8-Oxo-3-azabicyclo[3.2.1]octane compounds and their salts, and their preparation and use

Abstract

Provided are 8-oxa-3-azabicyclo[3.2.1]octane compounds of formula (I) as ATR inhibitors, processes for their preparation, pharmaceutical compositions containing them, and their use for treating or preventing ATR-related diseases. TIFF2024527044000257.tif51146

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims priority to Chinese Patent Application for Invention No. 202110860428.3 with a filing date of July 27, 2021, and Chinese Patent Application for Invention No. 202210779302.8 with a filing date of July 1, 2022.

[0002] The present invention relates to the field of medicinal chemistry, specifically to 8 - oxa - 3 - azabicyclo[3.2.1]octane compounds as ATR inhibitors, methods for preparing the same, pharmaceutical compositions containing the same, and their use for treating or preventing ATR - related diseases.

Background Art

[0003] Due to environmental factors such as ultraviolet rays and X - rays, and internal factors such as reactive oxygen species, human cells are continuously exposed to DNA damage events. In cancer cells, there is a high level of DNA replication stress (a marker of cancer), which is driven by oncogene promoters or externally induced by DNA - damaging drugs or ionizing radiation (IR). The persistence of replication stress causes DNA to be cleaved, tumor cells to suffer severe DNA damage, and the said DNA damage and replication stress are the causes of genomic instability.

[0004] If DNA damage is not repaired sufficiently high, it will cause high toxicity to cells and lead to cell death. To ensure the integrity of the eukaryotic cell genome, biological pathways collectively called DDR (DNA damage response) have evolved to recognize and transmit signals and repair DNA damage. ATR (ataxia - telangiectasia mutated and Rad3 - related kinase), ATM (ataxia - telangiectasia mutated kinase), and DNA - PK (DNA - dependent protein kinase), which are the main components of DDR, play functions in repairing DNA damage in response to different DNA damages. Among them, ATM and DNA - PK mainly respond to DNA double - strand breaks, and ATR mainly responds to replication stress.

[0005] ATR is a member of the phosphatidylinositol kinase-related kinase (PIKK) protein family, and its major target is CHK1. When ATR is activated by many DNA damages, especially replication stress, ATR transmits DNA damage signals by phosphorylating CHK1, arrests the cell cycle at the S phase or G2 / M, performs damage repair, alleviates the replication stress of cells, and resumes replication after stress removal.

[0006] In tumor cells, there is higher DNA damage and replication stress compared to healthy proliferating cells, and DNA repair by ATR is more necessary for replication survival and maintenance of cell division. Therefore, by inhibiting ATR, the repair function of tumor cells can be inhibited, DNA damage and replication stress increase and become irreparable, and ultimately tumor cells can be killed, but it has no or little effect on healthy proliferating cells. This is the basis for the application of ATR inhibitors in cancer treatment, and in recent years, ATR inhibition has become an important approach in cancer treatment.

[0007] Standard cancer treatments such as radiotherapy and chemotherapy exert their therapeutic effects by inducing DNA damage, but are particularly toxic to proliferating cells. Also, the existence of DNA damage repair mechanisms limits the effects of these treatments, thereby causing drug resistance to chemotherapy and radiotherapy drugs. By inhibiting ATR, increasing replication stress, and increasing DNA damage, the sensitivity of tumor cells to these DNA damage-inducing therapies can be enhanced, contributing to the overcoming of drug resistance of radiotherapy or chemotherapy drugs by damage repair, and can be used in the treatment of tumor patients with gene mutations or chemotherapy resistance. The dosage of chemotherapy drugs or radiotherapy drugs can be reduced, and the toxicity to the blood and gastrointestinal organ systems can be reduced.

[0008] Therefore, for cancer cells with increased replication stress or cancer cells with damaged or defective activity of other DNA damage repair pathways, ATR inhibitors can be used to increase replication stress and induce tumor cell death. Indeed, ATR inhibitors have synthetic lethal activity against p53-mutated tumors or tumors that have lost ATM function, and have been shown to have a synergistic effect when combined with multiple replication stress / DNA damage-inducing chemotherapeutic agents such as platinum, ionizing radiation, and PARP inhibitors.

[0009] Furthermore, since ATR is also an important member of the DNA damage checkpoint, ATR inhibition can also prevent cancer development and limit the amplification of original cancer cells by activating oncogenes.

[0010] In recent years, several ATR inhibitors (e.g., WO2017202748, CN111848605A, WO2020087170, WO2020049017) have been developed. However, it is still very difficult to develop new and potent ATR inhibitors. The high identity with the PIKK kinase family and related lipid kinases such as phosphatidylinositol 3-kinase (PI3KS) and mTOR increases the risk of inhibiting other kinases, which may increase toxicity or offset the therapeutic effect of ATR inhibition. In addition, the application of some ATR inhibitors is also limited by their physicochemical properties, pharmacokinetic properties, and drug interactions.

[0011] Therefore, there is still a need in the art for novel selective ATR inhibitors having enhanced ATR inhibitory activity, particularly improved physicochemical properties, improved metabolic stability, improved pharmacokinetic properties (oral availability), and / or minimized CYP450 inhibition. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0012] The inventors of the present invention have confirmed through research that the compounds of the present invention exhibit sufficient ATR inhibitory activity, show good performance in in vivo and / or in vitro pharmacokinetic experiments, and exhibit improved drug formability and improved bioavailability. Therefore, the compounds of the present invention not only achieve the purpose of preventing or treating ATR-related diseases, but also the prepared drugs are expected to provide improved absorbability, improved therapeutic effects at equivalent doses, or equivalent effects at lower doses, and / or reduce possible side effects. Accordingly, the present invention also provides the use of the compounds of the present invention in the preparation of drugs for preventing or treating ATR-related diseases, pharmaceutical compositions containing said compounds, and methods for preventing and / or treating ATR-related diseases by administering said compounds.

Means for Solving the Problems

[0013] Therefore, in one aspect of the present invention, there is provided a compound of formula (I), its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates.

Chemical formula

[0014] In another aspect of the present invention, there is provided a compound of formula (I) of the present invention, its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates having ATR inhibitory activity and for treating or preventing ATR-related diseases as a drug, particularly as an ATR inhibitor.

[0015] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient. In one specific aspect, the pharmaceutical composition may further contain another therapeutically active ingredient suitable for use in combination with the compound of the present invention. In one specific aspect, there is provided a pharmaceutical combination product, such as a kit, containing the compound of the present invention and another active agent.

[0016] In another aspect of the present invention, there is provided the use of a compound of the present invention or a pharmaceutical composition comprising the same for preventing or treating an ATR-related disease in a mammal, particularly a human.

[0017] In another aspect of the present invention, there is provided a method for inhibiting ATR in vivo or in vitro, which comprises contacting an effective amount of a compound of the present invention with the ATR.

[0018] In another aspect of the present invention, there is provided a method for preventing or treating an ATR-related disease in an individual, such as a mammal, particularly a human, which comprises administering an effective amount of a compound of the present invention or a pharmaceutical composition comprising the same as described herein.

[0019] In another aspect of the present invention, there is provided the use of the above-mentioned compound of the present invention or a pharmaceutical composition comprising the same in the preparation of a drug for preventing or treating an ATR-related disease.

[0020] In another aspect, there is provided a method for synthesizing a compound of the present invention, and representative synthetic schemes and routes are shown below.

[0021] Other objects and advantages of the present invention will become apparent to those skilled in the art upon reading the following detailed description.

BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] DETAILED DESCRIPTION DEFINITIONS Unless otherwise indicated, the terms used in the specification and claims have the meanings set forth below. When a particular term or phrase is not specifically defined, that term or phrase should not be considered to be uncertain or unclear, but should be understood according to the general meaning in the art and in the context of this specification.

[0023] Many of the groups defined herein are optionally substituted, and the list of substituents shown in this definitional section is merely illustrative and not exhaustive, nor is it intended to limit substituents defined elsewhere in this specification and the claims.

[0024] As used herein, the term "treat" means administering one or more of the compounds of the invention described herein to a subject, such as a mammal, such as a human, suffering from a disease or having symptoms of a disease, to cure, alleviate, reduce, or affect the disease or the symptoms of the disease. In certain embodiments of the invention, the disease is an ATR-related disease as defined below, particularly a tumor or cancer.

[0025] As used herein, the term "prevent" is well known in the art and means administering one or more of the compounds of the invention described herein to a subject, such as a mammal, such as a human, suspected of having or prone to having an ATR-related disease as defined herein, particularly cancer or a tumor, so as to reduce the risk of developing the defined disease. The term "prevent" includes the use of compounds of the invention prior to the diagnosis or determination of clinical and / or pathological symptoms.

[0026] As used herein, the terms "inhibit" and "reduce," or any variation of these terms, mean the ability of a bioactive agent to reduce the signaling activity of a target by directly or indirectly interacting with the target, and mean any measurable decrease or complete inhibition of the target activity. For example, the amount of reduction in activity (e.g., ATR activity) compared to normal may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therefrom.

[0027] As used herein, the term "selective inhibition" means the ability of a bioactive agent to preferentially reduce the signal transduction activity of a target over the signal activity deviated from the target by directly or indirectly interacting with the target. In the compounds of the present invention, in relation to other kinases with high identity such as the PIKK kinase family, related lipid kinases such as phosphatidylinositol 3-kinase (PI3KS) and mTOR, the activity of ATR can be selectively inhibited, thereby reducing the toxicity or offsetting of the ATR inhibitory effect that may be caused by the simultaneous action on other kinases. For example, the present invention has at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therefrom, better inhibition of the activity of ATR compared to another specific kinase, or has at least 1-, 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or 500-fold better activity against ATR compared to the activity against another specific kinase.

[0028] As used herein, the terms "cancer" or "tumor" mean neoplastic cell growth and proliferation, and all precancerous cells, cancer cells, and tissues, whether malignant or benign. For the compounds, methods, pharmaceutical compositions, pharmaceutical combinations, and uses of the present invention, said cancer or tumor includes, but is not limited to, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, lung cancer, leukemia, bladder cancer, gastric cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterine cancer , liver carcinoma, acoustic neuroma, oligodendroglioma, meningioma of the brain (spinal cord), neuroblastoma, eye cancer.

[0029] Accordingly, the "anticancer effect" or "antitumor effect" described in this specification includes, but is not limited to, the effects on response rate, disease progression time, and survival rate. The antitumor effects of the compounds, their pharmaceutical uses, and methods of the present invention include, but are not limited to, inhibition of tumor growth, delay of tumor growth, regression of tumors, atrophy of tumors, prolongation of the time of regrowth of tumors after treatment cessation, delay of disease progression, and prevention of tumor occurrence.

[0030] As used herein, the term "therapeutically effective amount" means an amount sufficient to reduce or completely relieve the symptoms or other adverse effects of a disease, reverse, completely stop, or delay the progression of symptoms, or reduce the risk of symptom exacerbation when administered to an individual for treating the disease, and the "effective amount" may vary depending on the compound, the disease and its severity, the age, weight, etc. of the individual to be treated.

[0031] As used herein, the term "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from a disease (e.g., the diseases described herein) or normal individuals. The "non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles), and mammals, such as non-human primates, domestic animals and / or domesticated animals (e.g., sheep, dogs, cats, dairy cows, pigs, etc.).

[0032] As used herein, the term "ATR-related disease" means a disease in which ATR activity promotes the occurrence and progression of the disease, or in which inhibition of ATR reduces the incidence of the disease, reduces or eliminates the disease state. In the context of the present invention, "ATR-related disease" preferably refers to an ATR-mediated disease, and more preferably can refer to cancer or tumor. As described herein, ATR kinase inhibitors should have therapeutic or prophylactic value for the following diseases. Hematological malignancies such as leukemia (including chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia), multiple myeloma, lymphoid malignancies (such as lymphoma, Hodgkin's disease, non-Hodgkin lymphoma), myelodysplastic syndrome, and solid tumors such as cancer, sarcoma and its metastases, such as breast cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, bronchioloalveolar carcinoma), central nervous system tumors (such as glioma, embryonal neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, and teratoma), gastrointestinal cancer (such as gastric cancer, esophageal cancer, liver cancer, bile duct cancer, colorectal cancer, small intestine cancer, pancreatic cancer), skin cancer, melanoma, thyroid cancer, bone cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma (such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal tissue cancer, gastrointestinal stromal tumor, Kaposi's sarcoma), and pediatric cancer (such as rhabdomyosarcoma and neuroblastoma).

[0033] The compounds of the present invention are particularly useful for the treatment of patients suffering from lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcoma, head and neck cancer, central nervous system tumors and their metastases, and acute myeloid leukemia.

[0034] As used herein, the term "pharmaceutical composition" or "pharmaceutical preparation" means a composition comprising one or more compounds of formula (I) of the present invention, or stereoisomers, tautomers, stable isotope derivatives, pharmaceutically acceptable salts or solvates thereof, and a pharmaceutically acceptable excipient or carrier generally acceptable in the art, and can be in solid, semi-solid, liquid or gaseous form.

[0035] As used herein, the term "pharmaceutical combination" means that, for achieving the object of the present invention, the compounds of the present invention can be used in combination with other active agents. The other active agents may be one or more additional compounds of the present invention, or may be a second compound or additional compounds (e.g., a third compound) that are compatible with the compounds of the present invention, i.e., do not adversely affect each other or have complementary activities. Such active agents are present in appropriately combined amounts effective to achieve the desired object. The other active agents may be co-administered with the compounds of the present invention in a single pharmaceutical composition, or may be administered separately in distinct units different from the compounds of the present invention, e.g., in the form of a kit, and when administered separately, may be administered simultaneously or sequentially. The sequential administration may be carried out in close proximity or remotely in terms of time.

[0036] As used herein, the term "pharmaceutically acceptable" means molecular entities and compositions that are approved by, or are approvable by, the corresponding agencies in each country, or are described in generally recognized pharmacopoeias for use in animals, more specifically in humans, or do not produce undesirable, allergic, or other side effects when administered in appropriate amounts to animals such as humans.

[0037] As used herein, the term "pharmaceutically acceptable excipient or carrier" means one or more compatible solid or liquid fillers or gel substances that are pharmaceutically inert, compatible with other components in the composition, acceptable for administration to warm-blooded animals such as humans, and used as a carrier or vehicle in the dosage form of the compounds of the present invention, and examples thereof include cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., magnesium stearate), calcium sulfate, vegetable oils, polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tweens), wetting agents (e.g., sodium dodecyl sulfate, etc.), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, etc., but are not limited thereto.

[0038] As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmaceutical activity of the parent compound. Specifically, such salts may be non-toxic and may be inorganic acid addition salts, organic acid addition salts, or base addition salts. Specifically, such salts include (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or acetic acid, propionic acid, caproic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, mesylic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucic acid and other organic acids, and (2) salts formed when acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth metal ions, aluminum ions, etc., or coordinated to organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc. For example, the general principles and techniques for preparing pharmaceutical salts described in Berge et al., Pharm ScL, 66, 1-19 (1977) are known to those skilled in the art.

[0039] As used herein, the term "stereoisomer" means an isomer formed from at least one asymmetric center. Racemic mixtures, single enantiomers, diastereomers, and individual diastereomers can be produced in compounds having one or more, for example, 1, 2, 3, or 4 asymmetric centers. Certain molecules can also exist as geometric isomers (cis / trans). The compounds of the present invention can also exist as a mixture of two or more structurally different forms in a rapid equilibrium state, generally called tautomers, and representative examples include keto-enol, phenol-ketone, nitroso-oxime tautomers, etc. Note that the scope of the present invention includes all such isomers and mixtures in any proportion thereof (for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, etc.).

[0040] As used herein, the term "solvate" means a solvate addition form containing a stoichiometric or non-stoichiometric solvent, and any solvate form of the compounds of the present invention, for example, a solvate with water such as a hydrate, or a solvate with an organic solvent such as methanol, ethanol, or acetonitrile, that is, a methanol solvate, an ethanol solvate, or an acetonitrile solvate, respectively; or any polymorphic form is included. Such solvates of the compounds of the present invention also include solvates of pharmaceutically acceptable salts of the compounds of the present invention.

[0041] As used herein, the term "prodrug" means a compound having a solubility group that is decomposed by a solvent or changed to a compound having pharmaceutical activity in vivo under physiological conditions. Prodrugs include acid derivatives known to those skilled in the art, such as esters produced by reacting a parent acid with a suitable alcohol, amides produced by reacting a parent acid compound with a substituted or unsubstituted amine, acid anhydrides, or mixed acid anhydrides. Simple aliphatic or aromatic esters, amides, and acid anhydrides derived from the side-chain acid groups of the compounds of the present invention are particularly suitable prodrugs. Certain such prodrugs are the C 1~8 alkyl, C 2~8An alkenyl, optionally substituted C 6~10 aryl and (C 6~10 aryl)-(C 1~4 alkyl) ester.

[0042] As used herein, the term "isotope variant" means a compound having non-natural ratio isotopes on one or more atoms constituting the compound. The compounds of the present invention can contain non-natural ratio atomic isotopes on one or more atoms constituting the compound, thereby forming isotope variants, which are intended to be included within the scope of the present invention regardless of whether they are radioactive. Examples of isotopes and pharmaceutically acceptable salts thereof that can be incorporated into the compounds of the present invention include isotopes of hydrogen (e.g., 2H, 3H); isotopes of carbon (e.g., 11C, 13C, and 14C); isotopes of chlorine (e.g., 36Cl); isotopes of fluorine (e.g., 18F); isotopes of iodine (e.g., 123I and 125I); isotopes of nitrogen (e.g., 13N and 15N); isotopes of oxygen (e.g., 15O, 17O, and 18O); isotopes of phosphorus (e.g., 32P); isotopes of sulfur (e.g., 35S), but are not limited thereto. It should be noted that the isotope variants of the compounds of the present invention can usually be prepared by conventional methods using appropriate isotope variants suitable for the reagents.

[0043] In the structural formula of the compound represented by the general formula (I) herein

Chemical formula

[0044] Used in the structural formula or structural fragment of the compounds herein

Chemical formula

Chemical formula

[0045] used in the structural fragments according to this specification

Chem.

[0046] As used herein, the term "halo" or "halogen" means fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). Preferred halo is fluorine or chlorine.

[0047] As used herein, the term "halogen-substituted" group is intended to include monohalo or polyhalo groups, where one or more (e.g., 2, 3, 4, 5, or 6) of the same or different halogens replace one or more (e.g., 2, 3, 4, 5, or 6) of the hydrogens of the group.

[0048] As used herein, the term "cyano" means a -CN group.

[0049] As used herein, the term "hydroxy" means -OH.

[0050] As used herein, the term "oxo" means =O.

[0051] As used herein, the term "alkyl" means a straight-chain or branched saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. Specifically, alkyl has 1 to 10 carbon atoms, for example, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. For example, the term "C1-C6 alkyl" as used herein refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, secondary butyl or tertiary butyl), pentyl (including n-pentyl, isoamyl, neopentyl), n-hexyl, 2-methylpentyl, etc. A particular alkyl has 1 to 3 carbon atoms.

[0052] As used herein, the term "alkoxy" means an -O-alkyl group, and alkyl has the meaning described herein. Specifically, this term is -O-C 1~6 alkyl group, more specifically -O-C 1~3 alkyl. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, neopentyloxy), hexyloxy (including n-hexyloxy, isohexyloxy), etc. A particular alkoxy has 1 to 3 carbon atoms.

[0053] As used herein, the term "alkylene" means a saturated straight-chain or branched divalent hydrocarbon group, alone or in combination with other groups. For example, the term "C 1~3 alkylene" refers to an alkylene having 1 to 3 carbon atoms such as methylene, ethylene, propylene, 1-methylethylene, 2-methylethylene, etc.

[0054] As used herein, the term "cycloalkyl" means a monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure having a specific number of ring atoms. Cycloalkyl has 3 to 12 carbon atoms (i.e., C3-C 12(cycloalkyl), for example C 3~10 cycloalkyl, C 3~8 cycloalkyl, C 3~6 cycloalkyl, C 5~6 It may be cycloalkyl. Examples of suitable cycloalkyls include monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or polycycles (e.g., bicyclic) including spiro rings, fused systems or bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1.1]heptyl, or bicyclo[3.2.1]octyl, but are not limited thereto.

[0055] As used herein, the term "aryl" means a monovalent aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom in an aromatic ring system. Specifically, aryl refers to a monocyclic or fused polycyclic aromatic ring structure having a specific number of ring atoms. Specifically, this term includes groups containing 6 to 14, such as 6 to 10, preferably 6 ring members. Specific aryls are phenyl and naphthyl, and the most specific aryl is phenyl.

[0056] As used herein, the term "substituted" or "substitued" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on a particular atom are replaced by a particular group, provided that it does not exceed the current normal valence bond of the particular atom and forms a stable compound, and combinations of substituents and variables are only permitted if such combinations form a stable compound.

[0057] As used herein, the term "optionally substituted" means that, unless otherwise indicated, the group is unsubstituted or may be substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more) of the substituents listed for that group, and the substituents may be the same or different.

[0058] Unless otherwise specified in the paragraphs, in the definition of the compounds of the present invention, C n~n+m or C n ~C mは、 includes various cases of n to n + m carbons. For example, C 1~6 includes C1, C2, C3, C4, C5 and C6, and also includes any range from n to n + m. For example, C 0~6 includes C1, C2, C3, C4, C5, C6, C 0~1 , C 0~2 , C 0~3 , C 0~4 , C 0~5 , C 1~2 , C 1~3 , C 1~4 , C 2~3 and so on. Similarly, the n-membered to n + m-membered rings in the definition of the compounds of the present invention may have any number of ring atoms from n to n + m, and mean including any range from n to n + m members.

[0059] As used in this specification and the following claims, the terms "comprising", "including", and "containing" mean "including but not limited to", and for example, do not exclude other additives, components, integers, or steps. Note that this term includes technical aspects of "consisting of the said components, steps, or conditions" or "substantially consisting of the said components, steps, or conditions".

[0060] In this specification, when describing the compounds of the present invention, pharmaceutical compositions containing them, pharmaceutical combinations, and related uses and methods, the dosages involved are, unless otherwise defined in the specification, not based on their salts, hydrates, or solvates, etc., but should be understood to be based on the weight of the free form.

[0061] The compounds of the present invention Unless otherwise indicated, terms such as "compound of the invention" and "compound of the present invention" used throughout this application include compounds of formula (I), their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, and prodrugs as defined in various embodiments of this specification and their specific or preferred embodiments. The stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates, and prodrugs are described in the above-defined sections. Preferably, the compound of the present invention is in the free form of the compound of formula (I) or its pharmaceutically acceptable salt or solvate, and most preferably, it is in the free form of the compound of formula (I) or its pharmaceutically acceptable salt.

[0062] Some compounds of the present invention can exist in polymorphic or amorphous forms, and these are also within the scope of the present invention. When in solid crystalline form, the compound of formula (I) may be in a co-crystalline form with other chemical substances, and this specification includes all of these co-crystals.

[0063] When chiral centers are present, the compounds of the present invention can exist in the form of a single enantiomer or a mixture of enantiomers, and those skilled in the art can determine the stable and practicable isomeric forms of the compounds of the present invention. According to one embodiment, there is provided a compound of formula (I) or its pharmaceutically acceptable salt which is a single enantiomer with an enantiomeric excess (%ee) of >95, >98%, or >99%. Preferably, the single enantiomer exists with an enantiomeric excess (%ee) of >99%.

[0064] The compounds of the present invention also include possible N-oxides, and those skilled in the art can determine the stable and practicable N-oxides of the compounds of the present invention. The compounds of the present invention also include metabolites of the compounds of the present invention, that is, substances formed by oxidation, reduction, hydrolysis, amidation, esterification, etc. in vivo when the compounds of the present invention are administered, and can be identified by techniques known to those skilled in the art.

[0065] Specifically, in one aspect, the present invention provides a compound of formula (I), its stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates. [Chemical formula] (where A1, A2 and A5 are each independently C or N, A3 and A4 are each independently CR4, N or NR5, X is O, C(R6)2 or NR7, Y is N or CR8, R1, R2 and R3 are each independently H, -OH, oxo, halogen, CN, -C 1~6 alkyl or -O-C 1~6 alkyl, where the C 1~6 alkyl is optionally substituted with one or more halogens or hydroxy, or R1 and R2 are linked together to form a C 1~3 alkylene bridge, R4 is H, oxo, halogen or -C 1~6 alkyl, where the C 1~6 alkyl is optionally substituted with one or more halogens or hydroxy, R5 is H or -C 1~6 alkyl, where the C 1~6 alkyl is optionally substituted with one or more halogens, R6 are each independently H, halogen, CN, -OH, -NH2, -NH-C 1~6 alkyl, -N(C 1~6 alkyl)2, -C 1~6 alkyl, -O-C 1~6 alkyl, -C(O)-C 1~6 alkyl, -C(O)-C 3~6 cycloalkyl, -SO2-C 1~6 alkyl, -SO2-C 3~6 cycloalkyl, -SO-C 1~6 alkyl, -SO-C 3~6 cycloalkyl, C 6~10 aryl or C3~6 is cycloalkyl, where -C 1~6 alkyl, C 6~10 aryl or C 3~6 cycloalkyl is optionally substituted with one or more of halogen, hydroxy, -O-C 1~6 alkyl, -C 1~6 alkyl, or C alkyl substituted with halogen or hydroxy 1~6 and is optionally substituted with one or more of the alkyl substitutions, R7 is H, -C 1~6 alkyl, -C(O)-C 1~6 alkyl, -C(O)-C 3~6 cycloalkyl, -SO2-C 1~6 alkyl, -SO2-C 3~6 cycloalkyl, -SO-C 1~6 alkyl or -SO-C 3~6 cycloalkyl, where -C 1~6 alkyl or C 3~6 cycloalkyl is optionally substituted with one or more of halogen, hydroxy, -O-C 1~6 alkyl, -C 1~6 alkyl, or C alkyl substituted with halogen or hydroxy 1~6 and is optionally substituted with one or more of the alkyls, R8 is H, -OH or halogen, and n and m are each independently an integer from 0 to 4.) In one embodiment of the compound of formula (I), at least two of A1, A2, A3, A4 and A5 are N or NR5, and the rest are C or CR4, preferably two of them are N or NR5, and the rest are C or CR4.

[0066] In one embodiment of the compound of formula (I), the 6-membered-5-membered heteroaryl moiety containing A1 - A5 has a structure selected from the following.

Chemical formula

[0067] In one embodiment of the compound of formula (I), the 6-membered-5-membered heteroaryl moiety containing A1 - A5 is [Chemical formula] selected from, preferably [Chemical formula] selected from, more preferably [Chemical formula] is.

[0068] In one embodiment of the compound of formula (I), the 6-membered-5-membered heteroaryl moiety containing A1 to A5 is preferably [Chemical formula] is.

[0069] In one embodiment of the compound of formula (I), the 6-membered-5-membered heteroaryl moiety containing A1 to A5 is preferably [Chemical formula] is.

[0070] In one embodiment of the compound of formula (I), the 6-membered-5-membered heteroaryl moiety containing A1 to A5 is preferably [Chemical formula] is.

[0071] In one embodiment of the compound of formula (I), the 6-membered-5-membered heteroaryl moiety containing A1 to A5 is preferably [Chemical formula] is.

[0072] In one embodiment of the compound of formula (I), R4 is H.

[0073] In one embodiment of the compound of formula (I), R4 is oxo or halogen.

[0074] In one embodiment of the compound of formula (I), R4 is -C 1~6 alkyl, optionally substituted with one or more halogens or hydroxy, for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl or t-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, -CH2F, -CHF2, -CF3, -C2F5, -CH2CF3, -CH2Cl, -CH2CH2CF3, -CH(CF3)2, -CH2OH or -CH2CH2OH, but not limited thereto. Preferably, R4 is -C 1~3 alkyl, such as methyl, ethyl, propyl, isopropyl, and most preferably, methyl.

[0075] In an embodiment of the aforementioned compound of formula (I), R4 is preferably H.

[0076] In one embodiment of the compound of formula (I), R5 is H.

[0077] In one embodiment of the compound of formula (I), R5 is -C 1~6 alkyl, optionally substituted with one or more halogens, for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl or t-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, -CH2F, -CHF2, -CF3, -C2F5, -CH2CF3, -CH2Cl, -CH2CH2CF3 or -CH(CF3)2, but not limited thereto In an embodiment of the aforementioned compound of formula (I), R5 is preferably C 1~3 alkyl, such as methyl, ethyl, propyl, isopropyl, and most preferably, methyl.

[0078] In one embodiment of the compound of formula (I), X is O.

[0079] In one embodiment of the compound of formula (I), X is C(R6)2, where each R6 is H.

[0080] In one embodiment of the compound of formula (I), X is C(R6)2, where one of the R6s is H and the other is halogen, CN, -OH, -C 1~6 alkyl, -O-C 1~6 alkyl, -C(O)-C 1~6 alkyl, -C(O)-C 3~6 cycloalkyl, -SO2-C 1~6 alkyl, -SO2-C 3~6 cycloalkyl, -SO-C 1~6 alkyl, -SO-C 3~6 cycloalkyl, C 6~10 aryl or C 3~6 cycloalkyl, selected from, where the -C 1~6 alkyl, C 6~10 aryl or C 3~6 cycloalkyl is optionally substituted with one or more of halogen, hydroxy, -O-C 1~6 alkyl, -C 1~6 alkyl, or -C 1~6 alkyl substituted with halogen or hydroxy.

[0081] In one embodiment of the compound of formula (I), X is C(R6)2, where one of the R6s is H and the other is selected from halogen, for example, fluorine, chlorine, bromine, iodine.

[0082] In one embodiment of the compound of formula (I), X is C(R6)2, where one of the R6s is H and the other is OH, CN, NH2, -NH-C 1~6 alkyl, -N(C 1~6 alkyl)2, for example, OH, CN, -NH2, -NH-CH3, -NH-CH2-CH3, -N(CH3)2, -N(CH2-CH3)2, -N(CH3)(CH2-CH3), but not limited thereto.

[0083] In one embodiment of the compound of formula (I), X is C(R6)2, where one of R6 is H and the other is -C 1~6 alkyl, optionally substituted with one or more of halogen, hydroxy or -O-C 1~6 alkyl, such as, but not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl or t-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, -CH2F, -CHF2, -CF3, -C2F5, -CH2CF3, -CH2Cl, -CH2CH2CF3, -CH(CF3)2, -CH2OH, -CH2CH2OH, -CH2OCH3, and -CH2OCH2CH3.

[0084] In one embodiment of the compound of formula (I), X is C(R6)2, where one of R6 is H and the other is -O-C 1~6 alkyl, where the -C 1~6 alkyl is optionally substituted with one or more of halogen, hydroxy or -O-C 1~6 alkyl, such as, but not limited to, -OCH3, -OCH2CH3, -OCF3, -OCH2CF3, -OCH2CH2OH, -OCH2CH2OCH3.

[0085] In one embodiment of the compound of formula (I), X is C(R6)2, where one of R6 is H and the other is -C(O)-C 1~6 alkyl, -C(O)-C 3~6 cycloalkyl, -SO2-C 1~6 alkyl, -SO2-C 3~6 cycloalkyl, -SO-C 1~6 alkyl, -SO-C 3~6 cycloalkyl, C 6~10 aryl or C 3~6Cycloalkyl, such as, -C(O)-CH3, -C(O)-CH2CH3, C(O)-CH2CH2CH3, -C(O)-CH(CH3)2, -C(O)-cyclopropyl, -C(O)-cyclopentyl, -C(O)-cyclohexyl, -SO2-CH3, -SO2-CH2CH3, SO2-CH2CH2CH3, SO2-CH(CH3)2, -SO2-cyclopropyl, -SO2-cyclopentyl, -SO-CH3, -SO-CH2CH3, SO-CH2CH2CH3, SO-CH(CH3)2, -SO-cyclopropyl, -SO-cyclopentyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, but not limited thereto, where -C 1~6 alkyl, C 6~10 aryl or C 3~6 cycloalkyl is optionally substituted with one or more of halogen, hydroxy, -O-C 1~6 alkyl, -C 1~6 alkyl, or -C 1~6 alkyl substituted with halogen or hydroxy, and the substituents are, for example, fluorine, chlorine, bromine, iodine, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -OCH(CH3)2, -CF3, -CH2CF3, -CH2OH, -CH2CH2OH, but not limited thereto.

[0086] In one embodiment of the compound of formula (I), X is C(R6)2, where R6 are each independently, -C 1~6 alkyl, halogen, CN, -OH, -NH2, -NH-C 1~6 alkyl, -N(C 1~6 alkyl)2, -O-C 1~6 alkyl, where -C 1~6 alkyl is optionally substituted with one or more of halogen, hydroxy or -O-C 1~6 alkyl, for example, two R6 are both halogen, both C optionally substituted with said (for example halogen) 1~6One is alkyl, one is halogen, and the other is C optionally substituted with the above (e.g., halogen) 1~6 One is alkyl, one is OH or -O-C 1~6 One is alkyl, and the other is C optionally substituted with the above (e.g., halogen) 1~6 One is alkyl, one is NH2, -NH-C 1~6 One is alkyl or -N(C 1~6 One is alkyl)2, and the other is C optionally substituted with the above (e.g., halogen) 1~6 One is alkyl, or one is CN, and the other is C optionally substituted with the above (e.g., halogen) 1~6 One is alkyl, but not limited thereto.

[0087] X is, for example, CF2, CCl2, CBr2, CFCl, C(CH3)2, C(CH2CH3)2, C(CH3)(CH2CH3), C(CF3)(CF3), C(CH3)(CF3), C(CH3)(CH2OH), C(CH3)(CH2OCH3), C(CH3)(F), C(CH3)(OCH3), C(CH3)(OH), C(CH3)(NH2), -C(CH3)(NHCH3)-, but not limited thereto.

[0088] In one embodiment of the compound of formula (I), X is C(R6)2, where R6 are each independently selected from H or halogen, for example, both are H, or both are halogen, for example both are F.

[0089] In one embodiment of the compound of formula (I), X is NR7, and R7 is H.

[0090] In one embodiment of the compound of formula (I), X is NR7, and R7 is -C 1~6 One is alkyl, halogen, hydroxy or -O-C 1~6Optionally substituted with one or more alkyls, for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl or t-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, -CH2F, -CHF2, -CF3, -C2F5, -CH2CF3, -CH2Cl, -CH2CH2CF3, -CH(CF3)2, -CH2OH, -CH2CH2OH, -CH2OCH3 and -CH2OCH2CH3, and preferably, R7 is methyl, ethyl, propyl or isopropyl.

[0091] In one embodiment of the compound of formula (I), X is NR7 and R7 is -C(O)-C 1~6 alkyl, -C(O)-C 3~6 cycloalkyl, -SO2-C 1~6 alkyl, -SO2-C 3~6 cycloalkyl, -SO-C 1~6 alkyl or -SO-C 3~6 cycloalkyl, for example, -C(O)-CH3, -C(O)-CH2CH3, C(O)-CH2CH2CH3, -C(O)-CH(CH3)2, -C(O)-cyclopropyl, -C(O)-cyclobutyl, -C(O)-cyclopentyl, -C(O)-cyclohexyl, -SO2-CH3, -SO2-CH2CH3, SO2-CH2CH2CH3, SO2-CH(CH3)2, -SO2-cyclopropyl, -SO2-cyclobutyl, -SO2-cyclopentyl, -SO2-cyclohexyl, -SO-CH3, -SO-CH2CH3, SO-CH2CH2CH3, SO-CH(CH3)2, -SO-cyclopropyl, -SO-cyclobutyl, -SO-cyclopentyl or -SO-cyclohexyl, but not limited thereto, and each -C 1~6 alkyl or C 3~6 cycloalkyl is halogen, hydroxy, -O-C 1~6 alkyl, -C 1~6 alkyl, or C substituted with halogen or hydroxy 1~6Optionally substituted with one or more alkyls, and the substituents are, for example, fluorine, chlorine, bromine, iodine, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O CH(CH3)2, -CF3, -CH2CF3, -CH2OH, -CH2CH2OH, -CH2OCH3, and -CH2OCH2CH3, but are not limited thereto.

[0092] In one embodiment of the compound of formula (I), X is NR7, and R7 is H, -C 1~6 alkyl, and -C(O)-C 1~6 selected from alkyl, preferably -C 1~6 alkyl, or preferably -C(O)-C 1~6 alkyl, such as methyl, ethyl, propyl, isopropyl, -C(O)-CH3, -C(O)-CH2CH3, C(O)-CH2CH2CH3 or -C(O)-CH(CH3)2, but is not limited thereto.

[0093] In an embodiment of the aforementioned compound of formula (I), X is preferably -O-, -NH-, -N(C 1~6 alkyl)-, -CH2-, -C(halogen)2-, for example -O-, -NH-, -N(CH3)-, -CH2-, -C(F)2-.

[0094] In an embodiment of the aforementioned compound of formula (I), X is preferably -O-, -N(C 1~6 alkyl)-, -N(CO-C 1~6 alkyl)-, -CH2-, -CH(C 1~6 alkyl)-, -C(C 1~6 alkyl)2- or -C(halogen)2-, for example -O-, -N(CH3)-, -N(CO-CH3)-, -CH2-, -C(F)2-.

[0095] In one embodiment of the compound of formula (I), Y is N.

[0096] In one embodiment of the compound of formula (I), Y is CR8, where R8 is H.

[0097] In one embodiment of the compound of formula (I), Y is CR8, where R8 is OH.

[0098] In one embodiment of the compound of formula (I), Y is CR8, where R8 is halogen, such as fluorine, chlorine, bromine, iodine, preferably F.

[0099] In the embodiment of the aforementioned compound of formula (I), Y is preferably N, or CR8, where R8 is OH, and more preferably Y is N.

[0100] In one embodiment of the compound of formula (I), the six-membered ring containing X and Y

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0101] In one embodiment of the compound of formula (I), R1 and R2 are each independently H.

[0102] In one embodiment of the compound of formula (I), R1 and R2 are each independently -OH, oxo, halogen, CN, -C 1~6Alkyl or -O-C 1~6 is alkyl, where C 1~6 alkyl is optionally substituted with one or more of halogen or hydroxy, for example, -OH, oxo, fluorine, chlorine, bromine, iodine, CN, -CH3, -CH2CH3, -O-CH3, -O-CH2CH3, -CF3, -CH2CF3, -CH2OH, -CH2CH2OH, but is not limited thereto, preferably, -CH3, -CF3 or -CH2CH3, most preferably, -CH3.

[0103] In one embodiment of the compound of formula (I), R1 and R2 are linked together to form C 1~3 an alkylene bridge, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-.

[0104] In one embodiment of the compound of formula (I), R1 and R2 are linked together to form C 1~3 an alkylene bridge, and the cross-linking mode is, for example,

Chemical formula

Chemical formula

[0105] In the embodiment of the aforementioned compound of formula (I), preferably, R1 and R2 are each independently H, -CH3, -CH2CH3, or R1 and R2 are linked together to form C 1~3 an alkylene bridge, preferably, a C2 ethylene bridge.

[0106] In one embodiment of the compound of formula (I), m and n are both 0.

[0107] In one embodiment of the compound of formula (I), one of m and n is 0 and the other is 1. In this case, R1 or R2 is not hydrogen and may be linked to the ortho-position of Y or the ortho-position of X on the ring, preferably linked to the ortho-position of Y. For example, R1 or R2 is C 1~6 alkyl, such as, but not limited to, -CH3, -CH2CH3 or -CH(CH3)2. Preferably, R1 or R2 is -CH3 and is linked to the ortho-position of Y or the ortho-position of X on the ring, preferably linked to the ortho-position of Y.

[0108] In one embodiment of the compound of formula (I), one of m and n is 0 and the other is 2. In this case, R1 or R2 is not hydrogen and may be linked to the ortho-position of Y or the ortho-position of X on the ring simultaneously, or may be linked to the ortho-position of Y and the ortho-position of X respectively, preferably linked to the ortho-position of Y simultaneously. For example, R1 or R2 is each independently C 1~6 alkyl, such as, but not limited to, -CH3, -CH2CH3 or -CH2-CH2-CH3. Preferably, R1 or R2 is -CH3 and is linked to the ortho-position of Y simultaneously.

[0109] In one embodiment of the compound of formula (I), one of m and n is 0 and the other is 3 or 4. In this case, R1 or R2 is not hydrogen and R1 or R2 is, for example, -CH3, -CH2CH3 or -CH2-CH2-CH3, but not limited thereto. For example, R1 or R2 is C 1~6 alkyl, preferably, R1 or R2 is -CH3.

[0110] In one embodiment of the compound of formula (I), both m and n are 1. In this case, R1 and R2 are not hydrogen and may each independently be linked to the ortho-position of Y or the ortho-position of X on the ring. For example, both are linked to the ortho-position of Y, or both are linked to the ortho-position of X, or are linked to the ortho-position of Y and the ortho-position of X respectively. Preferably, R1 and R2 are C 1~6is alkyl, more preferably, R1 and R2 are -CH3, both are linked to the ortho-position of Y, or both are linked to the ortho-position of X, or are respectively linked to the ortho-position of Y and the ortho-position of X.

[0111] In one embodiment of the compound of formula (I), m and n are both 1. In this case, R1 and R2 are not hydrogen, and R1 and R2 linked to the ortho-position of Y and the ortho-position of X, preferably, simultaneously linked R1 and R2 are integrally linked to form a C 1~3 alkylene bridge, such as -CH2-, -CH2CH2-, -CH2CH2CH2-.

[0112] In one embodiment of the compound of formula (I), m is 1 and n is 2, or m is 1 and n is 3, or m is 1 and n is 4, or m is 2 and n is 2, or m is 2 and n is 3, or m is 2 and n is 4, or m is 3 and n is 4, or m is 4 and n is 4, where, for example, R1 and R2 are C 1~6 alkyl, preferably, R1 and R2 are -CH3.

[0113] In one embodiment of the compound of formula (I), one of m and n is 0 and the other is 1, and R1 or R2 is each independently C 1~6 alkyl, optionally substituted with one or more halogens, and is linked to the ortho-position of Y or the ortho-position of X, or one of m and n is 0 and the other is 2, and R1 or R2 is each independently C 1~6 alkyl, optionally substituted with one or more halogens, and is linked to the ortho-position of Y or the ortho-position of X, or is respectively linked to the ortho-positions of X and Y, or m and n are both 1, and R1 and R2 are each independently C 1~6is alkyl, optionally substituted with one or more halogens, all of which are linked to the ortho-position of Y on the ring, all of which are linked to the ortho-position of X, or are linked to the ortho-position of Y and the ortho-position of X respectively.

[0114] In one embodiment of the compound of formula (I), preferably, among m and n, one is 0 and the other is 1, and R1 or R2 is C 1~6 is alkyl and is linked to the ortho-position of Y or the ortho-position of X.

[0115] In one embodiment of the compound of formula (I), among m and n, one is 0 and the other is 1, and R1 or R2 is C 1~6 is alkyl, optionally substituted with halogen, is linked to the ortho-position of Y, or among m and n, one is 0 and the other is 2, and R1 or R2 is each independently C 1~6 is alkyl, optionally substituted with halogen, and both are linked to the ortho-position of Y.

[0116] In the embodiments of the aforementioned compound of formula (I), when chemically possible, R1 and / or R2 may be in the R or S configuration, preferably in the R configuration.

[0117] In one embodiment of the compound of formula (I), the six-membered ring containing X and Y is, for example,

Chemical formula

Chemical formula

Chemical formula

[0118] In one embodiment of the compound of formula (I), R3 is H.

[0119] In one embodiment of the compound of formula (I), R3 is halogen, such as fluorine, chlorine, bromine, iodine, preferably fluorine or chlorine.

[0120] In addition, the compounds of the present invention include the above various independent embodiments or embodiments of various specific examples, and further include embodiments consisting of any combination or sub-combination of the above various embodiments or embodiments of specific examples, and embodiments consisting of any combination of the above any preferred embodiments or exemplary embodiments.

[0121] In one embodiment of the compound of formula (I),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0122] In one preferred embodiment of this embodiment, the 6-membered ring containing X and Y is

Chemical formula

[0123] In one preferred embodiment of this embodiment, the 6-membered ring containing X and Y is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0124] In one preferred embodiment of this embodiment, the 6-membered ring containing X and Y is

Chemical formula

Chemical formula

[0125] In one preferred embodiment of this embodiment, the 6-membered ring containing X and Y is

Chemical formula

Chemical formula

[0126] In one preferred embodiment of this embodiment, the 6-membered ring containing X and Y is

Chemical formula

[0127] In one preferred embodiment of this embodiment, the 6-membered ring containing X and Y is

Chemical formula

[0128] In the above preferred embodiment of this embodiment, R1 and R2 are each independently H.

[0129] In the above preferred embodiment of this embodiment, R1 and R2 are each independently -C 1~6 alkyl, optionally substituted with one or more halogens, such as -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CF3 or -CH2CF3, most preferably, -CH3.

[0130] In one preferred embodiment of this embodiment, R1 and R2 are linked together to form C 1~3 an alkylene bridge, preferably a C2 alkylene bridge.

[0131] In the above preferred embodiment of this embodiment, R3 is H.

[0132] In the above preferred embodiment of this embodiment, R5 is -C 1~6 alkyl, such as -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, most preferably, -CH3.

[0133] In the above preferred embodiment of this embodiment, R6 are each independently H or halogen, preferably H or F.

[0134] In the above preferred embodiment of this embodiment, R7 is H, or -C 1~6 alkyl, such as -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, most preferably, -CH3.

[0135] In the above preferred embodiment of this embodiment, R8 is -OH.

[0136] In the above preferred embodiment of this embodiment, of n and m, one is 0 and the other is 1, and R1 or R2 is linked to the ortho position of Y or the ortho position of X on the ring, preferably, linked to the ortho position of Y, for example, R1 or R2 is C 1~6is alkyl, preferably, R1 or R2 is -CH3, is linked to the ortho position of Y or the ortho position of X, preferably, is linked to the ortho position of Y.

[0137] In the above preferred embodiment of this embodiment, of n and m, one is 0 and the other is 2, and R1 or R2 is simultaneously linked to the ortho position of Y or the ortho position of X on the ring, or is linked to the ortho position of Y and the ortho position of X respectively, preferably, is simultaneously linked to the ortho position of Y. For example, R1 or R2 is C 1~6 is alkyl, preferably, R1 or R2 is -CH3, and is simultaneously linked to the ortho position of Y.

[0138] In the above preferred embodiment of this embodiment, both n and m are 1, and R1 and R2 may each independently be linked to the ortho position of Y on the ring, or the ortho position of X, for example, both are linked to the ortho position of Y, or both are linked to the ortho position of X, or are linked to the ortho position of Y and the ortho position of X respectively, preferably, both are linked to the ortho position of Y, preferably, R1 and R2 are C 1~6 is alkyl, more preferably, R1 and R2 are -CH3, both are linked to the ortho position of Y, or both are linked to the ortho position of X, or are linked to the ortho position of Y and the ortho position of X respectively, preferably, both are linked to the ortho position of Y, or, R1 and R2 linked to the ortho position of Y and the ortho position of X, preferably simultaneously linked, are integrally linked to form C 1~3 an alkylene bridge, for example -CH2-, -CH2CH2-, -CH2CH2CH2-.

[0139] In the above-mentioned preferred embodiment of this embodiment, when chemically possible, R1 and / or R2 may be in the R or S configuration, preferably, in the R configuration.

[0140] It should be noted that the compounds of the present invention include embodiments consisting of any combination of the above-mentioned optional or exemplary embodiments.

[0141] Specific embodiments of the compounds of the present invention include the following specific compounds, their stereoisomers, tautomers, stable isotope variants, pharmaceutically acceptable salts or solvates.

Chemical formula

[0142] Regarding the compounds of the present invention as the following drugs, the preventive or therapeutic methods, pharmaceutical compositions, pharmaceutical combinations or uses of the present invention, each preferred embodiment of the compound of formula (I) defined in this specification is preferred, and the specific compounds listed are more preferred.

[0143] Advantages of the Invention As described above, ATR kinase is known to act on tumor development and many other diseases. Surprisingly, it has been found that the compound of formula (I) strongly inhibits ATR kinase, and thereby has value as an anti-proliferative agent, apoptosis agent and / or anti-invasive agent in the inhibition and / or treatment of solid and / or liquid tumor diseases. In particular, the compounds of the present invention are expected to be useful for the prevention or treatment of tumors sensitive to ATR inhibition. Also, the compounds of the present invention are expected to be useful for the prevention or treatment of tumors mediated alone or in part by ATR.

[0144] Specifically, as a result of research, it has been revealed that the compounds of the present invention effectively inhibit the activities of ATR kinase and tumor cell lines and achieve one or more of the following technical effects. ● High ATR kinase inhibitory activity: As verified in Activity Example 1, in the kinase ATR inhibition measurement experiment, the IC50 is in the range of 0.1 nM to 1 μM, preferably in the range of 0.1 nM to 0.5 μM, preferably in the range of 0.1 nM to 0.1 μM, more preferably in the range of 0.1 nM to 50 nM, 0.1 nM to 20 nM. And / or ● As verified in Activity Example 2, it has high inhibitory activity against LOVO cell line proliferation. And / or ● As verified in Activity Example 3, it has excellent pharmacokinetic properties, for example, t 1 / 2 is longer, thereby, for example, the dosing interval can be lengthened, the half-life can be lengthened, and the compliance of patients can be made better. And / or ● As verified in Activity Example 4 below, it improves the AUC0-t data and has better drug formability and higher bioavailability. And / or ● It is excellent in safety such as membrane permeability, P450 (reducing the risk of drug interaction), low toxicity and / or low side effects. And / or ● As verified in Activity Example 5, it is excellent in excellent physicochemical properties such as solubility, physical and / or chemical stability.

[0145] Based on the beneficial effects of the compounds of the present invention described above, the present invention also provides technical solutions in various aspects as follows.

[0146] The compound of the present invention for treatment or as a drug In one aspect, the present invention provides a compound useful as a drug, particularly an ATR inhibitor, more particularly an anticancer agent or an antitumor agent.

[0147] In another aspect, the present invention provides a compound for treating and / or preventing ATR-related diseases.

[0148] In a specific embodiment, the present invention provides a compound for treating and / or preventing a disease in which ATR promotes the occurrence and progression, or a disease in which inhibition of ATR inhibits a decrease in the incidence rate, a reduction in the pathological condition of the disease, or removal thereof. The diseases include, for example, tumors or cancers, such as hematological malignancies, for example leukemia (including chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia), multiple myeloma, lymphoid malignancies (such as lymphoma, Hodgkin's disease, non-Hodgkin lymphoma), myelodysplastic syndrome, and solid tumors, such as cancer, sarcoma and its metastases, such as breast cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, bronchioloalveolar carcinoma), central nervous system tumors (such as glioma, embryonal neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, and teratoma), gastrointestinal cancer (such as gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, pancreatic cancer), skin cancer, melanoma, thyroid cancer, bone cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma (such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal tissue cancer, gastrointestinal stromal tumor, Kaposi's sarcoma), and pediatric cancer (such as rhabdomyosarcoma and neuroblastoma), but are not limited thereto.

[0149] The present invention particularly provides a compound of formula (I), a stereoisomer, a tautomer, a stable isotope variant, a pharmaceutically acceptable salt or a solvate thereof, which is useful for the treatment of patients suffering from lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcoma, head and neck cancer, central nervous system tumors and their metastases, and acute myeloid leukemia.

[0150] Pharmaceutical compositions and their administration On the other hand, the compounds of the present invention can be formulated as pharmaceutical compositions according to standard pharmaceutical practices for the purpose of achieving treatment or prevention. Further, based on the good pharmacokinetic properties, improved AUC0-last, and good drug formability of the compounds of the present invention, drugs having better pharmacokinetic properties and higher bioavailability can be produced from the compounds of the present invention.

[0151] Accordingly, the present invention provides a pharmaceutical composition comprising the compound of the present invention as described above and a pharmaceutically acceptable excipient.

[0152] The selection of the excipient included in a specific composition depends on various factors such as the method of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described in Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004, and include, for example, adjuvants, diluents (e.g., glucose, lactose, or mannitol), carriers, pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light blockers, flow aids, processing aids, coloring agents, flavoring agents, corrective agents, and other known additives.

[0153] The pharmaceutical composition of the present invention can be prepared by techniques known to those skilled in the art, such as the techniques disclosed in Remington’s Pharmaceutical Sciences, 2oth Edition.

[0154] The pharmaceutical composition of the present invention can be administered by standard methods. For example, suitable methods of administration include oral administration, intravenous administration, rectal administration, parenteral administration, topical administration, transdermal administration, ocular, nasal, buccal, or pulmonary (inhalation) administration, among which parenteral administration includes intramuscular administration, intravenous administration, intraarterial administration, intraperitoneal administration, or subcutaneous administration. For these purposes, the compound of the present invention can be formulated by methods known to those skilled in the art in the form of, for example, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops, aerosols, dry powder formulations, and sterile injectable aqueous or oily solutions or suspensions.

[0155] The prophylactic or therapeutic dosage of the compounds of the present invention will vary depending on a number of factors including the individual being treated, the severity of the condition or state, the rate of administration, the treatment with the compound, and the judgment of the prescribing physician. In the treatment of a particular disease, an effective amount is an amount of the drug sufficient to ameliorate or relieve the symptoms associated with that disease. Such an amount may be administered as a single dose or according to an effective treatment regimen. Generally, an effective dosage is about 0.0001 to about 5000 mg per kg of body weight per day, for example about 0.01 to about 1000 mg / kg / day (single or divided administration). In the case of a 70 kg person, this amounts to about 0.007 mg / day to about 7000 mg / day, for example about 0.7 mg / day to about 1500 mg / day. The content or amount used of the compounds of the present invention in the pharmaceutical composition is about 0.01 mg to about 1000 mg, preferably 0.1 to 500 mg, more preferably 0.5 to 300 mg, still more preferably 1 to 150 mg, particularly preferably 1 to 50 mg, for example 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc., depending on the mode of administration. Thus, the pharmaceutical composition of the present invention contains from 0.05 to 99% w / w (weight %), for example from 0.05 to 80% w / w, for example from 0.10 to 70% w / w, for example from 0.10 to 50% w / w of the compounds of the present invention based on the total composition. It should be understood that in some cases it may be necessary to use dosages that exceed these limitations.

[0156] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for oral administration. The composition can be provided in unit dosage form, for example in the form of tablets, capsules, or oral solutions. Such unit dosage forms can contain from 0.1 mg to 1 g, for example from 5 mg to 250 mg of the compound of the present invention as the active ingredient.

[0157] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, which composition is formulated for topical administration. The topical administration may be in the form of, for example, a cream, lotion, ointment or transdermal patch, and the concentration of the compound of the present invention may be about 0.01 to 100 mg per gram of carrier.

[0158] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, which composition is formulated for inhaled administration. The inhaled administration can be either oral inhalation or intranasal administration. When the compound of the present invention is administered by oral inhalation, it can be effectively used at a daily dose of 500 μg or less, such as, for example, 0.1 to 50 μg, 0.1 to 40 μg, 0.1 to 30 μg, 0.1 to 20 μg, or 0.1 to 10 μg. The pharmaceutical composition of the present invention for oral inhalation can be formulated as a dry powder, suspension (in a liquid or in a gas), or solution (in a liquid), and can be administered in any suitable form using any suitable inhaler device known to those skilled in the art, including, for example, a metered-dose inhaler (MDI), dry powder inhaler (DPI), nebulizer, and soft mist inhaler. A multi-chamber device can be used to deliver the compounds of the present specification and one or more other active ingredients (if present).

[0159] In certain embodiments, the pharmaceutical composition of the present invention may further comprise an additional therapeutically active ingredient suitable for use in combination with the compound of the present invention.

[0160] Other therapeutic active ingredients suitable for administration in combination with the compounds of the present invention can be other known anti-cancer drugs, particularly other anti-cancer drugs related to DNA damage and repair mechanisms including PARP inhibitors, HDAC inhibitors, etc. Other therapeutic active ingredients suitable for administration in combination with the compounds of the present invention can be selected from anti-cancer drugs related to cell division checkpoints including ChK1 / 2 inhibitors, CDK4 / 6 inhibitors, ATM / ATR inhibitors. Known anti-cancer agents that can be used in combination include alkylating agents, topoisomerase I / II inhibitors, RNA / DNA antimetabolites, anti-mitotic agents, antibody drugs, kinase inhibitors, etc. For combined administration, the compound of the present invention and at least one known anti-cancer agent may be administered as a single pharmaceutical combination, or as separate entities, separately, simultaneously, or sequentially, for example as a kit.

[0161] The compounds of the present invention can also be administered as biological conjugates. The biological conjugate consists of the compound of the present invention and at least one antibody known to have therapeutic activity such as Herceptin or Rituximab, a growth factor such as EGF or FGF, a cell hormone such as interleukin 2 or 4, or optionally a molecule that binds to the cell surface. The antibody and other molecules can deliver the compound of the present invention to its target to exert an effect, and can also improve the therapeutic activity of the antibody or other molecules.

[0162] The compounds of the present invention can also be used in combination with radiotherapy for treatment, and both can be administered at the same or different times.

[0163] The above pharmaceutical composition according to the present invention is useful for preventing or treating ATR-related diseases as defined above in mammals such as human individuals.

[0164] Therapeutic methods and uses From the beneficial effects exerted by the above compounds of the present invention, the compounds of the present invention are useful in methods for treating ATR-related diseases in animals, particularly mammals such as humans.

[0165] Thus, in another aspect, the present invention provides a method for modulating, particularly inhibiting, ATR kinase activity, which comprises contacting a cell with the compound of the present invention as described above to modulate, particularly inhibit, the activity of ATR in the cell.

[0166] Based on the same property, the present invention also provides a method for inhibiting abnormal growth of mammalian cells, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention.

[0167] In another aspect, the present invention provides a method for preventing or treating an ATR-related disease (for example, a disease that can be treated or prevented by ATR inhibition), which comprises administering to an individual in need thereof an effective amount of the compound of the present invention as described above or a pharmaceutical composition of the present invention comprising the same.

[0168] In another aspect, the present invention provides the use of the compound of the present invention as described above or a pharmaceutical composition comprising the same for inhibiting ATR activity or for treating and / or preventing an ATR-related disease, for example, a disease that can be treated or prevented by ATR inhibition.

[0169] In another aspect, the present invention also provides the use of the compound of the present invention as described above or a pharmaceutical composition comprising the same in the preparation of a drug, particularly in the preparation of a drug having ATR kinase inhibitor activity.

[0170] In another aspect, the present invention provides the use of the compound of the present invention as described above or a pharmaceutical composition comprising the same in the preparation of a drug for treating or preventing an ATR-related disease, for example, a disease that can be treated or prevented by ATR kinase inhibition, wherein the compound or pharmaceutical composition is used in combination with one or more chemotherapeutic or immunotherapeutic methods.

[0171] Method for preparing the compound of the present invention The present invention also provides a method for preparing a compound of formula (I). Hereinafter, a general synthetic scheme for synthesizing the compounds of the present invention is exemplified. In each reaction step, appropriate reaction conditions are known to those skilled in the art or can be generally determined. Unless otherwise specified, the raw materials and reagents used in the preparation of these compounds are generally commercially available or can be produced by the following methods, methods similar to the following methods, or methods known to those skilled in the art. If necessary, the raw materials and intermediates in the synthetic reaction stream can be separated and purified using conventional techniques including but not limited to filtration, distillation, crystallization, chromatography, etc. The said materials can be characterized using conventional methods including physical constants and spectral data.

[0172] Synthetic Scheme 1 [Chemical Formula]

[0173] As shown in Scheme 1, the compounds of the present invention may be synthesized by a method comprising the following steps. Step 1: A compound of formula (I-1) and an amine are heated and reacted in a solvent such as NMP in the presence of an alkali such as DIEA to obtain a compound of formula (I-2). Step 2: A compound of formula (I-2) and an amine are heated and reacted in a solvent such as NMP in the presence of an alkali such as DIEA to obtain a compound of formula (I-3). Step 3: A compound of formula (I-3) and an iodination reagent such as NIS are reacted at room temperature in a solvent such as ACN to obtain a compound of formula (I-4). Step 4: A compound of formula (I-4) is heated and reacted by Suzuki coupling in a solvent such as dioxane / water in the presence of a coupling agent such as Pd(dtbpf)Cl2 / H3PO4 to obtain a compound of formula (I-5). Step 5: The protecting group is removed from the compound of formula (I-5) under the action of an acid to obtain a compound of formula (I).

[0174] Synthetic Scheme 2 [Chemical formula]

[0175] As shown in Scheme 2, the compounds of the present invention may be synthesized by a method including the following steps. Step 1: React a compound of formula (II-1) with an iodination reagent such as NIS in the presence of an acid such as TFA in a solvent such as CHCl3 at room temperature to obtain a compound of formula (II-2). Step 2: Heat and react a compound of formula (II-2) with an amine in the presence of an alkali such as DIEA in a solvent such as THF to obtain a compound of formula (II-3). Step 3: Heat and react a compound of formula (II-3) by Suzuki coupling in the presence of a coupling agent such as Pd(dtbpf)Cl2 / H3PO4 in a solvent such as dioxane / water or at room temperature to obtain a compound of formula (II-4). Step 4: Heat and react a compound of formula (II-4) with an amine under the action of a catalyst such as RuPhos-G2 in the presence of an alkali such as cesium carbonate in a solvent such as toluene, and 5 obtain a compound of formula (II- Step 5: Remove the protecting group from the compound of formula (II-5) by the action of an acid such as HCl to obtain a compound of formula (II).

[0176] Synthesis Scheme 3 [Chemical formula] (Here, R1, R2, and X are as defined in the above general formula (I).)

[0177] As shown in Scheme 3, the compounds of the present invention may be synthesized by a method including the following steps. Step 1: Heat and react a compound of formula (III-1) with a chlorination reagent such as POCl3 to obtain a compound of formula (III-2). Step 2: React the compound of formula (III-2) with an amine in a solvent such as DMF in the presence of an alkali such as K2CO3 at about room temperature to obtain the compound of formula (III-3). Step 3: Heat and react the compound of formula (III-3) with an amine in a solvent such as DMF in the presence of an alkali such as DIEA to obtain the compound of formula (III-4). Step 4: Heat and react the compound of formula (III-4) with a cyanating agent such as Zn(CN)2 in the presence of a catalyst such as Pd2(dba)3 / DPPF in the presence of a solvent such as DMF to obtain the compound of formula (III-5). Step 5: Perform a reduction reaction on the compound of formula (III-5) and react it in a solvent such as MeOH / THF in the presence of a catalyst such as Raney nickel / aqueous ammonia to obtain the compound of formula (III-6). Step 6: Perform a condensation reaction on the compound of formula (III-6) and react it in a solvent such as DME in the presence of a condensing agent such as HATU / DIEA to obtain the compound of formula (III-7). Step 7: Heat and cyclize the compound of formula (III-7) at 100-150 °C in the presence of POCl3 to obtain the compound of formula (III).

[0178] Synthesis Scheme 4

Chemical Formula

[0179] As shown in Scheme 4, the compounds of the present invention may be synthesized by a method comprising the following steps. Step 1: React the compound of formula (IV-1) with a formate ester such as ethyl formate at low temperature in a solvent such as THF under the action of an alkali such as LDA to obtain the compound of formula (IV-2). Step 2: React the compound of formula (IV-2) with 3-hydrazine-1H-pyrazole in a solvent such as ethanol at room temperature to obtain the compound of formula (IV-3). Step 3: Perform a cyclization reaction on the compound of formula (IV-3) in a solvent such as NMP at an elevated temperature, for example under reflux, to obtain the compound of formula (IV-4). Step 4: React the compound of formula (IV-4) with an amine by heating in a solvent such as DMSO to obtain the compound of formula (IV-5). Step 5: React the compound of formula (IV-5) with a protecting reagent such as DHP / TsOH in a solvent such as DCM at room temperature to introduce a protecting group and obtain the compound of formula (IV-6). Step 6: Heat the compound of formula (IV-6) in a solvent such as NMP in the presence of a coupling agent such as Pd(dtbpf)Cl2 / CsCO3 and couple it with an amine to obtain the compound of formula (IV-7). Step 7: Remove the protecting group from the compound of formula (IV-7) to obtain the compound of formula (IV).

[0180] The above synthetic scheme merely illustrates the preparation methods of some compounds of the present invention. The compounds of the present invention, or their stereoisomers, tautomers, stable isotope derivatives, pharmaceutically acceptable salts or solvates, can be prepared by those skilled in the art by various methods such as the above methods, the methods described in the examples or methods similar thereto, with appropriate changes based on the above synthetic scheme and referring to the techniques in the art.

Examples

[0181] Hereinafter, the technical solutions of the present invention will be further described with reference to specific examples, but the protection scope of the present invention is not limited to these examples. All changes or equivalent substitutions that do not depart from the concept of the present invention are included in the protection scope of the present invention.

[0182] In the following examples, experimental methods without specific conditions generally follow the usual conditions for such reactions or the conditions suggested by the manufacturer. In the following examples, if the chiral center configuration is not described, it means that the compound may exist in the form of a single enantiomer or a mixture of enantiomers, and those skilled in the art can determine the stable and viable isomeric form of the compound. Unless otherwise specified, percentages and parts are weight percentages and weight parts, respectively. Unless otherwise specified, the proportions of liquids are volume ratios, and all temperatures used in this invention are in degrees Celsius.

[0183] The experimental materials and reagents used in the following examples are commercially available, can be prepared by prior art methods, or can be prepared by methods similar to those disclosed herein, unless otherwise specified. Unless otherwise specified, all raw materials used in the present invention are commercially available and can be used as is without further purification. The 5,7-dichloropyrazolo[1,5-A]pyrimidine used in the following examples was purchased from Shanghai Haohong Biopharmaceutical Technology Co., Ltd. (Rakuken, CAS: 57489-77-7, batch number: Ld102321002), 8-bromo-6-chloroimidazolo[1,2-B]pyridazine was purchased from Shaoyuan Technology (Shanghai) Co., Ltd. (CAS: 933190-51-3, batch number: J140-1157-27), and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride was purchased from Shanghai Bitumin Pharmaceutical Technology Co., Ltd. (CAS: 54745-74-3, batch number: BGX458).

[0184] Unless otherwise expressly defined herein, abbreviations used herein have the meanings that are commonly understood in the art. The meanings of the abbreviations used herein are as follows: [Table 1]

[0185] Synthesis Examples In the method for producing the target compound according to the present invention, silica gel (300-400 mesh) manufactured by Rushan Taiyang Desiccant Co., Ltd. is adopted for column chromatography, GF254 (0.25 mm) is adopted for thin-layer chromatography, and nuclear magnetic resonance chromatography (NMR) is measured using a Varian-400 nuclear magnetic resonance apparatus. Liquid chromatography-mass spectrometry (LC / MS) uses an Agilent Technologi ESI 6120 liquid chromatography-mass spectrometer.

[0186] Furthermore, all operations involving raw materials that are prone to oxidation or hydrolysis are carried out under nitrogen gas protection.

[0187] When the structure of the compound of the present invention does not match the compound name, usually the one shown by the structural formula is taken as the standard, except when it can be judged from the context that the compound name is correct.

[0188] Example 1: 3-(7-((R)-3-Methylmorpholino)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0189] Step 1: Synthesis of (R)-4-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3-methylmorpholine

Chemical formula

[0190] A solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (5.0 g, 26.6 mmol), (R)-3-methylmorpholine (8.07 g, 79.8 mmol), and DIEA (10.31 g, 79.8 mmol) in NMP (30.0 mL) was stirred at 100 °C for 0.5 h, and then the reaction was stopped. After the reaction mixture was cooled to room temperature, it was diluted with DCM (150 mL), washed with saturated brine (30.0 mL × 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 3:1~1:2) to obtain the target compound (6.50 g, yield 96.7%, yellow solid). LC-MS (ESI) m / z 253.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 2.3 Hz, 1H), 6.50 (d, J = 2.3 Hz, 1H), 6.04 (s, 1H), 5.22 - 5.08 (m, 1H), 4.13 - 3.95 (m, 2H), 3.89 - 3.80 (m, 1H), 3.80 - 3.75 (m, 1H), 3.74 - 3.68 (m, 1H), 3.67 - 3.62 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H).

[0191] Step 2: Synthesis of 3-(7-((R)-3-methylmorpholino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0192] (R)-4-(5-Chloropyrazolo[1,5-a]pyrimidin-7-yl)-3-methylmorpholine (200 mg, 0.791 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (268 mg, 1.79 mmol) were added to a solution of NMP (15.0 mL), and DIEA (306 mg, 2.37 mmol) was added thereto. The reaction mixture was reacted at 140 °C in a microwave reactor for 2 hours under nitrogen protection, and the reaction was stopped. Then, EA (35.0 mL) was added to the reaction solution, and the mixture was washed with saturated brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 3:1) to obtain the target compound (120 mg, yield 46.0%, yellow oil). LC-MS (ESI) m / z 330.1 [M+H] + 。

[0193] Step 3: Synthesis of 3-(3-Iodo-7-((R)-3-methylmorpholino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0194] NIS (82 mg, 0.364 mmol) was added to a solution of 3-(7-((R)-3-methylmorpholino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (120 mg, 0.364 mmol) in acetonitrile (5.00 mL). The reaction mixture was stirred at room temperature for 0.5 hour to effect the reaction, and the reaction was stopped. Then, water (10.0 mL) was added, and then the mixture was extracted with EA (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 3:1) to obtain the target compound (100 mg, yield 60.3%, yellow solid). LC-MS (ESI) m / z 456.0 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 5.38 (s, 1H), 5.10 (s, 1H), 4.51 (s, 2H), 4.08 - 3.91 (m, 3H), 3.90 - 3.80 (m, 2H), 3.74 (d, J = 11.6 Hz, 1H), 3.68 - 3.57 (m, 1H), 3.40 - 3.15 (m, 3H), 2.03 - 1.96 (m, 2H), 1.93 - 1.83 (m, 2H), 1.25 - 1.14 (m, 3H).

[0195] Step 4: Synthesis of 3-(7-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0196] Under nitrogen protection, Pd(dtbpf)Cl2 (14.0 mg, 0.0219 mmol) and potassium phosphate (139 mg, 0.658 mmol) were added to a solution of 3-(3-iodo-7-((R)-3-methylmorpholino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (100 mg, 0.219 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (91.6 mg, 0.329 mmol) in 1,4-dioxane (5.00 mL) and water (1.00 mL). The reaction mixture was stirred at 60 °C for 16 h to cause a reaction, and then the reaction was stopped. Thereafter, water (30.0 mL) was added, and then the mixture was extracted with EA (20.0 mL × 3). The combined organic phases were washed with saturated brine (25.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (100 mg, yield 94.9%, yellow solid). LC-MS (ESI) m / z 480.1 [M+H] + .

[0197] Step 5: Synthesis of 3-(7-((R)-3-methylmorpholino)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0198] At room temperature, 3-(7-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (100 mg, 0.208 mmol) and ethyl acetate solution of hydrochloric acid (5.00 mL, 3 M) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 2 hours to react, and then the reaction was stopped. It was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water, containing 0.05% formic acid) to obtain the target compound (75.8 mg, yield 91.9%, pale yellow solid). LC-MS (ESI) m / z 396.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 12.62 (Brs, 1H), 8.23 (s, 1H), 7.64 - 7.47 (m, 1H), 6.77 - 6.63 (m, BH), 5.77 (s, 1H), 5.15 - 5.07 (m, 1H), 4.49 - 4.44 (m, 2H), 4.19 - 4.10 (m, 1H), 4.09 - 4.01 (m, 1H), 3.96 - 3.91 (m, 1H), 3.85 - 3.80 (m, 1H), 3.70 - 3.63 (m, 2H), 3.57 - 3.50 (m, 1H), 3.40 - 3.34 (m, 1H), 3.14 - 3.07 (m, 2H), 1.88 - 1.81 (m, 2H), 1.79 - 1.72 (m, 2H), 1.10 (d, J = 6.8 Hz, 3H).

[0199] Example 2: 3-(8-((R)-3-methylmorpholino)-3-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0200] Step 1: Synthesis of 8-Bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine

Chem.

[0201] To a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg, 2.15 mmol) in chloroform (10.0 mL) and trifluoroacetic acid (1.00 mL) was added NIS (484 mg, 2.15 mmol). The reaction mixture was stirred at room temperature for 2 hours to allow the reaction to proceed, and then the reaction was stopped. Subsequently, saturated sodium bicarbonate solution (25.0 mL) was added, and then extracted with EA (30.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to give the target compound (500 mg, yield 64.8%, yellow solid). LC-MS (ESI) m / z 357.7, 359.7 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.56 (s, 1H).

[0202] Step 2: Synthesis of (R)-4-(6-Chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)-3-methylmorpholine

Chem.

[0203] To a solution of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (500 mg, 1.40 mmol) and (R)-3-methylmorpholine (211 mg, 2.09 mmol) in tetrahydrofuran (10.0 mL) was added DIEA (541 mg, 4.19 mmol). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 2 hours to react, and the reaction was stopped. Then, the reaction solution was added to EA (35.0 mL), washed with saturated brine (35 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to obtain the target compound (500 mg, yield 94.6%, yellow oil). LC-MS (ESI) m / z 378.8 [M+H] + .

[0204] Step 3: Synthesis of (3R)-4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-8-yl)-3-methylmorpholine

Chemical Structure

[0205] Under nitrogen protection, to a solution of (R)-4-(6-chloro-3-iodoimidazo[1,2-b]pyridazin-8-yl)-3-methylmorpholine (400 mg, 1.06 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (293 mg, 1.06 mmol) in 1,4-dioxane (10.0 mL) and water (2.00 mL) were added Pd(dtbpf)Cl2 (67.3 mg, 0.105 mmol) and potassium phosphate (448 mg, 2.11 mmol). The reaction mixture was stirred at room temperature for 16 hours to effect the reaction, and then the reaction was stopped. Thereafter, water (25.0 mL) was added, and then the mixture was extracted with EA (30.0 mL × 3). The combined organic phases were washed with saturated brine (25.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (320 mg, yield 75.1%, yellow solid). LC-MS (ESI) m / z 403.1 [M+H] + .

[0206] Step 4: Synthesis of 3-(8-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0207] Under nitrogen protection, cesium carbonate (727 mg, 2.23 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (168 mg, 1.12 mmol) were added to a toluene (15.0 mL) solution of (3R)-4-(6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-8-yl)-3-methylmorpholine (300 mg, 0.744 mmol) and RuPhosPdG2 (58.1 mg, 0.0744 mmol). The reaction mixture was stirred at 110 °C for 16 hours to carry out the reaction, and the reaction was stopped. Then, water (25.0 mL) was added, and then, it was extracted with EA (25.0 mL × 3). The combined organic phases were washed with saturated brine (25.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (100 mg, yield 28.0%, yellow solid). LC-MS (ESI) m / z 480.2 [M+H] + .

[0208] Step 5: Synthesis of 3-(8-((R)-3-methylmorpholino)-3-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0209] At room temperature, 3-(8-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (100 mg, 0.208 mmol) and an EA solution of hydrochloric acid (10.0 mL, 3 M) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 2 hours to effect reaction, and the reaction was stopped. It was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water, containing 0.05% formic acid) to obtain the target compound (38.7 mg, yield 47.0%, white solid). LC-MS (ESI) m / z 396.3 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 13.33 - 12.85 (m, 1H), 7.84 - 7.72 (m, 1H), 7.14 - 6.86 (m, 1H), 5.98 (s, 1H), 5.63 - 5.33 (m, 1H), 4.51 - 4.43 (m, 2H), 4.15 - 3.99 (m, 1H), 4.00 - 3.93 (m, 1H), 3.81 - 3.71 (m, 4H), 3.66 - 3.57 (m, 1H), 3.39 - 3.34 (m, 1H), 3.30 - 3.25 (m, 1H), 3.07 - 2.99 (m, 2H), 1.90 - 1.81 (m, 4H), 1.15 (d, J = 6.7 Hz, 3H).

[0210] Example 3: 3-(4-((R)-3-methylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0211] Step 1: Synthesis of 4-bromo-3,6-dichloropyridazine

Chemical formula

[0212] 4-Bromo-1,2-dihydropyridazine-3,6-dione (5.50 g, 28.8 mmol) was dissolved in phosphorus oxychloride (35.0 mL), and the reaction mixture was heated to 100 °C and reacted for 16 hours, and then the reaction was stopped. After the reaction solution was cooled to room temperature, it was slowly poured into ice water, and then the pH was adjusted to about 7. Next, it was extracted with EA (100 mL × 3), and the organic phase was washed with saturated brine (50.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 20:1 to 5:1) to obtain the target compound (5.00 g, yield 76.2%, light yellow solid). LC-MS (ESI) m / z 227.0 [M+H] + 。

[0213] Step 2: Synthesis of (R)-4-(3,6-dichloropyridazin-4-yl)-3-methylmorpholine

Chemical formula

[0214] Potassium carbonate (6.59 g, 47.7 mmol) was added to a DMF (37.0 mL) solution of 4-bromo-3,6-dichloropyridazine (2.73 g, 12.0 mmol) and (R)-3-methylmorpholine (2.40 g, 23.7 mmol). Under nitrogen protection, the reaction mixture was stirred at 30 °C for 16 hours to react, and then the reaction was stopped. Water (45.0 mL) was added, and then it was extracted with EA (60.0 mL × 3). The organic phase was washed with saturated brine (45.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1 to 2:1) to obtain the target compound (2.36 g, yield 79.4%, white solid). LC-MS (ESI) m / z 248.1 [M+H] + 。

[0215] Step 3: Synthesis of 3-(6-chloro-5-((R)-3-methylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0216] (R)-4-(3,6-dichloropyridazin-4-yl)-3-methylmorpholine (1.44 g, 5.80 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.30 g, 8.68 mmol) were dissolved in NMP (26.0 mL). DIEA (2.26 g, 17.5 mmol) was added thereto, and the reaction mixture was stirred at 145 °C for 16 hours, after which the reaction was stopped. After cooling the reaction mixture to room temperature, water (25.0 mL) was added, and the mixture was extracted with EA (30.0 mL × 2). The organic phase was washed with saturated brine (25.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1 to 1:1) to obtain the target compound (1.50 g, yield 79.6%, brown solid). LC-MS (ESI) m / z 325.2 [M+H] + .

[0217] Step 4: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-3-methylmorpholino)pyridazine-3-carbonitrile

Chemical Structure

[0218] To a mixed solution of water (8 drops) and DMF (40.0 mL) of 3-(6-chloro-5-((R)-3-methylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.49 g, 4.59 mmol), zinc cyanide (1.08 g, 9.18 mmol), DPPF (510 mg, 0.918 mmol) and Pd2(dba)3 (421 mg, 0.459 mmol) were successively added. Under nitrogen protection, the reaction mixture was stirred at 145 °C overnight for reaction, and then the reaction was stopped. After the reaction solution was cooled to room temperature, water (30.0 mL) was added, and then extracted with EA (35.0 mL × 3). The organic phase was washed with saturated brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1~1:2) to obtain the target compound (1.10 g, yield 76.0%, brown solid). LC-MS (ESI) m / z 316.3 [M+H] + 。

[0219] Step 5: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-3-methylmorpholino)pyridazin-3-yl)methylamine

Chemical Structure

[0220] To a solution of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-3-methylmorpholino)pyridazine-3-carbonitrile (1.03 g, 3.27 mmol) in tetrahydrofuran (30.0 mL), aqueous ammonia (5.00 mL) and Raney nickel (~1.15 g) were successively added. After nitrogen substitution was performed three times, the reaction mixture was reacted overnight at room temperature in a hydrogen gas atmosphere, and then the reaction was stopped. The reaction mixture was filtered to remove solid residues, and the filtrate was concentrated under reduced pressure to obtain the target compound (1.00 g, yield 95.9%, brown solid). LC-MS (ESI) m / z 320.3 [M+H] + 。

[0221] Step 6: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((R)-3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chem.

[0222] (6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-3-methylmorpholino)pyridazin-3-yl)methylamine (1.20 g, 3.74 mmol) and 1H-pyrazole-5-carboxylic acid (505 mg, 4.49 mmol) in DMF (28.0 mL) were added with HATU (2.85 g, 7.48 mmol) and DIEA (1.19 g, 9.35 mmol), and the reaction mixture was reacted at room temperature for 4 hours, then the reaction was stopped. Water (15.0 mL) was added to the reaction mixture for dilution, and then extracted with DCM:methanol = 10:1 (20.0 mL × 3). The combined organic phases were washed with saturated brine (15.0 mL × 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (DCM:methanol = 50:1~10:1) to obtain the target compound (660 mg, yield 42.7%, white solid). LC-MS (ESI) m / z 414.2 [M+H] + 。

[0223] Step 7: Synthesis of 3-(4-((R)-3-methylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0224] N-((6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((R)-3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (660 mg, 1.60 mmol) was dissolved in phosphorus oxychloride (23.0 mL) solution. After the reaction mixture was reacted at 145 °C for 3 hours, the reaction was stopped. After the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure to remove excess phosphorus oxychloride. The obtained residue was separated and purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (36.8 mg, yield 5.83%, white solid). LC-MS (ESI) m / z 396.3 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 13.22 (brs, 1H), 7.76 - 7.54 (m, 2H), 7.11 - 7.04 (m, 1H), 5.79 (s, 1H), 4.50 - 4.42 (m, 2H), 4.38 - 4.30 (m, 1H), 3.99 - 3.92 (m, 1H), 3.85 - 3.75 (m, 3H), 3.74 - 3.68 (m, 1H), 3.65 - 3.57 (m, 1H), 3.50 - 3.38 (m, 2H), 3.11 - 3.00 (m, 2H), 1.90 - 1.78 (m, 4H), 1.15 (d, J = 6.6 Hz, 3H).

[0225] Example 4: 3-(3-Chloro-4-((R)-3-methylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0226] To a solution of N-((6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((R)-3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (6.50 g, 15.72 mmol) in acetonitrile (100 mL) was added phosphorus oxychloride (25.0 mL). The reaction mixture was reacted at 90 °C for 1.5 h and then the reaction was stopped. After the reaction mixture was cooled to room temperature, the reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution at 0 °C. Then, the pH was adjusted to 9 with saturated sodium bicarbonate solution at 0 °C, and then extracted with EA (200 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by two reverse-phase preparative chromatographies (acetonitrile / water containing 0.05% aqueous ammonia) and (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (1.50 g, yield 22.2%, green solid). LC-MS (ESI) m / z 430.2 [M+H] + 。 1 H NMR (400 MHz, MeOD-d4) δ 7.74 (s, 1H), 7.64 (s, 1H), 7.17 (s, 1H), 4.50 - 4.40 (m, 2H), 4.10 - 4.01 (m, 1H), 4.00 - 3.91 (m, 2H), 3.84 - 3.71 (m, 3H), 3.66 - 3.60 (m, 1H), 3.42 - 3.35 (m, 2H), 3.34 - 3.32 (m, 1H), 2.97 (d, J = 11.8 Hz, 1H), 2.38 - 2.31 (m, 1H), 2.16 - 2.08 (m, 1H), 2.01 - 1.91 (m, 2H), 1.23 (d, J = 6.5 Hz, 3H).

[0227] Example 5: 3-(4-((R)-3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0228] Synthesis of Intermediate 3-Hydrazino-1H-pyrazole

Chem.

[0229] 3-Aminopyrazole (1.00 g, 12.0 mmol) was added to 6 mol / L aqueous hydrochloric acid solution (7 mL), and the mixture was cooled to -5°C. Then, 1 mol / L aqueous sodium nitrite solution (12 mL, 12.0 mmol) was added to the reaction mixture, and the reaction solution was stirred at room temperature for 2 hours for reaction. A concentrated hydrochloric acid solution (24 mL) of stannous chloride dihydrate (5.43 g, 24.1 mmol) was added to the reaction mixture. After the reaction solution was stirred at room temperature for 1 hour, it was concentrated under reduced pressure to obtain the crude product (9.00 g, crude product, bright yellow solid) of the target compound.

[0230] Step 1: Synthesis of 2,6-Difluoro-4-iodo-3-pyridinecarboxaldehyde

Chem.

[0231] 2,6-Difluoro-4-iodopyridine (5.00 g, 20.7 mmol) was added to a three-necked flask containing anhydrous tetrahydrofuran (75 mL). Under nitrogen protection, the obtained mixture was cooled to -78 °C, lithium diisopropylamide (2 mol / L tetrahydrofuran solution) (12.5 mL, 24.9 mmol) was added, and after stirring for 1 hour, ethyl formate (2.31 g, 31.1 mmol) was slowly added. After stirring at -78 °C for another 30 minutes and detecting by TLC thin-layer chromatography that the raw materials had completely reacted, formic acid (1.91 g, 41.5 mmol) was added to the reaction solution. After stirring at -78 °C for 10 minutes, EA (25 mL) was added, and then the temperature was raised to 0 °C, and water (30 mL) was added. Stirring was stopped, additional EA (25 mL) was added for extraction, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column (PE:EA = 5:1) to obtain the target compound (3.54 g, yield 63.4%, yellow solid).

[0232] Step 2: Synthesis of 3-((2-(1H-pyrazol-3-yl)hydrazino)methyl)-2,6-difluoro-4-iodopyridine

Chemical formula

[0233] 2,6-Difluoro-4-iodo-3-pyridinecarboxaldehyde (1.00 g, 3.72 mmol) and 3-hydrazino-1H-pyrazole (9.00 g, crude product) were added to 95% aqueous ethanol solution (20 mL). Under nitrogen protection, the obtained mixture was stirred at room temperature for 3 hours, the solvent was removed under reduced pressure, EA (30 mL) was added to the residue and stirred uniformly. Saturated sodium bicarbonate solution was slowly dropped into the uniformly stirred suspension, stirred vigorously to make the mixture alkaline, and after stirring for another 15 minutes, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and after distillation under reduced pressure, separated and purified by silica gel column (PE:EA = 1:2) to obtain the target compound (1.40 g, crude product, yellow solid). LC-MS (ESI) m / z: 349.9 [M+H] + 。

[0234] Step 3: Synthesis of 6-fluoro-4-iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine

Chemical Structure

[0235] 3-((2-(1H-pyrazolyl-3-yl)hydrazino)methyl)-2,6-difluoro-4-iodopyridine (1.40 g, 4.01 mmol) was dissolved in NMP (19 mL). The reaction mixture was heated to reflux and stirred for 1 hour for reaction. When the reaction was completed as monitored by LC-MS, the reaction mixture was added dropwise to water (50 mL) to precipitate a brown solid. The mixture was stirred at room temperature for 10 minutes, cooled to 0 °C, stirred for another 10 minutes, and the suspension was suction filtered through a suction filtration funnel. The solid was collected, and the aqueous phase was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. It was separated and purified by preparative plate (silica gel, EA:PE = 1:1) to obtain the target compound (838 mg, two-step yield 68.5%, yellowish-brown solid). LC-MS (ESI) m / z: 329.9 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 8.27 (s, 1H), 7.93 (t, J = 2.0 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 6.66 (t, J = 2.2 Hz, 1H).

[0236] Step 4: Synthesis of 3-(4-iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0237] 6-Fluoro-4-iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine (538 mg, 1.63 mmol) was dissolved in dimethyl sulfoxide (3 mL). Under nitrogen protection, the resulting mixture was stirred uniformly at room temperature, 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (367 mg, 2.45 mmol) was added, the reaction solution was heated to 120 °C and stirred for 45 minutes. When the reaction was completed as monitored by LC-MS, the reaction mixture was added dropwise to water (30 mL) to precipitate a yellowish-brown solid. After the mixture was stirred at room temperature for 10 minutes, it was cooled to 0 °C and stirred for another 10 minutes. The suspension was suction filtered through a suction filtration funnel, the solid was collected, and the aqueous phase was extracted with EA (10 mL × 2). The residue was separated and purified by silica gel column (PE:EA = 1:2) to obtain the target compound (300 mg, yield 43.5%, yellow solid). LC-MS (ESI) m / z: 423.0 [M+H] + .

[0238] Step 5: Synthesis of 3-(4-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0239] 3-(4-Iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (300 mg, 0.711 mmol), DHP (120 mg, 1.42 mmol), and p-toluenesulfonic acid monohydrate (14 mg, 0.071 mmol) were sequentially added to DCM (5 mL). The reaction mixture was stirred at room temperature for 16 h to effect the reaction. When the reaction was completed as monitored by LC-MS, water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative plate (silica gel, EA:PE = 1:2) to obtain the target compound (330 mg, yield 91.7%, colorless oil). LC-MS (ESI) m / z 507.0 [M+H] + .

[0240] Step 6: Synthesis of 3-(4-((R)-3-Methylmorpholino)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical Structure]

[0241] 3-(4-Iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (160 mg, 0.316 mmol), (R)-3-methylmorpholine (64 mg, 0.632 mmol), RuPhosPdG2 (25 mg, 0.032 mmol), and cesium carbonate (309 mg, 0.948 mmol) were added to NMP (2 mL). Under nitrogen protection, the resulting mixture was stirred at 110 °C for 2 hours and monitored by LC-MS. When the reaction was completed, water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (PE:EA = 1:2) to obtain the target compound (110 mg, yield 72.6%, colorless oil). LC-MS (ESI) m / z: 480.2 [M+H] + 。

[0242] Step 7: Synthesis of 3-(4-((R)-3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0243] To a solution of 3-(4-((R)-3-methylmorpholino)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (110 mg, 2.4 mmol) in methanol (2 mL) was added a 4 mol / L hydrochloric acid 1,4-dioxane solution (2 mL). Under nitrogen protection, the resulting mixture was stirred at room temperature for 2 hours, the solvent was removed under reduced pressure, and the residue was separated and purified by a prep-HPLC preparative column to obtain the target compound (12.2 mg, yield 13.4%, white solid). LC-MS (ESI) m / z: 396.2 [M+H]+ . 1 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.80 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 5.82 (s, 1H), 4.52 - 4.42 (m, 2H), 4.42 - 4.26 (m, 1H), 4.01 - 3.84 (m, 3H), 3.80 - 3.69 (m, 2H), 3.65 - 3.55 (m, 2H), 3.39 - 3.27 (m, 1H), 3.07 - 2.97 (m, 2H), 1.87 - 1.79 (m, 2H), 1.80 - 1.70 (m, 2H), 1.16 (d, J = 6.6 Hz, 3H).

[0244] Example 6: 3-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0245] Step 1: Synthesis of 3-(3,6-dichloropyridazin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0246] A solution of 4-bromo-3,6-dichloropyridazine (1.00 g, 4.39 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (745 mg, 4.98 mmol) in DMF (15.0 mL) was added with potassium carbonate (1.21 g, 8.78 mmol). Under nitrogen protection, the reaction mixture was stirred at room temperature for 16 hours to react, and the reaction was stopped. Then, the reaction solution was added to EA (35.0 mL), washed with saturated brine (35.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to obtain the target compound (700 mg, yield 61.3%, yellow oil). LC-MS (ESI) m / z 260.1 [M+H] + 。

[0247] Step 2: Synthesis of 3-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0248] DIEA (1.04 g, 8.07 mmol) was added to a solution of 3-(3,6-dichloropyridazin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (700 mg, 2.69 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (609 mg, 4.07 mmol) in NMP (15.0 mL). Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 hours to react, and the reaction was stopped. Then, the reaction solution was added to EA (35.0 mL), washed with saturated brine (25.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (550 mg, yield 60.7%, yellow solid). LC-MS (ESI) m / z 337.0 [M+H] + 。

[0249] Step 3: Synthesis of 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazine-3-carbonitrile

Chem.

[0250] To a solution of 3-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (550 mg, 1.63 mmol) and zinc cyanide (383 mg, 3.27 mmol) in DMF (10.0 mL) were added DPPF (181 mg, 0.326 mmol) and Pd2(dba)3 (149 mg, 0.163 mmol). Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours to allow the reaction to proceed, and then the reaction was stopped. Subsequently, the reaction solution was added to EA (25.0 mL), washed with saturated brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (350 mg, yield 65.5%, yellow solid). LC-MS (ESI) m / z: [M+H] 328.2 + 。

[0251] Step 4: Synthesis of (4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)methylamine

Chem.

[0252] To a solution of 4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazine-3-carbonitrile (350 mg, 1.07 mmol) in tetrahydrofuran (10.0 mL) was added Raney nickel (~314 mg, 5.35 mmol). The reaction mixture was reacted at room temperature for 16 h in a hydrogen gas atmosphere, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (300 mg, yield 84.7%, yellow oil) as a residue. LC-MS (ESI) m / z 332.2 [M+H] + 。

[0253] Step 5: Synthesis of N-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chemical Structure

[0254] To a solution of (4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)methylamine (300 mg, 0.905 mmol) and 1H-pyrazole-5-carboxylic acid (101 mg, 0.905 mmol) in tetrahydrofuran (10.0 mL) were added HATU (413 mg, 1.09 mmol) and DIEA (351 mg, 2.72 mmol). The reaction mixture was reacted at room temperature for 1 h, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 0:1) to obtain the target compound (200 mg, yield 51.9%, yellow oil). LC-MS (ESI) m / z 426.0 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.30 (s, 1H), 7.83 (s, 1H), 6.65 (s, 1H), 6.46 (s, 1H), 4.60 (d, J = 5.1 Hz, 2H), 4.46 - 4.37 (m, 4H), 3.93 - 3.86 (m, 2H), 3.00 - 2.96 (m, 6H), 2.05 - 2.02 (m, 2H), 1.89 - 1.80 (m, 4H), 1.76 - 1.73 (m, 2H).

[0255] Step 6: Synthesis of 3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula][[ID=⑧]]

[0256] At room temperature, N-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (200 mg, 0.470 mmol) and phosphorus oxychloride (10.0 mL) were added to the reaction flask. The reaction mixture was reacted at 100 °C for 1 hour and the reaction was stopped. The reaction solution was slowly added to a saturated aqueous sodium bicarbonate solution, adjusted to pH = 7 with a saturated aqueous sodium bicarbonate solution, and then the mixture was extracted with EA (20.0 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (21.3 mg, yield 11.1%, white solid). LC-MS (ESI) m / z 408.3 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 13.39 - 12.85 (s, 1H), 7.72 - 7.55 (m, 2H), 7.07 (d, J = 1.6 Hz, 1H), 5.72 (s, 1H), 4.49-4.42 (m, 4H), 3.81 - 3.71 (m, 4H), 3.23 - 3.19 (m, 2H), 3.07 - 3.01 (m, 2H), 1.91 - 1.80 (m, 8H).

[0257] Example 7: 3-(4-Morpholino-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0258] Step 1: Synthesis of 4-(3,6-dichloropyridazin-4-yl)morpholine

Chemical Structure

[0259] To a solution of 4-bromo-3,6-dichloropyridazine (700 mg, 3.07 mmol) and morpholine (535 mg, 6.14 mmol) in DMF (15.0 mL) was added potassium carbonate (1.69 g, 12.3 mmol). Under nitrogen protection, the reaction mixture was stirred at 30 °C for 12 hours to allow the reaction to proceed, and then the reaction was stopped. Water (10.0 mL) was added, and then the mixture was extracted with EA (15.0 mL × 3). The organic phase was washed with saturated brine (15.0 mL × 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1 to 1:1) to obtain the target compound (700 mg, yield 97.3%, white solid). LC-MS (ESI) m / z 234.0 [M+H] + .

[0260] Step 2: Synthesis of 3-(6-chloro-5-morpholinopyridin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0261] To a solution of 4-(3,6-dichloropyridazin-4-yl)morpholine (700 mg, 2.99 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (671 mg, 4.49 mmol) in NMP (10.0 mL) was added DIEA (1.16 g, 8.97 mmol). The reaction mixture was stirred at 145 °C for 16 h, and then the reaction was stopped. After the reaction mixture was cooled to room temperature, water (15.0 mL) was added, and the mixture was extracted with EA (20.0 mL × 3). The combined organic phases were then washed with water (15.0 mL × 2) and saturated brine (15.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 3:1~1:2) to give the target compound (800 mg, yield 86.1%, white solid). LC-MS (ESI) m / z 311.2 [M+H] + 。

[0262] Step 3: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-morpholinopyridazine-3-carbonitrile

Chem.

[0263] To a mixed solution of water (5 drops) and DMF (10.0 mL) of 3-(6-chloro-5-morpholinopyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (600 mg, 1.93 mmol), zinc cyanide (453 mg, 3.86 mmol), DPPF (214 mg, 0.386 mmol) and Pd2(dba)3 (177 mg, 0.193 mmol) were sequentially added. Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 hours to react, and then the reaction was stopped. After the reaction solution was cooled to room temperature, water (15.0 mL) was added, and then it was extracted with EA (20.0 mL × 3). The combined organic phases were washed with water (15.0 mL × 2) and saturated brine (10.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1~1:3) to obtain the target compound (360 mg, yield 61.9%, brown solid). LC-MS (ESI) m / z 302.3 [M+H] + 。

[0264] Step 4: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-morpholinopyridazin-3-yl)methylamine

Chemical formula

[0265] To a solution of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-morpholinopyridazine-3-carbonitrile (360 mg, 1.19 mmol) in tetrahydrofuran (20.0 mL), aqueous ammonia (2.00 mL) and Raney nickel (~300 mg) were sequentially added. After nitrogen substitution was carried out three times, the reaction mixture was reacted overnight at room temperature in a hydrogen gas atmosphere, and then the reaction was stopped. The reaction mixture was filtered to remove solid residues, and the filtrate was concentrated under reduced pressure to obtain the target compound (320 mg, yield 87.7%, brown solid). LC-MS (ESI) m / z 306.1 [M+H] + 。

[0266] Step 5: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-morpholinopyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chem.

[0267] (6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-morpholinopyridazin-3-yl)methylamine (320 mg, 1.05 mmol) and 1H-pyrazole-5-carboxylic acid (118 mg, 1.05 mmol) in tetrahydrofuran (13.0 mL) were added with HATU (599 mg, 1.58 mmol) and DIEA (271 mg, 2.10 mmol), and the reaction mixture was reacted at room temperature for 2 hours and the reaction was stopped. The reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (DCM:methanol = 100:1 - 30:1) to obtain the target compound (170 mg, yield 40.6%, brown solid). LC-MS (ESI) m / z 400.3 [M+H] + 。

[0268] Step 6: Synthesis of 3-(3-chloro-4-morpholino-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0269] To a solution of N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-morpholinopyridin-3-yl)methyl)-1H-pyrazole-5-carboxamide (170 mg, 0.426 mmol) in acetonitrile (4.00 mL) was added phosphorus oxychloride (1.00 mL). The reaction mixture was reacted at 90 °C for 1 hour and then the reaction was stopped. After the reaction mixture was cooled to room temperature, the reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution at 0 °C. Then, the pH was adjusted to 9 with a saturated sodium bicarbonate solution at 0 °C, followed by extraction with EA (15.0 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by a silica gel plate (DCM:methanol = 20:1) to obtain the target compound (80.0 mg, yield 45.2%, yellow solid). LC-MS (ESI) m / z 416.1 [M+H] + 。

[0270] Step 7: Synthesis of 3-(4-morpholino-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0271] To a mixed solution of 3-(3-chloro-4-morpholino-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (80.0 mg, 0.192 mmol) in methanol (3.00 mL) and tetrahydrofuran (3.00 mL) was added palladium carbon (50.0 mg). After nitrogen substitution was performed three times, the reaction mixture was reacted at 50 °C overnight in a hydrogen gas atmosphere and then the reaction was stopped. The reaction mixture was filtered to remove solid residues, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by reversed-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (4.60 mg, yield 6.27%, white solid). LC-MS (ESI) m / z 382.1 [M+H] + 。1 1H NMR (400 MHz, MeOD-d4) δ 7.83 - 7.64 (m, 1H), 7.60 - 7.43 (m, 1H), 7.25 - 7.02 (m, 1H), 5.84 (s, 1H), 4.55 - 4.45 (m, 2H), 3.94 - 3.79 (m, 6H), 3.51 - 3.43 (m, 4H), 3.23 - 3.14 (m, 2H), 2.03 - 1.93 (m, 4H).

[0272] Example 8: 8-(2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane

Chem.

[0273] Step 1: Synthesis of 8-(3,6-dichloropyridazin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane

Chem.

[0274] Potassium carbonate (1.82 g, 13.2 mmol) was added to a solution of 4-bromo-3,6-dichloropyridazine (1.00 g, 4.39 mmol) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (985 mg, 6.58 mmol) in DMF (15.0 mL). Under nitrogen protection, the reaction mixture was stirred at room temperature for 16 hours to react, and the reaction was stopped. Then, the reaction solution was diluted with EA (45.0 mL), washed with saturated brine (35.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to obtain the target compound (1.00 g, yield 87.6%, yellow oil). LC-MS (ESI) m / z 259.9 [M+H] + , 261.9 [M+2+H] +。 1 1H NMR (400 MHz, CDCl3) δ 6.72 (s, 1H), 4.44 - 4.33 (m, 2H), 3.91 - 3.82 (m, 2H), 3.72 - 3.62 (m, 2H), 2.21 - 2.12 (m, 2H), 2.06 - 1.95 (m, 2H).

[0275] Step 2: Synthesis of 8-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropy Rida ridin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane

Chemical Structure

[0276] To a solution of 8-(3,6-dichloropyridazin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (1.00 g, 3.84 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.15 g, 7.69 mmol) in NMP (15.0 mL) was added DIEA (1.49 g, 11.5 mmol). Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 h to allow the reaction to proceed, and then the reaction was stopped. Subsequently, the reaction solution was diluted with EA (45.0 mL), washed with saturated brine (35.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (770 mg, yield 59.5%, yellow solid). LC-MS (ESI) m / z 337.0 [M+H] + 。

[0277] Step 3: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)py Da ridine-3-carbonitrile

Chemical Structure

[0278] 8-(6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropy Rida A solution of 4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (750 mg, 2.23 mmol) and zinc cyanide (523 mg, 4.45 mmol) in DMF (15.0 mL) was added with DPPF (247 mg, 0.445 mmol) and Pd2(dba)3 (204 mg, 0.222 mmol). Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours to react, and the reaction was stopped. Then, the reaction solution was diluted with EA (35.0 mL), washed with saturated brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (600 mg, yield 82.3%, yellow solid). LC-MS (ESI) m / z 328.0 [M+H] + 。

[0279] Step 4: Synthesis of (6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridazin-3-yl)methylamine

Chemical Structure

[0280] 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyr Da Raney nickel (~323 mg, 5.50 mmol) was added to a solution of dazine-3-carbonitrile (600 mg, 1.83 mmol) in tetrahydrofuran (10.0 mL). In a hydrogen gas atmosphere, the reaction mixture was reacted at room temperature for 16 hours, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (480 mg, yield 79.0%, yellow oil) as a residue. LC-MS (ESI) m / z 332.1 [M+H] + 。

[0281] Step 5: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chemical Structure

[0282] (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridazin-3-yl)methylamine (480 mg, 1.45 mmol) and 1H-pyrazole-5-carboxylic acid (146 mg, 1.30 mmol) were dissolved in tetrahydrofuran (10.0 mL). HATU (661 mg, 1.74 mmol) and DIEA (562 mg, 4.34 mmol) were added thereto. The reaction mixture was stirred at room temperature for 1 hour and then the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 0:1) to obtain the target compound (400 mg, yield 64.9%, yellow oil). LC-MS (ESI) m / z 426.0 [M+H] + .

[0283] Step 6: Synthesis of 8-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-(1H-pyrazol-3-yl)imidazo[1,□5-b]pyridazin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane

Chemical Structure

[0284] At room temperature, N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (100 mg, 0.235 mmol) and phosphorus oxychloride (5.00 mL) were added to a reaction flask. The reaction mixture was reacted at 100 °C for 1 hour, and the reaction was stopped. Under an ice bath, the reaction solution was added to a saturated aqueous sodium bicarbonate solution to adjust the pH to 7. Then, the mixture was extracted with EA (20.0 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by reversed-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (10.5 mg, yield 11.0%, white solid). LC-MS (ESI) m / z 408.3 [M+H] + 。 1 H NMR (400 MHz, MeOD-d4) δ 7.70 (s, 1H), 7.58 (s, 1H), 7.13 (s, 1H), 5.78 (s, 1H), 4.56 - 4.48 (m, 4H), 3.90 - 3.80 (m, 4H), 3.67 - 3.61 (m, 2H), 3.23 - 3.14 (m, 2H), 2.18 - 2.09 (m, 4H), 2.01 - 1.94 (m, 4H).

[0285] Example 9: 3-(4-((R)-2-Methylpiperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octanecarboxylate

Chemical Structure

[0286] Step 1: Synthesis of (R)-4-(3,6-Dichloropyridazin-4-yl)-3-methylpiperazine-1-t-butylcarboxylate

Chemical Structure

[0287] To a solution of 4-bromo-3,6-dichloropyridazine (2.00 g, 8.78 mmol) and (R)-3-methylpiperazine-1-t-butylcarboxylate (2.64 g, 13.2 mmol) in DMF (25.0 mL) was added potassium carbonate (2.43 g, 17.6 mmol). The reaction mixture was stirred at room temperature under nitrogen protection for 16 hours, and then quenched. The reaction mixture was then diluted with EA (55.0 mL), washed with saturated brine (35.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to give the target compound (1.60 g, 52.5% yield, yellow solid). LC-MS (ESI) m / z 346.9 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.83 (s, 1H), 4.25 - 4.08 (m, 2H), 3.89 - 3.79 (m, 1H), 3.46 - 3.28 (m, 2H), 3.23 - 3.02 (m, 2H), 1.48 (s, 9H), 1.12 (d, J = 6.6 Hz, 3H).

[0288] Step 2: Synthesis of (3R)-4-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyridazin-4-yl)-3-methylpiperazine-1-t-butylcarboxylate [ka]

[0289] (R)-4-(3,6-Dichloropyridazin-4-yl)-3-methylpiperazine-1-t-butyl carboxylate (1.60 g, 4.61 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.38 g, 9.22 mmol) were added to DIEA (1.79 g, 13.8 mmol) in an NMP (15.0 mL) solution. Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 hours to react, and the reaction was stopped. Then, the reaction solution was diluted with EA (55.0 mL), washed with saturated brine (35.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (1.20 g, yield 61.4%, yellow solid). LC-MS (ESI) m / z 424.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.11 (s, 1H), 4.54 - 4.49 (m, 2H), 4.14 - 3.93 (m, 2H), 3.86 - 3.81 (m, 1H), 3.77 - 3.65 (m, 2H), 3.44 - 3.31 (m, 2H), 3.26 - 3.10 (m, 3H), 2.90 - 2.84 (m, 1H), 2.03 - 1.95 (m, 2H), 1.90 - 1.82 (m, 2H), 1.48 (s, 9H), 1.02 (d, J = 6.5 Hz, 3H).

[0290] Step 3: Synthesis of (3R)-4-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-cyanopyridazin-4-yl)-3-methylpiperazine-1-t-butyl carboxylate

Chemical Structure

[0291] (3R)-4-(6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyrazin-4-yl)-3-methylpiperazine-1-t-butyl carboxylate (1.20 g, 2.83 mmol) and zinc cyanide (665 mg, 5.66 mmol) in DMF (20.0 mL) were added with DPPF (314 mg, 0.556 mmol) and Pd2(dba)3 (259 mg, 0.283 mmol). Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours for reaction, and the reaction was stopped. Then, the reaction solution was diluted with EA (45.0 mL), washed with saturated brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (1.00 g, yield 85.2%, yellow solid). LC-MS (ESI) m / z 415.0 [M+H] + 。

[0292] Step 4: Synthesis of (3R)-4-(3-(aminomethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-4-yl)-3-methylpiperazine-1-t-butyl carboxylate

Chemical Structure

[0293] (3R)-4-(6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-cyanopyridin-4-yl)-3-methylpiperazine-1-t-butyl carboxylate (500 mg, 1.21 mmol) in tetrahydrofuran (10.0 mL) was added with Raney nickel (~212 mg, 3.62 mmol). In a hydrogen gas atmosphere, the reaction mixture was reacted at room temperature for 16 hours, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (400 mg, yield 79.2%, yellow oil) as a residue. LC-MS (ESI) m / z 419.1 [M+H] + 。

[0294] Step 5: Synthesis of (3R)-4-(3-((1H-pyrazole-5-carboxamido)methyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyr Da idazin-4-yl)-3-methylpiperazine-1-t-butylcarboxylate

Chem.

[0295] (3R)-4-(3-(aminomethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-4-yl)-3-methylpiperazine-1-t-butylcarboxylate (400 mg, 0.956 mmol) and 1H-pyrazole-5-carboxylic acid (96.4 mg, 0.860 mmol) in tetrahydrofuran (10.0 mL) were added with HATU (436 mg, 1.15 mmol) and DIEA (371 mg, 2.87 mmol). The reaction mixture was reacted at room temperature for 1 hour and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 0:1) to obtain the target compound (300 mg, yield 61.2%, yellow oil). LC-MS (ESI) m / z 513.1 [M+H] + .

[0296] Step 6: Synthesis of 3-(4-((R)-2-methylpiperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octanecarboxylate

Chem.

[0297] At room temperature, (3R)-4-(3-((1H-pyrazole-5-carboxamido)methyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyr Da (4-(Piperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-3-methylpiperazine-1-t-butylcarboxylate (100 mg, 0.195 mmol) and phosphorus oxychloride (5.00 mL) were added. The reaction mixture was reacted at 100 °C for 1 hour and the reaction was stopped. Under an ice bath, the reaction solution was added to an aqueous saturated sodium bicarbonate solution to adjust the pH to 7, and then the mixture was extracted with EA (20.0 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by reversed-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (8.50 mg, yield 11.0%, white solid). LC-MS (ESI) m / z 395.3 [M+H] + 。 1 H NMR (400 MHz, MeOD-d4) δ 7.72 (s, 1H), 7.59 (s, 1H), 7.14 (s, 1H), 5.93 (s, 1H), 4.54 - 4.49 (m, 2H), 3.93 - 3.86 (m, 4H), 3.84 - 3.81 (m, 1H), 3.73 - 3.59 (m, 2H), 3.53 - 3.44 (m, 2H), 3.23 - 3.17 (m, 2H), 2.01 - 1.93 (m, 4H), 1.32 (d, J = 6.9 Hz, 3H).

[0298] Example 10: 3-(4-(Piperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octanecarboxylate

Chemical Structure

[0299] Step 1: Synthesis of 4-(3,6-dichloropyridazin-4-yl)piperazine-1-t-butylcarboxylate

Chemical Structure

[0300] To a DMF solution (12.0 mL) of 4-bromo-3,6-dichloropyridazine (1.00 g, 4.39 mmol) and t-butyl piperazine-1-carboxylate (1.23 g, 6.58 mmol), potassium carbonate (1.82 g, 13.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours to allow the reaction to proceed, and then the reaction was stopped. Thereafter, water (35.0 mL) was added, and then extracted with EA (30.0 mL × 3). The combined organic phases were washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to obtain the target compound (1.50 g, yield 100%, yellow solid). LC-MS (ESI) m / z 334.5 [M+2+H] + 。

[0301] Step 2: Synthesis of 4-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyridazin-4-yl)piperazine-1-t-butyl carboxylate

Chemical Structure

[0302] To a NMP solution (20.0 mL) of 4-(3,6-dichloropyridazin-4-yl)piperazine-1-t-butyl carboxylate (1.48 g, 4.44 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (997 mg, 6.66 mmol), DIEA (1.72 g, 13.3 mmol) was added. The reaction mixture was stirred at 145 °C for 16 hours to allow the reaction to proceed, and then the reaction was stopped. Thereafter, water (35.0 mL) was added, and then extracted with EA (30.0 mL × 3). The combined organic phases were washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by chromatography plate (PE:EA = 5:1) to obtain the target compound (1.20 g, yield 65.9%, yellow solid). LC-MS (ESI) m / z 410 [M+H] + 。

[0303] Step 3: Synthesis of 4-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-cyanopyridazin-4-yl)piperazine-1-t-butylcarboxylate

Chem.

[0304] To a solution of 4-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyridazin-4-yl)piperazine-1-t-butylcarboxylate (1.10 g, 2.68 mmol) and zinc cyanide (630 mg, 5.37 mmol) in DMF (20.0 mL) were added DPPF (297 mg, 0.537 mmol) and Pd2(dba)3 (246 mg, 0.268 mmol). Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 h to react, and the reaction was stopped. Then, the reaction solution was diluted with EA (30.0 mL), washed with saturated brine (25.0 mL ×  3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (600 mg, yield 55.8%, yellow solid). LC-MS (ESI) m / z 401.1 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 5.89 (s, 1H), 4.54 - 4.50 (m, 2H), 4.01 - 3.93 (m, 2H), 3.64 - 3.61 (m, 4H), 3.35 - 3.26 (m, 6H), 2.04 - 1.99 (m, 2H), 1.85 - 1.79 (m, 2H), 1.48 (s, 9H).

[0305] Step 4: Synthesis of 4-(3-(aminomethyl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridazin-4-yl)piperazine-1-t-butylcarboxylate

Chem.

[0306] To a solution of 4-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-cyanopyridazin-4-yl)piperazine-1-t-butylcarboxylate (600 mg, 1.50 mmol) in tetrahydrofuran (12.0 mL) were added Raney nickel (439 mg, 7.49 mmol) and aqueous ammonia (5 drops). The reaction mixture was reacted at room temperature for 16 h in a hydrogen gas atmosphere, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (530 mg, yield 87.5%, yellow oil) as a residue. LC-MS (ESI) m / z 405.1 [M+H] + 。

[0307] Step 5: Synthesis of 4-(3-((1H-pyrazole-5-carboxamido)methyl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridazin-4-yl)piperazine-1-t-butylcarboxylate

Chemical formula

[0308] Under nitrogen protection, to a tetrahydrofuran solution (10.0 mL) of 4-(3-(aminomethyl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridazin-4-yl)piperazine-1-t-butylcarboxylate (480 mg, 1.19 mmol) and 1H-pyrazole-5-carboxylic acid (119 mg, 1.07 mmol) were added HATU (541 mg, 1.42 mmol) and DIEA (306 mg, 2.37 mmol). The reaction mixture was stirred at room temperature for 1 h to react, and the reaction was stopped. Then, water (25.0 mL) was added, and then extracted with EA (20.0 mL×3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by a chromatography plate (DCM:methanol = 10:1) to obtain the target compound (500 mg, yield 84.5%, yellow solid). LC-MS (ESI) m / z 499.2 [M+H] + 。

[0309] Step 6: Synthesis of 3-(4-(Piperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane carboxylate

Chemical Structure

[0310] At room temperature, 4-(3-((1H-pyrazole-5-carboxamide)methyl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridazin-4-yl)piperazine-1-t-butyl carboxylate (150 mg, 0.301 mmol) and phosphorus oxychloride (15.0 mL) were added to a reaction flask. The reaction mixture was reacted at 100 °C for 1 hour, and the reaction was stopped. Under an ice bath, the reaction solution was added to a saturated aqueous sodium bicarbonate solution to adjust the pH to 7. Then, the mixture was extracted with EA (25.0 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (5.66 mg, yield 4.94%, white solid). LC-MS (ESI) m / z 381.0 [M+H] + 。 1 H NMR (400 MHz, MeOD-d4) δ 7.72 (s, 1H), 7.55 (s, 1H), 7.14 (s, 1H), 5.94 (s, 1H), 4.53 - 4.48 (m, 2H), 3.88 - 3.82 (m, 2H), 3.70 - 3.63 (m, 4H), 3.41 - 3.36 (m, 4H), 3.23 - 3.17 (m, 2H), 2.01 - 1.92 (m, 4H).

[0311] Example 11: 3-(4-((R)-2,4-Dimethylpiperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane carboxylate

Chemical formula

[0312] Step 1: Synthesis of 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2-methylpiperazin-1-yl)pyridazine-3-carbonitrile

Chemical formula

[0313] At room temperature, (3R)-4-(6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-cyanopyridin-4-yl)-3-methylpiperazine-1-t-butyl carboxylate (500 mg, 1.21 mmol) and hydrochloric acid EA (10.0 mL, 3 M) were added to the reaction flask, and the reaction mixture was stirred at room temperature for 2 hours to react, and then the reaction was stopped. It was concentrated under reduced pressure to obtain the target compound (400 mg, yield 94.5%, white solid). LC-MS (ESI) m / z 315.1 [M+H] + .

[0314] Step 2: Synthesis of 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)pyridazine-3-carbonitrile

Chemical formula

[0315] 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2-methylpiperazin-1-yl)pyridazine-3-carbonitrile (400 mg, 1.27 mmol) and paraformaldehyde (144 mg, 3.82 mmol) in methanol (10.0 mL) were added sodium borohydride (115 mg, 3.82 mmol). The reaction mixture was stirred at room temperature for 1 hour to react, and the reaction was stopped. Then, water (20.0 mL) was added, and then extracted with EA (20.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (400 mg, yield 95.7%, white solid). LC-MS (ESI) m / z 329.2 [M+H] + 。

[0316] Step 3: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)pyridazin-3-yl)methylamine

Chemical Structure

[0317] Raney nickel (214 mg, 3.65 mmol) was added to a solution of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)pyridazine-3-carbonitrile (400 mg, 1.22 mmol) in tetrahydrofuran (10.0 mL). The reaction mixture was reacted at room temperature for 16 hours in a hydrogen gas atmosphere, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (300 mg, yield 74.1%, yellow oil) as a residue. LC-MS (ESI) m / z 333.1 [M+H] + 。

[0318] Step 4: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)pyrazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chem.

[0319] (6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)pyridazin-3-yl)methylamine (300 mg, 0.902 mmol) and 1H-pyrazole-5-carboxylic acid (91.0 mg, 0.812 mmol) in tetrahydrofuran (10.0 mL) were added with HATU (412 mg, 1.08 mmol) and DIEA (350 mg, 2.71 mmol). The reaction mixture was reacted at room temperature for 1 hour and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (EA = 100%) to obtain the target compound (200 mg, yield 51.9%, yellow oil). LC-MS (ESI) m / z 427.2 [M+H] + 。

[0320] Step 5: Synthesis of 3-(3-chloro-4-((R)-2,4-dimethylpiperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0321] At room temperature, N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2,4-dimethylpiperazin-1-yl)pyrazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (100 mg, 0.234 mmol) and phosphorus oxychloride (5.00 mL) were added to a reaction flask. The reaction mixture was reacted at 100 °C for 1 hour, and the reaction was stopped. Under an ice bath, the reaction solution was added to a saturated aqueous sodium bicarbonate solution to adjust the pH to 7. Then, the mixture was extracted with EA (20.0 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the target compound (100 mg, yield 96.3%, white solid) was obtained as the residue. LC-MS (ESI) m / z 443.3 [M+H] + 。

[0322] Step 6: Synthesis of 3-(4-((R)-2,4-dimethylpiperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane carboxylate

Chemical Structure

[0323] Palladium carbon (53.5 mg, 5%) was added to a methanol (10.0 mL) solution of 3-(3-chloro-4-((R)-2,4-dimethylpiperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (100 mg, 0.226 mmol). The reaction mixture was reacted at 60 °C for 16 hours in a hydrogen gas atmosphere, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure. The obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (12.5 mg, yield 13.6%, white solid). LC-MS (ESI) m / z 409.3 [M+H] + 。 11H NMR (400 MHz, MeOD-d4) δ 7.72 (s, 1H), 7.63 - 7.44 (m, 1H), 7.26 - 6.99 (m, 1H), 5.84 (s, 1H), 4.52 - 4.49 (m, 2H), 3.95 - 3.75 (m, 3H), 3.63 - 3.49 (m, 2H), 3.22 - 3.11 (m, 3H), 3.06 - 2.98 (m, 1H), 2.81 - 2.73 (m, 1H), 2.62 - 2.54 (m, 1H), 2.52 (s, 3H), 2.00 - 1.91 (m, 4H), 1.28 (d, J = 6.4 Hz, 3H).

[0324] Example 12: 3-(6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0325] The synthesis of the intermediate 6-fluoro-4-iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine was referred to Example 5.

[0326] Step 1: Synthesis of 3-(4-iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0327] 6-Fluoro-4-iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine (718 mg, 2.18 mmol) was dissolved in dimethyl sulfoxide (7 mL). Under nitrogen protection, the obtained mixture was stirred uniformly at room temperature, 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (326 mg, 2.18 mmol) was added, the reaction solution was heated to 120 °C and stirred for 45 minutes. When the reaction was completed as monitored by LC-MS, the reaction mixture was added dropwise to water (30 mL) to precipitate a yellowish-brown solid. After the mixture was stirred at room temperature for 10 minutes, it was cooled to 0 °C and stirred for another 10 minutes. The suspension was suction filtered through a suction filtration funnel, the solid was collected, the aqueous phase was extracted with EA (10 mL × 2), and the obtained crude product was separated and purified by silica gel column (PE:EA = 1:2) to obtain the target compound (215 mg, yield 23.3%, yellow solid). LC-MS (ESI) m / z: 423.0 [M+H] + .

[0328] Step 2: Synthesis of 3-(4-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0329] 3-(4-Iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (215 mg, 0.509 mmol), DHP (86 mg, 1.02 mmol), and p-toluenesulfonic acid monohydrate (10 mg, 0.051 mmol) were sequentially added to DCM (2 mL). The reaction mixture was stirred at room temperature overnight to effect the reaction. When the reaction was completed as monitored by LC-MS, water (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative plate (silica gel, EA:PE = 1:2) to obtain the target compound (210 mg, yield 81.4%, yellow solid). LC-MS (ESI) m / z: 507.1 [M+H] + 。

[0330] Step 3: Synthesis of 3-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0331] 3-(4-Iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (210 mg, 0.415 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (124 mg, 0.829 mmol), RuPhosPdG2 (32 mg, 0.042 mmol), and cesium carbonate (405 mg, 1.24 mmol) were added to 1,4-dioxane (2 mL). Under nitrogen protection, the resulting mixture was stirred at 110 °C for 2 hours and monitored by LC-MS. When the reaction was completed, water (10 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (PE:EA = 1:1) to obtain the target compound (55 mg, yield 27.0%, brown oil). LC-MS (ESI) m / z: 492.2 [M+H] + 。

[0332] Step 4: Synthesis of 3-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0333] To a solution of 3-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (55 mg, 0.112 mmol) in methanol (2 mL) was added 4 mol / L hydrochloric acid 1,4-dioxane solution (2 mL). Under nitrogen protection, the resulting mixture was stirred at room temperature for 2 hours, the solvent was removed under reduced pressure, and the residue was separated and purified by a prep-HPLC preparative column to obtain the target compound (3.3 mg, yield 7.24%, white solid). LC-MS (ESI) m / z: 408.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.31-8.23 (m, 1H), 7.90-7.77 (m, 1H), 6.80 (s, 1H), 4.63 - 4.49 (m, 4H), 3.92 (d, J = 12.2 Hz, 2H), 3.81 (d, J = 11.9 Hz, 2H), 3.48 (d, J =11.8 Hz, 2H), 3.35 (d, J = 12.0 Hz, 2H), 2.09 - 1.99 (m, 4H), 1.99 - 1.89 (m, 4H).

[0334] Example 13: 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0335] Synthesis of Intermediate 1-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethan-1-one [Chemical formula]

[0336] 8-Oxa-3-azabicyclo[3.2.1]octane hydrochloride (3.20 g, 32.6 mmol) was added to a DCM solution (60 mL), and the mixture was cooled to 0 °C. Potassium carbonate (28.2 g, 204 mmol) was added to the reaction mixture, and the reaction solution was stirred at 0 °C for 30 minutes for reaction. Then, acetyl chloride (8 mL, 114 mmol) was added to the reaction mixture. After the reaction solution was stirred at room temperature for 16 hours, when the reaction was completed by TLC thin-layer chromatography monitoring (EA:PE = 1:1, phosphomolybdic acid coloring), the solid was removed by suction filtration, and then concentrated under reduced pressure to obtain the target compound (3.50 g, crude product, yellow oil).

[0337] Step 1: Synthesis of 4-amino-1-methyl-1H-pyrazole-5-methyl carboxylate

Chem.

[0338] 1-Methyl-4-nitro-1H-pyrazole-5-methyl carboxylate (5.00 g, 27.0 mmol) was added to methanol (200 mL), and 10% palladium on carbon (100 mg) was added to the reaction mixture. After the reaction solution was replaced with hydrogen gas three times, it was stirred at room temperature overnight in a hydrogen gas atmosphere for reaction. When the reaction was completed as monitored by LC-MS, diatomaceous earth was spread and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound (4.50 g, crude product, blue-violet solid). LC-MS (ESI) m / z: 156.2 [M+H] + .

[0339] Step 2: Synthesis of 4-((1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethylene)amino)-1-methyl-1H-pyrazole-5-methyl carboxylate

Chem.

[0340] 4-Amino-1-methyl-1H-pyrazole-5-methyl carboxylate (3.48 g, 22.4 mmol) was added to a 1,2-dichloroethane solution (35 mL), and the mixture was cooled to 0 °C. 1-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethan-1-one (3.48 g, 22.4 mmol) was added to the reaction mixture. After stirring the reaction solution at 0 °C for 10 minutes to allow the reaction to proceed, phosphorus oxychloride (6.25 mL, 67.3 mmol) was added to the reaction mixture. After stirring the reaction solution at 80 °C for 0.5 hour and monitoring by LC-MS, when the reaction was completed, it was concentrated under reduced pressure and separated by silica gel column (PE:EA = 1:1) to obtain the target compound (3.56 g, yield 54.3%, yellow oil). LC-MS (ESI) m / z: 293.1 [M+H] + .

[0341] Step 3: Synthesis of 5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-7-ol

Chemical Structure

[0342] 4-((1-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethylene)amino)-1-methyl-1H-pyrazole-5-methyl carboxylate (3.56 g, 12.2 mmol) was dissolved in DMF (70 mL), and a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (36.5 mL) was slowly added at 0 °C. Under nitrogen protection, the resulting mixture was stirred at 0 °C for 1 hour. After monitoring by LC-MS and when the reaction was completely carried out, an appropriate amount of aqueous ammonium chloride solution was added for quenching. After distillation under reduced pressure, it was separated and purified by silica gel column (DCM:MeOH = 20:1 - 10:1) to obtain the target compound (2.16 g, yield 68.1%, yellow oil). LC-MS (ESI) m / z: 261.2 [M+H] + 。

[0343] Step 4: Synthesis of 3-(7-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0344] 5-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-7-ol (2.16 g, 8.30 mmol) was dissolved in acetonitrile (22 mL). After stirring at room temperature for half an hour, phosphorus oxychloride (2.3 mL, 24.9 mmol) was added to the reaction mixture, and the mixture was stirred at 80 °C overnight for reaction. When the reaction was completed as monitored by LC-MS, the solvent was rotary evaporated from the reaction mixture and separated and purified by silica gel column (silica gel, EA:PE = 1:2) to obtain the target compound (2.28 g, yield 98.6%, yellow solid). LC-MS (ESI) m / z: 279.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.10 (s, 1H), 4.43 - 4.39 (m, 2H), 4.17 (s, 3H), 3.82 (d, J = 12.2 Hz, 2H), 2.95 (d, J = 12.2 Hz, 2H), 1.85 - 1.76 (m, 2H), 1.79 - 1.69 (m, 2H).

[0345] Step 5: Synthesis of 3-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0346] 3-(7-Chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.20 g, 4.50 mmol) was dissolved in N-methylpyrrolidone (5 mL), and 8-oxa-3-azabicyclic[3.2.1]octane hydrochloride (537 mg, 3.59 mmol), RuphosPdG2 (139 mg, 0.179 mmol), and cesium carbonate (1.75 g, 5.38 mmol) were added. Under nitrogen protection, the obtained mixture was stirred at 110 °C for 2 hours and monitored by LC-MS. When the reaction was completed, the reaction mixture was added to water (50 mL), and the aqueous phase was extracted with EA (20 mL × 2) and washed with saturated brine (10 mL). After rotary evaporation of the organic phase, it was separated and purified by silica gel column (DCM: MeOH = 20:1) to obtain the target compound (245 mg, yield 38.4%, brown solid). LC-MS (ESI) m / z: 356.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 6.43 (s, 1H), 4.46 - 4.30 (m, 4H), 4.15 (s, 3H), 3.79 (d, J = 12.1 Hz, 2H), 3.10 (d, J = 11.4 Hz, 2H), 2.99 (d, J = 11.4 Hz, 2H), 2.90 (d, J = 11.7 Hz, 2H), 2.13 - 2.03 (m, 2H), 1.94 - 1.86 (m, 2H), 1.83 - 1.71 (m, 4H).

[0347] Step 6: Synthesis of 3-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0348] 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (95 mg, 0.267 mmol) was dissolved in DCM (5 mL). Under nitrogen protection, N-bromosuccinimide (48 mg, 0.267 mmol) was added to the reaction mixture, and the reaction solution was stirred at room temperature for 10 minutes. When the reaction was completed as monitored by LC-MS, water (5 mL) was added to the reaction mixture, and the mixture was extracted with DCM (5 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. It was separated and purified by preparative silica gel plate (EA:PE = 1:2) to obtain the target compound 3-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (67 mg, yield 57.7%, yellow solid). LC-MS (ESI) m / z: 434.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 6.49 (s, 1H), 4.46 - 4.36 (m, 4H), 4.12 (s, 3H), 3.87 (d, J = 12.3 Hz, 2H), 3.10 (d, J = 11.5 Hz, 2H), 3.04 - 2.89 (m,4H), 2.11 - 2.02 (m, 2H), 1.97 - 1.85 (m, 2H), 1.83 - 1.71 (m, 4H).

[0349] Step 7: Synthesis of 3-(7-(8-oxa-3-azabicyclo[3.2.1]octyl)-1-methyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolyl[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0350] 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (67 mg, 0.154 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.2 mL), and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (215 mg, 0.772 mmol), Pd(dtbpf)Cl2 (10 mg, 0.015 mmol) and potassium phosphate (98 mg, 0.463 mmol) were added. Under nitrogen protection, the obtained mixture was stirred at 110 °C for 2 hours and monitored by LC-MS. When the reaction was completed, water (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA = 1:2) to obtain the target compound (53 mg, yield 67.9%, brown oil). LC-MS (ESI) m / z: 506.2 [M+H] + 。

[0351] Step 8: Synthesis of 3-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0352] To a solution of 3-(7-(8-oxa-3-azabicyclo[3.2.1]octyl)-1-methyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolyl[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (53 mg, 0.105 mmol) in methanol (2 mL) was added 4 mol / L hydrochloric acid in 1,4-dioxane (2 mL). The resulting mixture was stirred at room temperature under nitrogen protection for 2 hours. Upon completion of the reaction as monitored by LC-MS, the solvent was removed under reduced pressure, and the residue was purified by prep-HPLC column separation to give the target compound (2.9 mg, 6.57% yield, white solid). LC-MS (ESI) m / z: 422.2 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 7.91-7.75 (m, 1H), 6.90-6.77 (m, 1H), 6.41 (s, 1H), 4.67 - 4.57 (m, 2H), 4.57 - 4.49 (m, 2H), 4.27 (s, 3H), 3.81 (d, J = 11.8 Hz, 2H), 3.58 (d, J =12.3 Hz, 2H), 3.48 (d, J = 11.8 Hz, 2H), 3.37 (d, J = 12.2 Hz, 2H), 2.22 - 2.04 (m, 4H), 2.04 - 1.91 (m, 4H).

[0353] Example 14: 3-(4-(4,4-difluoropiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane [ka]

[0354] Step 1: Synthesis of 3,6-dichloro-4-(4,4-difluoropiperidin-1-yl)pyridazine [ka]

[0355] To a solution of 4-bromo-3,6-dichloropyridazine (1.00 g, 4.39 mmol) and 4,4-difluoropiperidine (797 mg, 6.58 mmol) in DMF (15.0 mL) was added potassium carbonate (1.82 g, 13.2 mmol). Under nitrogen protection, the reaction mixture was stirred at room temperature for 16 hours to allow the reaction to proceed, and then the reaction was stopped. Water (20.0 mL) was added, and then the mixture was extracted with EA (25.0 mL × 3). The combined organic phases were washed with water (20.0 mL × 2) and saturated brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 10:1 to 3:1) to obtain the target compound (1.10 g, yield 93.5%, white solid). LC-MS (ESI) m / z 268.0 [M+H] + 。

[0356] Step 2: Synthesis of 3-(6-chloro-5-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0357] A solution of 3,6-dichloro-4-(4,4-difluoropiperidin-1-yl)pyridazine (1.10 g, 4.10 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (921 mg, 6.16 mmol) in NMP (23.0 mL) was added with DIEA (1.59 g, 12.3 mmol). The reaction mixture was stirred at 145 °C for 16 h and then the reaction was stopped. After the reaction mixture was cooled to room temperature, water (25.0 mL) was added and the mixture was extracted with EA (30.0 mL × 3). The combined organic phases were then washed with water (30.0 mL × 2) and saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 10:1~1:1) to obtain the target compound (1.20 g, yield 84.8%, white solid). LC-MS (ESI) m / z 345.0 [M+H] + .

[0358] Step 3: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(4,4-difluoropiperidin-1-yl)pyridazine-3-carbonitrile [Chemical formula]

[0359] To a mixed solution of 3-(6-chloro-5-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (700 mg, 2.03 mmol) in DMF (15.0 mL) with 3 drops of water, zinc cyanide (476 mg, 4.05 mmol), DPPF (225 mg, 0.406 mmol) and Pd2(dba)3 (186 mg, 0.203 mmol) were sequentially added. Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 hours to react, and then the reaction was stopped. After the reaction solution was cooled to room temperature, water (20.0 mL) was added, and then it was extracted with EA (25.0 mL × 3). The combined organic phases were washed with water (20.0 mL × 2) and saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 3:1~1:3) to obtain the target compound (450 mg, yield 66.1%, brown solid). LC-MS (ESI) m / z 336.3 [M+H] + 。

[0360] Step 4: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)methylamine

Chemical formula

[0361] To a solution of 6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(4,4-difluoropiperidin-1-yl)pyridazine-3-carbonitrile (450 mg, 1.34 mmol) in tetrahydrofuran (20.0 mL), aqueous ammonia (2.00 mL) and Raney nickel (400 mg) were sequentially added. After nitrogen substitution was carried out 3 times, the reaction mixture was reacted overnight at room temperature in a hydrogen gas atmosphere, and the reaction was stopped. The reaction mixture was filtered to remove solid residues, the filtrate was concentrated under reduced pressure and dried in vacuo to obtain the target compound (450 mg, yield 98.8%, brown solid). LC-MS (ESI) m / z 340.2 [M+H] + 。

[0362] Step 5: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chem.

[0363] (6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)methylamine (450 mg, 1.33 mmol) and 1H-pyrazole-5-carboxylic acid (134 mg, 1.20 mmol) in tetrahydrofuran (20.0 mL) were added with HATU (605 mg, 1.60 mmol) and DIEA (343 mg, 2.66 mmol). The reaction mixture was reacted at room temperature for 1 hour. Then, a sodium hydroxide (1.60 mL, 1 M) solution was added to the reaction solution, and the mixture was further stirred and reacted for 1 hour to stop the reaction. Water (25.0 mL) was added to the reaction mixture for dilution. Then, it was extracted with (DCM:methanol) = 10:1 (30.0 mL × 3). The organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (DCM:methanol = 100:1 - 30:1) to obtain the target compound (330 mg, yield 57.4%, brown solid). LC-MS (ESI) m / z 434.3 [M+H] + 。

[0364] Step 6: Synthesis of 3-(4-(4,4-difluoropiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0365] N-((6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (330 mg, 0.761 mmol) was dissolved in phosphorus oxychloride (12.0 mL) solution. The reaction mixture was reacted at 120 °C for 1 hour and then the reaction was stopped. After the reaction mixture was cooled to room temperature, the reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution at 0 °C. Then, the pH was adjusted to 9 with a saturated sodium bicarbonate solution at 0 °C, and then extracted with EA (40.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (127.46 mg, yield 40.3%, gray solid). LC-MS (ESI) m / z 416.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 13.16 (Brs, 1H), 7.71 - 7.64 (m, 1H), 7.62(s, 1H), 7.12-7.03 (m, 1H), 5.93 (s, 1H), 4.47 (s, 2H), 3.82 (d, J = 12.2 Hz, 2H), 3.65 - 3.59 (m, 4H), 3.06 (d, J = 11.1 Hz, 2H), 2.22 - 2.11 (m, 4H), 1.87 - 1.81 (m, 4H).

[0366] Example 15: 3-(4-((S)-3-Methylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0367] Step 1: Synthesis of (S)-4-(3,6-Dichloropyridazin-4-yl)-3-methylmorpholine

Chem.

[0368] To a solution of 3,4,6-trichloropyridazine (2.00 g, 10.9 mmol) and (S)-3-methylmorpholine (1.65 g, 16.3 mmol) in NMP (20.0 mL) was added potassium carbonate (4.52 g, 32.7 mmol). Under nitrogen protection, the reaction mixture was stirred at room temperature for 16 h to allow the reaction to proceed, and then the reaction was stopped. Water (25.0 mL) was added, and then the mixture was extracted with EA (30.0 mL × 3). The combined organic phases were washed with water (20.0 mL × 2) and saturated brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 10:1~3:1) to obtain the target compound (1.70 g, yield 62.8%, pale yellow solid). LC-MS (ESI) m / z 247.9 [M+H] + 。

[0369] Step 2: Synthesis of 3-(6-chloro-5-((S)-3-methylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0370] (S)-4-(3,6-Dichloropyridazin-4-yl)-3-methylmorpholine (900 mg, 3.63 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (814 mg, 5.44 mmol) were added to a solution of NMP (15.0 mL), and DIEA (1.41 g, 10.9 mmol) was added thereto. The reaction mixture was stirred at 145 °C for 16 hours and then the reaction was stopped. After the reaction mixture was cooled to room temperature, water (20.0 mL) was added, and the mixture was extracted with EA (25.0 mL × 3). The combined organic phases were then washed with water (20.0 mL × 2) and saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1 to 1:1) to obtain the target compound (770 mg, yield 65.4%, white solid). LC-MS (ESI) m / z 325.3 [M+H] + 。

[0371] Step 3: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((S)-3-methylmorpholino)pyridazine-3-carbonitrile

Chemical formula

[0372] To a mixed solution of water (3 drops) and DMF (15.0 mL) of 3-(6-chloro-5-((S)-3-methylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (770 mg, 2.37 mmol), zinc cyanide (557 mg, 4.74 mmol), DPPF (263 mg, 0.474 mmol) and Pd2(dba)3 (217 mg, 0.237 mmol) were sequentially added. Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 hours for reaction, and then the reaction was stopped. After the reaction solution was cooled to room temperature, water (20.0 mL) was added, and then extracted with EA (25.0 mL × 3). The combined organic phases were washed with water (20.0 mL × 2) and saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 3:1~1:4) to obtain the target compound (670 mg, yield 89.6%, brown solid). LC-MS (ESI) m / z 316.1 [M+H] + 。

[0373] Step 4: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((S)-3-methylmorpholino)pyridazin-3-yl)methylamine

Chemical Structure

[0374] To a solution of 6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((S)-3-methylmorpholino)pyridazine-3-carbonitrile (670 mg, 2.12 mmol) in tetrahydrofuran (15.0 mL), aqueous ammonia (1.50 mL) and Raney nickel (500 mg were sequentially added). After three nitrogen replacements, the reaction mixture was reacted overnight at room temperature in a hydrogen gas atmosphere, and the reaction was stopped. The reaction mixture was filtered to remove solid residues, and the filtrate was concentrated under reduced pressure and dried in vacuo to obtain the target compound (630 mg, yield 92.8%, brown solid). LC-MS (ESI) m / z 320.3 [M+H] + 。

[0375] Step 5: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((S)-3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chem.

[0376] (6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((S)-3-methylmorpholino)pyridazin-3-yl)methylamine (330 mg, 1.03 mmol) and 1H-pyrazole-5-carboxylic acid (116 mg, 1.03 mmol) in tetrahydrofuran (15.0 mL) were added with HATU (471 mg, 1.24 mmol) and DIEA (267 mg, 2.06 mmol). The reaction mixture was reacted at room temperature for 1 hour. Then, a sodium hydroxide (1 mol / L) solution was added to the reaction solution, and the mixture was further stirred and reacted for 1 hour to stop the reaction. Water (20.0 mL) was added to the reaction mixture for dilution, and then extracted with (DCM:methanol) = 10:1 (25.0 mL × 2). The organic phase was washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (DCM:methanol = 100:1 - 20:1) to obtain the target compound (275 mg, yield 64.4%, brown solid). LC-MS (ESI) m / z 414.3 [M+H] + 。

[0377] Step 6: Synthesis of 3-(4-((S)-3-methylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0378] N-((6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((S)-3-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (275 mg, 0.665 mmol) was dissolved in phosphorus oxychloride (12.0 mL) solution. The reaction mixture was reacted at 120 °C for 1 hour and then the reaction was stopped. After the reaction mixture was cooled to room temperature, the reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution at 0 °C. Then, the pH was adjusted to 9 with a saturated sodium bicarbonate solution at 0 °C, and then extracted with EA (30.0 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (112.12 mg, yield 42.6%, white solid). LC-MS (ESI) m / z 396.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 13.20 (Brs, 1H), 7.72 - 7.61 (m, 2H), 7.08 (s, 1H), 5.78 (s, 1H), 4.49 - 4.43 (m, 2H), 4.38 - 4.31 (m, 1H), 3.99 - 3.92 (m, 1H), 3.84 - 3.75 (m, 3H), 3.74 - 3.68 (m, 1H), 3.65 - 3.57 (m, 1H), 3.49 - 3.39 (m, 2H), 3.10 - 3.02 (m, 2H), 1.88 - 1.80 (m, 4H), 1.15 (d, J = 6.6 Hz, 3H).

[0379] Example 16: 3-(4-cis-2,6-dimethylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0380] Step 1: Synthesis of 4-(3,6-dichloropyridazin-4-yl)-cis-2,6-dimethylmorpholine

Chem.

[0381] Potassium carbonate (6.78 g, 49.1 mmol) was added to a solution of 3,4,6-trichloropyridazine (3.00 g, 16.4 mmol) and cis-2,6-dimethylmorpholine (3.01 g, 26.1 mmol) in NMP (30.0 mL). Under nitrogen protection, the reaction mixture was stirred at room temperature for 16 hours to allow the reaction to proceed, and then the reaction was stopped. Water (35.0 mL) was added, and then the mixture was extracted with EA (40.0 mL × 3). The combined organic phases were washed with water (30.0 mL × 2) and saturated brine (30.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 10:1 to 3:1) to obtain the target compound (3.70 g, yield 86.3%, white solid). LC-MS (ESI) m / z 262.2 [M+H] + .

[0382] Step 2: Synthesis of 3-(6-chloro-5-(cis-2,6-dimethylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0383] A solution of 4-(3,6-dichloropyridazin-4-yl)-cis-2,6-dimethylmorpholine (1.00 g, 3.81 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (913 mg, 6.10 mmol) in NMP (15.0 mL) was added with DIEA (1.48 g, 11.4 mmol), and the reaction mixture was stirred at 145 °C for 16 h, then the reaction was stopped. After the reaction mixture was cooled to room temperature, water (25.0 mL) was added, and it was extracted with EA (30.0 mL × 3). The combined organic phases were then washed with water (25.0 mL × 2) and saturated brine (25.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1~1:1) to obtain the target compound (1.00 g, yield 77.3%, brown solid). LC-MS (ESI) m / z 339.3 [M+H] + 。

[0384] Step 3: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(cis-2,6-dimethylmorpholino)pyridazine-3-carbonitrile

Chemical Structure

[0385] To a mixed solution of 3-(6-chloro-5-(cis-2,6-dimethylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.00 g, 2.95 mmol) in DMF (20.0 mL) with 5 drops of water, zinc cyanide (695 mg, 5.92 mmol), DPPF (328 mg, 0.592 mmol) and Pd2(dba)3 (271 mg, 0.295 mmol) were sequentially added. Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 hours to react, and then the reaction was stopped. After the reaction solution was cooled to room temperature, water (20.0 mL) was added, and then it was extracted with EA (25.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL × 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1~1:3) to obtain the target compound (860 mg, yield 88.5%, brown solid). LC-MS (ESI) m / z 330.3 [M+H] + 。

[0386] Step 4: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(cis-2,6-dimethylmorpholino)pyridazin-3-yl)methylamine

Chemical Structure

[0387] To a solution of 6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(cis-2,6-dimethylmorpholino)pyridazine-3-carbonitrile (860 mg, 2.61 mmol) in tetrahydrofuran (20.0 mL), aqueous ammonia (2.00 mL) and Raney nickel (~600 mg) were sequentially added. After nitrogen substitution was performed 3 times, the reaction mixture was reacted overnight at room temperature in a hydrogen gas atmosphere, and then the reaction was stopped. The reaction mixture was filtered to remove solid residues, and the filtrate was concentrated under reduced pressure and dried in vacuo to obtain the target compound (710 mg, yield 81.6%, brown solid). LC-MS (ESI) m / z 334.3 [M+H] + 。

[0388] Step 5: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(cis-2,6-dimethylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chem.

[0389] (6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(cis-2,6-dimethylmorpholino)pyridazin-3-yl)methylamine (350 mg, 1.05 mmol) and 1H-pyrazole-5-carboxylic acid (118 mg, 1.05 mmol) were dissolved in tetrahydrofuran (15.0 mL). HATU (479 mg, 1.26 mmol) and DIEA (271 mg, 2.10 mmol) were added thereto. The reaction mixture was reacted at room temperature for 1 hour. Then, a sodium hydroxide (1 mol / L) solution was added to the reaction solution, and the mixture was further stirred and reacted for 1 hour to stop the reaction. Water (20.0 mL) was added to the reaction mixture for dilution, and then extracted with (DCM:methanol) = 10:1 (25.0 mL × 3). The organic phase was washed with saturated brine (20.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (methanol:DCM = 5%) to obtain the target compound (280 mg, yield 62.4%, brown solid). LC-MS (ESI) m / z 428.4 [M+H] + 。

[0390] Step 6: Synthesis of 3-(4-(cis-2,6-dimethylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0391] N-((6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(cis-2,6-dimethylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (150 mg, 0.351 mmol) was dissolved in phosphorus oxychloride (6.00 mL) solution, and the reaction mixture was reacted at 120 °C for 1 hour, and then the reaction was stopped. After the reaction mixture was cooled to room temperature, the reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution at 0 °C, and then the pH was adjusted to 9 with a saturated sodium bicarbonate solution at 0 °C. Then, it was extracted with EA (30.0 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (54.42 mg, yield 37.9%, white solid). LC-MS (ESI) m / z 410.4 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 13.12 (Brs, 1H), 7.68-7.62 (m, 2H), 7.07 (d, J = 1.8 Hz, 1H), 5.85 (s, 1H), 4.47 (s, 2H), 3.90 - 3.74 (m, 6H), 3.09 - 3.02 (m, 2H), 2.66 - 2.57 (m, 2H), 1.88 - 1.81 (m, 4H), 1.19 (d, J = 6.2 Hz, 6H).

[0392] Example 17: 3-(4-(Piperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0393] Step 1: Synthesis of 3,6-dichloro-4-(piperidin-1-yl)pyridazine

Chemical Structure

[0394] To a solution of 3,4,6-trichloropyridazine (2.00 g, 10.9 mmol) and piperidine (1.39 g, 16.4 mmol) in NMP (25.0 mL) was added potassium carbonate (3.01 g, 21.8 mmol). Under nitrogen protection, the reaction mixture was stirred at room temperature for 16 h to react, and the reaction was stopped. Then, the reaction solution was diluted with EA (45.0 mL), washed with saturated brine (45.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to obtain the target compound (2.30 g, yield 90.9%, yellow solid). LC-MS (ESI) m / z 232.1 [M+H] + 。

[0395] Step 2: Synthesis of 3-(6-chloro-5-(piperidin-1-yl)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0396] To a NMP solution (60.0 mL) of 3,6-dichloro-4-(piperidin-1-yl)pyridazine (3.00 g, 12.9 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (3.87 g, 25.8 mmol) was added DIEA (6.75 mL, 38.7 mmol). The reaction mixture was stirred at 145 °C for 16 h to react, and the reaction was stopped. Then, water (50.0 mL) was added, and then extracted with EA (40.0 mL × 3). The combined organic phases were washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by a chromatography column (PE:EA = 5:1) to obtain the target compound (1.20 g, yield 30.1%, yellow solid). LC-MS (ESI) m / z 309.1 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 6.12 (s, 1H), 4.52 - 4.46 (m, 2H), 3.82 - 3.75 (m, 2H), 3.20 - 3.18 (m, 1H), 3.18 - 3.15 (m, 1H), 3.13 - 3.07 (m, 4H), 2.01 - 1.94 (m, 2H), 1.88 - 1.82 (m, 2H), 1.76 - 1.71 (m, 4H), 1.66 - 1.58 (m, 2H).

[0397] Step 3: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(piperidin-1-yl)pyridazine-3-carbonitrile

Chemical Structure

[0398] To a solution of 3-(6-chloro-5-(piperidin-1-yl)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.20 g, 3.89 mmol) and zinc cyanide (912 mg, 7.77 mmol) in DMF (25.0 mL) were added DPPF (431 mg, 0.777 mmol) and Pd2(dba)3 (356 mg, 0.388 mmol). Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 h to allow the reaction to proceed, and then the reaction was stopped. Subsequently, the reaction solution was diluted with EA (40.0 mL), washed with saturated brine (35.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (1.20 g, yield 100%, yellow solid). LC-MS (ESI) m / z 300.2 [M+H] + .

[0399] Step 4: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(piperidin-1-yl)pyridazin-3-yl)methylamine

Chemical Structure

[0400] To a solution of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(piperidin-1-yl)pyridazine-3-carbonitrile (1.2 g, 4.01 mmol) in tetrahydrofuran (20.0 mL) were added Raney nickel (~1.18 g, 20.0 mmol) and aqueous ammonia (5 drops). The reaction mixture was reacted at room temperature for 16 h in a hydrogen gas atmosphere, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (1.10 g, yield 90.4%, yellow oil) as a residue. LC-MS (ESI) m / z 304.1 [M+H] + 。

[0401] Step 5: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(piperidin-1-yl)pyr Da idazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chemical formula

[0402] To a solution of (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(piperidin-1-yl)pyridazin-3-yl)methylamine (500 mg, 1.65 mmol) and 1H-pyrazole-5-carboxylic acid (166 mg, 1.48 mmol) in tetrahydrofuran (12.0 mL) were added HATU (752 mg, 1.98 mmol) and DIEA (639 mg, 4.94 mmol). The reaction mixture was stirred at room temperature for 45 min to effect the reaction, and the reaction was stopped. A sodium hydroxide solution was added dropwise to the reaction solution, and the mixture was stirred for 2 min and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (DCM:methanol = 10:1) to obtain the target compound (300 mg, yield 45.8%, yellow solid). LC-MS (ESI) m / z 398.2 [M+H] + 。

[0403] Step 6: Synthesis of 3-(4-(Piperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0404] At room temperature, N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(piperidin-1-yl)pyridin-3-yl)methyl)-1H-pyrazole-5-carboxamide (150 mg, 0.327 mmol) and phosphorus oxychloride (9.00 mL) were added to a reaction flask. The reaction mixture was reacted at 100 °C for 1 hour, and the reaction was stopped. The reaction solution was dropped into a saturated aqueous sodium bicarbonate solution to adjust the pH to 7, and then the mixture was extracted with EA (20.0 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (51.7 mg, yield 36.1%, white solid). LC-MS (ESI) m / z 380.1 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 7.69 (s, 1H), 7.47 (s, 1H), 7.10 (s, 1H), 5.77 (s, 1H), 4.51 - 4.48 (m, 2H), 3.83 - 3.79 (m, 2H), 3.52 - 3.48 (m, 4H), 3.21 - 3.16 (m, 2H), 1.99 - 1.95 (m, 4H), 1.79 - 1.74 (m, 6H).

[0405] Example 18: 3-(4-(2-Methylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0406] Step 1: Synthesis of 4-(3,6-dichloropyridazin-4-yl)-2-methylmorpholine

Chemical formula

[0407] Potassium carbonate (3.01 g, 21.8 mmol) was added to a solution of 3,4,6-trichloropyridazine (2.00 g, 10.9 mmol) and 2-methylmorpholine (1.32 g, 13.1 mmol) in NMP (25.0 mL). Under nitrogen protection, the reaction mixture was stirred at room temperature for 16 hours to allow the reaction to proceed, and then the reaction was stopped. Subsequently, the reaction solution was diluted with EA (45.0 mL), washed with saturated brine (45.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to obtain the target compound (2.30 g, yield 85.0%, yellow solid). LC-MS (ESI) m / z 248.1 [M+H] + 。

[0408] Step 2: Synthesis of 3-(6-chloro-5-(2-methylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0409] To a solution of 4-(3,6-dichloropyridazin-4-yl)-2-methylmorpholine (2.30 g, 9.27 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (2.08 g, 13.9 mmol) in NMP (25.0 mL) was added DIEA (2.40 g, 18.5 mmol). Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 h to allow the reaction to proceed, and then the reaction was stopped. Subsequently, the reaction solution was diluted with EA (45.0 mL), washed with saturated brine (45.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (2.00 g, yield 76.4%, yellow solid). LC-MS (ESI) m / z 225.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.13 (s, 1H), 4.55 - 4.48 (m, 2H), 4.01 - 3.94 (m, 1H), 3.89 - 3.80 (m, 4H), 3.50 - 3.43 (m, 2H), 3.25 - 3.19 (m, 2H), 2.89 - 2.80 (m, 1H), 2.57 - 2.49 (m, 1H), 2.04 - 1.96 (m, 2H), 1.91 - 1.82 (m, 2H), 1.24 (d, J = 6.3 Hz, 3H).

[0410] Step 3: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(2-methylmorpholino)pyridazine-3-carbonitrile [Chemical Structure]

[0411] 3-(6-chloro-5-(2-methylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.80 g, 5.54 mmol) and zinc cyanide (1.30 g, 11.1 mmol) were added to a solution of DPPF (614 mg, 1.11 mmol) and Pd2(dba)3 (507 mg, 0.554 mmol) in DMF (35.0 mL). Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 hours to react, and the reaction was stopped. Then, the reaction solution was diluted with EA (55.0 mL), washed with saturated brine (40.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (1.50 g, yield 85.8%, yellow solid). LC-MS (ESI) m / z 316.0 [M+H] + 。

[0412] Step 4: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(2-methylmorpholino)pyridazin-3-yl)methylamine

Chem.

[0413] Raney nickel (~1.40 g, 23.8 mmol) was added to a solution of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(2-methylmorpholino)pyridazine-3-carbonitrile (1.50 g, 4.76 mmol) in tetrahydrofuran (30.0 mL). In a hydrogen gas atmosphere, the reaction mixture was reacted at room temperature for 16 hours, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (DCM:methanol = 10:1) to obtain the target compound (1.50 g, yield 98.7%, yellow solid). LC-MS (ESI) m / z 320.0 [M+H] + 。

[0414] Step 5: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(2-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chem.

[0415] (6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(2-methylmorpholino)pyridazin-3-yl)methylamine (500 mg, 1.57 mmol) and 1H-pyrazole-5-carboxylic acid (158 mg, 1.41 mmol) were dissolved in tetrahydrofuran (10.0 mL). HATU (714 mg, 1.88 mmol) and DIEA (607 mg, 4.70 mmol) were added thereto. The reaction mixture was reacted at room temperature for 1 hour and then the reaction was stopped. Thereafter, the reaction solution was filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 0:1) to obtain the target compound (500 mg, yield 77.2%, yellow solid). LC-MS (ESI) m / z 414.0 [M+H] + .

[0416] Step 6: Synthesis of 3-(4-(2-methylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0417] At room temperature, N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(2-methylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (200 mg, 0.484 mmol) and phosphorus oxychloride (6.00 mL) were added to a reaction flask. The reaction mixture was reacted at 100 °C for 1 hour, and the reaction was stopped. The reaction solution was dropped into a saturated aqueous sodium bicarbonate solution to adjust the pH to 7. Then, the mixture was extracted with EA (30.0 mL × 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (82.0 mg, yield 42.9%, white solid). LC-MS (ESI) m / z 396.1 [M+H] + . 1 H NMR (400 MHz, MeOD-d4) δ 7.86 - 7.63 (m, 1H), 7.62 - 7.41 (m, 1H), 7.13 (s, 1H), 5.84 (s, 1H), 4.54 - 4.47 (m, 2H), 4.04 - 3.98 (m, 1H), 3.87 - 3.78 (m, 6H), 3.22 - 3.16 (m, 2H), 3.13 - 3.04 (m, 1H), 2.79 - 2.70 (m, 1H), 2.01 - 1.93 (m, 4H), 1.25 (d, J = 6.1 Hz, 3H).

[0418] Example 19: 3-(1-Methyl-7-((R)-3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0419] The synthesis of the intermediate 3-(7-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane was referred to Example 13.

[0420] Step 1: Synthesis of 3-(3-bromo-7-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0421] 3-(7-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (200 mg, 0.718 mmol) was dissolved in DCM (5 mL). Under nitrogen protection, the reaction mixture was added to N-bromosuccinimide (128 mg, 0.718 mmol), and the reaction solution was stirred at room temperature for 10 minutes. When the reaction was completed as monitored by LC-MS, water (5 mL) was added to the reaction mixture, and it was extracted with DCM (5 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. It was separated and purified by silica gel column (EA:PE = 1:4) to obtain the target compound (241 mg, yield 93.9%, yellow solid). LC-MS (ESI) m / z: 357.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 7.20 (s, 1H), 4.45 - 4.36 (m, 2H), 4.20 (s, 3H), 3.87 (d,J = 12.4 Hz, 2H), 2.99 (d,J = 12.4 Hz, 2H), 1.86 - 1.76 (m, 2H), 1.75 - 1.69 (m, 2H).

[0422] Step 2: Synthesis of 3-(7-chloro-1-methyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0423] 3-(3-Bromo-7-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (201 mg, 0.562 mmol) was dissolved in 1,4-dioxane (2 mL) and water (0.2 mL), and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (313 mg, 1.12 mmol), Pd(dtbpf)Cl2 (36.3 mg, 0.056 mmol) and potassium phosphate (358 mg, 1.69 mmol) were added. Under nitrogen protection, the resulting mixture was stirred at 40 °C for 2 hours and monitored by LC-MS. When the reaction was completed, water (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column (PE:EA = 1:2) to obtain the target compound (102 mg, yield 42.3%, brown oil). LC-MS (ESI) m / z: 429.2 [M+H] + 。

[0424] Step 3: Synthesis of 3-(1-methyl-7-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0425] 3-(7-Chloro-1-methyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (80 mg, 0.187 mmol) was dissolved in N-methylpyrrolidone (1 mL), and (3R)-3-methylmorpholine (37.7 mg, 0.373 mmol), RuphosPdG2 (14.5 mg, 0.019 mmol), cesium carbonate (182 mg, 0.560 mmol), and cuprous iodide (35.5 mg, 0.187 mmol) were added. Under nitrogen protection, the resulting mixture was stirred at 110 °C for 2 hours and monitored by LC-MS. When the reaction was completed, the reaction mixture was added to water (10 mL), and the aqueous phase was extracted with EA (20 mL × 2) and washed with saturated brine (10 mL). The organic phase was dried, rotary evaporated, and then separated and purified by silica gel column (PE:EA = 1:1) to obtain the target compound (39 mg, yield 42.4%, brown solid). LC-MS (ESI) m / z: 494.3 [M+H] + 。

[0426] Step 4: Synthesis of 3-(1-methyl-7-((R)-3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0427] To a solution of 3-(1-methyl-7-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (39.0 mg, 0.079 mmol) in methanol (2 mL) was added 4 mol / L hydrochloric acid 1,4-dioxane solution (2 mL). Under nitrogen protection, the resulting mixture was stirred at room temperature for 2 hours and monitored by LC-MS. When the reaction was completed, the solvent was removed under reduced pressure, and the residue was separated and purified by a prep-HPLC preparative column to obtain the target compound (4.2 mg, yield 13.0%, white solid). LC-MS (ESI) m / z: 410.2 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ7.82 - 7.73 (m, 1H), 6.89 - 6.85 (m, 1H), 6.50 (s, 1H), 4.26 (s, 3H), 4.07 - 3.94 (m, 2H), 3.91 - 3.78 (m, 4H), 3.74 - 3.64 (m, 1H), 3.65 - 3.55 (m, 1H), 3.51 - 3.37 (m, 3H), 3.17 - 3.02 (m, 2H), 2.09 - 2.00 (m, 2H), 2.02 - 1.93 (m, 2H), 1.17 (d, J = 6.4 Hz, 3H).

[0428] Example 20: 3-(4-(3,3-Dimethylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0429] Step 1: Synthesis of 4-(3,6-dichloropyridazin-4-yl)-3,3-dimethylmorpholine

Chemical formula

[0430] To a solution of 3,4,6-trichloropyridine (7.64 g, 41.7 mmol) in N-methylpyrrolidone (30.0 mL) were added 3,3-dimethylmorpholine (4.00 g, 34.7 mmol) and DIEA (13.5 g, 104 mmol). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 16 hours to carry out the reaction, and then the reaction was stopped. Thereafter, the reaction solution was diluted with EA (70.0 mL), washed with saturated brine (50.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 3:1) to obtain the target compound (2.00 g, yield 22.0%, yellow solid). LC-MS (ESI) m / z 262.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 3.90 - 3.86 (m, 2H), 3.47 (s, 2H), 3.32 - 3.29 (m, 2H), 1.32 (s, 6H).

[0431] Step 2: Synthesis of 3-(6-chloro-5-(3,3-dimethylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0432] A solution of 4-(3,6-dichloropyridazin-4-yl)-3,3-dimethylmorpholine (2.50 g, 9.54 mmol) and (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (2.14 g, 14.3 mmol) in N-methylpyrrolidone (30.0 mL) was added with DIEA (3.70 g, 28.6 mmol). Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 h to react, and the reaction was stopped. Then, the reaction solution was diluted with water (50.0 mL), extracted with ethyl acetate (40.0 mL × 3), the combined organic phases were washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by a chromatography column (petroleum ether:ethyl acetate = 1:1) to obtain the target compound (2.50 g, yield 77.4%, yellow solid). LC-MS (ESI) m / z 339.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.49 (s, 1H), 4.54 - 4.51 (m, 2H), 3.87 - 3.84 (m, 2H), 3.79 (d, J = 12.1 Hz, 2H), 3.47 (s, 2H), 3.26 - 3.24 (m, 1H), 3.23 - 3.19 (m, 3H), 2.04 - 1.99 (m, 2H), 1.90 - 1.85 (m, 2H), 1.27 (s, 6H).

[0433] Step 3: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3,3-dimethylmorpholino)pyridazine-3-carbonitrile [Chemical formula]

[0434] A solution of 3-(6-chloro-5-(3,3-dimethylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.40 g, 4.13 mmol) and zinc cyanide (970 mg, 8.26 mmol) in N,N-dimethylformamide (30.0 mL) was added with 2-(diphenylphosphinoyl)cyclopentadienyliron (458 mg, 0.826 mmol) and tris(dibenzylideneacetone)dipalladium(0) (378 mg, 0.413 mmol). Under nitrogen protection, the reaction mixture was stirred at 135 °C for 16 hours for reaction, and the reaction was stopped. Then, the reaction solution was diluted with ethyl acetate (50.0 mL), washed with saturated brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (800 mg, yield 58.8%, yellow solid). LC-MS (ESI) m / z 330.2 [M+H] + 。

[0435] Step 4: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3,3-dimethylmorpholino)pyridazin-3-yl)methylamine

Chem.

[0436] A solution of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3,3-dimethylmorpholino)pyridazine-3-carbonitrile (800 mg, 2.43 mmol) in tetrahydrofuran (15.00 mL) was added with Raney nickel (428 mg, 7.29 mmol) and aqueous ammonia (1.00 mL). In a hydrogen gas atmosphere, the reaction mixture was reacted at room temperature for 16 hours, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (500 mg, yield 61.7%, yellow oil) as a residue. LC-MS (ESI) m / z 334.1 [M+H] + 。

[0437] Step 5: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3,3-dimethylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chemical Structure

[0438] (6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3,3-dimethylmorpholino)pyridazin-3-yl)methylamine (500 mg, 1.50 mmol) and 1H-pyrazole-5-carboxylic acid (151 mg, 1.35 mmol) in tetrahydrofuran (15.0 mL) were added with 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (684 mg, 1.80 mmol) and DIEA (581 mg, 4.50 mmol). The reaction mixture was stirred at room temperature for 1 hour to react, and then the reaction was stopped. Then, water (30.0 mL) was added, and then extracted with ethyl acetate (25.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (DCM:methanol = 10:1) to obtain the target compound (300 mg, yield 46.8%, yellow solid). LC-MS (ESI) m / z 428.4 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.60 - 7.56 (m, 1H), 6.81 - 6.77 (m, 1H), 6.65 (s, 1H), 5.29 (s, 1H), 4.91 - 4.78 (m, 2H), 4.55 - 4.50 (m, 2H), 3.97 - 3.89 (m, 2H), 3.84 - 3.76 (m, 2H), 3.55 (s, 2H), 3.26 - 3.21 (m, 2H), 3.19 - 3.09 (m, 2H), 2.04 - 1.99 (m, 2H), 1.91 - 1.85 (m, 2H), 1.16 (s, 6H).

[0439] Step 6: Synthesis of 3-(4-(3,3-Dimethylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical Structure]

[0440] Phosphorus oxychloride (6.00 mL) was added to a solution of N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3,3-dimethylmorpholino)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (250 mg, 0.585 mmol) in acetonitrile (5.00 mL) at room temperature. The reaction mixture was reacted at 100 °C for 1 hour and the reaction was stopped. The reaction solution was concentrated under reduced pressure and the obtained residue was purified by reverse phase preparative (acetonitrile / water, containing 0.05% formic acid) to obtain the target compound (58.9 mg, yield 24.6%, white solid). LC-MS (ESI) m / z 410.1 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 7.75 - 7.69 (m, 1H), 7.44 (s, 1H), 7.09 - 7.05 (m, 1H), 5.99 (s, 1H), 4.60 - 4.54 (m, 2H), 3.94 - 3.89 (m, 2H), 3.67 - 3.62 (m, 2H), 3.52 (s, 2H), 3.50 - 3.46 (m, 2H), 3.36 - 3.31 (m, 2H), 2.09 - 2.02 (m, 2H), 1.96 - 1.89 (m, 2H), 1.35 (s, 6H).

[0441] Example 23: 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol

Chemical formula

[0442] Step 1: Synthesis of 3-(pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0443] To a solution of 5-chloropyrazolo[1,5-a]pyrimidine (5.00 g, 32.6 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (7.31 g, 48.8 mmol) in N-methylpyrrolidone (60.0 mL) was added DIEA (12.6 g, 97.7 mmol). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 1 hour to react, and then the reaction was stopped. Thereafter, the reaction solution was diluted with ethyl acetate (85.0 mL), washed with saturated brine (55 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to obtain the target compound (3.60 g, yield 48.0%, yellow solid). LC-MS (ESI) m / z 231.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 2.0 Hz, 1H), 6.26 (d, J = 7.8 Hz, 1H), 6.13 (d, J = 1.9 Hz, 1H), 4.57 - 4.47 (m, 2H), 3.92 (d, J = 12.5 Hz, 2H), 3.27 (dd, J = 12.6, 2.4 Hz, 2H), 2.06 - 1.94 (m, 2H), 1.87 - 1.74 (m, 2H).

[0444] Step 2: Synthesis of 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol

Chemical Structure

[0445] In a nitrogen atmosphere, a solution of (1R,5S)-3-(pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.50 g, 6.51 mmol) in tetrahydrofuran (20.0 mL) was cooled to -78 °C. Then, n-butyllithium (8.14 mL, 13.0 mmol, 1.6 M) was added dropwise, and the reaction mixture was stirred at -78 °C for 1 hour to react. Tetrahydro-4H-pyran-4-one (1.30 g, 13.0 mmol) was slowly added dropwise, and the reaction solution was stirred at room temperature overnight to stop the reaction. An aqueous ammonium chloride solution (45.0 mL) was added for dilution, and then extracted with EA (45.0 mL × 3). The combined organic phases were washed with saturated brine (35.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (500 mg, yield 23.2%, yellow solid). LC-MS (ESI) m / z 331.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 2.3 Hz, 1H), 6.21 (d, J = 2.2 Hz, 1H), 6.15 (s, 1H), 4.56 - 4.50 (m, 2H), 4.31 - 4.27 (m, 2H), 4.23 - 4.19 (m, 2H), 3.77 - 3.76 (m, 2H), 3.33 - 3.26 (m, 2H), 2.27 - 2.20 (m, 2H), 2.12 - 2.07 (m, 2H), 2.03 - 1.96 (m, 2H), 1.88 - 1.82 (m, 2H).

[0446] Step 3: Synthesis of 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-iodopyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol

Chemical Structure

[0447] To a solution of 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol (400 mg, 1.21 mmol) in acetonitrile (10.0 mL) was added N-iodosuccinimide (272 mg, 1.21 mmol). The reaction mixture was stirred at room temperature for 1 hour to allow the reaction to proceed, and then the reaction was stopped. Thereafter, water (35.0 mL) was added for dilution, and then the mixture was extracted with EA (30.0 mL × 3). The combined organic phases were washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (400 mg, yield 72.4%, yellow solid). LC-MS (ESI) m / z 457.1 [M+H] + 。

[0448] Step 4: Synthesis of 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol

Chemical Structure

[0449] Under nitrogen protection, to a solution of 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-iodopyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol (400 mg, 0.877 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (366 mg, 1.31 mmol) in 1,4-dioxane (10.0 mL) and water (2.00 mL), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (55.9 mg, 0.0877 mmol) and potassium phosphate (558 mg, 2.63 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours to carry out the reaction, and then the reaction was stopped. Thereafter, water (35.0 mL) was added for dilution, and then extracted with EA (35.0 mL × 3). The combined organic phases were washed with saturated brine (35.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (150 mg, yield 35.6%, yellow solid). LC-MS (ESI) m / z 481.4 [M+H] + 。

[0450] Step 5: Synthesis of 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol

Chemical formula

[0451] At room temperature, 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol (150 mg, 0.312 mmol) and ethyl acetate hydrochloride (10.0 mL, 3 M) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 2 hours to cause a reaction, and then the reaction was stopped. The mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (66.6 mg, yield 53.8%, white solid). LC-MS (ESI) m / z 397.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.64 (s, 1H), 6.56 (s, 1H), 6.20 (s, 1H), 4.59 - 4.55 (m, 2H), 4.11 - 4.05 (m, 2H), 4.04 - 3.93 (m, 2H), 3.93 - 3.87 (m, 2H), 3.40 - 3.34 (m, 2H), 2.26 - 2.20 (m, 2H), 2.13 - 2.02 (m, 4H), 1.88 - 1.80 (m, 2H).

[0452] Example 26: 3-(7-(1-Methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0453] Step 1: Synthesis of 5-Chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine

Chemical Structure

[0454] At room temperature, under nitrogen protection, sodium carbonate (1.69 g, 16.0 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (340 mg, 0.532 mmol) were added to a mixed solution of water (1.00 mL) and dioxane (4.00 mL) containing 5,7-dichloropyrazolo[1,5-a]pyrimidine (1.00 g, 5.32 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3, dioxidaborolan-2-yl)-1H-pyrazole (1.33 g, 6.38 mmol). Under nitrogen protection, the reaction mixture was stirred at 90 °C for 10 hours to react, and then the reaction was stopped. After the reaction solution was cooled, water (20.0 mL) was added, and then extracted with EA (30.0 mL × 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was separated and purified by a normal-phase chromatography column (EA:PE = 1:1) to obtain a crude product (370 mg, yield 29.7%, yellow solid). LC-MS (ESI) m / z 233.9[M+H] + 。

[0455] Step 2: Synthesis of 3-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0456] A solution of 5-chloro-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine (370 mg, 1.58 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (358 mg, 2.39 mmol) in NMP (15.0 mL) was added with DIEA (613 mg, 4.75 mmol). The reaction mixture was reacted in a 140 °C microwave reactor for 2 hours under nitrogen protection, and the reaction was stopped. Then, the reaction solution was diluted with EA (35.0 mL), washed with saturated brine (30.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (260 mg, yield 52.9%, yellow oil). LC-MS (ESI) m / z 311.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 6.63 (d, J = 1.9 Hz, 1H), 6.30 (s, 1H), 6.23 (d, J = 2.2 Hz, 1H), 4.55 - 4.50 (m, 2H), 3.97 - 3.90 (m, 2H), 3.88 (s, 3H), 3.33 - 3.27 (m, 2H), 2.04 - 1.98 (m, 2H), 1.90 - 1.82 (m, 2H).

[0457] Step 3: Synthesis of 3-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0458] To a solution of 3-(7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (260 mg, 0.837 mmol) in acetonitrile (10.0 mL) was added NIS (188 mg, 0.837 mmol), and the reaction mixture was stirred at room temperature for 3 hours to effect the reaction, and then the reaction was stopped. Thereafter, water (15.0 mL) was added, and then the mixture was extracted with EA (20.0 mL × 3). The combined organic phases were washed with saturated brine (15.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to give the target compound (300 mg, yield 82.1%, yellow solid). LC-MS (ESI) m / z 436.9 [M+H] + , 1 H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.62 (d, J = 1.9 Hz, 1H), 6.61 (d, J = 1.9 Hz, 1H), 6.30 (s, 1H), 4.57 - 4.52 (m, 2H), 4.11 - 3.89 (m, 2H), 3.85 (s, 3H), 3.37 - 3.30 (m, 2H), 2.05 - 1.99 (m, 2H), 1.90 - 1.82 (m, 2H).

[0459] Step 4: Synthesis of 3-(7-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0460] Under nitrogen protection, to a solution of 3-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (300 mg, 0.687 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (286 mg, 1.03 mmol) in 1,4-dioxane (10.0 mL) and water (2.00 mL) were added Pd(dtbpf)Cl2 (43.8 mg, 0.0687 mmol) and potassium phosphate (437 mg, 2.06 mmol). The reaction mixture was stirred at 60 °C for 16 h to effect the reaction, and then the reaction was stopped. Thereafter, water (30.0 mL) was added for dilution, and then the mixture was extracted with EA (30.0 mL × 3). The combined organic phases were washed with saturated brine (25.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to give the target compound (150 mg, yield 47.3%, yellow solid). LC-MS (ESI) m / z 461.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 6.71 - 6.63 (m, 2H), 6.38 (s, 1H), 5.51 - 5.39 (m, 1H), 4.60 - 4.51 (m, 2H), 4.09 - 3.95 (m, 2H), 3.93 (s, 3H), 3.72 - 3.61 (m, 1H), 3.39 - 3.30 (m, 2H), 2.72 - 2.59 (m, 1H), 2.16 - 2.09 (m, 1H), 2.02 - 1.96 (m, 2H), 1.88 - 1.77 (m, 3H), 1.64 - 1.55 (m, 2H).

[0461] Step 5: Synthesis of 3-(7-(1-Methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0462] At room temperature, 3-(7-(1-Methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (150 mg, 0.325 mmol) and an EA solution of hydrochloric acid (5.00 mL, 3 M) were added to a reaction flask, and the reaction mixture was stirred at room temperature for 2 hours to react, and the reaction was stopped. It was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water, containing 0.05% formic acid) to obtain the target compound (82.68 mg, yield 67.4%, light yellow solid). LC-MS (ESI) m / z 377.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 12.89 - 12.58 (m, 1H), 8.38 - 8.19 (m, 1H), 7.80 - 7.45 (m, 2H), 6.89 - 6.68 (m, 3H), 4.52 - 4.46 (m, 2H), 4.31 - 4.03 (m, 2H), 3.85 (s, 3H), 3.23 - 3.15 (m, 2H), 1.89 - 1.74 (m, 4H).

[0463] Example 27: 3-(8-(1-Methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0464] Step 1: Synthesis of 8-Bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine

Chem.

[0465] To a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (2.00 g, 8.60 mmol) in acetonitrile (30.0 mL) was added NIS (1.94 g, 8.60 mmol). The reaction mixture was stirred at room temperature for 2 hours to allow the reaction to proceed, and then the reaction was stopped. Subsequently, water (45.0 mL) was added, and then the mixture was extracted with EA (40.0 mL × 3). The combined organic phases were washed with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to give the target compound (3.00 g, yield 97.3%, yellow solid). LC-MS (ESI) m / z 357.8 [M+H] + , 359.8 [M+2+H] + .

[0466] Step 2: Synthesis of 8-Bromo-6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine

Chem.

[0467] Under nitrogen protection, to a solution of 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine (2.00 g, 5.58 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.55 g, 5.58 mmol) in 1,4-dioxane (20.0 mL) and water (4.00 mL) were added tetrakis(triphenylphosphine)palladium(0) (644 mg, 0.558 mmol) and potassium phosphate (3.55 g, 16.7 mmol). The reaction mixture was stirred at room temperature for 16 hours to effect the reaction, and then the reaction was stopped. Thereafter, water (45.0 mL) was added, and then the mixture was extracted with EA (45.0 mL × 3). The combined organic phases were washed with saturated brine (45.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 3:1) to give the target compound (400 mg, yield 18.7%, yellow solid). LC-MS (ESI) m / z 382.0 [M+H] + , 384.0 [M+2+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.73 (s, 1H), 7.46 (s, 1H), 6.91 (s, 1H), 5.32 - 5.27 (m, 1H), 4.11 - 4.06 (m, 1H), 3.68 - 3.62 (m, 1H), 2.65 - 2.56 (m, 1H), 2.02 - 1.97 (m, 2H), 1.77 - 1.70 (m, 1H), 1.63 - 1.57 (m, x2H).

[0468] Step 3: Synthesis of 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2 -b]pyridazine

Chemical Structure

[0469] Note: In the original text, the "x2H" in the NMR data is likely a typo and should be "2H" in the translated text for better accuracy. However, following the instruction to preserve the original exactly, it is presented as "x2H" here.Under nitrogen protection, to a solution of 8-bromo-6-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine (400 mg, 1.05 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (217 mg, 1.05 mmol) in 1,4-dioxane (10.0 mL) and water (2.00 mL) were added 1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (76.5 mg, 0.105 mmol) and potassium phosphate (666 mg, 3.14 mmol). The reaction mixture was stirred at 60 °C for 2 hours to effect the reaction, and then the reaction was stopped. Thereafter, water (25.0 mL) was added, and then the mixture was extracted with EA (25.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to give the target compound (150 mg, yield 37.4%, yellow solid). LC-MS (ESI) m / z 384.0 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.73 (s, 1H), 7.46 (s, 1H), 6.91 (s, 1H), 5.32 - 5.27 (m, 1H), 4.11 - 4.06 (m, 1H), 3.68 - 3.62 (m, 1H), 2.65 - 2.56 (m, 1H), 2.02 - 1.97 (m, 2H), 1.77 - 1.70 (m, 1H), 1.63 - 1.57 (m, 2H).

[0470] Step 4: Synthesis of 3-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chem.

[0471] Under nitrogen protection, cesium carbonate (382 mg, 1.17 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (66.3 mg, 0.443 mmol) were added to a solution of 6-chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine (150 mg, 0.391 mmol) and (2-amino-2-[1,1'-biphenyl]-2-yl)(dicyclohexyl(2,6-diisopropoxy-2-[1,1'-biphenyl]-2-yl)-phosphinoyl)palladium(II) chloride (39.1 mg, 0.0391 mmol) in toluene (6.00 mL). The reaction mixture was stirred at 110 °C for 16 hours to effect the reaction, and then the reaction was stopped. Thereafter, water (15.0 mL) was added, and then the mixture was extracted with EA (15.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to give the target compound (60.0 mg, yield 33.3%, yellow solid). LC-MS (ESI) m / z 461.2 [M+H] + 。

[0472] Step 5: Synthesis of 3-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0473] At room temperature, 3-(8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (60.0 mg, 0.130 mmol) and an EA solution of hydrochloric acid (5.00 mL, 3 M) were added to a reaction flask. The reaction mixture was stirred at room temperature for 2 hours to effect the reaction, and then the reaction was stopped. The mixture was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase preparative HPLC (acetonitrile / water containing 0.05% formic acid) to give the target compound (18.0 mg, yield 36.7%, white solid). LC-MS (ESI) m / z 377.2 [M+H] + 。 1 H NMR (400 MHz, MeOD-d4) δ 7.98 (s, 1H), 7.82 - 7.74 (m, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.17 (s, 1H), 6.71 (d, J = 1.9 Hz, 1H), 4.58 - 4.52 (m, 2H), 3.93 (s, 4H), 3.90 - 3.88 (m, 1H), 3.30 - 3.28 (m, 1H), 3.28 - 3.25 (m, 1H), 2.04 - 1.97 (m, 4H).

[0474] Example 28: 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0475] Step 1: Synthesis of 3-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0476] To a solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (1.00 g, 5.32 mmol) and (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (2.39 g, 16.0 mmol) in N-methylpyrrolidone (15.0 mL) was added DIEA (2.06 g, 16.0 mmol). The reaction mixture was stirred at 145 °C for 16 h to effect the reaction, and then the reaction was stopped. After the reaction mixture was cooled to room temperature, water (20.0 mL) was added for dilution, and the mixture was extracted with EA (25.0 mL × 3). The combined organic phases were washed with water (20.0 mL × 3) and saturated brine (20.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 10:1~1:1) to give the target compound (550 mg, yield 30.3%, white solid). LC-MS (ESI) m / z 342.3 [M+H] + 。

[0477] Step 2: Synthesis of 3-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0478] To a solution of 3-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (550 mg, 1.61 mmol) in acetonitrile (20.0 mL) was added N-iodosuccinimide (399 mg, 1.77 mmol). The reaction mixture was stirred at room temperature for 2 h to effect the reaction, and then the reaction was stopped. The reaction mixture was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1~1:1) to give the target compound (500 mg, yield 66.4%, yellow solid). LC-MS (ESI) m / z 468.3 [M+H]+ . 1 1H NMR (400 MHz, DMSO-d6) δ7.90 (s, 1H), 5.70 (s, 1H), 4.45 - 4.38 (m, 4H), 4.08 - 3.98 (m, 4H), 3.09 - 3.00 (m, 4H), 2.07 - 1.98 (m, 2H), 1.90 - 1.78 (m, 4H), 1.75 - 1.65 (m, 2H).

[0479] Step 3: Synthesis of 3-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chemical formula]

[0480] 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (300 mg, 0.642 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (268 mg, 0.963 mmol) were added to a mixed solution of water (1.00 mL) and 1,4-dioxane (5.00 mL), followed by potassium carbonate (177 mg, 1.28 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (42.0 mg, 0.0642 mmol). Under nitrogen protection, the reaction mixture was stirred at 60 °C for 8 hours to allow the reaction to proceed, and then the reaction was stopped. After cooling the reaction solution to room temperature, water (10.0 mL) was added, and then the mixture was extracted with EA (15.0 mL × 3). The organic phase was washed with saturated brine (15.0 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1 to 1:3) to obtain the target compound (150 mg, yield 47.5%, yellow solid). LC-MS (ESI) m / z 492.4 [M+H] + 。

[0481] Step 4: Synthesis of 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0482] 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (120 mg, 0.244 mmol) was reacted by stirring with a hydrogen chloride methanol solution (3.0 M, 3.00 mL) at room temperature for 1 hour, and the reaction was stopped. The reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by reverse phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (33.96 mg, yield 34.1%, white solid). LC-MS (ESI) m / z 408.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (Brs, 1H), 8.23 (s, 1H), 7.55 (s, 1H), 6.69 (s, 1H), 5.72 (s, 1H), 4.49 - 4.41 (m, 4H), 4.16 - 4.04 (m, 4H), 3.09 (d, J = 10.9 Hz, 4H), 2.11 - 2.01 (m, 2H), 1.92 - 1.80 (m, 4H), 1.77 - 1.68 (m, 2H).

[0483] Example 29: 1-((R)-4-(2-((1R,S)-8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one

Chemical Structure

[0484] Step 1: Synthesis of (R)-4-(3,6-dichloropyridazin-4-yl)-3-methylpiperazine-1-t-butyl carboxylate

Chemical Structure

[0485] (R)-3-Methylpiperazine-1-t-butylcarboxylate (5.00 g, 24.9 mmol) in N-methylpyrrolidone (35.0 mL) was added with 3,4,6-trichloropyridazine (5.49 g, 29.9 mmol) and DIEA (9.68 g, 74.9 mmol). Under nitrogen protection, the reaction mixture was stirred at room temperature for 16 hours to react, and the reaction was stopped. Then, water (60.0 mL) was added for dilution, and then extracted with ethyl acetate (50.0 mL × 3). Next, the organic phase was washed with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the target compound (3.50 g, yield 40.4%, yellow solid). LC-MS (ESI) m / z 346.9 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 6.83 (s, 1H), 4.21 - 4.16 (m, 1H), 4.14 - 4.08 (m, 1H), 3.83 (d, J = 13.1 Hz, 1H), 3.42 - 3.29 (m, 2H), 3.13 - 3.09 (m, 2H), 1.47 (s, 9H), 1.12 (d, J = 6.6 Hz, 3H).

[0486] Step 2: Synthesis of (R)-3,6-dichloro-4-(2-methylpiperazin-1-yl)pyridazine

Chemical Structure

[0487] To the reaction flask were added t-butyl (R)-4-(3,6-dichloropyridazin-4-yl)-3-methylpiperazine-1-carboxylate (3.50 g, 10.1 mmol) and hydrochloric acid / ethyl acetate (8.00 mL, 4M). The reaction mixture was stirred at room temperature for 5 hours to react, and the reaction was stopped. The reaction solution was concentrated under reduced pressure to obtain the target compound (2.30 g, yield 80.5%, yellow solid). LC-MS (ESI) m / z 247.0 [M+H] + 。

[0488] Step 3: Synthesis of (R)-1-(4-(3,6-dichloropyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one

Chemical formula

[0489] (R)-3,6-Dichloro-4-(2-methylpiperazin-1-yl)pyridazine hydrochloride (2.30 g, 8.11 mmol) in dichloromethane (20.0 mL) was added with acetyl chloride (0.955 g, 12.2 mmol) and triethylamine (2.46 g, 24.3 mmol). The reaction mixture was stirred at room temperature for 16 hours for reaction and then the reaction was stopped. Then, water (50.0 mL) was added for dilution, and then extracted with ethyl acetate (×3 45.0 mL). Next, the organic phase was washed with saturated brine (30.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by a chromatography plate (petroleum ether:ethyl acetate = 5:1) to obtain the target compound (2.00 g, yield 85.2%, yellow solid). LC-MS (ESI) m / z 288.9 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 6.85 (s, 1H), 4.75 - 4.49 (m, 1H), 4.36 - 4.15 (m, 2H), 3.47 - 3.30 (m, 2H), 3.23 - 2.94 (m, 2H), 2.17 - 2.10 (m, 3H), 1.19 - 1.12 (m, 3H).

[0490] Step 4: Synthesis of 1-((3R)-4-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one

Chemical formula

[0491] (R)-1-(4-(3,6-Dichloropyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one (2.00 g, 6.92 mmol) in N-methylpyrrolidone (25.0 mL) was added to (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.55 g, 10.4 mmol) and N,N-diisopropylethylamine (2.68 g, 20.7 mmol). The reaction mixture was stirred at 145 °C for 16 h to effect the reaction, and the reaction was stopped. Then, water (50.0 mL) was added for dilution, and then extracted with ethyl acetate (45.0 mL × 3). Next, the organic phase was washed with saturated brine (40.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (1.80 g, yield 71.1%, yellow solid). LC-MS (ESI) m / z 366.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.15 - 6.08 (m, 1H), 4.54 - 4.44 (m, 3H), 3.97 - 3.82 (m, 2H), 3.78 - 3.64 (m, 2H), 3.58 - 3.47 (m, 2H), 3.25 - 3.18 (m, 2H), 2.20 - 2.13 (m, 2H), 2.13 - 2.10 (m, 2H), 2.02 - 1.97 (m, 2H), 1.89 - 1.81 (m, 3H), 1.06 - 1.01 (m, 3H).

[0492] Step 5: Synthesis of 4-((R)-4-acetyl-2-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazine-3-carbonitrile [Chemical Structure]

[0493] 1-((3R)-4-(6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one (1.8 g, 4.92 mmol) and zinc cyanide (1.16 g, 9.84 mmol) in DMF (30.0 mL) were added with 2-(diphenylphosphinoyl)cyclopentadienyliron (546 mg, 0.984 mmol) and tris(dibenzylideneacetone)dipalladium(0) (450 mg, 0.492 mmol). Under nitrogen protection, the reaction mixture was stirred at 135 °C for 16 h for reaction, and the reaction was stopped. Then, the reaction solution was diluted with EA (40.0 mL), washed with saturated brine (35 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (DCM:methanol = 10:1) to obtain the target compound (1.05 g, yield 59.9%, yellow solid). LC-MS (ESI) m / z 357.0 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 5.95 - 5.84 (m, 1H), 4.74 - 4.61 (m, 1H), 4.53 (s, 2H), 4.30 - 4.18 (m, 1H), 4.07 - 3.83 (m, 2H), 3.� (s, 1H), 3.54 - 3.41 (m, 1H), 3.36 - 3.17 (m, 4H), 3.03 - 2.89 (m, 1H), 2.18 - 2.10 (m, 3H), 2.03 - 1.98 (m, 2H), 1.87 - 1.79 (m, 2H), 1.19 - 1.12 (m, 3H).

[0494] Step 6: Synthesis of 1-((3R)-4-(3-(aminomethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one

Chem.

[0495] To a solution of 4-((R)-4-acetyl-2-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazine-3-carbonitrile (1.10 g, 3.09 mmol) in tetrahydrofuran (15.0 mL) were added Raney nickel (543 mg, 9.26 mmol) and aqueous ammonia (1.00 mL). The reaction mixture was reacted at room temperature for 5 h in a hydrogen gas atmosphere, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (660 mg, yield 59.3%, yellow oil) as a residue. LC-MS (ESI) m / z 361.0 [M+H] + 。

[0496] Step 7: Synthesis of N-((4-((R)-4-acetyl-2-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chemical Structure

[0497] 1-((3R)-4-(3-(Aminomethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one (360 mg, 0.999 mmol) and 1H-pyrazole-5-carboxylic acid (101 mg, 0.899 mmol) in tetrahydrofuran (10.0 mL) were added with 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.456 mg, 1.20 mmol) and DIEA (387 mg, 3.00 mmol). The reaction mixture was stirred at room temperature for 1 hour to react, and then the reaction was stopped. Then, water (30.0 mL) was added, and then extracted with EA (25.0 mL × 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (DCM:methanol = 10:1) to obtain the target compound (170 mg, yield 37.4%, yellow solid). LC-MS (ESI) m / z 455.0 [M+H] + 。

[0498] Step 8: Synthesis of 1-((R)-4-(2-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one

Chemical Structure

[0499] At room temperature, N-((4-((R)-4-acetyl-2-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (170 mg, 0.374 mmol) and phosphorus oxychloride (6.00 mL) were added to a reaction flask. The reaction mixture was reacted at 100 °C for 1 hour, and the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (6.68 mg, yield 4.09%, white solid). LC-MS (ESI) m / z 437.3 [M+H] + 。 1 H NMR (400 MHz, MeOD-d4) δ 7.83 - 7.51 (m, 2H), 7.13 (s, 1H), 5.80 (s, 1H), 4.55 - 4.48 (m, 3H), 3.87 - 3.80 (m, 2H), 3.74 - 3.42 (m, 4H), 3.30 - 3.05 (m, 4H), 2.24 - 2.12 (m, 3H), 2.04 - 1.93 (m, 4H), 1.26 - 1.13 (m, 3H).

[0500] Example 30: 3-(4-(4,4-difluoro-2-methylpiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0501] Step 1: Synthesis of 1-(3,6-dichloropyridazin-4-yl)-2-methylpiperidin-4-one

Chemical Structure

[0502] A solution of 2-methylpiperidin-4-one hydrochloride (3.00 g, 20.1 mmol) and 3,4,6-trichloropyridazine (4.41 g, 24.1 mmol) in N-methylpyrrolidone (50.0 mL) was added with DIEA (6.09 g, 60.2 mmol). Under nitrogen protection, the reaction mixture was stirred at 60 °C for 16 hours for reaction, and then the reaction was stopped. Thereafter, the reaction solution was diluted with ethyl acetate (100 mL), washed with saturated brine (60.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 5:1) to obtain the target compound (3.00 g, yield 57.5%, yellow solid). LC-MS (ESI) m / z 260.0 [M+H] + 。

[0503] Step 2: Synthesis of 3,6-dichloro-4-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazine

Chemical formula

[0504] Under nitrogen protection at 0 °C, diethylamine sulfur trifluoride (2.60 g, 16.2 mmol) was added to a solution of 1-(3,6-dichloropyridazin-4-yl)-2-methylpiperidin-4-one (2.8 g, 10.7 mmol) in dichloromethane (50.0 mL). Under nitrogen protection, the reaction mixture was stirred at 0 °C for 1 hour for reaction, and then the reaction was stopped. Thereafter, the reaction solution was concentrated under reduced pressure to obtain the target compound (1.80 g, yield 59.3%, yellow oil) as the obtained residue. LC-MS (ESI) m / z 281.9 [M+H] + 。

[0505] Step 3: Synthesis of 3-(6-chloro-5-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0506] To a solution of 3,6-dichloro-4-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazine (1.80 g, 6.38 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.43 g, 9.57 mmol) in N-methylpyrrolidone (50.0 mL) was added DIEA (2.47 g, 19.1 mmol). Under nitrogen protection, the reaction mixture was stirred at 145 °C for 16 h to allow the reaction to proceed, and then the reaction was stopped. Subsequently, the reaction solution was diluted with ethyl acetate (85.0 mL), washed with saturated brine (55.0 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (1.80 g, yield 78.6%, yellow solid). LC-MS (ESI) m / z 359.0 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 6.23 (s, 1H), 4.54 - 4.50 (m, 2H), 4.09 - 3.96 (m, 1H), 3.86 - 3.74 (m, 2H), 3.47 - 3.37 (m, 1H), 3.26 - 3.19 (m, 2H), 3.13 - 2.99 (m, 1H), 2.32 - 2.23 (m, 1H), 2.23 - 2.08 (m, 2H), 2.04 - 1.97 (m, 3H), 1.90 - 1.84 (m, 2H), 1.14 (d, J = 16.6, 6.7 Hz, 3H).

[0507] Step 4: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazine-3-carbonitrile

Chemical Structure

[0508] 3-(6-chloro-5-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.8 g, 5.02 mmol) and zinc cyanide (1.18 g, 10.0 mmol) in N,N-dimethylformamide (30.0 mL) were added with 2-(diphenylphosphinoyl)cyclopentadienyliron (556 mg, 1.00 mmol) and tris(dibenzylideneacetone)dipalladium(0) (459 mg, 0.501 mmol). Under nitrogen protection, the reaction mixture was stirred at 140 °C for 16 h to react, and the reaction was stopped. Then, the reaction solution was diluted with ethyl acetate (65.0 mL), washed with saturated brine (40.0 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (PE:EA = 1:1) to obtain the target compound (1.50 g, yield 85.6%, yellow solid). LC-MS (ESI) m / z 350.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 5.93 (s, 1H), 4.53 - 4.50 (m, 2H), 4.42 - 4.33 (m, 1H), 4.01 - 3.90 (m, 2H), 3.51 - 3.42 (m, 2H), 3.31 - 3.26 (m, 2H), 2.29 - 2.15 (m, 2H), 2.11 - 1.99 (m, 4H), 1.84 - 1.80 (m, 2H), 1.24 (dd, J = 6.9, 1.7 Hz, 3H).

[0509] Step 5: Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazin-3-yl)methylamine

Chemical Structure

[0510] To a solution of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazine-3-carbonitrile (1.50 g, 4.29 mmol) in tetrahydrofuran (30.0 mL) was added Raney nickel (1.26 g, 21.5 mmol). The reaction mixture was reacted at room temperature for 16 h in a hydrogen gas atmosphere, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (1.20 g, yield 79.1%, yellow oil) as a residue. LC-MS (ESI) m / z 354.0 [M+H] + 。

[0511] Step 6: Synthesis of N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide

Chemical formula

[0512] (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazin-3-yl)methylamine (1.20 g, 3.40 mmol) and 1H-pyrazole-5-carboxylic acid (342 mg, 3.06 mmol) in tetrahydrofuran (30.0 mL) were added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.55 g, 4.07 mmol) and DIEA (1.32 g, 10.2 mmol). The reaction mixture was reacted at room temperature for 1 h, and the reaction was stopped. Then, the reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (EA) to obtain the target compound (1.00 g, yield 65.8%, yellow solid). LC-MS (ESI) m / z 448.0 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.59 (d, J = 2.1 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 6.44 (s, 1H), 4.87 - 4.72 (m, 2H), 4.55 - 4.50 (m, 2H), 3.86 - 3.77 (m, 2H), 3.49 (s, 2H), 3.38 - 3.31 (m, 1H), 3.26 - 3.21 (m, 2H), 2.35 - 2.22 (m, 2H), 2.03 - 1.99 (m, 2H), 1.90 - 1.84 (m, 2H), 1.50 - 1.47 (m, 2H), 1.02 (d, J = 6.2 Hz, 3H).

[0513] Step 7: Synthesis of 3-(4-(-4,4-difluoro-2-methylpiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0514] At room temperature, N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(4,4-difluoro-2-methylpiperidin-1-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide (200 mg, 0.447 mmol), phosphorus oxychloride (685 mg, 4.47 mmol) and acetonitrile (5 mL) were added to a reaction flask. The reaction mixture was reacted at 100 °C for 1 hour and the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase preparative chromatography (acetonitrile / water containing 0.05% formic acid) to obtain the target compound (110 mg, yield 57.3%, white solid). LC-MS (ESI) m / z 430.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 7.81 - 7.59 (m, 2H), 7.10 (s, 1H), 5.92 (s, 1H), 4.71 - 4.59 (m, 1H), 4.47 (s, 2H), 3.88 - 3.79 (m, 3H), 3.47 - 3.40 (m, 1H), 3.07 (d, J = 11.1 Hz, 2H), 2.44 - 2.28 (m, 1H), 2.22 - 2.04 (m, 3H), 1.89 - 1.81 (m, 4H), 1.21 (d, J = 5.6 Hz, 3H).

[0515] Examples 31 and 32: 3-(4-((R)-4,4-difluoro-2-methylpiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane, and 3-(4-((S)-4,4-difluoro-2-methylpiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical formula

[0516] Racemic 3-(4-(-4,4-difluoro-2-methylpiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane 50 mg was subjected to chiral resolution using Waters SFC 150 (room temperature, 100 bar, 214 nm) and 250*25 mm 10 mm DAICEL CHIRALPAK IG (supercritical carbon dioxide: MeOH (+0.1% 7.0 mol / l ammonia in MeOH), 45:55, 3.2 min, 100 mL / min). The first eluted (short retention time) P1 (14.40 mg, e.e. 100.00%) and the second eluted (long retention time) P2 (14.37 mg, e.e. 99.07%) were obtained respectively. LC-MS (ESI) m / z 430.2 [M+H] + . LC-MS (ESI) m / z 430.2 [M+H]+. (P1): 1H NMR (400 MHz, MeOD-d4) δ 7.71 (s, 1H), 7.55 (s, 1H), 7.13 (s, 1H), 5.88 (s, 1H), 4.71 - 4.63 (m, 1H), 4.50 (s, 2H), 3.87 - 3.76 (m, 3H), 3.58 - 3.50 (m, 1H), 3.24 - 3.16 (m, 2H), 2.44 - 2.28 (m, 1H), 2.24 - 2.08 (m, 3H), 2.01 - 1.94 (m, 4H), 1.30 (d, J = 6.9 Hz, ...... (P2): 11H NMR (400 MHz, MeOD-d4) δ 7.70 (s, 1H), 7.54 (s, 1H), 7.13 (s, 1H), 5.88 (s, 1H), 4.71 - 4.63 (m, 1H), 4.50 (s, 2H), 3.86 - 3.76 (m, 3H), 3.58 - 3.46 (m, 1H), 3.22 - 3.17 (m, 2H), 2.44 - 2.27 (m, 1H), 2.25 - 2.08 (m, 3H), 2.02 - 1.94 (m, 4H), 1.30 (d, J = 7.3 Hz, 3H).

[0517] Example 34: 1-((R)-4-(6-((1R, 5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one

Chemical Structure

[0518] Step 1: Synthesis of 1-((R)-4-(6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one

Chemical Structure

[0519] (1R,5S)-3-(4-Iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1 g, 1.97 mmol), (R)-1-(3-methylpiperazin-1-yl)ethan-1-one (561 mg, 3.95 mmol), Ruphos G2 (155 mg, 0.2 mmol), and cesium carbonate (1.93 g, 5.91 mmol) were successively added to NMP (10 mL). The reaction mixture was reacted at 150 °C for 1 hour under microwave irradiation. After completion of the reaction, the reaction mixture was cooled, water (20 mL) was added, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by reverse-phase column chromatography (MeOH:H2O = 5%:95% to 95%:5%) to obtain the target compound (60 mg, yield 6.0%). LC-MS (ESI) m / z 521.2 [M+H] + .

[0520] Step 2: Synthesis of 1-((R)-4-(6-((1R, 5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one [Chemical formula]

[0521] 1-((R)-4-(6-((1R, 5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one (60 mg, 0.12 mmol) was added to 6 M hydrochloric acid aqueous solution / tetrahydrofuran (1 mL / 2 mL), and stirred at room temperature overnight. After the reaction was completed, the pH was adjusted to >8 with saturated aqueous sodium bicarbonate solution, and extracted with EA (20 mL×3). The combined organic layers were concentrated under reduced pressure to obtain a crude product, and the crude product was washed with EA (2 mL) to obtain the target product (7 mg, yield 14.0%, green solid) as a solid. LC-MS (ESI) m / z 437.3 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.66 (s, 1H), 6.82 (s, 1H), 5.63 (s, 1H), 4.62 - 4.49 (m, 2H), 4.46 - 4.33 (m, 1H), 4.01 - 3.81 (m, 2H), 3.74 (s, 2H), 3.66 - 3.45 (m, 2H), 3.46 - 3.34 (m, 1H), 3.34 - 3.18 (m, 2H), 3.18 - 3.03 (m, 1H), 2.24 - 2.10 (m, 3H), 2.05 - 1.95 (m, 2H), 1.92 - 1.83 (m, 2H), 1.25 - 1.17 (m, 3H).

[0522] Example 35: (4-(6-((1R, 5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

Chemical Structure

[0523] Step 1: Synthesis of (4-(6-((1R, 5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

Chem.

[0524] (1R,5S)-3-(4-Iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane (300 mg, 0.6 mmol), morpholin-3-ylmethanol (144 mg, 1.2 mmol), RuphosPdG2 (48 mg, 0.06 mmol), cesium carbonate (582 mg, 1.8 mmol) were sequentially added to NMP (12 mL), and stirred and reacted at 150 °C for 1 hour under microwave. After completion of the reaction, it was extracted with EA (20 mL×3), the organic layers were combined, washed with water (20 mL×5), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by silica gel column (DCM:MeOH = 30:1) to obtain the target compound (29 mg, yield 9.7%, white solid). LC-MS (ESI) m / z: 496.3 [M+H] + 。

[0525] Step 2: Synthesis of (4-(6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol

Chem.

[0526] (4-(6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol (29 mg, 0.06 mmol) was added to 6 M aqueous hydrochloric acid / tetrahydrofuran (2 mL / 4 mL), and the mixture was stirred at 50 °C overnight. After completion of the reaction, the pH was adjusted to >8 with saturated aqueous sodium bicarbonate, and the mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (DCM:MeOH = 15:1) to obtain the target product (10 mg, yield 40.5%, white solid). LC-MS (ESI) m / z: 412.2. 1 H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.61 (d, J = 1.5 Hz, 1H), 6.80 (s, 1H), 5.69 (s, 1H), 4.57 - 4.47 (m, 2H), 4.21 (d, J = 11.7 Hz, 1H), 4.17 - 4.09 (m, 1H), 4.10 - 3.98 (m, 2H), 3.91 - 3.79 (m, 4H), 3.80 - 3.69 (m, 1H), 3.53 (d, J = 5.8 Hz, 2H), 3.28 - 3.18 (m, 2H), 2.06 - 1.91 (m, 3H), 1.91 - 1.79 (m, 2H).

[0527] Example 36: 3-(7-(3,3-Dimethylmorpholino)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0528] Step 1: Synthesis of 4-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3,3-dimethylmorpholine [Chem.]

[0529] 5,7-Dichloropyrazolo[1,5-a]pyrimidine (540 mg, 2.9 mmol), 3,3-dimethylmorpholine hydrochloride (1.0 g, 8.6 mmol), and DIEA (1.1 g, 8.6 mmol) were added to NMP (15 mL). Under nitrogen protection, the resulting mixture was reacted in a microwave at 100 °C for 0.5 h. After completion of the reaction, water (15 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by silica gel column (PE:EA = 7:3) to obtain the target compound (0.9 g, yield 116.3%, white solid). LC-MS (ESI) m / z: 267.0 [M+H] + .

[0530] Step 2: Synthesis of 3-(7-(3,3-dimethylmorpholino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane [Chem.]

[0531] 4-(5-Chloropyrazolo[1,5-a]pyrimidin-7-yl)-3,3-dimethylmorpholine (200 mg, 0.8 mmol), (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (225 mg, 1.5 mmol), and DIEA (290 mg, 2.3 mmol) were sequentially added to NMP (10 mL). The reaction mixture was reacted at 140 °C for 2 hours in a microwave apparatus. After completion of the reaction, water (15 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (PE:EA = 57%:43%) to obtain the target product (202 mg, yield 78.6%, white solid).

[0532] Step 3: Synthesis of 3-(7-(3,3-dimethylmorpholino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0533] 3-(7-(3,3-Dimethylmorpholino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (202 mg, 0.6 mmol) and N-iodosuccinimide (135 mg, 0.6 mmol) were added to acetonitrile (5 mL), and the mixture was stirred at room temperature for 0.5 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by silica gel column chromatography (PE:EA = 1:1) to obtain the target compound (224 mg, yield 79.7%, white solid).

[0534] Step 4: Synthesis of 3-(7-(3,3-dimethylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0535] 3-(7-(3,3-Dimethylmorpholino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (172 mg, 0.4 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (153 mg, 0.6 mmol), potassium phosphate (233 mg, 1.1 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (24 mg, 0.04 mmol) were sequentially added to dioxane / water (10 mL / 2 mL). The reaction mixture was reacted in an oil bath at 80 °C for 1 h. After the reaction was completed, water (15 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL × 3). The combined organic phases were washed with water (30 mL × 5) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by silica gel column (PE:EA = 1:4) to obtain the target compound (68 mg, yield 37.2%, white solid). LC-MS (ESI) m / z: 494.0 [M+H] + 。

[0536] Step 5: Synthesis of 3-(7-(3,3-Dimethylmorpholino)-3-(1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Chemical Structure

[0537] 3-(7-(3,3-Dimethylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane (68 mg, 0.1 mmol) was added to an aqueous 6 M hydrochloric acid / tetrahydrofuran (2 mL / 4 mL) solution, and the mixture was stirred at 50 °C for 1 hour to effect the reaction. After completion of the reaction, the pH was adjusted to >8 with a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH = 30 / 1) to obtain the target compound (38 mg, yield 67.9%, white solid). LC-MS (ESI) m / z: 410.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.57 (s, 1H), 6.70 (s, 1H), 5.97 (s, 1H), 4.54 - 4.40 (m, 2H), 4.05 (d, J = 11.3 Hz, 2H), 3.88 - 3.75 (m, 2H), 3.59 - 3.50 (m, 2H), 3.45 (s, 2H), 3.12 (d, J = 10.4 Hz, 2H), 1.90 - 1.69 (m, 4H), 1.32 (s, 6H).

[0538] Active Example Unless otherwise specified, the experimental materials, reagents, operations, and methods used in the following active examples are commercially available or can be easily obtained or prepared based on prior art.

[0539] Active Example 1: Measurement of Kinase ATR Inhibition In this experiment, detection was performed using the homogeneous time-resolved fluorescence technology (HTRF®) of Cisbio.

[0540] Experimental method: The buffer solution was prepared as follows.

[0541]

Table 2

[0542] A test compound solution was prepared. Using DMSO as the solvent, solutions of the compounds in the following examples were prepared, and the mother liquor was usually 10 mM. In this experiment, the maximum starting concentration was 3 μM, and it was serially diluted 3-fold with DMSO to a total of 10 concentrations, which were added to the wells of a corresponding 384-well plate (Geriner bio-one, Cat#784075). The final concentrations were 3000, 1000, 333, 111, 37, 12.3, 4.12, 1.37, 0.457, and 0.152 nM, respectively. The corresponding amount of DMSO was added to another well, which was used as a negative control well or a positive control well, respectively.

[0543] Using the buffer solution prepared above, the enzyme and the substrate were separately dissolved and diluted in two tubes, and their concentrations are shown in the following table.

[0544]

Table 3

[0545] Using an electric multi-channel pipette, the ATR solution in tube A was added to the compound wells and negative control wells of the experimental plate at a volume of 5 μL per well, and the buffer solution prepared above (medium only, without adding enzyme) was added to the positive control well at the same volume. After centrifuging at a rotation speed of 1000 revolutions per minute for 1 minute using a centrifuge, the experimental plate was placed in a constant temperature incubator and incubated at 25 °C for 15 minutes. Then, in the same manner, 5 μL of the substrate mixed solution in tube B was added to the positive control well, negative control well, and compound wells of the experimental plate, centrifuged, and incubated at 25 °C for 90 minutes.

[0546] During the reaction process, after ATR phosphorylates the substrate p53, two types of antibodies are added. Among them, anti-phospho-p53-Eu specifically binds to the phosphorylation site on p53 as an energy donor, and anti-GST-d2 specifically binds to the GST tag carried on p53 as an energy acceptor. When the energy donor is excited using a laser of a certain wavelength (the excitation light wavelength in this experiment is 340 nm), it emits emission light with a wavelength of 615 nm. At the same time, when the spatial distance between the energy donor and the energy acceptor is sufficiently close (i.e., when the two antibodies are simultaneously bound to p53), energy transfer occurs between the energy donor and the energy acceptor, and the energy acceptor emits emission light with a wavelength of 665 nm. Two emission lights are detected using a plate reader, the ratio of the two signals at 665 nm and 615 nm is obtained, and the IC 50 of the test sample is determined through plotting and calculation.

[0547] As shown in the following table, two types of antibodies were diluted with HTRF detection buffer (Cisbio, Cat#62SDBRDF, Lot#17A) for detection.

[0548]

Table 4

[0549] Using an electric multi-channel pipette, the detection solution was added to the positive control wells, negative control wells, and compound wells of the experimental plate at a volume of 10 μL per well, centrifuged, incubated overnight at 4°C, and read using a plate reader Envision 2104.

[0550] Calculation of the compound inhibition rate using the interpolation method: The average values of the positive control and the negative control were calculated using the formula. Inhibition rate of a single well = 1 - (Signal value of a single well - Average value of the positive control signal) / (Average value of the negative control signal - Average value of the positive control signal)

[0551] The inhibition rate of the compound wells was calculated. A compound inhibition curve was created using the four-parameter logistic equation. The compound concentration was converted to the logarithm with base 10, and the concentration and inhibition rate were substituted into XLfit software. The equation is shown below. Inhibition rate = Minimum response + (Compound concentration ^ Curve gradient) * (Maximum response - Minimum response) / (Compound concentration ^ Curve gradient + Half-inhibition concentration ^ Curve gradient)

[0552] The IC 50 for the enzyme activity of each compound was obtained.

[0553]

Table 5

[0554] Activity Example 2: Cell proliferation test The cell proliferation inhibitory effect of the compounds of the present invention was tested using the CellTiter-Glo™ Viability Assay Kit. This kit employed luciferase as the detection substance, and luciferase required the participation of ATP in the luminescence process. The CellTiter-Glo™ reagent was added to the cell culture medium, and the luminescence value was measured. As a result, the light signal was directly proportional to the amount of ATP in the system, and ATP was also positively correlated with the number of viable cells, thereby determining the proliferation activity of the cells.

[0555] Cell culture and seeding: Cells LOVO (human colon cancer cells) (ATCC CCL-229) in the logarithmic growth phase were collected and counted using a hemocytometer. The viability of the cells was detected using the trypan blue exclusion method to ensure that the cell viability was 90% or more. 90 μL of the cell suspension (RPMI1640 + 10% fetal bovine serum) was added to each well of a 96-well clear flat-bottom black-wall plate (Thermo, 165305), and the cell concentration was adjusted to 3000 / well / 90 μl. The cells in the 96-well plate were cultured overnight at 37 °C, 5% CO2, and 95% humidity conditions (Thermo, Model 3100 Series).

[0556] First, a 10 mM test compound stock solution was prepared using DMSO as a solvent. Next, it was diluted 100-fold with PBS to prepare a solution with a final concentration of 10-fold, with the highest concentration set at 100 μM. The test compound solution was added at 10 μL per well to a 96-well plate seeded with cells, i.e., further diluted 10-fold to a final concentration of 10 μM. The final concentration of the test compound was serially diluted 3-fold from 10 μM, diluted to a total of 9 concentrations, and 3 wells were duplicated for each concentration. The 96-well plate with the test compound and cells was cultured at 37 °C, 5% CO2, and 95% humidity for 96 hours, and then CellTiter-Glo analysis was performed.

[0557] The CellTiter-Glo reagent (CellTiter-Glo® Luminescent Cell Viability Assay, Promega, G7572) was dissolved, and the cell plate was equilibrated for 30 minutes to room temperature. An equal volume of the CellTiter-Glo solution was added to each well, and the cells were lysed by shaking on an orbital shaker for 5 minutes. The cell plate was left at room temperature for 20 minutes to stabilize the luminescence signal, and the luminescence value was read using a SpectraMax multimarker microplate detector (MD, M3).

[0558] The data was analyzed using GraphPad Prism 7.0 software, and the data was fitted using non-linear S-curve regression to obtain a dose-effect curve, and the IC 50 was calculated. Cell viability (%) = (Lum 被検薬 - Lum 培養液対照 ) / (Lum 細胞対照 - Lum 培養液対照 ) × 100%

[0559]

Table 6

[0560] Active Example 3: Liver microsome metabolic stability experiments in humans and mice The hepatic microsomal metabolic stability test of this compound was conducted as follows according to the standard methods of general in vitro metabolic stability studies in the art, for example, the methods described in (Kerns, Edward H. and Di Li (2008). Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization. San Diego: Academic Press; Di, Li et al., Optimization of a Higher Throughput Microsomal Stability Screening Assay for Profiling Drug Discovery Candidates, J. Biomol. Screen. 2003, 8(4), 453.).

[0561]

Table 7

[0562] Hepatic microsomes (protein concentration 0.56 mg / mL) were added to a 1 μM compound working solution (a 10 mM DMSO stock solution diluted to 100 μM with 100% acetonitrile, organic phase content: 99% ACN, 1% DMSO), pre-incubated at 37 °C for 10 min, and then the cofactor (NADPH) (prepared with a magnesium chloride solution) was added to initiate the reaction. Sampling was performed after incubation for an appropriate time (e.g., 5, 10, 20, 30, and 60 minutes), and an appropriate stop solution (ice-cold acetonitrile containing 200 ng / mL of tolbutamide and 200 ng / mL of labetalol, i.e., acetonitrile at 4 °C) was added to stop the reaction.

[0563] Sample treatment (n = 1): Appropriate samples were added respectively, vortex-mixed, centrifuged at high speed, the supernatant was taken, and the substrate was detected using HPLC-MS / MS. The peak area at the 0 min time point was set as 100%. The peak areas at other time points were converted to the remaining amount percentage, and the incubation time was plotted with the natural logarithm of the remaining amount percentage at each time point to obtain the slope (-k). The intrinsic clearance (Clint) = (k * incubation liquid volume) / liver microsome mass, and Clint (μL / min / mg) and the compound half-life (T 1 / 2 , min) were calculated. The results are shown in Table 3.

[0564]

Table 8

[0565] Active Example 4: Pharmacokinetics (PK) measurement of the compound of the present invention in mice The PK measurement method for each compound is as follows. Six CD-1 mice (Shanghai Lingchang Biotechnology Co., Ltd.) were divided into two groups of three mice each. One group was administered intravenously (IV) at a dose of 1 mg / kg, and the solvent was 5% DMSO / 95% (20% Captisol). The other group was administered intragastrically by oral administration (Po) at a dose of 5 mg / kg, and the solvent was 1% HPMC. Blood was collected from the saphenous vein of each group at 0, 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. Approximately 40 μL of blood was collected into an anticoagulant tube containing EDTA-K2. After the collection was completed, the collected blood tube was inverted at least 5 times to mix uniformly and placed on ice. The blood collected at each time point was centrifuged at 4°C / 8000 rpm for 5 minutes to obtain plasma. Another 1.5 mL centrifuge tube was marked with the compound name, animal number, and time point, and the plasma was transferred to the tube. The plasma was stored at -80°C until analysis.

[0566] The compound concentration in plasma was measured using the UPLC-MS / MS method, and pharmacokinetic parameters were calculated for the obtained data using Phoenix WinNolin 6.4 pharmacokinetics software.

[0567] The specific experimental results are as follows, and the results indicated that the pharmacokinetic absorption of the compound was relatively good and had pharmacokinetic advantages.

[0568]

Table 9

[0569] Active Example 5: Measurement of the equilibrium solubility of the compound of the present invention in FaSSIF According to the standard method for measuring solubility commonly known to those skilled in the art (for example, Kerns, Edward H. and Di Li (2008). Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization. San Diego: Academic Press), using FaSSIF (pH 6.5) (simulating small intestinal juice in a fasting state before meals) as the test system, the solubility of the compound of the present invention was considered as follows.

[0570] The sample powder of each compound was weighed in a volumetric flask respectively, 450 μL of pH 6.5 FaSSIF solution was added to obtain a supersaturated suspension, the sample was vortex-mixed for at least 2 minutes, and the volumetric flask was shaken on a vibrating sieve at a speed of 800 rpm for 24 hours. Then, it was centrifuged at 4000 rpm for 20 minutes. The concentrated filtrate was added to a high-performance liquid chromatography system, and the results of calculating the concentration using the calibration curve method are shown in Table 5.

[0571] The composition of the high-speed simulated intestinal fluid FaSSIF was lecithin 0.056% (w / v), sodium taurocholate 0.161% (w / v), potassium phosphate 0.39% (w / v), potassium chloride 0.77% (w / v), deionized H2O, pH 6.5.

[0572]

Table 10

[0573] From the above experimental results, it was shown that the compounds of the examples of the present invention have unexpectedly significantly higher solubility compared to the control, and thus have better drug formability.

[0574] The structural formula of the reference compound BAY-1895344 used in the above experiment is

Chemical formula

[0575] Those skilled in the art will understand that the above description is essentially exemplary and explanatory and is intended to illustrate the present invention and its preferred embodiments. Through conventional experiments, those skilled in the art will understand that obvious modifications and changes are possible without departing from the spirit of the present invention. Such corrections are intended to be included within the scope of the claims of the pending application. Therefore, it is desirable that the present invention be defined by the following claims and their equivalents rather than by the above description.

[0576] All publications cited herein are hereby incorporated by reference into this specification. Examples of aspects of the present disclosure include the following. [1] A compound of formula (I), or a pharmaceutically acceptable salt or isomer thereof.

Chemical formula

Chem.

Chem.

Chem.

Chem.

[10] R 3 The compound of formula (I) according to any one of aspects 1 to 9, which is H, or a pharmaceutically acceptable salt or isomer thereof.

[11] A 1 ~A 5 The 6-membered-5-membered heteroaryl moiety containing

Chem.

Chem.

[12] A 1 ~A 5 The 6-membered-5-membered heteroaryl moiety containing

change

[13] The 6-membered ring containing X and Y

change

change

[14] R 1 and R 2 are each independently H or -C 1~6 alkyl, the compound of formula (I) according to any one of aspects 11 to 13, or a pharmaceutically acceptable salt or isomer thereof.

[15] Of n and m, one is 0 and the other is 1, and R 1 or R 2is linked to the ortho position of Y or the ortho position of X, or Of n and m, one is 0 and the other is 2, and R 1 or R 2 is simultaneously linked to the ortho position of Y or the ortho position of X on the ring, or is linked to the ortho position of Y and the ortho position of X respectively, preferably, both are linked to the ortho position of Y, or n and m are both 1, and R 1 and R 2 are each independently linked to the ortho position of Y or the ortho position of X on the ring, preferably, both are linked to the ortho position of X, or R 1 and R 2 simultaneously linked to the ortho position of Y or the ortho position of X are joined together to form a C 1~3 alkylene bridge, preferably, a C 2 alkylene bridge, the compound of formula (I) according to any one of aspects 11 to 14, or a pharmaceutically acceptable salt or isomer thereof.

[16] R 3 is the compound of formula (I) according to any one of aspects 11 to 15, or a pharmaceutically acceptable salt or isomer thereof, which is H.

[17] R 5 is -C 1~6 alkyl, preferably -CH 3 is the compound of formula (I) according to any one of aspects 11 to 16, or a pharmaceutically acceptable salt or isomer thereof.

[18] R 6 is, independently of each other, H or halogen, preferably H or F, and is the compound of formula (I) according to any one of aspects 11 to 16, or a pharmaceutically acceptable salt or isomer thereof.

[19] R 7 is H or -C 1~6 alkyl, preferably -CH 3 is the compound of formula (I) according to any one of aspects 11 to 16, or a pharmaceutically acceptable salt or isomer thereof.

[20] A compound selected from the following, or a pharmaceutically acceptable salt or isomer thereof.

Chem.

[21] A pharmaceutical composition comprising the compound according to any one of aspects 1 to 20, or a pharmaceutically acceptable salt or isomer thereof, and any one or more pharmaceutically acceptable carriers.

[22] The pharmaceutical composition according to aspect 21, further comprising at least one other pharmaceutically active ingredient.

[23] Use of the compound according to any one of aspects 1 to 20, or a pharmaceutically acceptable salt or isomer thereof, or the pharmaceutical composition according to any one of aspects 21 to 22, in the treatment or prevention of an ATR kinase-related disease.

[24] Use of the compound according to any one of aspects 1 to 20, or a pharmaceutically acceptable salt or isomer thereof, or the pharmaceutical composition according to any one of aspects 21 to 22, in the preparation of a drug for treating or preventing an ATR kinase-related disease.

[25] The use according to embodiment 23 or 24, wherein the ATR kinase-related disease is selected from hematological malignancies such as leukemia (including chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia), multiple myeloma, lymphoid malignancies (such as lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma), myelodysplastic syndromes, and solid tumors such as cancer, sarcoma and its metastases, such as breast cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, bronchioloalveolar carcinoma), central nervous system tumors (such as glioma, embryonal neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, and teratoma), gastrointestinal cancer (such as gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, pancreatic cancer), skin cancer, melanoma, thyroid cancer, bone cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma (such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal tissue cancer, gastrointestinal stromal tumor, Kaposi's sarcoma), and pediatric cancer (such as rhabdomyosarcoma and neuroblastoma).

[26] The use according to embodiment 25, wherein the ATR kinase-related disease is selected from lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcoma, head and neck cancer, central nervous system tumors and their metastases, and acute myeloid leukemia.

Claims

1. The compound of formula (I), or a pharmaceutically acceptable salt or isomer thereof. 【Chemical 1】 (wherein, A １ , A ２ and A ５ is each independently C or N, A ３ and A ４ each independently is CR ４ , N or NR ５ and X is O, C(R ６ ), ２ or NR ７ and Y is N or CR ８ and R １ , R ２ and R ３ are each independently H, -OH, oxo, halogen, CN, -C １～６ alkyl or -O-C １～６ alkyl, where the C １～６ alkyl is optionally substituted with one or more halogens or hydroxy, or R １ and R ２ are joined together to form a C １～３ alkylene bridge, R ４ is H, oxo, halogen or -C １～６ alkyl, where the C １～６ alkyl is optionally substituted with one or more halogens or hydroxy, R ５ is H or -C １～６ alkyl, where the C １～６ alkyl is optionally substituted with one or more halogens, R ６ is, independently of each other, H, halogen, CN, -OH, -NH ２ , -NH-C １～６ alkyl, -N(C １～６ alkyl) ２ , -C １～６ alkyl, -O-C １～６ alkyl, -C(O)-C １～６ alkyl, -C(O)-C ３～６ cycloalkyl, -SO ２ -C １～６ alkyl, -SO ２ -C ３～６ cycloalkyl, -SO-C １～６ alkyl, -SO-C ３～６ cycloalkyl, C ６～１０ aryl or C ３～６ cycloalkyl, where the -C １～６ alkyl, C ６～１０ aryl or C ３～６ cycloalkyl is optionally substituted with one or more of halogen, hydroxy, -O-C １～６ alkyl, -C １～６ alkyl, or -C １～６ alkyl substituted with halogen or hydroxy, R ７ is H, -C １～６ alkyl, -C(O)-C １～６ alkyl, -C(O)-C ３～６ cycloalkyl, -SO ２ -C １～６ alkyl, -SO ２ -C ３～６ cycloalkyl, -SO-C １～６ alkyl or -SO-C ３～６ cycloalkyl, where the -C １～６ alkyl or C ３～６ cycloalkyl is optionally substituted with one or more of halogen, hydroxy, -O-C １～６ alkyl, -C １～６ alkyl, or -C １～６ alkyl substituted with halogen or hydroxy, R ８ is H, -OH or halogen, n and m are each independently an integer from 0 to 4.)

2. A １ 、 A ２ 、 A ３ 、 A ４ and A ５ at least two of which are N or NR ５ and the remainder are C or CR ４ and preferably two of them are N or NR ５ and the remainder are C or CR ４ The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or isomer thereof.

3. A １ ~A ５ The 6-membered-5-membered heteroaryl moiety containing 【Chemical 2】 Selected from, preferably, [Chemical Formula 3] The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or isomer thereof, having the structure of

4. R ４ is H, and R ５ is H or C １～６ alkyl, the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or isomer thereof.

5. The 6-membered ring containing X and Y 【Chemical 4】 is 【Chemical Formula 5】 Selected from, the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or isomer thereof.

6. X is selected from -O-, -NH-, -N(C １～６ alkyl)-, -CH ２ -, -C(halogen) ２ and / or Y is N or CR8, and R8 is OH, the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or isomer thereof.

7. Of m and n, one is 0 and the other is 1, R １ or R ２ is, independently of one another, C １～６ alkyl, optionally substituted by one or more halogens, linked to the ortho position of Y or the ortho position of X, or Of m and n, one is 0 and the other is 2, R １ or R ２ is, independently of one another, C １～６ alkyl, optionally substituted with one or more halogens, linked to the ortho-position of Y or the ortho-position of X, or linked to the ortho-positions of X and Y respectively, or m and n are both 1, and R １ and R ２ are each independently C １～６ alkyl, optionally substituted with one or more halogens, both are linked to the ortho-position of Y on the ring, both are linked to the ortho-position of X, or are each linked to the ortho-position of Y and the ortho-position of X, or m = 1 and n = 1, and R1 and R2 are each linked to the ortho position of Y and together form a C1-3 alkylene bridge, preferably a C2 alkylene bridge, or R1 and R2 are each linked to the ortho position of X and together form a C1-3 alkylene bridge, preferably a C2 alkylene bridge, Preferably, among m and n, one is 0 and the other is 1, and R １ or R ２ is C １～６ alkyl and is linked to the ortho-position of Y or the ortho-position of X, the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or isomer thereof.

8. R ３ The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or isomer thereof, wherein R is H.

9. A １ to A ５ The 6-membered-5-membered heteroaryl moiety containing 【Chemical Formula 6】 Selected from The 6-membered ring containing X and Y 【Chemical Formula 7】 Selected from, the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or isomer thereof. (R １ and R ２ are each independently H or -C １～６ alkyl, where the C １～６ alkyl is optionally substituted with one or more hydroxyls or halogens, or R １ and R ２ are joined together to form a C １～３ alkylene bridge, R ３ is H or halogen, R ４ is H, R ５ is H or -C １～６ alkyl, R ６ is, independently of one another, H or halogen, -C １～６ alkyl or -O-C １～６ alkyl, where the -C １～６ alkyl is optionally substituted with one or more halogens, R ７ is H or -C １～６ alkyl, wherein the -C １～６ alkyl is optionally substituted with one or more halogens, R ８ is H, -OH or halogen, n and m are each independently an integer from 0 to 2.)

10. A １ ~A ５ The 6-membered-5-membered heteroaryl moiety containing 【Chemical 8】 Selected from, and / or The 6-membered ring containing X and Y 【Chemical Formula 9】 is 【Chemical Formula 10】 Selected from, the compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt or isomer thereof.

11. R １ and R ２ each independently is H or -C １～６ alkyl, the compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt or isomer thereof.

12. Of n and m, one is 0 and the other is 1, R １ or R ２ is linked to the ortho position of Y or the ortho position of X, or Of n and m, one is 0 and the other is 2, R １ or R ２ is simultaneously linked to the ortho position of Y or the ortho position of X on the ring, or is linked to the ortho position of Y and the ortho position of X respectively, preferably, both are linked to the ortho position of Y, or n and m are both 1, and R １ and R ２ are each independently linked to the ortho position of Y on the ring or the ortho position of X, preferably, both are linked to the ortho position of Y, or R １ and R ２ are linked together to form a C １～３ alkylene bridge, preferably a C ２ alkylene bridge, the compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt or isomer thereof.

13. R ３ is H, the compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt or isomer thereof.

14. R5 is -C1-6 alkyl, preferably -CH3, and / or R ６ is each independently H or halogen, preferably H or F, and / or R7 is H or -C1-6 alkyl, preferably -CH3, the compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt or isomer thereof.

15. Selected from the following, the compound according to claim 1, or a pharmaceutically acceptable salt or isomer thereof. 【Chemical 11】 【Chem.】

16. Use in the treatment or prevention of ATR kinase-related diseases, the compound according to claim 1, or a pharmaceutically acceptable salt or isomer thereof, or a pharmaceutical composition comprising said compound.

17. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt or isomer thereof, optionally one or more pharmaceutically acceptable carriers, and optionally at least one other pharmaceutically active ingredient.

18. Use of the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or isomer thereof, or the pharmaceutical composition according to claim 17, in the preparation of a drug for treating or preventing ATR kinase-related diseases.

19.

19. The ATR kinase-related diseases are selected from hematological malignancies such as leukemia (including chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, and chronic myeloid leukemia), multiple myeloma, lymphoid malignancies (such as lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma), myelodysplastic syndrome, and solid tumors such as cancer, sarcoma and its metastases, such as breast cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, bronchioloalveolar carcinoma), central nervous system tumors (such as glioma, embryonal neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, and teratoma), gastrointestinal cancer (such as gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, pancreatic cancer), skin cancer, melanoma, thyroid cancer, bone cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma (such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, gastrointestinal tissue cancer, gastrointestinal stromal tumor, Kaposi's sarcoma), and pediatric cancer (such as rhabdomyosarcoma and neuroblastoma), for the use according to claim 18.

20.

20. The ATR kinase-related diseases are selected from lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcoma, head and neck cancer, central nervous system tumors and their metastases, and acute myeloid leukemia, for the use according to claim 19.

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