Amine derivatives and their use in medicine

Abstract

This invention discloses a compound of Formula I and the use of this type of compound in the treatment of c-kit kinase-related diseases. The implementation of this invention can achieve potent inhibition of c-kit kinase activity with good selective inhibition and reduced toxic side effects.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to an amine derivative and its application in medicine. BACKGROUND

[0002] KIT was initially identified as the homolog of the cat sarcoma virus oncogene v-kit, commonly known as proto-oncogene c-kit, which encodes the mast / stem cell growth factor receptor kit protein (CD117). Kit belongs to the type III tyrosine kinase receptor family, i.e. the platelet-derived growth factor receptor (PDGFR family), which includes PDGFRα, PDGFRβ, CSF1R, KIT, FLT3. The KIT protein is composed of 5 Ig-like domains (involved in ligand binding and receptor dimerization), a transmembrane domain (anchoring KIT to the plasma membrane), a juxtamembrane domain (J), and two kinase domains (K) (responsible for SCF / KIT signaling). The SCF-KIT pathway regulates cell survival proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and melanin formation. Therefore, c-kit kinase is a drug target with good clinical potential. SUMMARY

[0003] The purpose of the present application is to provide a novel amine derivative or all its stereoisomers or pharmaceutical compositions, which can significantly reduce or avoid the inhibition of other kinases in the same family while maintaining strong inhibition activity on c-kit kinase, thereby reducing side effects and providing patients with safer and more effective treatment options.

[0004] To achieve the above purpose, the present application provides the following technical solutions:

[0005] In a first aspect, the present application provides a compound represented by formula (I), or all its stereoisomers, solvates, prodrugs, metabolites, deuterides, pharmaceutically acceptable salts or co-crystals thereof:

[0006]

[0007] Wherein:

[0008] A is selected from a 5-6 membered aromatic ring or a 5-6 membered heteroaromatic ring;

[0009] B is selected from a 5-15 membered heterocyclic ring or a fused bicyclic ring;

[0010] C is selected from a fused ring formed by a bicyclic or a tricyclic ring, and the fused ring contains 1 to 6 heteroatoms selected from N, O or S;

[0011] X1is selected from a single bond, carbonyl, or alkene;

[0012] R1and R4are selected from H, -NR5R6, -OR7, C1-C6alkyl, halogen, -CN, alkene, alkyne, C1-C6haloalkyl, 3-5 membered halocycloalkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl, R1and R4are optionally further substituted with one or more R8;

[0013] R2is selected from one or more H, C1-C6alkyl, halogen, -OH, -OCH3, -NR5R6, -OR7, -CN, alkene, alkyne, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl, R2is optionally further substituted with one or more R8;

[0014] R3is selected from one or more C1-C6alkyl, C1-C6haloalkyl, or halogen;

[0015] R5, R6, R7, and R8are each independently selected from H, -OH, C1-C6alkyl, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl, said C1-C6alkyl is optionally further substituted with 1 or more H, halogen, -OH, -CN, alkene, alkyne, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl.

[0016] One or more embodiments of the present application provide a compound represented by Formula (I-1) or a stereoisomer, solvate, prodrug, metabolite, deuterated analog, pharmaceutically acceptable salt, or co-crystal thereof:

[0017]

[0018] wherein:

[0019] A ring is selected from a 5-6 membered aryl ring or a 5-6 membered heteroaryl ring;

[0020] B ring is selected from a 5-15 membered heterocycle;

[0021] R1is selected from H, C1-C6alkyl, 3-5 membered cycloalkyl, C1-C6haloalkyl, 3-5 membered halocycloalkyl;

[0022] R4is selected from H, -NR5R6, -OR7, C1-C6alkyl, halogen, -CN, alkene, alkyne, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl, R4is optionally further substituted with one or more R8;

[0023] R2 is selected from one or more H, -NR5R6, -OR7, C1-C6 alkyl, halogen, -CN, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R2 is optionally further substituted by one or more R8.

[0024] R3 is selected from one or more C1-C3 alkyl groups, C1-C3 haloalkyl groups, or halogens;

[0025] R5, R6, R7, and R8 are each independently selected from H, -OH, C1-C6 alkyl, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the C1-C6 alkyl is optionally further substituted by one or more H, halogen, -OH, -CN, olefin, alkyne, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl.

[0026] One or more embodiments of the present invention provide compounds of formula (I-2) or their stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or eutectics:

[0027]

[0028] R4 is selected from H, -NR5R6, -OR7, C1-C6 alkyl, halogen, -CN, olefin, alkyne, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R4 is optionally further substituted by one or more R8.

[0029] R2 is selected from one or more H, C1-C6 alkyl, halogen, -OH, -OCH3, -NR4R5, -OR6, -CN, olefin, alkyne, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R2 is optionally further substituted by one or more R8.

[0030] B is selected from B1 is selected from 5-6-membered heterocyclic alkyl groups, and B2 is selected from 3-10-membered (hetero)cyclic alkyl groups or 5-10 (hetero)cyclic alkyl groups;

[0031] R3 is selected from one or more H, C1-C6 alkyl, C1-C6 haloalkyl or halogen;

[0032] R5, R6, R7, and R8 are each independently selected from H, C1-C6 alkyl, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the C1-C6 alkyl is optionally further substituted by one or more H, halogen, -OH, -CN, olefin, alkyne, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl;

[0033] X2 and X3 are each independently selected from C or N.

[0034] In one or more embodiments of the present invention, the compound represented by formula (I-1) of the present invention, wherein,

[0035] Ring A is selected from benzene ring, pyridine ring, pyrimidine ring, pyrrole ring, furan ring or thiophene ring;

[0036] Ring B is selected from 5-10 element double rings or 10-15 element triple rings; among them, any two connecting rings in the triple rings can be fused or screwed together;

[0037] R1 is selected from H and C1-C6 alkyl groups;

[0038] R4 is selected from H, C1-C6 alkyl, 3-10 heterocyclic alkyl or 5-10 heteroaryl, and R4 is optionally further substituted by one or more R8;

[0039] R2 is selected from one or more H, C1-C6 alkyl, halogen, hydroxyl or methoxy;

[0040] R3 is selected from one or more H, C1-C3 alkyl groups, or halogens.

[0041] In one or more embodiments of the present invention, the compound represented by formula (I-1) of the present invention, wherein:

[0042] Ring A is selected from a benzene ring or a pyrrole ring;

[0043] Ring B is selected from

[0044] R1 is selected from -CH3;

[0045] R4 is selected from In this case, R8 is selected from H, -CH3, -CH2OH, or -CH2CH2OH;

[0046] In one or more embodiments of the present invention, the compound represented by formula (I-2) of the present invention, wherein B1 and B2 together form a 5-8 membered bicyclic or a 10-15 membered tricyclic ring; wherein the two connecting rings in the tricyclic ring may be fused or bridged; further, B is selected from... Q 1 Q2 Q 3 Each is independently selected from C, O, or N.

[0047] In one or more embodiments of the present invention, the compound represented by formula (I-2) of the present invention, wherein B is selected from...

[0048] Q 1 Q 2 Q 3 Each is independently selected from C, O, or N.

[0049] In one or more embodiments of the present invention, the compound represented by formula (I-2) of the present invention, wherein B is selected from...

[0050] In one or more embodiments of the present invention, the compound represented by formula (I-1) of the present invention, wherein,

[0051] R1 is selected from H, 3-10-membered heterocyclic alkyl or 5-10-membered heteroaryl, and R1 is optionally further substituted by one or more R8;

[0052] R2 is selected from one or more H, C1-C6 alkyl, halogen, hydroxyl or methoxy;

[0053] R3 is selected from one or more H, C1-C3 alkyl groups, or halogens.

[0054] In one or more embodiments of the present invention, R1 is selected from H, When; R8 is selected from H, -CH3, -CH2OH or -CH2CH2OH.

[0055] Furthermore, based on the above-mentioned preferred structure, this invention provides a series of specific representative compounds. These compounds have been demonstrated through in vitro kinase screening experiments to possess potent inhibitory activity against c-kit kinase. The representative compound structures of this application are as follows:

[0056]

[0057]

[0058]

[0059]

[0060] One or more embodiments of this application provide pharmaceutical compositions comprising:

[0061] (1) The compound of this application or its stereoisomers, or pharmaceutically acceptable salts thereof;

[0062] (2) Pharmaceutically acceptable carriers and / or excipients.

[0063] One or more embodiments of this application provide pharmaceutical compositions comprising:

[0064] (1) The compound of this application or its stereoisomers, or pharmaceutically acceptable salts thereof;

[0065] (2) One or more other active ingredients selected by choice; and

[0066] (3) Pharmaceutically acceptable carriers and / or excipients.

[0067] This composition can be prepared into various dosage forms suitable for administration, such as tablets, capsules, injections, etc.

[0068] In a second aspect, the present invention provides the use of the above-mentioned compound or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals or pharmaceutical compositions in the treatment of c-kit kinase-related diseases.

[0069] In one or more embodiments of the present invention, the c-kit kinase-related disease is a tumor or an autoimmune disease.

[0070] In one or more embodiments of the present invention, the diseases include, but are not limited to, autoimmune diseases, gastrointestinal stromal tumors, systemic mastocytosis, acute myeloid leukemia, melanoma, etc.

[0071] The compound of formula (I) and its preferred embodiment provided by this invention have the following significant beneficial effects:

[0072] (1) Strong inhibitory activity: The compounds of the present invention have very strong inhibitory activity against c-kit kinase, ensuring their effectiveness as a therapeutic agent.

[0073] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0074] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I involved in the groups and compounds described in this invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, or nitrogen involved in the groups and compounds described in this invention may optionally be further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 16 O、 17 O and 18O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0075] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 20 carbon atoms, preferably an alkyl group with 1 to 8 carbon atoms, more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; when the alkyl group is substituented, it may optionally be further substituted by one or more substituents.

[0076] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which can be a 3- to 10-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 20-membered polycyclic system, preferably with 3 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl, and cyclohepttrienyl, etc. When substituted, it may optionally be further substituted with 0 or more substituents.

[0077] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated non-aromatic cyclic group, which can be a 3- to 8-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic system, and contains 1 to 3 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The selectively substituted N or S in the ring of the "heterocyclic alkyl" can be oxidized to various oxidation states; the "heterocyclic alkyl" can be attached to a heteroatom or a carbon atom; the "heterocyclic alkyl" can be a bridged ring or a spirocyclic ring. Non-limiting examples of “heterocyclic alkyl” include epoxyethyl, aziridine, oxacyclobutyl, aziridine, 1,3-dioxolanecycloyl, 1,4-dioxolanecycloyl, 1,3-dioxahexacycloyl, aziridine, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithiaalkyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, aziridine[3.2.1]octyl, aziridine[5.2.0]nonyl, oxacyclo[5.3.1.1]dodecyl, aziridine, and oxaspiro[3.3]heptyl.

[0078] "Heterocycle" or "heterocyclic group" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle. When it is an aromatic heterocycle, its definition is the same as that of "heteroaryl" above. When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The 1 to 4 (e.g., 1, 2, 3, 4) N and S atoms selectively substituted in the ring of the "heterocyclic group" or "heterocycle" can be oxidized to various oxidation states; the "heterocyclic group" or "heterocycle" can be attached to a heteroatom or a carbon atom; the "heterocyclic group" or "heterocycle" can be a fused ring, a bridged ring, or a spirocycle. The "heterocyclic group" or "heterocycle" may optionally be further substituted by one or more substituents.

[0079] "Aryl" refers to a substituted or unsubstituted aromatic ring, which can be a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic system. It can be a bridged ring or a spirocyclic ring. Non-limiting examples include phenyl and naphthyl. The aryl group may optionally be further substituted by one or more substituents.

[0080] "Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which can be a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O, or S, preferably 5- to 8-membered heteroaryls. The heteroaryl group can be attached to a heteroatom or a carbon atom, and can be a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopyridyl, furanyl, thiophenyl, pyranyl, pyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, and imidazolyl. The heteroaryl group may optionally be further substituted by one or more substituents.

[0081] When the terms "alkyl", "heterocyclic", "heterocyclic", "cycloalkyl", "heterocyclic", "aryl", or "heteroaryl" mentioned above are substituted, they may optionally be further replaced by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C 1-6 Alkylamino, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR q4 R q5 =NR q6 -C(=O)OC 1-6 Alkyl group, -OC (=O)C 1-6 Alkyl, -C(=O)NR q4 R q5 C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -C(=O)OC 6-10 Aryl, -OC(=O)C 6-10 Aryl, -OC(=O)C 5-10 heteroaryl, -C(=O)OC 5-10 heteroaryl, -OC(=O)C 3-8 Heterocyclic alkyl, -C(=O)OC 3-8 Heterocyclic alkyl groups, -OC (=O)C 3-8 Cycloalkyl, -C(=O)OC 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 cycloalkyl, -NHC(=O)C 3-8 Heterocyclic alkyl groups, -NHC(=O)C 2-6 alkenyl or -NHC(=O)C 2-6The alkynyl group is replaced by a substituent, and the substituent C is described in the figure. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl, C 6-10 Aryl, C 5-10 heteroaryl, -NHC(=O)C 6-10 Aryl, -NHC(=O)C 5-10 heteroaryl, -NHC(=O)C 3-8 Heterocyclic alkyl groups or -NHC(=O)C 3-8 The cycloalkyl group may optionally be further surrounded by one to three elements selected from OH, F, Cl, Br, I, C. 1-6 Alkyl, C 1-6 Alkoxy, -NR q4 R q5 Or replaced by the =O substituent; R q1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy or C 6-10 Aryl; R q2 R q3 Selected from H or C 1-6 Alkyl; R q4 R q5 Selected from H, C 1-6 Alkyl group, -NH (C=NR) q1 )NR q2 R q3 -S(=O)2NR q2 R q3 -C(=O)R q1 Or -C(=O)NR q2 R q3 The C mentioned therein 1-6 The alkyl group may optionally be further influenced by one or more elements selected from OH, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 5-10 heteroaryl, C 3-8 cycloalkyl or C 3-8 Substituents of heterocyclic alkyl groups; or R q4 With R q5 The N atom forms a 3- to 8-membered heterocycle, wherein the ring may contain one or more heteroatoms selected from N, O or S.

[0082] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, their pharmaceutically acceptable salts or prodrugs, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0083] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0084] "Excipients" are inert substances added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

[0085] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0086] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group. Detailed Implementation

[0087] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0088] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using Bruker Avance III 400 and Bruker Avance 300 NMR spectrometers in the following solvents: deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD). Tetramethylsilane (TMS) was used as the internal standard.

[0089] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0090] HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18100×4.6mm, 3.5μM);

[0091] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0092] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0093] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, and Jiangsu Aikon Biomedical R&D.

[0094] Intermediate A

[0095] 6-(1-Methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carbonyl chloride intermediate A

[0096] 6-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carbonylchloride

[0097]

[0098] first step

[0099] 6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester A-2

[0100] methyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0101] Compound A-1 (750 mg, 2.9 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxapentoboran-2-yl)-1H-pyrazole (734 mg, 3.4 mmol), sodium carbonate (623 mg, 5.8 mmol), and DPPF palladium dichloride (623 mg, 5.8 mmol) were dissolved in 1,4-dioxane (40 mL) and water (4 mL). The mixture was heated to 110 °C for 3 h under nitrogen protection, and the reaction progress was monitored by TLC.

[0102] The reaction was stopped, the solvent was evaporated, and the mixture was concentrated under reduced pressure and then subjected to column chromatography (petroleum ether: ethyl acetate = 3:1) to give A-2 (brown solid, 810 mg, yield 99%).

[0103] LC-MS m / z(ESI) = 257.10 [M+1].

[0104] Step 2

[0105] 6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid A-3

[0106] 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0107] A-2 (810 mg, 3.7 mmol) was dissolved in a mixed solution of methanol (20 mL), THF (10 mL), and water (10 mL), and lithium hydroxide hydrate (520 mg, 12.6 mmol) was added. The reaction was carried out at 70 °C, and the reaction progress was monitored by TLC.

[0108] Stop the reaction, evaporate the solvent, add water, and adjust the pH to 2 with dilute hydrochloric acid (2 m / L). The precipitated solid was filtered to obtain A-3 (white solid, 620 mg, yield 82%).

[0109] LC-MS m / z(ESI) = 243.08 [M+1].

[0110] Step 3

[0111] 6-(1-Methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carbonyl chloride intermediate A

[0112] 6-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyridine-3-carbonylchloride

[0113] A-3 (100 mg, 0.4 mmol) was dissolved in THF (20 mL), and thionyl chloride (99.0 mg, 0.82 mmol) was added. The reaction was carried out at 80 °C, and the reaction progress was monitored by TLC.

[0114] The reaction was stopped, and the solvent was directly evaporated to give intermediate A (yellow solid, 103 mg, yield 96%).

[0115] LC-MS m / z(ESI) = 261.68 [M+1].

[0116] Intermediate B

[0117] 8-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine intermediate B

[0118] 8-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0119]

[0120]

[0121] first step

[0122] 1-Amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester B-2

[0123] methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate

[0124] B-1 (1.0 g, 49.0 mmol) was dissolved in DMF (200 mL), and sodium hydride (2.3 g, 58.8 mmol) was added in portions at 0 °C. The mixture was stirred at room temperature for 30 min, and then 2,4-dinitrophenylhydroxylamine (11.7 g, 58.8 mmol) was added dropwise. The mixture was gradually reacted at room temperature for 10 h, and the reaction progress was monitored by TLC.

[0125] The reaction was stopped, quenched with water, extracted with ethyl acetate, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, eluted by column chromatography (EA:PE = 1:5), and evaporated to dryness to give B-2 (yellow solid, 9.4 g, yield 88%).

[0126] LC-MS m / z(ESI) = 218.97 [M+1].

[0127] Step 2

[0128] 6-Bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carbamate B-3

[0129] 6-bromo-4-hydroxypyrrolo[1,2-b]pyridazine-3-carbonitrile

[0130] B-1 (1.9 g, 7.2 mmol), dimethoxypropionate acetonitrile (5.0 g, 43.4 mmol), and p-toluenesulfonic acid were mixed and stirred at 80 °C for 6 h. Then DBU (6.6 g, 43.4 mmol) was added, and the reaction was continued at 80 °C for 10 h. The reaction progress was monitored by TLC.

[0131] The reaction was stopped, quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then eluted by column chromatography (DCM:MeOH = 10:1). The solution was then evaporated to dryness to give B-3 (black liquid, 900 mg, yield 45%).

[0132] LC-MS m / z(ESI) = 237.95 [M+1].

[0133] Step 3

[0134] 6-Bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carbamate B-4

[0135] 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carbonitrile

[0136] B-3 (900 mg, 3.7 mmol) and phosphorus oxychloride (7.6 g, 49.4 mmol) were mixed and reacted at 75 °C for three hours, and the reaction progress was monitored by TLC.

[0137] The reaction was stopped, phosphorus oxychloride was removed by rotary evaporation, and then dissolved in DCM and cooled to 0°C. Saturated sodium bicarbonate solution was added, and the organic phase was separated by mixing and stirring. The organic phase was then eluted by column chromatography (DCM:MeOH = 10:1) and dried to obtain B-4 (yellow solid, 270 mg, yield 28%).

[0138] LC-MS m / z (ESI) = 255.92 [M+1].

[0139] Step 4

[0140] 8-Bromo-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine B-5

[0141] 8-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0142] B-4 (270 mg, 1.0 mmol) was dissolved in DMF (10 mL), and methylhydrazine (126 mg, 1.1 mmol) and sodium carbonate (222.6 mg, 2.1 mmol) were added. The mixture was reacted at room temperature for 16 h, and the reaction progress was monitored by TLC.

[0143] The reaction was stopped, water (7.8 mL) and acetic acid (2.3 mL) were added, ethyl acetate (20 × 2 mL) was added for extraction, followed by column chromatography (DCM:MeOH = 20:1) for elution, and the solution was evaporated to dryness to give B-5 (brown solid, 253 mg, yield 90%).

[0144] LC-MS m / z(ESI) = 266.00 [M+1].

[0145] Step 5

[0146] Intermediate B of 1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrazin-3-amine compound

[0147] 2-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrid azin-3-amine

[0148] B-5 (6 g, 22.5 mmol) was dissolved in a mixture of 1,4-dioxane / water = 4:1 (300 mL), followed by the addition of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (5.6 g, 27 mmol) and cesium carbonate (11 g, 67.5 mmol), then Pd(dppf)Cl2·CH2Cl2 (3 g, 3.6 mmol), and nitrogen was purged. The resulting mixture was heated to 100 °C and stirred for 12 hours. The solvent was removed by rotary evaporation, and the resulting black solid was purified by silica gel column chromatography (dichloromethane / methanol = 100:0 → 70:30). The solvent was removed by rotary evaporation to give intermediate B (brown solid, 5 g, yield 72%).

[0149] LC-MS m / z(ESI) = 268.10 [M+1].

[0150] Intermediate C

[0151] 6-Bromo-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide intermediate C

[0152] 6-bromo-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylpheny l)pyrazolo[1,5-a]pyridine-3-carboxamide

[0153]

[0154] first step

[0155] 6-Bromopyrazolo[1,5-a]pyridine-3-carboxylic acid compound C-2

[0156] 6-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid

[0157] Compound C-1 (2.0 g, 7.8 mmol) and sodium hydroxide (627 mg, 15.7 mmol) were dissolved in MeOH:H2O = 2:1 (30 mL), and the mixture was heated to 60 °C for 6 h. The reaction progress was monitored by TLC. After the reaction was complete, the solvent was evaporated, a few mL of water was added, and then 2 M / HCl was slowly added dropwise to adjust the pH to 6-7. The product precipitated to give compound C-2 (white solid, 1.76 g, yield 93%).

[0158] LC-MS m / z(ESI) = 242.11[M+1].

[0159] Step 2

[0160] 6-Bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride compound C-3

[0161] 6-bromopyrazolo[1,5-a]pyridine-3-carbonyl chloride

[0162] Compound C-3 (white solid, 1.9 g, 98% yield) was obtained by following the method used to synthesize intermediate A.

[0163] Step 3

[0164] 6-Bromo-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide intermediate C

[0165] 6-bromo-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylpheny l)pyrazolo[1,5-a]pyridine-3-carboxamide

[0166] Compounds 1-4 (1.24 g, 5.79 mmol) were dissolved in pyridine (20 mL), and compound C-3 (1.5 g, 5.82 mmol) was added in portions. The reaction was carried out at room temperature for 2 h. After the reaction was complete, saturated sodium carbonate aqueous solution was added, followed by extraction with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (dichloromethane:methanol = 50:1) to give intermediate C (white solid, 1.9 g, yield 75%).

[0167] LC-MS m / z(ESI) = 437.16 [M+1].

[0168] Example 1

[0169] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-3-yl compound 1)

[0170] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-meth yl-8-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0171]

[0172] first step

[0173] 5-(3-bromo-4-methylphenyl)pentan-4-yn-1-ol 1-2

[0174] 5-(3-bromo-4-methylphenyl)pent-4-yn-1-ol

[0175] 1-1 (3.0 g, 10.10 mmol), 4-pentyn-1-ol (1.0 g, 12.12 mmol), palladium dichloride (354.5 mg, 0.51 mmol), cuprous iodide (96.2 mg, 0.51 mmol), and triethylamine (5.2 g, 50.50 mmol) were dissolved in tetrahydrofuran (30 mL). After purging with nitrogen, the mixture was reacted at room temperature for 3 h. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 1-2 as a yellow solid, 2.5 g, yield 98%.

[0176] LC-MS m / z(ESI) = 253.02 [M+1].

[0177] Step 2

[0178] 3-(3-bromo-4-methylphenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole 1-3

[0179] 3-(3-bromo-4-methylphenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole

[0180] 1-2 (100.0 mg, 0.40 mmol), diphenyl azidophosphate (131.0 mg, 0.48 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (72.5 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted in a microwave oven at 150 °C for 3 h. After the reaction was complete, water was added, followed by extraction with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to give 1-3 (yellow solid, 98 mg, yield 88%).

[0181] 1 H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.33(d,1H),8.12–8.03(m,3H),7.84(s,1H),7.27(dd,1H),7.19(d ,1H),7.11(d,1H),4.33(t,2H),3.91(s,3H),3.65(s,3H),3.14(t,2H),2.85–2.74(m,2H),2.32(s,3H).

[0182] LC-MS m / z(ESI) = 278.02 [M+1].

[0183] Step 3

[0184] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-3-yl)combin 1N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0185] Compounds 1-3 (98 mg, 0.75 mmol) were dissolved in DMF (10 mL), and intermediate B (133 mg, 0.5 mmol) and cesium carbonate (495 mg, 1.5 mmol) were added. Then, Brettphos (53.6 mg, 0.1 mmol) and Brettphos-Pd-G3 (90 mg, 0.1 mmol) were added, and the mixture was purged with nitrogen. The resulting mixture was heated to 90 °C and stirred for 8 hours. The solvent was removed by rotary evaporation, and the resulting black solid was purified by silica gel column chromatography (dichloromethane / methanol = 100:0 → 90:10). The solvent was removed by rotary evaporation to give compound 1 (yellow solid, 65 mg, 76% yield).

[0186] LC-MS m / z(ESI) = 465.22 [M+1].

[0187] Example 2

[0188] 2-(4-(3-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyrazin-1-yl)ethanol-1-ol compound 2

[0189] 2-(4-(3-((5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyrazol-1-yl)eth an-1-ol

[0190]

[0191] first step

[0192] 2-(4-(3-amino-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrido[8-yl]-1H-pyrazol-1-yl)ethanol-1-ol compound 2-1

[0193] 2-(4-(3-amino-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyr azol-1-yl)ethan-1-ol

[0194] B-5 (6 g, 22.5 mmol) was dissolved in a mixture of 1,4-dioxane / water = 4:1 (300 mL), followed by the addition of 1-hydroxyethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (6.4 g, 27 mmol) and cesium carbonate (11 g, 67.5 mmol), then Pd(dppf)Cl2·CH2Cl2 (3 g, 3.6 mmol), and nitrogen was purged. The resulting mixture was heated to 100 °C and stirred for 12 hours. The solvent was removed by rotary evaporation, and the resulting black solid was purified by silica gel column chromatography (dichloromethane / methanol = 100:0 → 70:30). The solvent was removed by rotary evaporation to give compound 2-1 (brown solid, 5.1 g, 77% yield).

[0195] LC-MS m / z(ESI) = 298.13 [M+1].

[0196] Step 2

[0197] 2-(4-(3-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyrazin-1-yl)ethanol-1-ol compound 2

[0198] 2-(4-(3-((5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyrazol-1-yl)eth an-1-ol

[0199] Following the synthesis of compound 1, compound 2 (yellow solid, 3 mg, yield 2%) was obtained.

[0200] 1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.25(s,1H),8.07–8.01(m,3H),7.83(s,1H),7.30–7.22(m,2H),7.15-7.12(m,1H),4.98-4.9 0(m,1H),4.34-4.29(m,2H),4.18-4.12(m,2H),4.09(s,3H),3.78-3.73(m,2H),3.11-3.06(m,2H),2.82–2.75(m,2H),2.35(s,3H).

[0201] LC-MS m / z(ESI) = 495.23 [M+1].

[0202] Example 3

[0203] (S)-2-(4-(1-methyl-3-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyrrolo-1-yl)ethanol-1-ol compound 3

[0204] (S)-2-(4-(1-methyl-3-((2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3- yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyrazol-1-yl)ethan-1-ol

[0205]

[0206] first step

[0207] (R)-4-methyl-3-((S)-2-methylpentan-4-ynyl)oxazolidin-2-one 3-2

[0208] (R)-4-methyl-3-((S)-2-methylpent-4-ynoyl)oxazolidin-2-one

[0209] Compound 3-1 (8.0 g, 34.3 mmol) was dissolved in tetrahydrofuran (100 mL) at -78 °C under nitrogen protection. Then, sodium bis(trimethylsilyl)amino (34 mL, 34.3 mmol) was added dropwise at the same temperature, and the reaction was carried out at -78 °C for 1 h. Next, 3-bromopropyne (12.2 g, 102.9 mmol) was added dropwise, and the temperature was slowly raised to 0 °C and then to room temperature, and the reaction was carried out overnight. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phase was evaporated to dryness. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound 3-2 (yellow oily liquid, 5.4 g, yield 58%). The product did not precipitate on MS. When developed with potassium permanganate, the product preferentially showed a yellow color to the starting material.

[0210] LC-MS m / z (ESI) = 196.09 [M+1].

[0211] Step 2

[0212] (S)-2-Methylpentan-4-yn-1-ol 3-3

[0213] (S)-2-methylpent-4-yn-1-ol

[0214] Lithium aluminum hydride (2.27 g, 59.8 mmol) was dissolved in tetrahydrofuran (100 mL) under nitrogen protection. The solution was cooled to 0 °C, and then compound 3-2 (5.40 g, 19.9 mmol) was slowly added dropwise while the temperature was gradually raised to room temperature. The reaction was allowed to proceed for 3 h. A TLC test was performed using petroleum ether:ethyl acetate (5:1). Potassium permanganate was used for color development to indicate the reaction was complete. The reaction was quenched with 1 mL of water, 3 mL of sodium hydroxide (15%) solution, and 1 mL of water. Ethyl acetate and magnesium sulfate were then added, and the mixture was stirred thoroughly. The solution was filtered and evaporated to dryness to obtain the crude product, which was used directly in the next step. Compound 3-3 (yellow solid, 5.40 g, 95% yield).

[0215] LC-MS m / z (ESI) = 99.08 [M+1].

[0216] Step 3

[0217] (R)-2-Methyl-5-(4-methyl-3-nitrophenyl)pentan-4-yn-1-ol 3-4

[0218] (R)-2-methyl-5-(4-methyl-3-nitrophenyl)pent-4-yn-1-ol

[0219] Compound 3-3 (2.0 g, 20.3 mmol) was reacted with 2-bromo-4-iodotoluene (2.2 g, 10.2 mmol) in the same manner as the synthesis of compound 1-2 to give compound 3-4 (yellow oily liquid, 900 mg, yield 37.8%).

[0220] LC-MS m / z(ESI) = 267.03 [M+1].

[0221] Step 4

[0222] (S)-5-methyl-3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole compound 3-5

[0223] (S)-5-methyl-3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]tri azole

[0224] Compounds 3-5 (yellow solid, 500 mg, yield 59%) were obtained by following the method used to synthesize compounds 1-3.

[0225] LC-MS m / z(ESI) = 291.04 [M+1].

[0226] Step 5

[0227] (S)-2-(4-(1-methyl-3-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyrrolo-1-yl)ethanol-1-ol compound 3

[0228] (S)-2-(4-(1-methyl-3-((2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-py razol-1-yl)ethan-1-ol

[0229] Following the synthesis of compound 1, compound 3 (yellow solid, 60 mg, yield 34%) was obtained.

[0230] 1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.29–8.25(m,1H),8.08–8.03(m,3H),7 .84(s,1H),7.32–7.22(m,2H),7.17-7.14(m,1H),4.98-4.93(m,1H),4.54-4 .47(m,1H),4.19-4.13(m,2H),4.11(s,3H),3.95-3.89(m,1H),3.80-3.74(m ,2H),3.32-3.25(m,2H),2.77–2.66(m,1H),2.36(s,3H),1.27-1.24(m,3H).

[0231] LC-MS m / z (ESI) = 509.24 [M+1]

[0232] Example 4

[0233] (R)-2-(4-(1-methyl-3-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyrrolo-1-yl)ethanol-1-ol compound 4

[0234] (R)-2-(4-(1-methyl-3-((2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-py razol-1-yl)ethan-1-ol

[0235]

[0236]

[0237] first step

[0238] (S)-4-methyl-3-((R)-2-methylpentan-4-ynyl)oxazolidin-2-one 4-2

[0239] (S)-4-methyl-3-((R)-2-methylpent-4-ynoyl)oxazolidin-2-one

[0240] Compound 4-2 (yellow solid, 451 mg, yield 61%) was obtained by following the method used to synthesize compound 3-2.

[0241] LC-MS m / z (ESI) = 196.09 [M+1].

[0242] Step 2

[0243] (R)-2-Methylpentan-4-yn-1-ol 4-3

[0244] (R)-2-methylpent-4-yn-1-ol

[0245] Compound 4-3 (yellow solid, 281 mg, yield 66%) was obtained by following the method used to synthesize compound 3-3.

[0246] LC-MS m / z (ESI) = 99.08 [M+1].

[0247] Step 3

[0248] (R)-2-Methyl-5-(4-methyl-3-nitrophenyl)pentan-4-yn-1-ol 3-4

[0249] (R)-2-methyl-5-(4-methyl-3-nitrophenyl)pent-4-yn-1-ol

[0250] Compound 4-3 (yellow solid, 281 mg, yield 66%) was obtained by following the method used to synthesize compound 3-3.

[0251] LC-MS m / z(ESI) = 267.03 [M+1].

[0252] Step 4

[0253] (R)-5-methyl-3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole compound 4-5

[0254] (R)-5-methyl-3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]tri azole

[0255] Compounds 4-5 (yellow solid, 256 mg, yield 63%) were obtained by the same method used to synthesize compounds 3-5.

[0256] LC-MS m / z(ESI) = 291.04 [M+1].

[0257] Step 5

[0258] (R)-2-(4-(1-methyl-3-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-pyrrolo-1-yl)ethanol-1-ol compound 4

[0259] (R)-2-(4-(1-methyl-3-((2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-8-yl)-1H-py razol-1-yl)ethan-1-ol

[0260] Following the synthesis of compound 1, compound 4 (yellow solid, 52 mg, yield 30%) was obtained.

[0261] 1 H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.27(s,1H),8.09–8.02(m,3H),7.84 (s,1H),7.32–7.22(m,2H),7.17-7.14(m,1H),4.99-4.92(m,1H),4.54-4.4 5(m,1H),4.20-4.14(m,2H),4.11(s,3H),3.97-3.88(m,1H),3.81-3.73(m, 2H),3.32-3.25(m,2H),2.76-2.67(m,1H),2.36(s,3H),1.27-1.24(m,3H).

[0262] LC-MS m / z(ESI) = 509.24 [M+1].

[0263] Example 5

[0264] N-(5-(6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine compound 5

[0265] N-(5-(6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0266]

[0267] first step

[0268] 2-((3-(3-bromo-4-methylphenyl)prop-2-yn-1-yl)oxy)ethanol-1-ol 5-2

[0269] 2-((3-(3-bromo-4-methylphenyl)prop-2-yn-1-yl)oxy)ethan-1-ol

[0270] Compound 5-1 (5.0 g, 16.89 mmol), ethoxypropynyl ether (2.0 g, 20.00 mmol), palladium dichloride (701.0 mg, 1.00 mmol), cuprous iodide (190.0 mg, 1.00 mmol), and triethylamine (10.1 g, 100.00 mmol) were dissolved in tetrahydrofuran (30 mL). After purging with nitrogen, the mixture was reacted at room temperature for 4 h. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 5-2 as a yellow solid, 2.1 g, yield 40%.

[0271] LC-MS m / z(ESI) = 269.01 [M+1].

[0272] Step 2

[0273] 3-(3-bromo-4-methylphenyl)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine 5-3

[0274] 3-(3-bromo-4-methylphenyl)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine

[0275] Following the synthesis of compounds 1-3, compound 5-3 (yellow solid, 1.1 g, yield 81%) was obtained.

[0276] LC-MS m / z(ESI) = 294.02 [M+1].

[0277] Step 3

[0278] N-(5-(6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine compound 5

[0279] N-(5-(6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0280] Following the synthesis of compound 1, using compound 5-3 and intermediate B, compound 5 (yellow solid, 70 mg, yield 67%) was obtained.

[0281] 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.14(s,1H),8.05(dd,3H),7.82(s,1H),7.29–7.19(m,2 H),7.14(d,1H),5.18(s,2H),4.49–4.41(m,2H),4.16–4.07(m,5H),3.87(s,3H),2.37(s,3H).

[0282] LC-MS m / z(ESI) = 481.21 [M+1].

[0283] Example 6

[0284] (S)-1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)-1H-pyrazololo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 6

[0285] (S)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydr o-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrid azin-3-amine

[0286]

[0287] first step

[0288] (R)-5-(3-bromo-4-methylphenyl)-2-methylpentan-4-yn-1-ol 6-1

[0289] (R)-5-(3-bromo-4-methylphenyl)-2-methylpent-4-yn-1-ol

[0290] Following the synthesis of compounds 1-2, compound 6-1 (yellow solid, 2.5 g, yield 96%) was obtained.

[0291] LC-MS m / z(ESI) = 267.03 [M+1].

[0292] Step 2

[0293] (S)-3-(3-bromo-4-methylphenyl)-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole 6-3

[0294] (S)-3-(3-bromo-4-methylphenyl)-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole

[0295] Following the synthesis of compounds 1-3, compound 6-2 (yellow solid, 2.1 g, 95% yield) was obtained.

[0296] LC-MS m / z(ESI) = 292.04 [M+1].

[0297] Step 3

[0298] (S)-1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)-1H-pyrazololo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 6

[0299] (S)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydr o-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrid azin-3-amine

[0300] Following the synthesis of compound 1, compound 6 (yellow solid, 66 mg, yield 72%) was obtained.

[0301] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.28(d,1H),8.08–8.01(m,3H),7.82(s,1H),7.29(dd,1H),7.23(d,1H),7.14(d,1H), 4.50(dd,1H),4.10(s,3H),3.96–3.89(m,1H),3.87(s,3H),3.33–3.27(m,2H),2.75-2.66(m,1H),2.36(s,3H),1.26(d,3H).

[0302] LC-MS m / z(ESI) = 479.23 [M+1].

[0303] Example 7

[0304] (R)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)-1H-pyrazololo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 7

[0305] (R)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0306]

[0307] first step

[0308] (S)-5-(3-bromo-4-methylphenyl)-2-methylpentan-4-yn-1-ol 7-1

[0309] (S)-5-(3-bromo-4-methylphenyl)-2-methylpent-4-yn-1-ol

[0310] Following the synthesis of compounds 1-2, compound 7-1 (yellow solid, 1.8 g, yield 89%) was obtained.

[0311] LC-MS m / z(ESI) = 267.03 [M+1].

[0312] Step 2

[0313] (R)-3-(3-bromo-4-methylphenyl)-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole 7-2

[0314] (R)-3-(3-bromo-4-methylphenyl)-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole

[0315] Following the synthesis of compounds 1-3, compound 7-2 was obtained as a yellow solid, 1.3 g, yield 88%.

[0316] LC-MS m / z(ESI) = 292.04 [M+1].

[0317] Step 3

[0318] (R)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)-1H-pyrazololo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 7

[0319] (R)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydr o-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrid azin-3-amine

[0320] Following the synthesis of compound 1, compound 7 (yellow solid, 76 mg, yield 77%) was obtained.

[0321] 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.27(d,1H),8.09–8.04(m,3H),7.82(s,1H),7.29(dd,1H),7.23(d,1H),7.13(d,1H), 4.52(dd,1H),4.11(s,3H),3.97–3.88(m,1H),3.90(s,3H),3.36–3.25(m,2H),2.79-2.68(m,1H),2.35(s,3H),1.24(d,3H).

[0322] LC-MS m / z(ESI) = 479.23 [M+1]

[0323] Example 8

[0324] (S)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 8

[0325] (S)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0326]

[0327] first step

[0328] (R)-5-(3-bromo-4-methylphenyl)-2-ethylpentan-4-yn-1-ol 8-1

[0329] (R)-5-(3-bromo-4-methylphenyl)-2-ethylpent-4-yn-1-ol

[0330] Following the synthesis of compounds 1-2, compound 8-1 was obtained as a yellow solid, 1.3 g, yield 84%.

[0331] LC-MS m / z(ESI) = 281.05 [M+1].

[0332] Step 2

[0333] (S)-3-(3-bromo-4-methylphenyl)-5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole 8-2

[0334] (S)-3-(3-bromo-4-methylphenyl)-5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]tri azole

[0335] Following the synthesis of compounds 1-3, compound 8-2 (yellow solid, 1.1 g, yield 89%) was obtained.

[0336] LC-MS m / z (ESI) = 306.05 [M+1].

[0337] Step 3

[0338] (S)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 8

[0339] (S)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphe nyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrida zin-3-amine

[0340] Following the synthesis of compound 1, compound 8 (yellow solid, 54 mg, yield 81%) was obtained.

[0341] 1 H NMR(400MHz,DMSO-d6)δ8.55(s,1H),8.28(d,1H),8.04(dd,3H),7.81(s,1H),7.32(dd,1H),7.24(d,1H),7.14(d,1H),4.51(dd,1H ),4.11(s,3H),4.03–3.92(m,1H),3.87(s,3H),3.28–3.12(m,2H),2.79-2.73(m,1H),2.36(s,3H),1.69-1.61(m,2H),0.96(t,3H).

[0342] LC-MS m / z(ESI) = 493.25 [M+1].

[0343] Example 9

[0344] (R)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 9

[0345] (R)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0346]

[0347] first step

[0348] (S)-5-(3-bromo-4-methylphenyl)-2-ethylpentan-4-yn-1-ol 9-1

[0349] (S)-5-(3-bromo-4-methylphenyl)-2-ethylpent-4-yn-1-ol

[0350] Following the synthesis of compounds 1-2, compound 9-1 (yellow solid, 1.7 g, yield 56%) was obtained.

[0351] LC-MS m / z(ESI) = 281.05 [M+1].

[0352] Step 2

[0353] (R)-3-(3-bromo-4-methylphenyl)-5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole 9-2

[0354] (R)-3-(3-bromo-4-methylphenyl)-5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]tri azole

[0355] Following the synthesis of compounds 1-3, compound 9-2 (yellow solid, 900 mg, yield 46%) was obtained.

[0356] LC-MS m / z (ESI) = 306.05 [M+1].

[0357] Step 3

[0358] (R)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 9

[0359] (R)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphe nyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrida zin-3-amine

[0360] Following the synthesis of compound 1, compound 9 (white solid, 40 mg, 50% yield) was obtained.

[0361] 1 H NMR(400MHz, DMSO-d6)δ8.55(s,1H),8.28(s,1H),8.06–8.01(m,3H),7.81(s,1H),7.35–7.28(m,1H),7.27–7.20(m,1H),7.15–7.13(m,1H),4.5 5–4.49(m,1H),4.11(s,3H),4.01–3.95(m,1H),3.87(s,3H),3.21–3.14 (m,1H),2.80–2.72(m,1H),2.36(s,3H),1.70–1.58(m,3H),0.96(t,3H).

[0362] LC-MS m / z(ESI) = 493.25 [M+1].

[0363] Example 10

[0364] 1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 10

[0365] 1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0366]

[0367] first step

[0368] 6-(3-bromo-4-methylphenyl)hex-5-yn-1-ol 10-1

[0369] (6-(3-bromo-4-methylphenyl)hex-5-yn-1-ol

[0370] Following the synthesis of compounds 1-2, compound 10-1 (yellow solid, 1.1 g, yield 88%) was obtained.

[0371] LC-MS m / z(ESI) = 267.03 [M+1].

[0372] Step 2

[0373] 3-(3-bromo-4-methylphenyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine 10-2

[0374] 3-(3-bromo-4-methylphenyl)-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridine

[0375] Following the synthesis of compounds 1-3, compound 10-2 (yellow solid, 0.9 g, yield 86%) was obtained.

[0376] LC-MS m / z(ESI) = 292.04 [M+1].

[0377] Step 3

[0378] 1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 10

[0379] 1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyridin-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0380] Following the synthesis of compound 1, compound 10 (yellow solid, 65 mg, yield 84%) was obtained.

[0381] 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.28(d,1H),8.07–8.02(m,3H),7.82(s,1H),7.32(dd,1H),7.25(d,1H),7.1 3(d,1H),4.36(t,2H),4.08(s,3H),3.87(s,3H),3.04(t,2H),2.37(s,3H),2.05-1.99(m,2H),1.94-1.88(m,2H).

[0382] LC-MS m / z(ESI) = 479.23 [M+1].

[0383] Example 11

[0384] N-(5-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine compound 11

[0385] N-(5-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0386]

[0387]

[0388] first step

[0389] (2-(2-(3-bromo-4-methylbenzoyl)hydrazino)-2-oxoethoxy)ethyl)tert-butyl carbamate 11-2

[0390] tert-butyl(2-(2-(2-(3-bromo-4-methylbenzoyl)hydrazineyl)-2-oxoethoxy)ethyl)carbamate

[0391] 5-tert-Butoxycarbonylamino-3-oxavaranic acid (437 mg, 1.99 mmol) was dissolved in tetrahydrofuran (20 mL), and propylphosphonic anhydride (2.5 g, 7.96 mmol) was added. The mixture was reacted at room temperature for 30 minutes. Then, 69a (500 mg, 2.19 mmol) and N,N-diisopropylethylamine (1.5 g, 11.94 mmol) were added, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction was quenched with saturated brine (40 mL), extracted with ethyl acetate (20 mL * 3), dried over anhydrous sodium sulfate, and distilled under reduced pressure to give the crude product. The crude product was subjected to column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 11-2 (yellow solid, 560 mg, yield 69%).

[0392] LC-MS m / z(ESI) = 430.09 [M+1].

[0393] Step 2

[0394] (2-((5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazol-2-yl)methoxy)ethyl)tert-butyl carbamate 11-3

[0395] tert-butyl(2-((5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazol-2-yl)methoxy)ethyl)carbamate

[0396] Compound 11-2 (560 mg, 1.36 mmol), p-toluenesulfonyl chloride (310 mg, 1.63 mmol), and triethylamine (412 mg, 4.08 mmol) were dissolved in dichloromethane (20 mL) and reacted at room temperature for 4 h. After the reaction was complete, the crude product was obtained by vacuum distillation. The crude product was then subjected to column chromatography (dichloromethane:methanol = 50:1) to give compound 11-3 (yellow solid, 520 mg, yield 93%).

[0397] LC-MS m / z(ESI) = 412.08 [M+1].

[0398] Step 3

[0399] 3-(3-bromo-4-methylphenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine compound 11-4

[0400] 3-(3-bromo-4-methylphenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine

[0401] Compound 11-3 (390 mg, 1.25 mmol) and triethylamine (380 mg, 3.76 mmol) were dissolved in toluene (20 mL) and reacted at 110 °C for 4 h. After the reaction was complete, the crude product was obtained by vacuum distillation. The crude product was then subjected to column chromatography (dichloromethane:methanol = 60:1) to give compound 11-4 (yellow solid, 120 mg, yield 33%).

[0402] LC-MS m / z(ESI) = 294.01 [M+1].

[0403] Step 4

[0404] N-(5-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine compound 11

[0405] N-(5-(5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0406] Following the synthesis of compound 1, compound 11 (yellow solid, 35 mg, yield 77%) was obtained.

[0407] 1 H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.31(d,1H),8.15(s,1H),8.08–8.02(m,2H),7.82(s,1H),7.38–7 .30(m,2H),7.14(d,1H),4.96(s,2H),4.24(t,2H),4.08(s,3H),4.04(t,2H),3.87(s,3H),2.42(s,3H).

[0408] LC-MS m / z(ESI) = 481.21 [M+1].

[0409] Example 12

[0410] N-(5-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 12

[0411] N-(5-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-methylphenyl)-1-meth yl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0412]

[0413]

[0414] first step

[0415] (4-(2-(3-bromo-4-methylbenzoyl)hydrazino)-4-oxobutyl)tert-butyl carbamate 12-1

[0416] The synthesis of tert-butyl(4-(2-(3-bromo-4-methylbenzoyl)hydrazineyl)-4-oxobutyl)carbamate followed the synthesis of compound 11-2 to give compound 12-1 (yellow solid, 420 mg, yield 89%).

[0417] LC-MS m / z(ESI) = 414.10 [M+1].

[0418] Step 2

[0419] (3-(5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazol-2-yl)propyl)tert-butyl carbamate 12-2

[0420] tert-butyl(3-(5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazol-2-yl)propyl)carbamate

[0421] Following the synthesis of compound 11-2, compound 12-3 (yellow solid, 410 mg, yield 78%) was obtained.

[0422] LC-MS m / z (ESI) = 396.09 [M+1].

[0423] Step 3

[0424] 3-(3-bromo-4-methylphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole compound 12-4

[0425] 3-(3-bromo-4-methylphenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

[0426] Following the synthesis of compound 11-3, compound 12-4 (yellow solid, 210 mg, yield 43%) was obtained.

[0427] LC-MS m / z(ESI) = 278.02 [M+1].

[0428] Step 4

[0429] N-(5-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 12

[0430] N-(5-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine, following the synthesis of compound 1, yielded compound 12 (yellow solid, 38 mg, 75% yield).

[0431] 1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.43(s,1H),8.13(s,1H),8.10–8.02(m,2H),7.82(s,1H),7.38 (d,2H),7.15(d,1H),4.28(t,2H),4.10(s,3H),3.87(s,3H),2.87(d,2H),2.74(t,2H),2.41(s,3H).

[0432] LC-MS m / z (ESI) = 465.22 [M+1]

[0433] Example 13

[0434] (S)-1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)-1H-pyrazololo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 13

[0435] (S)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydr o-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrid azin-3-amine

[0436]

[0437] first step

[0438] (S)-(5-(2-(3-bromo-4-methylbenzoyl)hydrazino)-5-oxopent-2-yl)tert-butyl carbamate compound 13-2

[0439] tert-butyl(S)-(5-(2-(3-bromo-4-methylbenzoyl)hydrazineyl)-5-oxopentan-2-yl)carbamate

[0440] Following the synthesis of compound 11-2, compound 13-2 (yellow solid, 481 mg, yield 48%) was obtained.

[0441] LC-MS m / z(ESI) = 428.11 [M+1].

[0442] Step 2

[0443] (S)-(4-(5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazol-2-yl)but-2-yl)tert-butyl carbamate compound 13-3

[0444] tert-butyl(S)-(4-(5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazol-2-yl)butan-2-yl)carbamate

[0445] Following the synthesis of compound 11-2, compound 13-3 was obtained (red solid, 430 mg, yield 93%).

[0446] LC-MS m / z(ESI) = 410.10[M+1].

[0447] Step 3

[0448] (S)-3-(3-bromo-4-methylphenyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole compound 13-4

[0449] (S)-3-(3-bromo-4-methylphenyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

[0450] Following the synthesis of compound 11-3, compound 13-4 (white solid, 150 mg, 50% yield) was obtained.

[0451] LC-MS m / z(ESI) = 292.04 [M+1].

[0452] Step 4

[0453] (S)-1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)-1H-pyrazololo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 13

[0454] (S)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydr o-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrid azin-3-amine

[0455] Following the synthesis of compound 1, compound 13 (white solid, 70 mg, yield 43%) was obtained.

[0456] 1 H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.38(s,1H),8.11(s,1H),8.08–8.04(m,2H),7.83(s,1H),7.41–7.30(m,2H), 7.17–7.13(m,1H),4.97–4.89(m,1H),4.10(s,3H),3.87(s,3H),3.03–2.80(m,3H),2.43–2.30(m,4H),1.32(d,3H).

[0457] LC-MS m / z(ESI) = 479.23 [M+1].

[0458] Example 14

[0459] (R)-1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)-1H-pyrazololo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 14

[0460] (R)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydr o-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrid azin-3-amine

[0461]

[0462] first step

[0463] (R)-(5-(2-(3-bromo-4-methylbenzoyl)hydrazino)-5-oxopent-2-yl)tert-butyl carbamate compound 13-2

[0464] tert-butyl(R)-(5-(2-(3-bromo-4-methylbenzoyl)hydrazineyl)-5-oxopentan-2-yl)carbamate

[0465] Following the synthesis of compound 11-2, compound 14-2 (yellow solid, 366 mg, yield 54%) was obtained.

[0466] LC-MS m / z(ESI) = 428.11 [M+1].

[0467] Step 2

[0468] (R)-(4-(5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazol-2-yl)but-2-yl)tert-butyl carbamate compound 14-3

[0469] tert-butyl(R)-(4-(5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazol-2-yl)butan-2-yl)carbamate

[0470] Following the synthesis of compound 11-2, compound 14-3 was obtained (yellow solid, 291 mg, yield 78%).

[0471] LC-MS m / z(ESI) = 410.10[M+1].

[0472] Step 3

[0473] (R)-3-(3-bromo-4-methylphenyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole compound 14-4

[0474] (R)-3-(3-bromo-4-methylphenyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole

[0475] Following the synthesis of compound 11-3, compound 14-4 (white solid, 101 mg, yield 44%) was obtained.

[0476] LC-MS m / z(ESI) = 292.04 [M+1].

[0477] Step 4

[0478] (R)-1-Methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)-1H-pyrazololo[3,4-d]pyrrolo[1,2-b]pyridazine-3-amine compound 14

[0479] (R)-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydr o-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyrid azin-3-amine

[0480] Following the synthesis of compound 1, compound 14 (white solid, 55 mg, yield 71%) was obtained.

[0481] 1 H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.43(s,1H),8.08(s,1H),8.06–8.03(m,2H),7.79(s,1H),7.48–7.33(m,2H), 7.18–7.10(m,1H),4.91–4.83(m,1H),4.45(s,3H),3.79(s,3H),3.23–2.91(m,3H),2.53–2.35(m,4H),1.31(d,3H).

[0482] LC-MS m / z(ESI) = 479.23 [M+1].

[0483] Example 15

[0484] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-3-yl) compound 15

[0485] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-meth yl-8-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0486]

[0487] first step

[0488] 5-(4-methyl-3-nitrophenyl)pentan-4-yn-1-ol 1-2

[0489] 5-(4-methyl-3-nitrophenyl)pent-4-yn-1-ol

[0490] Compound 15-1 (3.0 g, 10.10 mmol), 4-pentyn-1-ol (1.0 g, 12.12 mmol), palladium dichloride (354.5 mg, 0.51 mmol), cuprous iodide (96.2 mg, 0.51 mmol), and triethylamine (5.2 g, 50.50 mmol) were dissolved in tetrahydrofuran (30 mL). After purging with nitrogen, the mixture was reacted at room temperature for 3 h. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 8:1) to give compound 15-2 (yellow solid, 2.5 g, yield 98%).

[0491] LC-MS m / z(ESI) = 220.01 [M+1].

[0492] Step 2

[0493] 3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole 15-3

[0494] 3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole

[0495] 15-1 (100.0 mg, 0.40 mmol), diphenyl azidophosphate (131.0 mg, 0.48 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (72.5 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (5 mL) and reacted in a microwave oven at 150 °C for 3 h. After the reaction was complete, water was added, followed by extraction with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 15-3 (yellow solid, 98 mg, yield 87%).

[0496] LC-MS m / z(ESI) = 245.01 [M+1].

[0497] Step 3

[0498] 5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylaniline 15-4

[0499] 5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylaniline

[0500] 15-3 (500.0 mg, 2.01 mmol) and iron powder (344.3 mg, 6.15 mmol) were dissolved in glacial acetic acid (50 mL) and reacted at room temperature for 2 h. After the reaction was complete, a saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain crude product 15-4 (yellow solid, 378.5 mg, yield 88%).

[0501] LC-MS m / z(ESI) = 215.12 [M+1].

[0502] Step 4

[0503] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-methyl-8-(1-methyl-1H-pyrazol-3-yl) compound 15

[0504] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-1-meth yl-8-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine

[0505] 15-4 (100.0 mg, 0.47 mmol) was dissolved in pyridine (5 mL), and intermediate A (134.0 mg, 0.51 mmol) was added in portions. The reaction was carried out at room temperature for 2 h. After the reaction was complete, saturated sodium carbonate aqueous solution was added, followed by extraction with ethyl acetate, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (dichloromethane:methanol = 50:1) to give compound 15 (yellow solid, 151.4 mg, yield 74%).

[0506] 1 H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.38(dd,1H),8.53(s,1H),8.40(s,1H),8.12(d,1H),7.97(dd,1H),7.81(d,1H ),7.52(dd,1H),7.43(dd,1H),7.37(d,1H),4.35(t,2H),3.90(s,3H),3.11(t,2H),2.87–2.75(m,2H),2.30(s,3H).

[0507] LC-MS m / z(ESI) = 439.19 [M+1].

[0508] Example 16

[0509] (S)-6-(1-methyl-1H-pyrazol-5-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 16

[0510] (S)-6-(1-methyl-1H-pyrazol-5-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrr olo[1,2-c][1,2,3]triazol-3-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0511]

[0512] first step

[0513] (R)-4-methyl-3-((S)-2-methylpentan-4-ynyl)oxazolidin-2-one 16-2

[0514] (R)-4-methyl-3-((S)-2-methylpent-4-ynoyl)oxazolidin-2-one

[0515] Compound 16-1 (8.0 g, 34.3 mmol) was dissolved in tetrahydrofuran (100 mL) at -78 °C under nitrogen protection. Then, sodium bis(trimethylsilyl)amino (34 mL, 34.3 mmol) was added dropwise at the same temperature, and the reaction was carried out at -78 °C for 1 h. Next, 3-bromopropyne (12.2 g, 102.9 mmol) was added dropwise, and the temperature was slowly raised to 0 °C and then to room temperature, and the reaction was allowed to proceed overnight. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic phase was evaporated to dryness. The crude product was subjected to column chromatography (petroleum ether:ethyl acetate = 8:1) to give compound 16-2 (yellow oily liquid, 5.4 g, yield 58%). The product did not precipitate on MS. When developed with potassium permanganate, the product preferentially showed a yellow color to the starting material.

[0516] LC-MS m / z(ESI) = 196.19 [M+1].

[0517] Step 2

[0518] (S)-2-Methylpentan-4-yn-1-ol 16-3

[0519] (S)-2-methylpent-4-yn-1-ol

[0520] Lithium aluminum hydride (2.27 g, 59.8 mmol) was dissolved in tetrahydrofuran (100 mL) under nitrogen protection. The solution was cooled to 0 °C, and then compound 16-2 (5.40 g, 19.9 mmol) was slowly added dropwise while the temperature was gradually raised to room temperature. The reaction was allowed to proceed for 3 h. A TLC test was performed using petroleum ether:ethyl acetate (5:1). Potassium permanganate was used for color development to indicate the reaction was complete. The reaction was quenched with 1 mL of water, 3 mL of sodium hydroxide (15%) solution, and 1 mL of water. Ethyl acetate and magnesium sulfate were then added, and the mixture was stirred thoroughly. The solution was filtered and evaporated to dryness to obtain the crude product, which was used directly in the next step. Compound 16-3 (yellow solid, 5.40 g, 95% yield).

[0521] LC-MS m / z(ESI) = 99.11 [M+1].

[0522] Step 3

[0523] (R)-2-Methyl-5-(4-methyl-3-nitrophenyl)pent-4-yn-1-ol 16-4

[0524] (R)-2-methyl-5-(4-methyl-3-nitrophenyl)pent-4-yn-1-ol

[0525] Compound 16-3 (2.0 g, 20.3 mmol) was reacted with 4-bromo-2-nitrotoluene (2.2 g, 10.2 mmol) in the same manner as the synthesis of compound 16-2 to give compound 16-4 (yellow oily liquid, 900 mg, yield 37.8%).

[0526] LC-MS m / z(ESI) = 234.15 [M+1].

[0527] Step 4

[0528] (S)-5-methyl-3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole compound 16-5

[0529] (S)-5-methyl-3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]tri azole

[0530] Compound 16-5 (yellow solid, 500 mg, yield 59%) was obtained by following the method used to synthesize compound 15-3.

[0531] LC-MS m / z(ESI) = 259.19 [M+1].

[0532] Step 5

[0533] (S)-2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)aniline compounds 16-6

[0534] (S)-2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)aniline

[0535] Compound 16-6 (a grayish-white solid, 300 mg, yield 60%) was obtained by following the method used to synthesize compound 15-4.

[0536] LC-MS m / z(ESI) = 229.20 [M+1].

[0537] Step 6

[0538] (R)-6-(1-methyl-1H-pyrazol-5-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 16

[0539] (R)-6-(1-methyl-1H-pyrazol-5-yl)-N-(2-methyl-5-(5-methyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0540] Compound 16 (white solid, 200 mg, yield 48%) was obtained by the same method used to synthesize compound 15.

[0541] 1 H NMR(400MHz,DMSO-d6)9.67(s,1H),9.15(s,1H),8.74(s,1H),8.31(s,1H),8.22(d,1H),8.06(s,1H),7.84–7.75(m,2H),7.5 0(dd,1H),7.35(d,1H),4.52(dd,1H),3.97–3.91(m,1H),3.90(s,3H),3.30(dd,2H),2.72(q,1H),2.30(s,3H),1.26(d,3H).

[0542] LC-MS m / z(ESI) = 453.22 [M+1].

[0543] Example 17

[0544] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-oxa-6-azaspiro[3,4]octane-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 17

[0545] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0546]

[0547] first step

[0548] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-oxa-6-azaspiro[3,4]octane-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 17

[0549] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-ox a-6-azaspiro[3.4]octan-6-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0550] Intermediate C (200 mg, 0.459 mmol), 2-oxa-6-aza-spiro[3,4]octane (78 mg, 0.688 mmol), cesium carbonate (450 mg, 1.38 mmol), and Brett Phos. Pd. G3 (42 mg, 0.046 mmol) were dissolved in 1,4-dioxane (20 mL), and the mixture was heated to 120 °C for 8 h under nitrogen protection. The reaction progress was monitored by TLC.

[0551] The reaction was stopped, the solvent was evaporated, and the mixture was concentrated under reduced pressure and then subjected to column chromatography (dichloromethane:methanol = 50:1) to give compound 17 (yellow solid, 70 mg, yield 32%).

[0552] 1H NMR(400MHz,DMSO-d6)9.51(s,1H),8.55(s,1H),8.07(d,1H),7.93(d,1H),7.83(d,1H),7.48(dd,1H),7.33(d,1H),7.25(dd,1 H),4.61(d,2H),4.55(d,2H),4.34(t,2H),3.56(s,2H),3.29(d,2H),3.10(t,2H),2.85–2.74(m,2H),2.29(d,3H),1.23(d,2H).

[0553] LC-MS m / z(ESI) = 470.22 [M+1].

[0554] Example 18

[0555] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 18

[0556] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(4-hy droxy-4-methylpiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0557]

[0558] first step

[0559] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 18

[0560] N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(4-hydroxy-4-methylpiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0561] Compound 18 (yellow solid, 28 mg, yield 13%) was obtained by the same method used to synthesize compound 17.

[0562] 1 H NMR(400MHz,DMSO-d6)9.56(s,1H),8.60(s,1H),8.20(s,1H),8.05(d,1H),7.82(d,1H),7.55–7.45(m,2H),7.33 (d,1H),4.39–4.31(m,3H),3.27(d,2H),3.09(dd,4H),2.85–2.74(m,2H),2.28(s,3H),1.61(d,4H),1.18(s,3H).

[0563] LC-MS m / z(ESI) = 472.25 [M+1].

[0564] Example 19

[0565] (R)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 19

[0566] (R)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphe nyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0567]

[0568] first step

[0569] (S)-2-Ethyl-5-(4-methyl-3-nitrophenyl)pentan-4-yn-1-ol 19-1

[0570] (S)-2-ethyl-5-(4-methyl-3-nitrophenyl)pent-4-yn-1-ol

[0571] Following the method for compound 15-2, compound 19-1 (yellow solid, 2.1 g, yield 96%) was obtained.

[0572] LC-MS m / z(ESI) = 248.12 [M+1].

[0573] Step 2

[0574] (R)-5-ethyl-3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole 5-2

[0575] (R)-5-ethyl-3-(4-methyl-3-nitrophenyl)-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triaz ole

[0576] Following the method for compound 15-3, compound 19-2 (yellow liquid, 1.8 g, yield 85%) was obtained.

[0577] LC-MS m / z(ESI) = 273.13 [M+1].

[0578] Step 3

[0579] (R)-5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylaniline 19-3

[0580] (R)-5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylaniline was used to give compound 19-3 (yellow solid, 1.5 g, 80% yield) according to the method of compound 15-4.

[0581] LC-MS m / z(ESI) = 243.15 [M+1].

[0582] Step 4

[0583] (R)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 19

[0584] (R)-N-(5-(5-ethyl-5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0585] Following the method for compound 15, compound 19 was obtained (white solid, 20 mg, yield 46%).

[0586] 1 H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.15(s,1H),8.74(s,1H),8.31(s,1H),8.2 4–8.18(m,1H),8.06(s,1H),7.83–7.75(m,2H),7.54–7.48(m,1H),7.38–7.32(m ,1H),4.57–4.49(m,1H),4.03–3.97(m,1H),3.90(s,3H),3.29–3.25(m,1H),2.8 1–2.73(m,1H),2.30(s,3H),2.06–1.94(m,1H),1.70–1.61(m,2H),0.96(t,3H).

[0587] LC-MS m / z(ESI) = 467.22 [M+1].

[0588] Example 20

[0589] (R)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 20

[0590] (R)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0591] first step

[0592] (R)-(5-(2-(4-methyl-3-nitrobenzoyl)hydrazino)-5-oxopent-2-yl)tert-butyl carbamate compound 20-3

[0593] tert-butyl(R)-(5-(2-(4-methyl-3-nitrobenzoyl)hydrazineyl)-5-oxopentan-2-yl)carbamate

[0594] Compound 20-2 (577.8 mg, 2.53 mmol) and T3P (2.9 g, 9.21 mmol) were dissolved in THF (30 mL) at 0 °C and stirred at 0 °C for 30 min. Then, compound 20-1 (500 mg, 2.30 mmol) and DIPEA (1.80 g, 13.80 mmol) were added, and the reaction was allowed to proceed overnight at room temperature. The reaction progress was monitored by TLC.

[0595] The reaction was stopped, quenched with water, extracted with EA, and the organic phase was collected. The organic phase was then eluted by column chromatography with DCM:MeOH = 50:1 to give compound 20-3 (yellow solid, 481 mg, yield 48%).

[0596] LC-MS m / z (ESI) = 395.19 [M+1].

[0597] Step 2

[0598] (R)-(4-(5-(4-methyl-3-nitrophenyl)-1,3,4-oxadiazol-2-yl)but-2-yl)tert-butyl carbamate compound 20-4

[0599] tert-butyl(R)-(4-(5-(4-methyl-3-nitrophenyl)-1,3,4-oxadiazol-2-yl)butan-2-yl)carbamate

[0600] Compound 20-3 (481 mg, 1.12 mmol) was dissolved in DCM (20 mL), and then TsCl (257.7 mg, 1.25 mmol) and TEA (341.9 mg, 3.37 mmol) were added. The reaction was carried out at room temperature for 8 h, and the reaction progress was monitored by TLC.

[0601] The reaction was stopped, and direct column chromatography was performed to elute with DCM:MeOH = 50:1 to give compound 20-4 (red solid, 430 mg, yield 93%).

[0602] LC-MS m / z(ESI) = 377.17 [M+1].

[0603] Step 3

[0604] (R)-4-(5-(4-methyl-3-nitrophenyl)-1,3,4-oxadiazol-2-yl)but-2-amine compound 20-5

[0605] (R)-4-(5-(4-methyl-3-nitrophenyl)-1,3,4-oxadiazol-2-yl)butan-2-amine

[0606] Compound 20-4 (430 mg, 1.05 mmol) was dissolved in EA (8 mL), and then 1,4-Dioxane solution of 4 mol / L HCl (24 mL) was added. The reaction was carried out at room temperature, and the reaction progress was monitored by TLC.

[0607] The reaction was stopped, a small amount of DCM was added, and the mixture was filtered to give compound 20-5 (white solid, 330 mg, yield 98%).

[0608] LC-MS m / z(ESI) = 277.13 [M+1].

[0609] Step 4

[0610] (R)-5-methyl-3-(4-methyl-3-nitrophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole compound 20-6

[0611] (R)-5-methyl-3-(4-methyl-3-nitrophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]tri azole

[0612] Compound 20-5 (318 mg, 0.77 mmol) and TEA (314.9 mg, 2.3 mmol) were dissolved in toluene (50 mL) and reacted at 110 °C for 2 days. The reaction progress was monitored by TLC.

[0613] The reaction was stopped, the solvent was evaporated, and column chromatography was performed to elute with DCM:MeOH = 50:1, giving compound 20-6 (white solid, 150 mg, yield 50%).

[0614] LC-MS m / z(ESI) = 259.11 [M+1].

[0615] Step 5

[0616] (R)-2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)aniline compound 20-7

[0617] (R)-2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)anili ne

[0618] Following the synthesis of compound 15-4, compound 20-7 (yellow liquid, 120 mg, yield 76%) was obtained.

[0619] LC-MS m / z(ESI) = 229.14 [M+1].

[0620] Step 6

[0621] (R)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide compound 20

[0622] (R)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0623] Following the synthesis of compound 15, compound 20 (white solid, 28 mg, yield 45%) was obtained.

[0624] 1 H NMR(400MHz, DMSO-d6)δ9.70(s,1H),9.15(s,1H),8.74(s,1H),8.31(s,1H),8.23–8.17(m,1H),8.05(s,1H),7.96–7.89(m,1H),7.83–7.76(m ,1H),7.62–7.57(m,1H),7.47–7.39(m,1H),5.00–4.90(m,1H),3.89(s ,3H),3.05–2.84(m,3H),2.35(s,3H),2.34–2.28(m,2H),1.28(d,3H).

[0625] LC-MS m / z (ESI) = 454.21 [M+1]

[0626] Example 21

[0627] (R)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(3-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide compound 21

[0628] (R)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(3-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide

[0629]

[0630]

[0631] first step

[0632] (R)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(3-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide compound 21

[0633] (R)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(3-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide

[0634] Compound 21 (white solid, 70 mg, yield 61%) was obtained by the same method used to synthesize compound 17.

[0635] 1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.65(s,1H),8.22(d,1H),8.17–8.09(m,1H),7.84(d,1H),7.56(d,1H),7.51(d,1H),7.3 7(d,1H),4.37(t,2H),3.96–3.77(m,3H),3.72–3.60(m,2H),3.17–3.08(m,4H),2.87–2.76(m,2H),2.31(s,3H),1.02(d,3H).

[0636] LC-MS m / z(ESI) = 458.22 [M+1].

[0637] Example 22

[0638] (S)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide compound 22

[0639] (S)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide

[0640]

[0641]

[0642] first step

[0643] (S)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide compound 22

[0644] (S)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide

[0645] Compound 22 (pale yellow solid, 70 mg, yield 58%) was obtained by the same method used to synthesize compound 17.

[0646] 1 H NMR(400MHz,DMSO)δ9.59(s,1H),8.49(s,1H),8.30(d,1H),8.22–8.12(m,1H),7.88(d,1H),7.60(d,1H),7.57(d,1H),7.42 (d,1H),4.41(t,2H),3.98–3.79(m,3H),3.73–3.65(m,2H),3.20–3.11(m,4H),2.87–2.79(m,2H),2.35(s,3H),1.12(d,3H).

[0647] LC-MS m / z(ESI) = 458.23 [M+1].

[0648] Example 23

[0649] (R)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-(hydroxymethyl)morpholine)-pyrazolo[1,5-a]pyridine-3-carboxamide compound 23

[0650] (R)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-(hydroxymethyl)morpholino)pyrazolo[1,5-a]pyridine-3-carboxamide

[0651]

[0652]

[0653] first step

[0654] (R)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-(hydroxymethyl)morpholine)-pyrazolo[1,5-a]pyridine-3-carboxamide compound 23

[0655] (R)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(2-(hydroxymethyl)morpholino)pyrazolo[1,5-a]pyridine-3-carboxamide

[0656] Compound 23 (yellow solid, 31 mg, yield 21%) was obtained by the same method used to synthesize compound 17.

[0657] 1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.62(s,1H),8.20(d,1H),8.09(d,1H),7.82(s,1H),7.55(d,1H),7.48(d,1H),7.34(d,1H),4.79(t,1 H),4.34(t,2H),4.05–3.92(m,1H),3.72–3.57(m,3H),3.55–3.43(m,3H),3.10(t,2H),2.84–2.69(m,3H),2.48–2.44(m,1H),2.28(s,3H).

[0658] LC-MS m / z(ESI) = 474.22 [M+1].

[0659] Example 24

[0660] (S)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(3-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide compound 24

[0661] (S)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(3-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide

[0662]

[0663]

[0664] first step

[0665] (S)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(3-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide compound 24

[0666] (S)-N-(5-(5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazol-3-yl)-2-methylphenyl)-6-(3-methylmorpholino)pyrazolo[1,5-a]pyridine-3-carboxamide

[0667] Compound 24 (yellow solid, 25 mg, yield 23%) was obtained by the same method used to synthesize compound 17.

[0668] 1 H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.62(s,1H),8.19(d,1H),8.14–8.06(m,1H),7.81(d,1H),7.53(d,1H),7.48(d,1H),7.3 4(d,1H),4.34(t,2H),3.93–3.74(m,3H),3.69–3.57(m,2H),3.14–3.05(m,4H),2.84–2.73(m,2H),2.28(s,3H),0.99(d,3H).

[0669] LC-MS m / z(ESI) = 458.22 [M+1].

[0670] Biological tests

[0671] I. Cell Proliferation Experiment

[0672] Experimental objective: The purpose of this test item is to measure the inhibitory effect of the compound on the proliferation of M07e-cKIT and SW579-PDGF Rα cells.

[0673] 1. Experimental instruments and reagents:

[0674] 1.1 Instruments:

[0675]

[0676]

[0677] 1.2 Reagents:

[0678]

[0679] 2. Experimental Methods:

[0680] 2.1 Cell Culture: Human giant cell leukemia cells M07e (Nanjing Kebai Biotechnology Co., Ltd., CBP60791) were cultured in RPMI-1640 medium containing 20% ​​FBS, 1% penicillin antibiotics, and 10 ng / mL GM-CSF factor (Beyotime, P5286) at 37℃ and 5% CO2. Human thyroid squamous cell carcinoma cells SW579 (BNCC, BNCC100182) were cultured in L-15 medium containing 10% FBS and 1% penicillin antibiotics at 37℃ and 5% CO2.

[0681] 2.2 Cell proliferation experiment:

[0682] a) Seed cells in the logarithmic growth phase at a density of 3000 cells / well in 96-well plates and incubate overnight in a cell culture incubator.

[0683] b) The following day, the cells were treated with the appropriate drugs, starting with 3 μM of the compound and diluting it 3-fold, for a total of 9 concentration gradients. A blank control group and a negative control group were also set up. After adding the compound to the M07e cell treatment group, the cells were incubated in an incubator for 2 hours, followed by stimulation with rh-SCF (proteintech, HZ-1024) at a final concentration of 100 ng / mL.

[0684] c) Place the drug-treated well plate in an incubator (37°C, 5% CO2) and incubate for 4 days.

[0685] d) Add CellCounting-Lite 2.0 Luminescent solution (Vazyme, DD1101-03), place on a constant temperature shaker and shake for 2 min, then incubate at room temperature in the dark for 10 min.

[0686] e) Place the sample in an ELISA reader, shake for 5 seconds, and then perform a chemiluminescence reading.

[0687] f) Statistically analyze the data using Excel and Graphpad Prism, derive the dose-response curve using nonlinear S-curve regression, and calculate the IC50 from it. 50 value.

[0688] 3. Experimental Results and Discussion:

[0689] Table 1 KIT IC 50 result

[0690]

[0691]

[0692] Note: KIT IC 50 If (nM)≤10, it is grade A; 10 <KIT IC 50 If (nM) ≤ 100, it is grade B; 100 <KIT IC 50 If (nM) ≤ 1000, it is grade C; 1000 <KIT IC 50 (nM) is grade D.

[0693] Table 2 Results of Selectivity Multiples

[0694] Embodiments Rank 1 B 2 B 11 B 12 A 14 A

[0695] Note: Selectivity factor = PDGFRαIC 50(nM) / KIT IC 50 (nM); if the selectivity multiple is ≥15, it is grade A; if 5≤selectivity<15, it is grade B; if 3≤selectivity multiple<5, it is grade C; if selectivity multiple<3, it is grade D.

[0696] Experimental conclusions: The compounds of this invention exhibit varying degrees of activity against KIT at the cellular level and varying degrees of selectivity against PDGFRα.

[0697] This invention specification provides a detailed description of specific embodiments. Those skilled in the art should recognize that the above embodiments are exemplary and should not be construed as limiting the invention. For those skilled in the art, various improvements and modifications can be made to the invention without departing from its principles, and the resulting technical solutions also fall within the scope of protection of the claims of this invention.

Claims

1. A compound of formula (I), or all its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or eutectics: in: A is selected from 5-6 quinary aromatic rings or 5-6 heterocyclic aromatic rings; B is selected from 5-15 membered heterocyclic or fused bicyclic rings; C is selected from a fused ring formed by a bicyclic or tricyclic ring, wherein the fused ring contains 1 to 6 heteroatoms selected from N, O or S; X1 is selected from single bonds, carbonyl groups, or alkenes; R1 and R4 are selected from H, -NR5R6, -OR7, C1-C6 alkyl, halogen, -CN, olefin, alkyne, C1-C6 haloalkyl, 3-5 member halocycloalkyl, 3-10 member cycloalkyl, 3-10 member heterocycloalkyl, 5-10 member aryl or 5-10 member heteroaryl, and R1 and R4 are optionally further substituted by one or more R8s; R2 is selected from one or more H, C1-C6 alkyl, halogen, -OH, -OCH3, -NR5R6, -OR7, -CN, olefin, alkyne, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R2 is optionally further substituted by one or more R8. R3 is selected from one or more C1-C6 alkyl groups, C1-C6 haloalkyl groups, or halogens; R5, R6, R7, and R8 are each independently selected from H, -OH, C1-C6 alkyl, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the C1-C6 alkyl is optionally further substituted by one or more H, halogen, -OH, -CN, olefin, alkyne, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl.

2. The compound according to claim 1 or all its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, wherein the compound is selected from the compounds represented by formula (I-1): in: Ring A is selected from 5-6 quinary aromatic rings or 5-6 heterocyclic aromatic rings; Ring B is selected from 5-15 membered heterocycles; R1 is selected from H, C1-C6 alkyl, 3-5 membered cycloalkyl, C1-C6 haloalkyl, and 3-5 membered halocycloalkyl; R4 is selected from H, -NR5R6, -OR7, C1-C6 alkyl, halogen, -CN, olefin, alkyne, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R4 is optionally further substituted by one or more R8. R2 is selected from one or more H, -NR5R6, -OR7, C1-C6 alkyl, halogen, -CN, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R2 is optionally further substituted by one or more R8. R3 is selected from one or more C1-C3 alkyl groups, C1-C3 haloalkyl groups, or halogens; R5, R6, R7, and R8 are each independently selected from H, -OH, C1-C6 alkyl, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the C1-C6 alkyl is optionally further substituted by one or more H, halogen, -OH, -CN, olefin, alkyne, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl.

3. The compound according to claim 1 or all its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, wherein the compound is selected from the compounds shown in formula (I-2): R4 is selected from H, -NR5R6, -OR7, C1-C6 alkyl, halogen, -CN, olefin, alkyne, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R4 is optionally further substituted by one or more R8. R2 is selected from one or more H, C1-C6 alkyl, halogen, -OH, -OCH3, -NR4R5, -OR6, -CN, olefin, alkyne, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl or 5-10 membered heteroaryl, and R2 is optionally further substituted by one or more R8. B is selected from B1 is selected from 5-6-membered heterocyclic alkyl groups, and B2 is selected from 3-10-membered (hetero)cyclic alkyl groups or 5-10 (hetero)cyclic alkyl groups; R3 is selected from one or more H, C1-C6 alkyl, C1-C6 haloalkyl or halogen; R5, R6, R7, and R8 are each independently selected from H, C1-C6 alkyl, halogen, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl, wherein the C1-C6 alkyl is optionally further substituted by one or more H, halogen, -OH, -CN, olefin, alkyne, 3-10 membered heterocycloalkyl, 5-10 membered aryl, or 5-10 membered heteroaryl; X2 and X3 are each independently selected from C or N.

4. The compound according to claim 2, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein: Ring A is selected from benzene ring, pyridine ring, pyrimidine ring, pyrrole ring, furan ring or thiophene ring; Ring B is selected from 5-10 element double rings or 10-15 element triple rings; among them, any two connecting rings in the triple rings can be fused or screwed together; R1 is selected from H and C1-C6 alkyl groups; R4 is selected from H, C1-C6 alkyl, 3-10 heterocyclic alkyl or 5-10 heteroaryl, and R4 is optionally further substituted by one or more R8; R2 is selected from one or more H, C1-C6 alkyl, halogen, hydroxyl or methoxy; R3 is selected from one or more H, C1-C3 alkyl groups, or halogens.

5. The compound according to claim 4, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein: Ring A is selected from a benzene ring or a pyrrole ring; Ring B is selected from R1 is selected from -CH3; R4 is selected from When R8 is selected from H, -CH3, -CH2OH or -CH2CH2OH.

6. The compound according to claim 3, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein, B1 and B2 together form a 5-8 element double ring or a 10-15 element triple ring; wherein, the two connecting rings in the triple ring can be fused or bridged; further, B is selected from... Q 1 Q 2 Q 3 Each is independently selected from C, O, or N.

7. The compound according to claim 6, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein, B is selected from Q 1 Q 2 Q 3 Each is independently selected from C, O, or N.

8. The compound according to claim 7, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein, B is selected from 9. The compound according to claim 3, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein, R1 is selected from H, 3-10-membered heterocyclic alkyl or 5-10-membered heteroaryl, and R1 is optionally further substituted by one or more R8; R2 is selected from one or more H, C1-C6 alkyl, halogen, hydroxyl or methoxy; R3 is selected from one or more H, C1-C3 alkyl groups, or halogens.

10. The compound according to claim 9, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein, R1 is selected from H, When; R8 is selected from H, -CH3, -CH2OH or -CH2CH2OH.

11. The compound according to any one of claims 1, 2, or 4-5, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from:

12. The compound according to any one of claims 1, 3, or 6-10, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from:

13. A pharmaceutical composition comprising: (1) The compound according to any one of claims 1-12, or its stereoisomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or cocrystals; and (2) Pharmaceutically acceptable carriers and / or excipients.

14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition comprises: (1) The compound according to any one of claims 1-13, or its stereoisomers, solvates, prodrugs, metabolites, deuterated products, pharmaceutically acceptable salts or cocrystals; (2) One or more other active ingredients may be selected; and (3) Pharmaceutically acceptable carriers and / or excipients.

15. The use of the compound of claims 1-13, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, or the pharmaceutical composition of claim 14 or 15, in the treatment of c-kit kinase-related diseases.

16. The use of the compound of claims 1-13, or its stereoisomers, solvates, prodrugs, metabolites, deuterated derivatives, pharmaceutically acceptable salts or cocrystals, or the pharmaceutical composition of claim 14 or 15, in the preparation of a medicament for treating c-kit kinase-related diseases.

17. The application according to claim 16 or 17, wherein the c-kit kinase-related disease is a tumor or an autoimmune disease.

18. The application according to claim 16 or 17, wherein the tumor includes gastrointestinal stromal tumor, systemic mastocytosis, acute myeloid leukemia, or melanoma.

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