identifying citation are incorporated herein by reference in their entirety.

[0490] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to one skilled in the art that certain minor changes or modifications may be implemented. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt, wherein: R 1 It is C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted with 0-7 R 1a replace; R 1a Deuterium is independently present in each occurrence; R 2 Yes-C(O)R 2a ; R 2a Independently C 3-6 Cycloalkyl; R 3 yes wherein n is an integer selected from 0, 1 and 2; and R 3a is independently at each occurrence hydrogen, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -P(O)R 3d R 3e 、-(L 1 ) r -CyA; or CyA; L 1 is independently at each occurrence -O-, -S-, or -C(O)-; CyA is a 3-10 membered heterocyclic group containing carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the 3-10 membered heterocyclic group is surrounded by 0-3 R 3b replace; R 3b is independently at each occurrence hydrogen, halogen, -C 1-6 Alkyl, -oxo-, -OR 3c 、-C(O)R 3d 、-S(O)2R 3d 、-NR 3d R 3e , a 3-10 membered heterocyclic group containing 1-4 heteroatoms selected from nitrogen, oxygen or sulfur, a 6-10 membered aryl group, or a 4-10 membered heteroaryl group containing carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen or sulfur; wherein the -C 1-6 Alkyl, 3-10 membered heterocyclyl, 6-10 membered aryl and 4-10 membered heteroaryl are each optionally substituted by 0-3 -R 3d replace; R 3c and R 3d is independently at each occurrence hydrogen, halogen, hydroxyl, -C 1-6 Alkyl, -C 1-6 an alkoxyl group, a 5-6 membered aryl group, a 3-6 membered heterocyclic group containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, or a 5-6 membered heteroaryl group containing carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the -C 1-6 Alkyl, -C 1-6 Alkoxy, 5-6 membered aryl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl are optionally substituted with -halogen, -CN, -C 1-6 Alkyl or -C 1-6 Alkoxy substitution; R 3e In each occurrence, independently selected from -C 1-6 Alkyl or -S(O)2R 3f , where R 3f Independently C 1-6 Alkyl; and r is the integer 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 yes 3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl, ethyl, propyl, isopropyl or isobutyl, each of which is optionally substituted by 0-3 R 1a replace.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group, or -CD3.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 yes 6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3a It is hydrogen, halogen, -C 1-6 Alkyl, -P(O)R 3d R 3e , -L 1 -CyA or CyA, wherein CyA is a 3-6 membered heterocyclic group comprising carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen or sulfur, and is optionally substituted by 0-3 R 3b replace.

7. The compound according to claim 5 or 6 or a pharmaceutically acceptable salt thereof, wherein L 1 is independently at each occurrence -O- or -C(O)-.

8. The compound according to claim 5 or 6 or a pharmaceutically acceptable salt thereof, wherein R 3a is a 3- to 6-membered heterocyclic group containing carbon atoms and 1-4 heteroatoms selected from nitrogen, oxygen or sulfur.

9. The compound or pharmaceutically acceptable salt thereof according to claim 5 or 6, wherein CyA is a 5-6 membered heterocyclic group comprising carbon atoms and 1-4 heteroatoms selected from nitrogen or oxygen.

10. The compound according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein CyA is azetidinyl, piperidinyl and piperazinyl, each of which is replaced by 0-3 R 3b replace.

11. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein CyA is a 7-10 membered bridged heterocyclic group comprising carbon atoms and 1-2 heteroatoms selected from N and O, and 0-3 R 3b replace.

12. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein CyA is 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein the N heteroatom on CyA is attached to R 3 .

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3b It is hydrogen, halogen, -C 1-3 Alkyl, -OR 3c 、-C(O)R 3d or NR 3d R 3e , wherein the-C 1-3 The alkyl group is optionally substituted with 0-3 -R 3d replace.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3c and R 3d is independently selected at each occurrence from hydrogen, halogen, hydroxy, -C 1-3 Alkyl, -C 1-3 Alkoxy, phenyl, 3-6 membered heterocyclic group containing 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, or 5-6 membered heteroaryl containing carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen or sulfur, wherein the -C 1-3 Alkyl, -C 1-3 Alkoxy, phenyl, 3-6 membered heterocyclic group, 5-6 membered heteroaryl group are optionally substituted with -halogen, -CN, -C 1-3 Alkyl or -C 1-3 Alkoxy substitution.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3e Yes-C 1-3 Alkyl or -S(O)2C 1-3 alkyl.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3b is hydrogen, halogen, methyl, ethyl, propyl, isopropyl, isobutyl, -OR 3c or NR 3d R 3e , wherein methyl, ethyl, propyl or isopropyl is optionally substituted by 0-3 -R 3d replace.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3b is hydrogen, halogen, methyl, ethyl, propyl, isopropyl, isobutyl, methoxy or NR 3d R 3e , wherein methyl, ethyl, propyl or isopropyl is optionally substituted by 0-3 -R 3d replace.

19. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 yes 20. A compound, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 20 or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

22. Use of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 in the preparation of a medicament for inhibiting TYK2 or treating a disease associated with undesirable TYK2 activity, wherein the disease is an inflammatory disease or an autoimmune disease.

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