A compound which is a casein kinase inhibitor

Abstract

This disclosure provides casein kinase inhibitors or pharmaceutically acceptable salts thereof. Corresponding compositions, treatment methods, and intermediates are also provided.

Description

Background Technology

[0001] The biological clock links our daily sleep and activity cycles to the external environment. Circadian rhythm disorders are associated with many human diseases, including depression, seasonal affective disorder (SAD), and metabolic disorders. For example, the biological clock can regulate a variety of downstream rhythms, such as sleep and wakefulness, body temperature, and hormone secretion (Ko and Takahashi, Hum Mol Gen 15: R271–R277). Furthermore, diseases such as depression, SAD, and metabolic disorders may have circadian rhythm origins (Barnard and Nolan, PLoS Genet. May 2008; 4(5): e1000040).

[0002] Casein kinase (CK) is a closely related serine-threonine protein kinase that acts as a key clock regulator, significantly altering circadian rhythms. CK inhibitors have been needed in the treatment of diseases. Summary of the Invention

[0003] This invention discloses a series of compounds as effective inhibitors of casein kinase.

[0004] On the one hand, the present invention provides a compound having the structure of formula (I),

[0005]

[0006] Or a pharmaceutically acceptable salt, or its prodrug, or a solvate or hydrate of any of the foregoing substances.

[0007] In this case, each A and B independently selects any arbitrarily substituted C6-C. 14 The group consisting of aryl and optionally substituted C2-C9 heteroaryl groups;

[0008] Each dashed line (---) represents a single or double bond, X 1 X 2 X 3 X 4 X 5 and X 6 Each group is independently selected from C, N, and substituted CH; R 1Choose from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl groups and optionally substituted (C1-C9) heteroaryl groups;

[0009] R 2 Choose from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted sulfur, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocycle, optionally substituted (C6-C 10 The group consisting of aryl groups and optionally substituted (C1-C9) heteroaryl groups.

[0010] Or R 1 and R 2 They combine with the atoms they are attached to to form optionally substituted rings;

[0011] Each R 3 R 4 and R 5 Independently empty or independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups,

[0012] Or R 3 and R 4 The atoms bonded to them combine to form optionally substituted rings.

[0013] Or R 3 and R 5 The atoms bonded to them combine to form optionally substituted rings.

[0014] Or R 4 and R 5 The atoms connected to them combine to form optionally substituted rings.

[0015] In some embodiments, B is an optionally substituted C2-C9 heteroaryl group.

[0016] In some embodiments, B is selected from the group consisting of optionally substituted pyrazoles, optionally substituted imidazoles, optionally substituted thiophenes, optionally substituted pyrroles, and optionally substituted triazoles.

[0017] In some embodiments, B is an optionally substituted imidazole.

[0018] In some embodiments, wherein the B is one or more R 6 Replace, each R 6 Independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups.

[0019] In some implementations, each R 6 It is independently selected from the group consisting of hydrogen, halogen, =O, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) acyl and optionally substituted amino groups.

[0020] In some embodiments, each R 6 The group consisting of arbitrarily substituted methyl groups, arbitrarily substituted ethyl groups, and arbitrarily substituted isopropyl groups is selected independently.

[0021] In some implementations, wherein the R 6 by one or more R 7 Replace, each R 7 Independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups.

[0022] In some embodiments, wherein the R 7 It is independently selected from the group consisting of hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) acyl, optionally substituted amino and optionally substituted hydroxyl groups.

[0023] In some implementations, wherein the R 7 by one or more R 8 Replace, each R 8 Independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups.

[0024] In some embodiments, wherein the R 8 Independently selected from hydrogen, optionally substituted (C1-C6) alkyl groups, optionally substituted (C3-C6) alkyl groups. 10 The group consisting of a carbocyclic group and optionally substituted (C1-C6) acyl groups.

[0025] In some embodiments, wherein the R 8The group consisting of arbitrarily substituted methyl groups and arbitrarily substituted cyclopropyl groups is selected independently.

[0026] In some implementations, wherein the R 8 by one or more R 9 Replace, each R 9 Independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocycle, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups.

[0027] In some embodiments, wherein the R 9 The group consisting independently of hydrogen, halogens and optionally substituted (C1-C6) alkyl groups.

[0028] In some embodiments, each X 1 and X 2 Choose independently the group composed of C and N.

[0029] In some embodiments, wherein the X 1 For C and the X 2 Let N be the number of elements in the array.

[0030] In some embodiments, the compound has the following structure:

[0031]

[0032] In some embodiments, each R 4 and R 5 Independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ... 10) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups.

[0033] In some embodiments, each R 4 and R 5 The group consisting of hydrogen and halogens is selected independently.

[0034] In some embodiments, wherein the R 4 It is hydrogen and the R 5 It is hydrogen.

[0035] In some embodiments, wherein the R 1 It is an optional substituted (C1-C6) alkyl group.

[0036] In some embodiments, wherein the R 1 The methyl group is optionally substituted.

[0037] In some embodiments, wherein the R 2 It is hydrogen.

[0038] In some embodiments, R 1 and R 2 The atoms bonded to them combine to form an optionally substituted C ring, wherein the C ring is selected from optionally substituted (C3-C) rings. 10 Carbon rings, optionally substituted (C2-C9) heterocycles, optionally substituted (C6-C9) heterocycles 10 The group consists of aryl groups and optionally substituted (C1-C9) heteroaryl groups.

[0039] In some embodiments, the C ring is an optionally substituted (C2-C9) heterocyclic group.

[0040] In some embodiments, the C ring is an optionally substituted piperazine.

[0041] In some embodiments, the C-ring is formed by one or more R-rings. 10 Replace, each R 10 Independently empty or independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ... 10) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups.

[0042] In some embodiments, wherein the R 10 Independently selected from the group consisting of optionally substituted (C1-C6) acyl groups and optionally substituted (C1-C6) alkyl groups.

[0043] In some embodiments, wherein A is an optionally substituted C6-C 14 Aryl.

[0044] In some embodiments, A is an optionally substituted phenyl group.

[0045] In some implementations, the A is controlled by one or more R 11 Replace, each R 11 Independently empty or independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) acyl-substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups.

[0046] In some embodiments, wherein the R 11 It is a halogen.

[0047] In some embodiments, wherein the R 11 It is F.

[0048] On the other hand, this application provides a compound or a pharmaceutically acceptable salt thereof, its prodrug or a metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein the compound is selected from:

[0049]

[0050]

[0051]

[0052] In another aspect, this application provides a composition comprising any compound of formula (I) or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or any of the foregoing solvates or hydrates, and optionally a pharmaceutically acceptable carrier.

[0053] On the other hand, this application provides a method for inhibiting casein kinase (CK) activity, the method comprising administering to a subject in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing substances.

[0054] In some embodiments, the casein kinase (CK) is selected from the group consisting of casein kinase Iα (CK1α), casein kinase Iδ (CK1δ), and casein kinase Iε (CK1ε).

[0055] In some embodiments, the method is selected from the group consisting of in vitro methods, ex vivo methods, and in vivo methods.

[0056] On the other hand, this application provides a method for preventing and / or treating a disease or condition, the method comprising administering to a subject in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug or a metabolite thereof, or a solvate or hydrate of any of the foregoing substances.

[0057] In some embodiments, the disease or symptom is selected from the group consisting of neurological diseases and mental illnesses.

[0058] In some embodiments, the disease or condition is selected from the group consisting of mood disorders, sleep disorders, and circadian rhythm disorders.

[0059] In some implementations, the disease or condition is selected from the group consisting of depression and bipolar disorder.

[0060] Additional aspects and advantages of this disclosure will become apparent to those skilled in the art from the following detailed description, in which only exemplary embodiments of the disclosure are shown and described. As will be appreciated, the disclosure is capable of other and different embodiments, and certain details thereof can be modified in various obvious ways without departing from the disclosure. Accordingly, the accompanying drawings and descriptions of this disclosure should be considered exemplary and not restrictive.

[0061] References merged

[0062] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated by reference. Attached Figure Description

[0063] The novel features of the invention are specifically set forth in the appended claims. The features and advantages of the invention will be better understood by referring to the following detailed description of illustrative embodiments and the accompanying drawings (also referred to as the “Figures”), in which the principles of the invention are employed, wherein:

[0064] like Figures 1 to 29 The synthetic schemes for compounds I-1 to I-29 are described.

[0065] like Figure 30a Figure 30b The synthetic scheme for compound I-30 is described.

[0066] like Figures 31 to 34 Describe the synthetic schemes for compounds I-31 to I-34.

[0067] Detailed description

[0068] While various embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0069] definition

[0070] As used herein, the term "alkyl," whether used alone or in other terms, generally refers to a straight-chain or branched saturated hydrocarbon substituent containing 1 to 20 carbon atoms (i.e., a substituent obtained by removing hydrogen from a hydrocarbon); for example, 1 to 12 carbon atoms; in another example, from 1 to 10 carbon atoms; in another embodiment, 1 to 6 carbon atoms; in yet another embodiment, 1 to 4 carbon atoms (e.g., 1, 2, 3, or more carbon atoms). Examples of such substituents may include, for example, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl, isopentyl, hexyl, etc. In some cases, the number of carbon atoms in a hydrocarbon substituent (i.e., alkyl, alkenyl, cycloalkyl, aryl, etc.) may be determined by the prefix "C". a -C b The symbol “C1-C6 alkyl” indicates that α is the minimum number of carbon atoms in the substituent and β is the maximum number of carbon atoms. Therefore, for example, “C1-C6 alkyl” can refer to an alkyl substituent containing 1 to 6 carbon atoms. The “alkyl” group may optionally be substituted by one or more substituents.

[0071] As used herein, the term "alkenyl," whether used alone or in other terms, generally refers to a straight-chain or branched carbon group having at least one carbon-carbon double bond. The term "alkenyl" may comprise conjugated and non-conjugated carbon-carbon double bonds or combinations thereof. The term "alkenyl," for example, but not limited to, may contain 2 to about 20 carbon atoms, or, in certain embodiments, 2 to about 12 carbon atoms. In embodiments, alkenyl may comprise 2 to about 4 carbon atoms (e.g., 2, 3, or more carbon atoms). Examples of alkenyl include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" comprises groups having "cis" and "trans" orientations, or "E" and "Z" orientations. In some cases, the number of carbon atoms may be indicated by the prefix "C". a -C b The symbol “a” indicates that a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms. The “alkenyl” group may optionally be replaced by one or more substituents.

[0072] As used herein, the term "alkynyl," alone or in other terms, generally refers to a straight-chain or branched carbonyl group having at least one carbon-carbon triple bond. The term "alkynyl" may include conjugated and non-conjugated carbon-carbon triple bonds or combinations thereof. An alkynyl group, for example but not limited to, may contain 2 to about 20 carbon atoms, or in certain embodiments, 2 to about 12 carbon atoms. In embodiments, an alkynyl group may contain 2 to about 10 carbon atoms. Some examples may be alkynyl groups having 2 to about 4 carbon atoms (e.g., 2, 3, or more carbon atoms). In some cases, the number of carbon atoms may be indicated by the prefix "C". a -C b The symbol “” indicates that 'a' is the minimum number of carbon atoms in the substituent and 'b' is the maximum number of carbon atoms. Examples of such groups include propynyl, butynyl, etc. The 'ynyl' group may optionally be substituted by one or more substituents.

[0073] As used herein, the term "amino," alone or in other terms, generally refers to the -NH2 group. The "amino" group may optionally be substituted with one or more substituents.

[0074] As used herein, the term "carbon ring," alone or in other contexts, generally refers to a saturated or unsaturated non-aromatic monocyclic, bicyclic, or polycyclic ring system having 3 to 14 ring atoms (and combinations and sub-combinations of all ranges and specific numbers of carbon atoms therein), wherein all ring atoms are carbon atoms. Monocyclic carbon rings may have 3 to 6 ring atoms, or 5 to 6 ring atoms. Bicyclic carbon rings may have 7 to 12 ring atoms, for example, arranged in bicyclic [4, 5], [5, 5], [5, 6], or [6, 6] systems, or 9 or 10 ring atoms arranged in bicyclic [5, 6] or [6, 6] systems. The term "carbon ring" may include, for example, monocyclic carbon rings fused with aromatic rings (e.g., monocyclic carbon rings fused with benzene rings). Carbon rings may have 3 to 8 carbon ring atoms. In some cases, the number of carbon atoms may be indicated by the prefix "C". a -C b The symbol "b" indicates that a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms. The "carbocyclic" group may optionally be substituted by one or more substituents.

[0075] As used herein, the term "heterocycle," alone or in other terms, generally refers to a monocyclic, bicyclic, or polycyclic ring system having 3 to 14 ring atoms (also called ring members), wherein at least one ring atom in at least one ring may be a heteroatom selected from N, O, P, or S (and all combinations and sub-combinations of the range and specific number of carbon atoms and heteroatoms therein). A heterocycle may have 1 to 4 cyclic heteroatoms independently selected from N, O, P, or S. One or more N, C, or S atoms in the heterocycle may be oxidized. Monocyclic heterocycles may be 3 to 7-membered rings (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S), and bicyclic heterocycles may be 5 to 10-membered rings (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S). Heterocycles containing heteroatoms may be non-aromatic. Unless otherwise stated, the heterocycle is attached to its side group at any heteroatom or carbon atom that produces a stable structure. In some cases, the number of carbon atoms may be indicated by the prefix "C". a -C b The symbol "" indicates that "a" represents the minimum number of carbon atoms in the substituent and "b" represents the maximum number of carbon atoms. The "heterocyclic" group may optionally be substituted by one or more substituents. The number of carbon atoms can be indicated by the prefix "C". a -C b The symbol "" indicates that "a" represents the minimum number of carbon atoms in the substituent and "b" represents the maximum number of carbon atoms. The "heterocyclic" group may optionally be substituted by one or more substituents. The number of carbon atoms can be indicated by the prefix "C". a -C b The symbol "b" indicates that "a" represents the minimum number of carbon atoms in the substituent and "b" represents the maximum number of carbon atoms. The "heterocyclic" group may optionally be substituted by one or more substituents.

[0076] As used herein, the term "aryl," alone or in other contexts, generally refers to an aromatic substituent containing a monocyclic or two- or three-fused rings. Aryl substituents can have 6 to 18 carbon atoms. For example, aryl substituents can have 6 to 14 carbon atoms. The term "aryl" can also refer to substituents such as phenyl, naphthyl, and anthracene. The term "aryl" can also include C4-C... 10 Fused substituents, such as phenyl, naphthyl, and anthracene, are fused to a carbocyclic ring, such as a C5 or C6 carbocyclic ring or a 4- to 10-membered heterocyclic ring, wherein the group having such a fused aryl group as a substituent is bonded to the aromatic carbon of the aryl group. When such a fused aryl group is substituted by one or more substituents, unless otherwise specified, each of the one or more substituents may be bonded to the aromatic carbon of the fused aryl group. Fused C4-C 10 The carbocyclic ring or 4- to 10-membered heterocycle may optionally be substituted. Examples of aryl groups may accordingly include phenyl, naphthyl, tetrahydronaphthyl (also known as "naphthyl"), indenyl, isoindenyl, indenyl, anthracene, phenanthryl, benzonaphthyl (also known as "benzylnaphthyl"), and fluorenyl. In some cases, the number of carbon atoms may be determined by the prefix "C". a -C b The symbol “a” indicates that a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms. The “aryl” group may optionally be replaced by one or more substituents.

[0077] As used herein, "heteroaryl" alone or in other terms generally refers to an aromatic ring structure containing 5 to 14 ring atoms, wherein at least one ring atom is a heteroatom (e.g., oxygen, nitrogen, or sulfur), and the remaining ring atoms are independently selected from carbon, oxygen, nitrogen, and sulfur. Heteroaryl can be a monocyclic ring or a fused ring of 2 or 3 rings. Examples of heteroaryl substituents may include, but are not limited to: 6-membered ring substituents, such as pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents, such as triazolyl, imidazolyl, furanyl, thiophene, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6 / 5-membered fused ring substituents, such as benzothiofuranyl, isobenzothiofuranyl, benzoisoxazolyl, benzoxazolyl, purinyl, and anthraceneyl; and quinolinyl, isoquinolinyl, cinnamyl, quinazolinyl, 1,4-benzoxazinyl, and other 6 / 6-membered fused ring substituents. In a group having a heteroaryl substituent, the ring atom of the heteroaryl substituent bonded to that group may contain at least one heteroatom, or it may be a carbon ring, wherein the carbon ring may be in the same ring as at least one heteroatom or wherein the ring carbon atom may be in a different ring from at least one heteroatom. Similarly, if the heteroaryl substituent is subsequently replaced by a group or substituent, then that group or substituent may be bonded to at least one heteroatom, or it may be bonded to a ring carbon atom, wherein the ring carbon atom may be in the same ring as at least one heteroatom or wherein the ring carbon atom may be in a different ring from at least one heteroatom. In some cases, the number of carbon atoms may be determined by the prefix "C". a -C b The symbol “a” indicates that a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms. The “heteroaryl” group may optionally be substituted by one or more substituents.

[0078] As used herein, the term "halogen," alone or in other terms, generally refers to fluorine (which may be represented as -F), chlorine (which may be represented as -Cl), bromine (which may be represented as -Br), or iodine (which may be represented as -I). In one embodiment, the halogen may be chlorine. In another embodiment, the halogen may be fluorine. In yet another embodiment, the halogen may be bromine.

[0079] As used herein, the term "cyano", alone or in other terms, generally refers to the -CN group.

[0080] As used herein, the term "nitro" alone or in other terms generally refers to the -NO2 group.

[0081] As used herein, the term "hydroxyl group," alone or in other terms, generally refers to the -OH group. The "hydroxyl group" may optionally be substituted by one or more substituents.

[0082] As used herein, the term "phosphorus-containing group," alone or in other terms, generally refers to a functional group containing one or more phosphorus atoms. Phosphorus-containing groups may refer to -OP-(OH)2, -O-PH-(OH), -O-PH2, -P-(OH)2, -PH-(OH), -PH4, -PH2=CH2, -CH=PH3, -OP(=O)2, -OP(=O)-(OH)2, -O-PH(=O)-OH, -P(=O)-(OH)2, -O-PH2(=O), -PH(=O)-OH, -PH2(=O), -OP(=O)(OH)-P(=O)(OH)2, -OP(=O)(OH)-OP(=O)(OH)2, -PH-PH2, or -P=PH. A "phosphorus-containing group" may optionally be substituted with one or more substituents.

[0083] As used herein, the term "silicon-containing group," alone or in other terms, generally refers to a functional group containing one or more silicon atoms. A silicon-containing group may refer to -SiH3. A "silicon-containing group" may optionally be substituted with one or more substituents.

[0084] As used herein, the term "thio" (or, alone or in other terms, generally refers to the -SH group). A "thio" group may optionally be substituted with one or more substituents.

[0085] As used herein, the term "carboxyl" alone or in other terms generally refers to the -C(=O)OH group. The "carboxyl" group may optionally be substituted by one or more substituents.

[0086] As used herein, the term "sulfonyl" (or, alone or in other terms, generally refers to a group of the formula -S(=O)2-H). The "sulfonyl" group may optionally be substituted with one or more substituents.

[0087] As used herein, the term "sulfinyl" (or, alone or in other terms) generally refers to the -S(=O)-H group. The "sulfinyl" group may optionally be substituted with one or more substituents.

[0088] As used herein, the term "acyl," alone or in other terms, generally refers to a carboxylic acid ester of the formula -C(O)R, wherein the non-carbonyl portion (i.e., R) of the ester group may be selected from a straight-chain, branched, or cyclic alkyl group. The term acyl may include, but is not limited to, acetyl, propionyl, butyryl, and valeryl. In some cases, the number of carbon atoms may be determined by the prefix "C". a -C b The symbol “a” indicates that a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms. The “acyl” group may optionally be replaced by one or more substituents.

[0089] As used herein, the term "thioacyl," alone or in other terms, generally refers to the formula -C(S)R, where the ester group portion (i.e., R) may be selected from a straight-chain, branched, or cyclic alkyl group. In some cases, the number of carbon atoms may be determined by the prefix "C". a -C b The symbol “b” indicates that a is the minimum number of carbon atoms in the substituent and b is the maximum number of carbon atoms. The “thioacyl” group may optionally be replaced by one or more substituents.

[0090] As used herein, the term "ring," alone or in other terms, generally refers to any covalently closed structure. Rings can include, for example, carbocyclic, heterocyclic, aryl, and heteroaryl rings. Rings can be monocyclic or polycyclic. The "ring" group may optionally be substituted by one or more substituents.

[0091] As used herein, unless otherwise stated, the term "treatment" generally refers to reversing, slowing the progression of, or preventing a disease or condition to which the term applies, or one or more symptoms of that disease or condition. Unless otherwise stated, the term "treatment" as used herein generally refers to therapeutic actions, as defined above. The term "treatment" may also include adjunctive and neoadjunctive therapies for the subject.

[0092] As used herein, unless otherwise stated, the term "prevention" generally refers to the exclusion, avoidance, elimination, prevention, cessation, or obstruction of something from happening, especially through proactive action. It is understood that the terms "reduce," "inhibit," or "prevent" are used herein, and the use of the other two terms may be explicitly stated unless otherwise specified.

[0093] As used herein, the term "pharmaceutically acceptable salt" generally refers to a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts may include: acid addition salts formed with inorganic or organic acids, or base addition salts formed with the conjugate base of any inorganic acid, wherein the conjugate base comprises a cationic component.

[0094] As used herein, the term "pharmaceutically acceptable carrier" generally refers to aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders intended for reconstitution into sterile injectable solutions or dispersions prior to use. Acceptable aqueous and non-aqueous carriers, diluents, solvents, or excipients may include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters, such as ethyl oleate. To maintain appropriate flowability, for example, this can be achieved by using coating materials such as lecithin, maintaining the desired particle size in the case of dispersions, and by using surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. Microbial protection can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. Isotonic agents, such as sugars, sodium chloride, etc., may also be required. Absorption of injectable drug forms can be prolonged by including agents that delay absorption, such as aluminum monostearate and gelatin. Injectable reservoir forms can be prepared by forming microcapsule matrices of drugs in biodegradable polymers such as polylactide-polyglycoli, poly(orthoester), and poly(anhydride). The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Long-acting injectable formulations can also be prepared by encapsulating the drug in tissue-compatible liposomes or microemulsions. Injectable formulations can be sterilized, for example, by filtration through a bacterial trap or by incorporating a sterilizing agent into a sterile solid composition, which can then be dissolved or dispersed in sterile water or other sterile injectable media prior to use. Suitable inert carriers may include sugars, such as lactose. Ideally, at least 95% by weight of the active ingredient particles may have an effective particle size in the range of 0.01 to 10 micrometers.

[0095] As used herein, the term "prodrug" generally refers to a compound that is metabolized in a host, such as by hydrolysis or oxidation, to form the compounds of the present invention. Typical examples of prodrugs may include compounds having a biologically unstable protecting group on the functional moiety of the active compound. Prodrugs may include compounds that can be oxidized, reduced, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, dealkylation, phosphorylation, or dephosphorylation to produce the active compound.

[0096] As used herein, the term "casein kinase" generally refers to a protein that has the activity of catalyzing the selective phosphorylation of serine / threonine residues in proteins. This activity may be referred to as "casein kinase activity." The gene ID of the gene encoding casein kinase may be 1453 or 1454.

[0097] As used herein, the term "subject" generally refers to an animal, which may include, but is not limited to, cattle, pigs, sheep, chickens, turkeys, buffalo, llamas, ostriches, dogs, cats, and humans, and a subject may be a person. It is contemplated that the method of treating the subject in the sixth embodiment may be any compound, alone or in combination with another compound of the present invention.

[0098] As used herein, the term "effective amount" generally refers to the amount of a drug or compound administered to treat a disease or condition, some or all of its symptoms. The result may be a reduction and / or relief of the signs, symptoms, or cause of the disease or condition, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition including the compounds disclosed herein that is required to clinically significantly reduce the symptoms of a disease or condition without excessive adverse side effects.

[0099] As used herein, the term “application” generally means that a compound can be administered by any suitable route, such as oral, parenteral, intravenous, intradermal, subcutaneous, or topical, in liquid or solid form.

[0100] As used herein, a substituent is “substitutable” or may be “substituted” if it contains at least one atom bonded to one or more hydrogen atoms. If a substituent is described as “substituted,” then a hydrogen or non-hydrogen substituent replaces a hydrogen substituent on an atom of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one hydrogen or non-hydrogen substituent replaces a hydrogen substituent on an alkyl substituent. For illustration, a monofluoroalkyl group is an alkyl group substituted with a fluorine substituent, while a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It should be recognized that if a substituent has more than one substitution, each substituent may be the same or different (unless otherwise stated).

[0101] If substituents are described as being "selected independently" from a set, then each substituent can be selected independently of the other substituents. Therefore, each substituent can be the same as or different from the other substituents.

[0102] As used herein, the term "optionally substituted" generally means that a given portion may consist only of hydrogen substituents (unsubstituted) by available valences, or may further contain one or more non-hydrogen substituents (substituted) by available valences, unless otherwise specified by the name of the given portion. For example, "R x "Optional replacement" or R x Optionally R y "Replace" can mean R x It can be represented by 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 R's. y Replacement, for example, R x It can be 0, 1, 2, 3, 4 or 5 R's. yReplacement, for example, R x It can be 1, 2 or 3 Rs y Replacement, for example, R x It can be an R y Replacement, for example, R x Can be 2 R y Replacement, for example, R x It can be 3 Rs y Replacement, for example, R x It can be replaced by 4 Ry, for example, at R x It can be 5 Rs y Replacement, for example, R x It can be 6 Rs y Replacement, for example, R x It can be 7 Rs y Replacement, for example, R x It can be 8 R y Replacement, for example, R x It can be 9 Rs y Substitution. Generally, non-hydrogen substituents can be any substituent that can combine with an atom of a given moiety to be substituted. Examples of substituents include, but are not limited to, hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, trifluoromethyl, hydroxyl, phosphorus-containing groups, silicon-containing groups, thio, amino, carboxyl, sulfonyl, sulfinyl, (C1-C6) acyl, (C1-C6) thioyl, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) ynyl, (C3-C6) alkyl, (C2-C6) alkyne, (C3-C6) alkyl, (C2-C6) alkyne, (C2-C6) alkyl, (C2-C6) alkyl, (C2-C6) alkyl, (C3-C6) alkyl, (C2 ... 10 (C2-C9) heterocyclic group, (C6-C9) heterocyclic group 10 aryl, (C1-C9)heteroaryl, trifluoromethyl (C1-C6)alkyl, cyano (C1-C6)alkyl, halo(C1-C6)alkyl, nitro(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, thio(C1-C6)alkyl, amino(C1-C6)alkylalkylamino, (C1-C6)alkyl2amino, (C1-C6)acyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C3-C 10 (C1-C6) alkyl, (C2-C9) heterocyclic (C1-C6) alkyl, (C6-C 10(C1-C6)alkyl and (C1-C9)heteroaryl (C1-C6)alkyl. Furthermore, the substituent itself may optionally be substituted with other substituents. In one specific embodiment, examples of further substituents include, but are not limited to, hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, trifluoromethyl, hydroxyl, thioyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C9)heteroaryl (C1-C6)alkyl. 10 (C2-C9) heterocyclic group, (C6-C9) heterocyclic group 10 aryl, (C1-C9)heteroaryl, trifluoromethyl (C1-C6)alkyl, cyano (C1-C6)alkyl, halo(C1-C6)alkyl, nitro(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, thio(C1-C6)alkyl, amino(C1-C6)alkylalkylamino, (C1-C6)alkyl2amino, (C1-C6)acyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, hydroxysulfonyl, hydroxysulfinyl, (C3-C 10 (C1-C6) alkyl, (C2-C9) heterocyclic (C1-C6) alkyl, (C6-C 10 ) aryl (C1-C6) alkyl and (C1-C9) heteroaryl (C1-C6) alkyl.

[0103] As used herein, the term "structural formula" may be referred to hereinafter as "the compound of the present invention." Such terms are also defined to include all forms of compounds having the above-described structural formula, including hydrates, solvates, isomers, crystalline and amorphous forms, isomorphs, polymorphs, and their metabolites. For example, compounds having the above-described structural formula or pharmaceutically acceptable salts thereof may exist in both non-solventized and solvated forms. When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, such as in channel solvates and hygroscopic compounds, the water / solvent content may depend on humidity and drying conditions. In this case, non-stoichiometry becomes the norm.

[0104] Compounds having the above-described structural formulas may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds may be depicted herein using solid lines, solid wedges, or dashed wedges. Using solid lines to depict bonds with asymmetric carbon atoms may be intended to indicate the inclusion of all possible stereoisomers of that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.). Using solid or dashed wedges to depict bonds with asymmetric carbon atoms may be intended to indicate that only the stereoisomers shown are intended to be included. The compounds of this application may contain more than one asymmetric carbon atom. In those compounds, using solid lines to depict bonds with asymmetric carbon atoms may be intended to indicate the inclusion of all possible stereoisomers. For example, unless otherwise stated, it may indicate that the compound can exist as an enantiomer and diastereomer or as a racemic mixture and mixtures thereof. Using solid lines to indicate bonds with one or more asymmetric carbon atoms in the compounds of the following formula, and using solid or dashed wedges to indicate bonds with other asymmetric carbon atoms in the same compound, may mean that diastereomers are present in the mixture.

[0105] The compounds of this application (e.g., compounds having the above-described structural formulas) may exist in the form of inclusion compounds or other complexes. Included within the scope of this invention are complexes such as inclusion compounds, drug-host inclusion compounds, wherein, unlike the solvates described above, the drug and host may be present in stoichiometric or non-stoichiometric amounts. Complexes of the following formula may also be included, containing two or more organic and / or inorganic components, which may be stoichiometric or non-stoichiometric. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci., 64(8), 1269-1288 by Haleblian (August 1975).

[0106] Stereoisomers of compounds having the above-described structural formulas may include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers, including compounds exhibiting more than one isomerism; and mixtures thereof (e.g., racemic and diastereomer pairs). They may also include acid addition salts or base addition salts, wherein the counterion is optically active, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine.

[0107] When any racemic compound crystallizes, two different types of crystals are possible. The first type is the racemic compound mentioned above (a true racemate), in which a homogeneous crystal containing equimolar amounts of the two enantiomers is produced. The second type is a racemic mixture or agglomerate, in which the two forms of crystal are produced in equimolar amounts, each containing a single enantiomer.

[0108] Compounds having the above-described structural formulas may exhibit tautomerism and structural isomerism. For example, compounds having the above-described structural formulas can exist in various tautomeric forms, including enols and imines, ketones and enamines, as well as their geometric isomers and mixtures. All of these tautomeric forms can be included within the scope of the compound of formula. Tautomers can exist as mixtures of tautomer groups in solution. In solid form, typically one tautomer is dominant. Although one tautomer may be described, the present invention includes all tautomers of the compound of formula.

[0109] The present invention also includes isotopically labeled compounds, which are the same as those listed in the above formulas, but in which one or more atoms can be replaced by atoms having atomic masses or mass numbers different from atomic masses or mass numbers, which is quite common in nature. Examples of isotopes that can be incorporated into compounds having the above structural formulas include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, but not limited to, isotopes of these elements. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Certain isotope-labeled compounds of the following formula, such as those doped with radioactive isotopes, such as... 3 H and 14 Compounds of C can be used for the determination of drug and / or substrate tissue distribution. Tritiumization, i.e. 3 H, and carbon-14, i.e. 14 C isotopes are particularly suitable due to their ease of preparation and detectability. Additionally, heavier isotopes such as deuterium, i.e., 2 H substitution can provide certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dose requirements, and therefore can be used in certain situations. Isotopically labeled compounds having the above-described structural formula can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents using the procedures disclosed in the embodiments and / or the examples below. For example, this increases the in vivo half-life or reduces the dose requirements, and therefore can be used in certain situations. Isotopically labeled compounds having the above-described structural formula can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents using the procedures disclosed in the embodiments and / or the examples below.

[0110] The compounds of this application can be used in the form of salts derived from inorganic or organic acids. Depending on the specific compound, the salt of the compound may be more advantageous due to one or more physical properties of the salt, such as enhanced drug stability at different temperatures and humidity levels, or desirable solubility in water or oil. In some cases, the salt of the compound can also be used as an aid in the separation, purification, and / or resolution of the compound.

[0111] compound

[0112] On the one hand, this application provides a compound having the structure of formula (I),

[0113]

[0114] Or a pharmaceutically acceptable salt, or its prodrug, or a solvate or hydrate of any of the foregoing substances.

[0115] in,

[0116] Each A and B can independently choose any arbitrarily substituted C6-C. 14 The group consisting of aryl and optionally substituted C2-C9 heteroaryl groups;

[0117] Each dashed line (---) represents a single or double bond, and each X 1 X 2 X 3 X 4 X 5 and X 6 It can be independently selected from groups consisting of C, N, and arbitrarily substituted CH;

[0118] R 1 Optionally free of hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocycle, optionally substituted (C6-C 10 The group consisting of aryl groups and optionally substituted (C1-C9) heteroaryl groups;

[0119] R 2Optionally free of hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl. 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl groups and optionally substituted (C1-C9) heteroaryl groups.

[0120] Or R 1 and R 2 They combine with the atoms they are attached to to form optionally substituted rings;

[0121] Each R 3 R 4 and R 5 It can be empty independently or can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocycle, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups, or R 3 and R 4 The atoms to which they are attached can combine to form optionally substituted rings, or R... 3 and R 5 The atoms bonded to them can combine to form optionally substituted rings.

[0122] Or R 4 and R 5 They can combine with the atoms they are attached to to form rings with optional substitutions.

[0123] In some embodiments, B may be an optionally substituted C2-C9 heteroaryl group.

[0124] In some embodiments, B may be selected from the group consisting of substituted pyrazoles, substituted imidazoles, substituted thiophenes, substituted pyrroles, and substituted triazoles.

[0125] In some embodiments, B may be an optionally substituted imidazole.

[0126] In some embodiments, B can be one or more R 6 Replace, each R 6 It can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkenyl. 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 ) aryl and optionally substituted (C1-C9) heteroaryl groups. For example, B can be substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 R groups. 6 Replacement. For example, B can be replaced by 1, 2, 3, 4, or 5 Rs. 6 Replacement. For example, B can be replaced by 1, 2, or 3 R. 6 Replacement. For example, B can be replaced by an R. 6 Replacement. For example, B can be replaced by 2 R. 6 Replacement. For example, B can be replaced by 3 Rs. 6 replace.

[0127] In some embodiments, each R 6 It can be independently selected from the group consisting of hydrogen, halogen, =O, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) acyl and optionally substituted amino groups.

[0128] In some embodiments, each R 6 It can be independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted isopropyl groups.

[0129] In some embodiments, B may be an optionally substituted imidazole, and B may be substituted with one or more R 6 Replace, each R 6 It can be independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted isopropyl groups.

[0130] In some embodiments, each R 6Can be independently controlled by one or more R 7 Replace, each R 7 It can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups. For example, R 6 It can be represented by 1, 2, 3, 4, 5, 6, 7, 8, or 9 R's. 7 Replacement. For example, R 6 It can be 1, 2, 3, 4 or 5 R's. 7 Replacement. For example, R 6 It can be 1, 2 or 3 Rs 7 Replacement. For example, R 6 It can be an R 7 Replacement. For example, R 6 Can be 2 R 7 Replacement. For example, R 6 It can be 3 Rs 7 replace.

[0131] In some embodiments, each R 7 It may be independently selected from the group consisting of hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) acyl, optionally substituted amino and optionally substituted hydroxyl groups.

[0132] In some embodiments, B may be an optionally substituted imidazole, and B may be substituted with one or more R 6 Replace, each R 6 It can be independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted isopropyl groups, each R 6 It can be independently replaced for one or more R. 7 Each R 7 It may be independently selected from the group consisting of hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) acyl, optionally substituted amino and optionally substituted hydroxyl groups.

[0133] In some embodiments, each R 7 Can be independently controlled by one or more R8 Replace, each R 8 It can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups. For example, R 7 It can be represented by 1, 2, 3, 4, 5, 6, 7, 8, or 9 R's. 8 Replacement. For example, R 7 It can be 1, 2, 3, 4 or 5 R's. 8 Replacement. For example, R 7 It can be 1, 2 or 3 Rs 8 Replacement. For example, R 7 It can be an R 8 Replacement. For example, R 7 Can be 2 R 8 Replacement. For example, R 7 It can be 3 Rs 8 replace.

[0134] In some embodiments, each R 8 It can be independently selected from the group of hydrogens, optionally substituted (C1-C6) alkyl groups, optionally substituted (C3-C6) alkyl groups, and optionally substituted (C3-C6) alkyl groups. 10 The group consisting of a carbocyclic group and optionally substituted (C1-C6) acyl groups.

[0135] In some embodiments, each R 8 It can be independently selected from the group consisting of optionally substituted methyl groups and optionally substituted cyclopropyl groups.

[0136] In some embodiments, B may be an optionally substituted imidazole, and B may be substituted with one or more R 6 Replace, each R 6 It can be independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted isopropyl groups, each R 6 It can be independently replaced by one or more R. 7 Together, every R 7It may be independently selected from the group consisting of hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)acyl, optionally substituted (C1-C6)thioacyl, optionally substituted amino, and optionally substituted hydroxyl, each R 7 Can be independently controlled by one or more R 8 Replace, each R 8 It can be independently selected from the group consisting of optionally substituted methyl groups and optionally substituted cyclopropyl groups.

[0137] In some embodiments, each R 8 Can be independently controlled by one or more R 9 Replace, each R 9 It can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 ) aryl and optionally substituted (C1-C9) heteroaryl groups. For example, R 8 It can be represented by 1, 2, 3, 4, 5, 6, 7, 8, or 9 R's. 9 Replacement. For example, R 8 It can be 1, 2, 3, 4 or 5 R's. 9 Replacement. For example, R 8 It can be 1, 2 or 3 Rs 9 Replacement. For example, R 8 It can be an R 9 Replacement. For example, R 8 Can be 2 R 9 Replacement. For example, R 8 It can be 3 Rs 9 replace.

[0138] In some embodiments, each R 9 It can be independently selected from the group consisting of hydrogen, halogens and optionally substituted (C1-C6) alkyl groups.

[0139] In some embodiments, B may be an optionally substituted imidazole, and B may be substituted with one or more R 6 Replace, each R 6 It can be independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted isopropyl groups, each R6 It can be independently replaced by one or more R. 7 Together, every R 7 It may be independently selected from the group consisting of hydrogen, optionally substituted (C1-C6)alkyl, optionally substituted (C1-C6)acyl, optionally substituted (C1-C6)thioacyl, optionally substituted amino, and optionally substituted hydroxyl, each R 7 Can be independently controlled by one or more R 8 Replace, each R 8 Each R can be independently selected from the group consisting of optionally substituted methyl groups and optionally substituted cyclopropyl groups. 8 Can be independently controlled by one or more R 8 Replace for more R 9 Each R 9 It can be independently selected from the group consisting of hydrogen, halogens and optionally substituted (C1-C6) alkyl groups.

[0140] In some embodiments, each X 1 and X 2 It can be independently selected from the groups composed of C and N.

[0141] In some embodiments, X 1 It can be C and X 2 It can be N. In some embodiments, X 1 It can be N and X 2 It can be C. In some embodiments, X 1 It can be C and X 2 It can be C. In some embodiments, X 1 It can be NX 2 It can be N.

[0142] In some embodiments, the compound has a structure selected from the following:

[0143]

[0144] In some embodiments, each R 4 and R 5 It can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ... 10) carbocyclic group, optionally substituted (C2-C9) heterocycle, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups.

[0145] In some embodiments, each R 4 and R 5 It can be independently selected from groups composed of hydrogen and halogens.

[0146] In some embodiments, R 4 It can be hydrogen and R 5 It can be hydrogen. In some embodiments, R 4 It can be hydrogen and R 5 It can be F or Cl.

[0147] In some embodiments, R 1 It can be an optional substituted (C1-C6) alkyl group.

[0148] In some embodiments, R 1 The methyl group may be optionally substituted.

[0149] In some embodiments, R 2 It can be hydrogen.

[0150] In some embodiments, R 1 and R 2 The atoms bonded to them combine to form an optionally substituted C ring, which may be freely substituted (C3-C) 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups.

[0151] In some embodiments, the C ring may be an optionally substituted (C2-C9) heterocycle.

[0152] In some embodiments, the C ring may be an optionally substituted piperazine.

[0153] In some embodiments, the C-ring can be one or more R 10 Replace, each R 10 It may be empty independently or may be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ...10 ) carbocyclic group, optionally substituted (C2-C9) heterocycle, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups. For example, the C ring can be composed of 1, 2, 3, 4, 5, 6, 7, 8, or 9 R groups. 10 Replacement. For example, a C-ring can be replaced by 1, 2, 3, 4, or 5 R-rings. 10 Replacement. For example, a C-ring can be replaced by 1, 2, or 3 R-rings. 10 Replacement. For example, a C-ring can be replaced by an R-ring. 10 Replacement. For example, a C-ring can be replaced by two R-rings. 10 Replacement. For example, a C-ring can be replaced by 3 R-rings. 10 replace.

[0154] In some embodiments, each R 10 It can be independently selected from the group consisting of optionally substituted (C1-C6) acyl groups and optionally substituted (C1-C6) alkyl groups.

[0155] In some embodiments, A may be an optional alternative to C6-C. 14 Aryl.

[0156] In some embodiments, A may be an optionally substituted phenyl group.

[0157] In some implementations, A can be one or more R 11 Replace, each R 11 It can be empty independently or can be independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, =S, =O, N3, optionally substituted hydroxyl, optionally substituted phosphorus-containing group, optionally substituted silicon-containing group, optionally substituted thio, optionally substituted amino, optionally substituted carboxyl, optionally substituted sulfonyl, optionally substituted sulfinyl, optionally substituted (C1-C6) acyl, optionally substituted (C1-C6) acyl-substituted (C1-C6) thioacyl, optionally substituted (C1-C6) alkyl, optionally substituted (C2-C6) alkenyl, optionally substituted (C2-C6) ynyl, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyne, optionally substituted (C3-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C2-C6) alkyl, optionally substituted (C3-C6) alkyl, ... 10 ) carbocyclic group, optionally substituted (C2-C9) heterocyclic group, optionally substituted (C6-C 10 The group consisting of aryl and optionally substituted (C1-C9) heteroaryl groups. For example, A can be composed of 1, 2, 3, 4, 5, 6, 7, 8, or 9 R groups. 11 Replacement. For example, A can be replaced by 1, 2, 3, 4, or 5 R's. 11 Replacement. For example, A can be replaced by 1, 2, or 3 R. 11 Replacement. For example, A can be replaced by an R. 11 Replacement. For example, A can be replaced by 2 R. 11Replacement. For example, A can be replaced by 3 R. 11 replace.

[0158] In some embodiments, each R 11 It can be halogenated independently. In some embodiments, each R 11 It can be either F or Cl.

[0159] In some embodiments, each R 11 It can be F independently.

[0160] In some embodiments, A may be an optionally substituted phenyl group, and A may be substituted by one or more R groups. 11 Replace, each R 11 It can be F independently.

[0161] In some embodiments, this application provides a compound having the structure of formula (III),

[0162]

[0163] B can be an optionally substituted imidazole, and B can be substituted by one or more R 6 Replace, each R 6 It can be independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted isopropyl groups, each R 6 R can be independently replaced by one or more 7 Each R 7 It may be independently selected from the group consisting of hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) acyl, optionally substituted amino, and optionally substituted hydroxyl groups, each R 7 Can be independently controlled by one or more R 8 Replace, each R 8 Each R can be independently selected from the group consisting of optionally substituted methyl groups and optionally substituted cyclopropyl groups. 8 Can be independently controlled by one or more R 9 Replace, each R 9 R can be independently selected from the group consisting of hydrogen, halogens, and optionally substituted (C1-C6) alkyl groups. 4 It can be hydrogen and R 5 It can be hydrogen, R 1 Optional substituted methyl group, R 2 A can be hydrogen, A can be an optionally substituted phenyl group, and A can be substituted by one or more R groups. 11 Replace, R 11 It can be F.

[0164] In some embodiments, this application provides a compound having the structure of formula (III),

[0165]

[0166] B can be an optionally substituted imidazole, and B can be substituted by one or more R 6 Replace, each R 6 It can be independently selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally substituted isopropyl groups, each R 6 R can be independently replaced by one or more 7 Each R 7 It can be independently selected from the group consisting of optionally substituted amino groups and optionally substituted hydroxyl groups, R 4 It can be hydrogen and R 5 It can be hydrogen, R 1 The methyl group can be optionally substituted, R 2 A can be hydrogen, A can be an optionally substituted phenyl group, and A can be substituted by one or more R groups. 11 Replace, R 11 It can be F.

[0167] In some cases, the compound can be one of the compounds in Table 1.

[0168] Table 1

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178] Medical use

[0179] On one hand, this application provides a method for inhibiting casein kinase (CK) activity, the method comprising administering to a subject in need an effective amount of the compound of this application or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or any of the aforementioned solvates or hydrates. For example, the casein kinase (CK) may be selected from the group consisting of casein kinase Iα (CK1α), casein kinase Iδ (CK1δ), and casein kinase Iε (CK1ε). For example, the method may be selected from the group consisting of in vitro methods, ex vivo methods, and in vivo methods.

[0180] In another embodiment, this application provides the compound of this application or a pharmaceutically acceptable salt thereof, its prodrug or metabolite thereof, or a solvate or hydrate of any of the foregoing substances of this application in the preparation of a medicament and / or a kit for inhibiting casein kinase (CK) activity. For example, casein kinase (CK) may be selected from the group consisting of casein kinase Iα (CK1α), casein kinase Iδ (CK1δ), and casein kinase Iε (CK1ε). For example, the method may be selected from the group consisting of in vitro methods, ex vivo methods, and in vivo methods.

[0181] In another embodiment, this application provides a compound of this application or a pharmaceutically acceptable salt thereof, a prodrug thereof or a metabolite thereof, or a solvate or hydrate of any of the foregoing substances of this application, for inhibiting casein kinase (CK) activity. For example, casein kinase (CK) may be selected from the group consisting of casein kinase Iα (CK1α), casein kinase Iδ (CK1δ), and casein kinase Iε (CK1ε). For example, the method may be selected from the group consisting of in vitro methods, ex vivo methods, and in vivo methods.

[0182] On the other hand, this application provides a method for preventing and / or treating a disease or condition, the method comprising administering to a subject in need an effective amount of the compound of this application or a pharmaceutically acceptable salt thereof, its prodrug, its metabolite, or a solvate or hydrate of any of the foregoing substances. For example, the disease or condition may be selected from the group consisting of neurological diseases and mental illnesses. For example, the disease or condition may be selected from the group consisting of mood disorders, sleep disorders, and circadian rhythm disorders. For example, the disease or condition may be selected from the group consisting of depression and bipolar disorder.

[0183] In another embodiment, this application provides the preparation of medicaments and / or combinations thereof for the prevention and / or treatment of diseases or conditions using the compounds of this application or their pharmaceutically acceptable salts, their prodrugs or metabolites, or solvates or hydrates of any of the foregoing substances of this application. For example, diseases or conditions may be selected from the group consisting of neurological diseases and mental illnesses. For example, diseases or conditions may be selected from the group consisting of mood disorders, sleep disorders, and circadian rhythm disorders. For example, diseases or conditions may be selected from the group consisting of depression and bipolar disorder.

[0184] In another embodiment, this application provides the compound of this application or its pharmaceutically acceptable salt, its prodrug or metabolite, or a solvate or hydrate of any of the foregoing substances of this application, for the prevention and / or treatment of diseases or conditions. For example, the diseases or conditions may be selected from the group consisting of neurological diseases and mental illnesses. For example, the diseases or conditions may be selected from the group consisting of mood disorders, sleep disorders, and circadian rhythm disorders. For example, the diseases or conditions may be selected from the group consisting of depression and bipolar disorder.

[0185] In another embodiment, this application provides a composition comprising a compound of the application or a pharmaceutically acceptable salt thereof, its prodrug or metabolite thereof, or any of the foregoing solvates or hydrates, and optionally a pharmaceutically acceptable carrier.

[0186] The compounds of this application can be administered orally. Oral administration may include swallowing, thereby allowing the compounds to enter the gastrointestinal tract, or it may be administered orally or sublingually, allowing the compounds to enter the bloodstream directly through the mouth.

[0187] In some cases, the compounds of this application may also be administered directly to the blood, muscle, or internal organs. Suitable methods of parenteral administration may include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​substernal, intracranial, intramuscular, and subcutaneous injection. Suitable devices for parenteral administration may include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0188] The compounds of this application can also be administered topically to the skin or mucous membranes, i.e., transdermal or dermal administration. In some cases, the compounds of this application can also be administered intranasally or by inhalation. In some cases, the compounds of this application can be administered rectally or vaginally. In another embodiment, the compounds of this application can also be applied directly to the eyes or ears.

[0189] Dosing regimens for compounds and / or compositions containing compounds are based on a variety of factors, including patient type, age, weight, sex, and medical condition; severity of the condition; route of administration; and the activity of the specific compound used. Therefore, dosage regimens can vary considerably. Dosage levels of approximately 0.01 mg to approximately 100 mg per kilogram of body weight per day may be used to treat the conditions described above.

[0190] This invention is applicable to mammalian subjects. The mammals to which this invention is applicable may include, but are not limited to, canines, felines, bovines, caprines, equines, sheep, suidae, rodents, rabbits, primates, etc., and include mammals in the womb. In one embodiment, humans are suitable subjects. Human subjects can be of any sex and at any developmental stage.

[0191] In another embodiment, this application provides the use of one or more compounds in the preparation of a medicament for treating the conditions described herein.

[0192] For the treatment of the aforementioned conditions, the compounds of this application can be administered as the compound itself. Alternatively, pharmaceutically acceptable salts may be suitable for medical applications due to their greater water solubility relative to the parent compound.

[0193] In another embodiment, this application provides compositions. Such compositions may comprise the compounds of this application present in conjunction with a pharmaceutically acceptable carrier. The carrier may be a solid product, a liquid, or both, and may be formulated with the compound into a unit-dose composition, such as a tablet, which may contain 0.05% to 95% by weight of the active compound. The compounds of this application may be coupled with a suitable polymer as a targeted drug carrier. Other pharmacologically active substances may also be present.

[0194] The compounds of the present invention can be administered via any suitable route, perhaps in the form of a pharmaceutical composition suitable for such a route, and in a dose effective for the intended treatment. The active compounds and compositions can be administered, for example, orally, rectally, parenterally, or topically.

[0195] The compounds of this application can be used alone or in combination with other therapeutic agents to treat various conditions or disease states. The compounds of this application and other therapeutic agents can be administered simultaneously (in the same dosage form or in different dosage forms) or sequentially.

[0196] "Combined" administration of two or more compounds may mean that the two compounds are administered close enough that the presence of one compound alters the biological effect of the other. Two or more compounds can be administered simultaneously, concurrently, or sequentially. Furthermore, simultaneous administration can be achieved by mixing the compounds before administration or by administering the compounds at the same time point but at different anatomical sites or using different routes of administration.

[0197] The terms "simultaneous administration," "co-administration," "combined administration," and "simultaneous administration" can mean that the compounds are administered in combination. Example

[0198] The following examples are provided to provide a complete disclosure and description of how to make and use the invention to those skilled in the art, and are not intended to limit the scope of the inventors' invention, nor are they intended to represent that the following experiments were all or only the experiments performed. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and deviations should be taken into account. Unless otherwise stated, parts are parts by weight, molecular weight is the weight average molecular weight, temperature is in degrees Celsius, and pressure is atm or near atm. Standard abbreviations may be used, such as bp, base pairs; kb, kilobase pairs; pl, picoliter; s or sec, seconds; min, minutes; h or hr, hours; aa, amino acids; nt, nucleotides; im, intramuscular injection; ip, intraperitoneal injection; sc, subcutaneous injection; etc.

[0199] Example 1: Preparation of the compound

[0200] Example 1-1 Preparation of Compound I-1

[0201] Figure 1 The synthetic scheme for compound I-1 is described. For example... Figure 1 As shown, the specific synthesis steps are as follows:

[0202] Step 1:

[0203] Under a nitrogen atmosphere, Pd(dppf)Cl2-CH2Cl2 (53.05 mg, 0.065 mmol, 0.10 equivalent) and Cs2CO3 (636.49 mg, 1.953 mmol, 3.00 equivalent) were added in portions to a stirred mixture of 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole (236.11 mg, 1.20 equivalent) and 7-chloropyrazolo[1,5-a]pyrimidine (100.00 mg, 0.651 mmol, 1.00 equivalent) in DMF (2.00 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA to give 3-(4-fluorophenyl)-1-methyl-4-[pyrazolo[1,5-a]pyrimidin-7-yl]pyrazole (68 mg, 35.60%), a white solid. LC / MS (ESI, m / z): [(M+1)] + =294.1. 1H NMR (300MHz, CDCl3) δ8.46 (dd, J=7.3, 0.9Hz, 1H), 8.10 (d, J=2.3Hz, 1H), 8.05 (s,1H),7.60–7.50(m,2H),7.19–7.08(m,2H),6.65–6.57(m,2H),4.02(s,3H).

[0204] Example 1-2 Preparation of compound I-2

[0205] Figure 2 The synthetic scheme for compound I-2 is described. For example... Figure 2 As shown, the specific synthesis steps are as follows:

[0206] Step 1:

[0207] Under a nitrogen atmosphere, 3-(4-fluorophenyl)-4-[imidazo[1,2-b]pyridazin-8-yl]-1-methylpyrazole (50 mg, 0.17 mmol, 1.0 equivalent) and NBS (32 mg, 0.18 mmol, 1.1 equivalent) were stirred in CHCl3 (1.00 mL) at 60 °C for 30 min. The resulting mixture was diluted with saturated Na2CO3 aqueous solution (10 mL). The resulting mixture was extracted with CHCl3 (3 × 10 mL). The combined organic layers were washed with brine (2 × 25 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residues were purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile and aqueous solution, gradient from 5% to 95% over 20 min; detector, UV 254 nm. The fraction containing the desired product was concentrated to give 4-[3-bromoimidazolo[1,2-b]pyridazin-8-yl]-3-(4-fluorophenyl)-1-methylpyrazole (43.8 mg, 69%), as a white solid. 1 H NMR (300MHz, CDCl3) δ 8.70 (s, 1H), 8.22 (d, J = 5.0 Hz, 1H), 7.78 (s, 1H), 7.53-7.46 (m, 2H), 7.15-7.07 (m, 2H), 6.78 (d, J = 5.0Hz, 1H), 4.03 (s, 3H). LC / MS (ESI, m / z): [(M+1)] + =372,374.

[0208] Preparation of compound I-3 in Examples 1-3

[0209] Figure 3 The synthetic scheme for compound I-3 is described. For example... Figure 3 As shown, the specific synthesis steps are as follows:

[0210] Step 1:

[0211] 3-(4-fluorophenyl)-1-methyl-4-[thieno[3,2-b]pyridin-7-yl]pyrazole (20 mg, 0.07 mmol, 1.0 equivalence) and m-CPBA (17 mg, 0.1 mmol, 1.5 equivalence) were stirred in DCM (1 mL) for 16 h at room temperature and under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile, gradient of 5% to 40% over 20 min; detector, UV 254 nm. The fraction containing the desired product was concentrated to give 7-[3-(4-fluorophenyl)-1-methylpyrazole-4-yl]-1λ4-thieno[3,2-b]pyridin-1-one carboxylate (10.7 mg, 45%) as a white solid. 1 H NMR (300MHz, CDCl3) δ8.22(d,J=6.5Hz,1H),7.91(d,J=5.7Hz,1H),7.78(s,1H ),7.68(d,J=5.6Hz,1H)),7.42-7.34(m,2H),7.03-6.95(m,3H),4.05(s,3H). LC / MS(ESI,m / z):[(M+1-FA)] + =326.

[0212] Preparation of compound I-4 in Examples 1-4

[0213] Figure 4 The synthetic scheme for compound I-4 is described. For example... Figure 4 As shown, the specific synthesis steps are as follows:

[0214] Step 1: 8-Bromo-6-chloro-2-methylimidazolium[1,2-b]pyridazine

[0215] Na₂CO₃ (3.1 g, 28 mmol, 3.0 equivalence) was added to a stirred mixture of 4-bromo-6-chloropyridazin-3-amine (2 g, 9.6 mmol, 1.0 equivalence) and bromoacetone (3.9 g, 28 mmol, 3.0 equivalence) in 50 mL of IPA at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1), to give 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (1.6 g, 68%) as a pale yellow solid. 1 HNMR (300MHz, CDCl3) δ7.77(s,1H),7.32(s,1H),2.53(s,3H). LC / MS(ESI,m / z):[(M+1)] +=246,248.

[0216] Step 2: 4-[6-chloro-2-methylimidazo[1,2-b]pyridazin-8-yl]-3-(4-fluorophenyl)-1-methylpyrazole

[0217] Under a nitrogen atmosphere, Cs₂CO₃ (1.3 g, 4.1 mmol, 2.0 equivalence) and Pd(dppf)Cl₂CH₂Cl₂ (165 mg, 0.2 mmol, 0.1 equivalence) were added to a stirred mixture of 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (500 mg, 2 mmol, 1.0 equivalence) and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazole (613 mg, 2 mmol, 1.0 equivalence) in DMF (8 mL). The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give 4-[6-chloro-2-methylimidazo[1,2-b]pyridazin-8-yl]-3-(4-fluorophenyl)-1-methylpyrazole (400 mg, 58%) as a pale yellow solid. 1 HNMR (400MHz, CDCl3) δ8.77(s,1H),7.71(s,1H),7.53-7.48(m,2H),7.16-7.11(m,2H),6.69(s,1H),4.04(s,3H),2.55(s,3H). LC / MS(ESI,m / z):[(M+1)] + =342.

[0218] Step 3:

[0219] 10% Pd / C (25 mg) was added to a stirred mixture of 4-[6-chloro-2-methylimidazo[1,2-b]pyridazin-8-yl]-3-(4-fluorophenyl)-1-methylpyrazole (100 mg, 0.29 mmol, 1.0 equivalent) and TEA (30 mg, 0.29 mmol, 1.0 equivalent) in EA (5 mL) at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 16 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EA (3 x 5 mL). The resulting filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous solution of acetonitrile (ACN) containing 0.1% formic acid (FA), gradient from 5% to 40% over 20 min; detector, UV 254 nm. The fraction containing the desired product was concentrated to give 3-(4-fluorophenyl)-1-methyl-4-[2-methylimidazo[1,2-b]pyridazin-8-yl]pyrazole (17.6 mg, 20%), a white solid. 1 H NMR (300MHz, CDCl3) δ8.70 (s, 1H), 7.99 (d, J = 4.9Hz, 1H), 7.76 (d, J = 0.9Hz, 1H), 7.54-7.47 (m, 2H), 7. 14-7.05(m,2H),6.64(d,J=5.0Hz,1H),4.03(s,3H),2.55(d,J=0.9Hz,3H).LC / MS(ESI,m / z):[(M+1)] + =308.

[0220] Preparation of compound I-5 in Examples 1-5

[0221] Figure 5 The synthetic scheme for compound I-5 is described. For example... Figure 5 As shown, the specific synthesis steps are as follows:

[0222] Step 1: 8-Bromo-6-chloro-2-methylimidazolium[1,2-b]pyridazine

[0223] Na₂CO₃ (3.1 g, 28 mmol, 3.0 equivalent) was added to a stirred mixture of 4-bromo-6-chloropyridazin-3-amine (2 g, 9.6 mmol, 1.0 equivalent) and bromoacetone (3.9 g, 28 mmol, 3.0 equivalent) in 50 mL of IPA at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (1.6 g, 68%) as a pale yellow solid. 1HNMR(300MHz, CDCl3)δ7.77(s,1H),7.32(s,1H),2.53(s,3H).LC / MS(ESI,m / z):[(M+1)] + =246,248.

[0224] Step 2:

[0225] Under a nitrogen atmosphere, Cs₂CO₃ (1.3 g, 4.1 mmol, 2.0 equivalence) and Pd(dppf)Cl₂CH₂Cl₂ (165 mg, 0.2 mmol, 0.1 equivalence) were added to a stirred mixture of 8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (500 mg, 2 mmol, 1.0 equivalence) and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyrazole (613 mg, 2 mmol, 1.0 equivalence) in DMF (8 mL). The resulting mixture was stirred at 80 °C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give 4-[6-chloro-2-methylimidazo[1,2-b]pyridazin-8-yl]-3-(4-fluorophenyl)-1-methylpyrazole (400 mg, 58%) as a pale yellow solid. 1 HNMR(400MHz, CDCl3)δ8.77(s,1H),7.71(s,1H),7.53-7.48(m,2H),7.16-7. 11(m,2H),6.69(s,1H),4.04(s,3H),2.55(s,3H).LC / MS(ESI,m / z):[(M+1)] + =342.

[0226] Preparation of compound I-6 in Examples 1-6

[0227] Figure 6 The synthetic scheme for compound I-6 is described. For example... Figure 6 As shown, the specific synthesis steps are as follows:

[0228] Step 1: 3-(4-fluorophenyl)-1-methyl-4-[3-nitroimidazo[1,2-b]pyridazin-8-yl]pyrazole

[0229] Under a nitrogen atmosphere, HNO3 (311 mg, 3.4 mmol, 5.0 equivalent) was added dropwise to a stirred mixture of 3-(4-fluorophenyl)-4-[imidazo[1,2-b]pyridazin-8-yl]-1-methylpyrazole (200 mg, 0.68 mmol, 1.0 equivalent) in 2 mL of H2SO4 at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 20 min. The reaction was quenched by adding 7 mL of 8 M NaOH aqueous solution at 0 °C. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give 3-(4-fluorophenyl)-1-methyl-4-[3-nitroimidazo[1,2-b]pyridazin-8-yl]pyrazole (200 mg, 87%) as a pale yellow solid. 1 H NMR (300MHz, CDCl3) δ8.69-8.65(m,1H),8.30(dd,J=7.2,2.2Hz,1H),8.15(d,J=4.8Hz,1H),8.04(d,J=1.3Hz,1H ),7.83-7.77(m,2H),7.32(dd,J=10.5,8.6Hz,1H),6.73(d,J=4.9Hz,1H),4.06(s,3H).LC / MS(ESI,m / z):[(M+1)] + =339.

[0230] Step 2: 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazine-3-amine

[0231] Fe (165 mg, 3.0 mmol, 5.0 equivalence) was added to a stirred mixture of 3-(4-fluorophenyl)-1-methyl-4-[3-nitroimidazo[1,2-b]pyridazin-8-yl]pyrazole (200 mg, 0.59 mmol, 1.0 equivalence) and NH4Cl (95 mg, 1.8 mmol, 3.0 equivalence) in EtOH (5 mL) / H2O (1 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 hour. The resulting mixture was filtered, and the filter cake was washed with EtOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (10:1) to give 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-3-amine (160 mg, 88%) as a pale yellow solid. 1HNMR (400MHz, CDCl3) δ8.76 (s, 1H), 8.09 (d, J = 5.0Hz, 1H), 7.99 (d, J = 1.3Hz, 1H), 7.78 (d, J = 1.3Hz ,1H),7.04-6.95(m,2H),6.84-6.80(m,2H),4.02(s,3H),3.81(br,2H).LC / MS(ESI,m / z):[(M+1)] + =309.

[0232] Step 3: 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]-N-methylimidazo[1,2-b]pyridazine-3-amine

[0233] Under a nitrogen atmosphere, at room temperature, AcOH (41 mg, 0.68 mmol, 1.5 equivalence) was added to a stirred mixture of 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-3-amine (140 mg, 0.45 mmol, 1.0 equivalence) and formaldehyde (14 mg, 0.45 mmol, 1.0 equivalence) in MeOH (7 mL). The resulting mixture was stirred for 30 minutes under a nitrogen atmosphere at room temperature. NaBH3CN (57 mg, 0.91 mmol, 2.0 equivalence) was added to the mixture at room temperature. The resulting mixture was stirred for another 1 hour at room temperature. The resulting mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Bridge Prep C18OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 24% B to 51% B over 8 min; 220 nm; RT1: 7.12 min; injection volume: 0.4 mL; number of runs: 8) to give 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]-N-methylimidazo[1,2-b]pyridazin-3-amine (58 mg, 40%), a grayish-white solid. 1 HNMR (400MHz, CDCl3) δ8.79(s,1H),8.07(d,J=4.9Hz,1H),7.99(d,J=1.2Hz,1H),7.77(d,J=1.2Hz,1H),6.99(dd,J=11. 5,8.2Hz,1H),6.86-6.81(m,2H),6.75(ddd,J=8.2,4.6,2.1Hz,1H),4.03(s,3H),2.83(s,3H).LC / MS(ESI,m / z):[(M+1)] + =323.

[0234] Preparation of Compound I-7 in Examples 1-7

[0235] Figure 7 The synthetic scheme for compound I-7 is described. For example... Figure 7 As shown, the specific synthesis steps are as follows:

[0236] Step 1:

[0237] Under a nitrogen atmosphere, AcOH (41 mg, 0.68 mmol, 1.5 equivalence) was added to a stirred mixture of 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-3-amine (140 mg, 0.45 mmol, 1.0 equivalence) and formaldehyde (14 mg, 0.45 mmol, 1.0 equivalence) in 7 mL of MeOH solution. The resulting mixture was stirred for 30 minutes under a nitrogen atmosphere at room temperature. NaBH3CN (57 mg, 0.91 mmol, 2.0 equivalence) was added to the mixture at room temperature. The resulting mixture was stirred for another 1 hour at room temperature. The resulting mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Bridge Prep C18OBD column, 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 24B to 51B over 8 min; 220 nm; RT1: 7.68 min; injection volume: 0.4 mL; number of runs: 8) to give 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]-N,N-dimethylimidazo[1,2-b]pyridazin-3-amine (28 mg, 19%) as a grayish-white solid. 1 H NMR (400MHz, CDCl3) δ8.78(s,1H),8.07(d,J=4.9Hz,1H),7.99(d,J=1.2Hz,1H),7.78(d,J=1.3Hz,1H),7.10 -7.04(m,2H),7.03-6.98(m,1H),6.79(d,J=5.0Hz,1H),4.03(s,3H),2.83(s,6H).LC / MS(ESI,m / z):[(M+1)] + =337.

[0238] Preparation of Compound I-8 in Examples 1-8

[0239] Figure 8 The synthetic scheme for compound I-8 is described. For example... Figure 8 As shown, the specific synthesis steps are as follows:

[0240] Step 1: 3-(4-fluorophenyl)-1-methyl-4-[3-nitroimidazo[1,2-b]pyridazin-8-yl]pyrazole

[0241] HNO3 (311 mg, 3.4 mmol, 5.0 equivalence) was added dropwise to a stirred mixture of 3-(4-fluorophenyl)-4-[imidazo[1,2-b]pyridazin-8-yl]-1-methylpyrazole (200 mg, 0.68 mmol, 1.0 equivalence) in 2 mL of H2SO4 at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 20 min at room temperature under a nitrogen atmosphere. The reaction was quenched by adding 7 mL of 8 M NaOH aqueous solution at 0 °C. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give 3-(4-fluorophenyl)-1-methyl-4-[3-nitroimidazo[1,2-b]pyridazin-8-yl]pyrazole (200 mg, 87%) as a pale yellow solid. 1 H NMR (300MHz, CDCl3) δ8.69-8.65(m,1H),8.30(dd,J=7.2,2.2Hz,1H),8.15(d,J=4.8Hz,1H),8.04(d,J=1.3Hz,1H ),7.83-7.77(m,2H),7.32(dd,J=10.5,8.6Hz,1H),6.73(d,J=4.9Hz,1H),4.06(s,3H).LC / MS(ESI,m / z):[(M+1)] + =339.

[0242] Step 2:

[0243] Fe (165 mg, 3.0 mmol, 5.0 equivalent) was added to a stirred mixture of 3-(4-fluorophenyl)-1-methyl-4-[3-nitroimidazo[1,2-b]pyridazin-8-yl]pyrazole (200 mg, 0.59 mmol, 1.0 equivalent) and NH4Cl (95 mg, 1.8 mmol, 3.0 equivalent) in EtOH (5 mL) / H2O (1 mL) solution. The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The mixture was filtered and the filter cake was washed with EtOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (10:1) to give 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-3-amine (160 mg, 88%) as a pale yellow solid. 1H NMR (400MHz, CDCl3) δ8.76(s,1H),8.09(d,J=5.0Hz,1H),7.99(d,J=1.3Hz,1H),7.78(d,J=1.3Hz ,1H),7.04-6.95(m,2H),6.84-6.80(m,2H),4.02(s,3H),3.81(br,2H).LC / MS(ESI,m / z):[(M+1)] + =309.

[0244] Preparation of Compound I-9 in Examples 1-9

[0245] Figure 9 The synthetic scheme for compound I-9 is described. For example... Figure 9 As shown, the specific synthesis steps are as follows:

[0246] Step 1: 4-Chloropyrrolo[1,2-b]pyridazine

[0247] At room temperature, 1H-pyrrolo[1,2-b]pyridazin-4-one (300.00 mg, 2.237 mmol, 1.00 equivalent) and POCl3 (3.00 mL) were added to a 40 mL vial. The resulting mixture was stirred at 80 °C for 16 h under air. The reaction was monitored by LCMS. The reaction was quenched with NaHCO3 at 0 °C. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (1 × 40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / MBTE (10:1) to give 4-chloropyrrolo[1,2-b]pyridazine (130 mg, 38.10%) as a colorless oil. 1 H NMR (400MHz, chloroform-d) δ7.91 (d, J = 4.9 Hz, 1H), 7.79 (dd, J = 2.8, 1.6 Hz, 1H), 6.89 (dd, J = 4.4, 2.7 Hz, 1H), 6.70 (dd, J = 4.4, 1.6 Hz, 1H), 6.61 (d, J = 4.9 Hz, 1H).

[0248] Step 2:

[0249] Under a nitrogen atmosphere, Cs₂CO₃ (640.6 mg, 1.97 mmol, 3 Equivalents) and Pd(dppf)Cl₂CH₂Cl₂ (53.4 mg, 0.07 mmol, 0.1 Equivalents) were added in portions to a stirred mixture of 4-chloropyrrolo[1,2-b]pyridazine (100.0 mg, 0.66 mmol, 1.00 Equivalents) and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)pyrazole (297.1 mg, 0.98 mmol, 1.50 Equivalents) in DMF (0.50 mL) in portions. The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile, gradient from 10% to 80% over 25 minutes; detector, UV 254 nm, yielding 3-(4-fluorophenyl)-1-methyl-4-[pyrrolo[1,2-b]pyridazin-4-yl]pyrazole (60.5 mg, 35.09%) as a brown solid. 1 H NMR (300MHz, chloroform-d) δ7.93(d,J=4.6Hz,1H),7.85–7.77(m,2H),7.56–7.43(m,2H),7.09–6.95(m,2H),6.85(dd, J=4.3,2.7Hz,1H),6.47(dd,J=4.3,1.6Hz,1H),6.28(d,J=4.7Hz,1H),4.06(s,3H).LC / MS(ESI,m / z):[(M+1)] + =293.2.

[0250] Preparation of compound I-10 in Examples 1-10

[0251] Figure 10 The synthetic scheme for compound I-10 is described. For example... Figure 10 As shown, the specific synthesis steps are as follows:

[0252] Step 1: 6-Chloro-3-hydrazolazine-4-amine

[0253] Under a nitrogen atmosphere, a mixture of 5 g (30 mmol, 1.0 equivalent) and hydrazine hydrate (22 mL, 444 mmol, 15 equivalent) dissolved in 25 mL of H₂O was stirred at 105 °C for 1 h. The mixture was then cooled to room temperature. The resulting mixture was diluted with ice water (20 mL). The precipitated solid was collected by filtration and washed with ice water (3 × 5 mL). The residue was concentrated under vacuum to give 3.3 g (68%) of 6-chloro-3-hydrazidopyridazine-4-amine as a grayish-white solid. 1H NMR(300MHz,DMSO-d6)δ7.29(s,1H),6.38(s,1H),6.26(br,2H),4.24(br,2H).LC / MS(ESI,m / z):[(M+1)] + =160.

[0254] Step 2: 6-Chloro-[1,2,4]triazolo[4,3-b]pyridazine-8-amine

[0255] A solution of 6-chloro-3-hydrazinopyridazin-4-amine (3.3 g, 21 mmol, 1.0 equivalence) in formic acid (10 mL) was stirred at 110 °C for 1 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The mixture was neutralized to pH 7 with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-8-amine (2.2 g, 63%) as a grayish-white solid. 1 H NMR(300MHz,DMSO-d6)δ9.39(s,1H),7.95(br,2H),6.13(s,1H).LC / MS(ESI,m / z):[(M+1)] + =170.

[0256] Step 3: [1,2,4]triazolo[4,3-b]pyridazine-8-amine

[0257] Under a nitrogen atmosphere, Pd / C (550 mg, 10%) was added to a solution of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazine-8-amine (2.2 g, 13 mmol, 1.0 equivalence) and DIEA (2.3 mL, 13 mmol, 1.0 equivalence) in EtOH (70 mL). The mixture was hydrogenated at 50 °C using a hydrogen tire under hydrogen atmosphere for 16 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated to give a gray semi-solid [1,2,4]triazolo[4,3-b]pyridazine-8-amine (3.8 g, crude). 1 H NMR(400MHz, DMSO-d6)δ9.38(s,1H),8.04(d,J=5.4Hz,1H),7.48(br,2H),6.09(d,J=5.5Hz,1H).LC / MS(ESI,m / z):[(M+1)] + =136.

[0258] Step 4: 8-Iodo-[1,2,4]triazolo[4,3-b]pyridazine

[0259] Under a nitrogen atmosphere at room temperature, isopentyl nitrite (6.9 g, 59 mmol, 5.0 equivalent) was added to a stirred solution of [1,2,4]triazolo[4,3-b]pyridazine-8-amine (1.6 g, 12 mmol, 1.0 equivalent) and CH₂I₂ (10 mL) in 100 mL of ACN. The resulting mixture was stirred at 80 °C for 1 hour under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The mixture was diluted with water (50 mL). The mixture was extracted with DCM (3 × 80 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (10:1) to give 8-iodo-[1,2,4]triazolo[4,3-b]pyridazine (410 mg, 14%), a brown solid. 1 H NMR(400MHz, DMSO-d6)δ9.80(s,1H),8.23(d,J=4.5Hz,1H),7.94(d,J=4.5Hz,1H).LC / MS(ESI,m / z):[(M+1)] + =247.

[0260] Step 5:

[0261] Under a nitrogen atmosphere, Cs₂CO₃ (266 mg, 0.81 mmol, 2.0 equivalent) and Pd(dppf)Cl₂CH₂Cl₂ (33 mg, 0.04 mmol, 0.1 equivalent) were added to a stirred mixture of 8-iodo-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.41 mmol, 1.0 equivalent) and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dimethylbenzyl-2-yl)pyrazole (147 mg, 0.49 mmol, 1.2 equivalent) in DMF (2.5 mL). The resulting mixture was stirred at 80 °C for 2 hours. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Select CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 20B to 45B, 254 / 220 nm over 7 min; RT1: 5.93 min; injection volume: 0.4 mL; number of runs: 8) to obtain 3-(4-fluorophenyl)-1-methyl-4-[[1,2,4]triazol[4,3-B]pyridazin-8-yl]pyrazole (37.8 mg, 32%) as a pink solid.1 H NMR (300MHz, CD3OD) δ9.45 (s, 1H), 8.79 (s, 1H), 8.29 (d, J = 4.8Hz, 1H), 7.59-7.52 (m, 2H),7.25-7.17(m,2H),6.87(d,J=4.8Hz,1H),4.05(s,3H).LC / MS(ESI,m / z):[(M+1)] + =295.

[0262] Preparation of compound I-11 in Examples 1-11

[0263] Figure 11 The synthetic scheme for compound I-11 is described. For example... Figure 11 As shown, the specific synthesis steps are as follows:

[0264] Step 1:

[0265] Cyclopropanecarboxylic acid (56 mg, 0.65 mmol, 2.0 equivalence) and HATU (185 mg, 0.49 mmol, 1.5 equivalence) were dissolved in DMF (2 mL) and stirred for 15 minutes at room temperature and under a nitrogen atmosphere. 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-3-amine (100 mg, 0.32 mmol, 1.0 equivalence) and DIPEA (105 mg, 0.81 mmol, 2.5 equivalence) were added to the mixture at room temperature. The resulting mixture was then stirred at 50 °C for 16 hours. The mixture was purified by preparative HPLC under the following conditions (column: X Select CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 15B to 39B, 254 / 220 nm over 7 min; RT1: 6.17 min; injection volume: 0.4 mL; number of runs: 8) to obtain N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-3-yl]cyclopropaneformamide (26.4 mg, 22%) as a pale yellow solid. 1H NMR (400MHz, CDCl3) δ8.78(s,1H),8.54(s,1H),8.07(d,J=4.9Hz,1H),7.98(d,J=1.2Hz,1H),7.77(d,J=1.3Hz,1H),7.56(s,1H),7.22-7.17(m, 1H),7.16-7.09(m,1H),6.84(d,J=4.9Hz,1H),4.01(s,3H),1.59-1.52( m,1H),1.10-1.04(m,2H),0.90-0.83(m,2H).LC / MS(ESI,m / z):[(M+1)] + =377.

[0266] Preparation of compound I-12 in Examples 1-12

[0267] Figure 12 The synthetic scheme for compound I-12 is described. For example... Figure 12 As shown, the specific synthesis steps are as follows:

[0268] Step 1: Methyl 8-bromo-6-chloroimidozoprothiolane[1,2-b]pyridazine-2-carboxylate

[0269] 4-Bromo-6-chloropyridazin-3-amine (5 g, 24 mmol, 1.0 equivalence) and methyl 3-bromo-2-oxopropionate (17 g, 96 mmol, 4.0 equivalence) were stirred in a DME (50 mL) at room temperature and under air atmosphere. The mixture was heated to 90 °C and stirred for 16 h. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give methyl 8-bromo-6-chloroimidazolo[1,2-b]pyridazin-2-carboxylate (5.7 g, 81%) as a grayish-white solid. 1 H NMR(300MHz, CDCl3)δ8.50(s,1H),7.47(s,1H),4.00(s,3H).LC / MS(ESI,m / z):[(M+1)] + =290,292.

[0270] Step 2: 6-Chloro-8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazine-2-carboxylate

[0271] Under a nitrogen atmosphere, Cs₂CO₃ (2.3 g, 6.9 mmol, 2.0 equivalence) and Pd(dppf)Cl₂CH₂Cl₂ (280 mg, 0.34 mmol, 0.1 equivalence) were added to a stirred mixture of methyl 8-bromo-6-chloroimidozopo[1,2-b]pyridazine-2-carboxylate (1 g, 3.4 mmol, 1.0 equivalence) in toluene (15 mL) at room temperature. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:2) to give methyl 6-chloro-8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazolium[1,2-b]pyridazine-2-carboxylate (390 mg, 29%) as a light brown solid. 1 H NMR (400MHz, CDCl3) δ8.87 (s, 1H), 8.43 (d, J = 0.8Hz, 1H), 7.51 (dd, J = 8.6, 5.6Hz, 2H), 7 .16(t,J=8.6Hz,2H),6.79(s,1H),4.05(s,3H),4.01(s,3H).LC / MS(ESI,m / z):[(M+1)] + =386.

[0272] Step 3:

[0273] Pd / C (97 mg, 10%) was added to a solution of methyl 6-chloro-8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazine-2-carboxylate (390 mg, 1.0 mmol, 1.0 equivalence) in EA (10 mL) at room temperature and under a nitrogen atmosphere. The mixture was hydrogenated at 50 °C under hydrogen protection for 16 h using a hydrogen tire. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Select CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; mobile phase rate: 25 mL / min; gradient: from 30B to 55B over 7 min, 254 / 220 nm; RT1: 6.47 min; injection volume: 0.4 mL; number of runs: 8) to give methyl 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazol[1,2-B]pyridazine-2-carboxylate (29.5 mg, 8%) as a grayish-white solid. 1H NMR (400MHz, CDCl3) δ8.84 (s, 1H), 8.52 (s, 1H), 8.12 (d, J = 4.9Hz, 1H), 7.52-7.47 (m, 2H), 7. 15-7.09(m,2H),6.77(d,J=5.0Hz,1H),4.04(s,3H),4.01(s,3H).LC / MS(ESI,m / z):[(M+1)] + =352.

[0274] Preparation of compound I-13 in Examples 1-13

[0275] Figure 13 The synthetic scheme for compound I-13 is described. For example... Figure 13 As shown, the specific synthesis steps are as follows:

[0276] Step 1:

[0277] A mixture of N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]tert-butyl carbamate solution (40 mg, 0.1 mmol, 1.0 equivalent) and HCl (5 mL, 4 M HCl) was stirred for 1 hour at room temperature and under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Select CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 12B to 38B, 254 / 220 nm over 7 min; RT1: 6.72 min; injection volume: 0.4 mL; number of runs: 8) to obtain 8-[3-(4-fluorophenyl))-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-amine; formic acid (17.1 mg, 49%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.56-8.52(m,1H),7.92(td,J=3.0,1.5Hz,1H),7.53-7.46(m,2H),7.36(q ,J=1.5Hz,1H),7.12-7.05(m,2H),6.61-6.57(m,1H),4.02(s,3H).LC / MS(ESI,m / z):[(M+1-FA)] + =309.

[0278] Preparation of compound I-14 in Examples 1-14

[0279] Figure 14 The synthetic scheme for compound I-14 is described. For example... Figure 14As shown, the specific synthesis steps are as follows:

[0280] Step 1: 8-Bromo-2-(Bromomethyl)-6-chloroimidazolo[1,2-b]pyridazine

[0281] Under a nitrogen atmosphere, 2-propanone and 1,3-dibromo-3-amine (12.05 g, 57.810 mmol, 1.00 equivalence) in a DME mixture (100.00 mL) were added to a solution of 4-bromo-6-chloropyridazine-3-amine (24.96 g, 115.624 mmol, 2.00 equivalence). The solution was stirred at 90 °C for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to provide 8-bromo-2-(bromomethyl)-6-chloroimidazolo[1,2-b]pyridazine (7.4 g, 39.34%) as a white solid. LC / MS (ESI, m / z): [(M+1)] + =324.1.

[0282] Step 2: 2-([[8-bromo-6-chloromidazol[1,2-b]pyridazin-2-yl]methyl)isoindole-1,3-dione

[0283] K₂CO₃ (11.30 g, 81.748 mmol, 2.00 equivalent) was added to a stirred solution of 8-bromo-2-(bromomethyl)-6-chloroimidazolo[1,2-b]pyridazine (13.30 g, 40.874 mmol, 1.00 equivalent) and phthalimide (6.62 g, 0.045 mmol, 1.10 equivalent) in dioxane (200.00 mL) at room temperature and in an air atmosphere. The mixture was stirred at 80 °C for 1 h, and the reaction was monitored by LCMS. The resulting reaction mixture was concentrated under reduced pressure. The residues were purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient of 30% to 50% over 20 min; detector, UV 254 nm. 2-([8-bromo-6-chloroimidazolo[1,2-b]pyridazin-2-yl]methyl)isoindol-1,3-dione (10 g, 62.47%) was given as a white solid. LC / MS (ESI, m / z): [(M+1)] + =393.1.

[0284] Step 3: 2-([6-chloro-8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)isoindole-1,3-dione

[0285] In a nitrogen atmosphere, at room temperature, Pd(dppf)Cl2.CH2Cl2 (1.19 g, 1.456 mmol, 0.10 equivalent) and Cs2CO3 (14.23 g, 43.665 mmol, 3.00 equivalent) were added to a stirred solution of 2-([8-bromo-6-chloroimidazolo[1,2-b]pyridazin-2-yl]methyl)isoindole-1,3-dione (5.70 g, 14.555 mmol, 1.00 equivalent) and 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrazole (6.60 g, 0.023 mmol, 1.50 equivalent) in toluene (90.00 mL). The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 10% to 50% over 10 min; detector, UV 254 nm, to give 2-([6-chloro-8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)isoindol-1,3-dione (2 g, 28.22%), yellow solid. LC / MS (ESI, m / z): [(M+1)] + =487.3.

[0286] Step 4: 2-([8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)isoindole-1,3-dione

[0287] Under stirring, Pd / C (437.14 mg, 0.411 mmol, 0.10 equivalence, 10%) was added to a solution of 2-([6-chloro-8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)isoindol-1,3-dione (2.00 g, 4.108 mmol, 1.00 equivalence) in EtOH (60.00 mL). The resulting mixture was stirred at 50 °C for 48 h under a hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 30 mL). The filtrate was concentrated under reduced pressure. 2-([8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)isoindole-1,3-dione (1 g, 53.81%) was obtained as a yellow solid. The crude product was used directly in the next step without further purification. LC / MS (ESI, m / z): [(M+1)] + =453.1.

[0288] Step 5:

[0289] Under stirring at room temperature, N₂H₄·H₂O (66.39 mg, 1.326 mmol, 6 Equivalents) was added to a solution of 2-([8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)isoindole-1,3-dione (100.00 mg, 0.221 mmol, 1.00 Equivalent) in EtOH (1.00 mL). The resulting mixture was stirred at 80 °C for 1 h in air. The reaction was monitored by LCMS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 10% to 50% over 25 minutes; detector, UV 254 nm, yielding 1-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methylamine (13.4 mg, 18.81%) as a grayish-white solid. 1 H NMR(300MHz,Methanol-d4)δ8.88(s,1H),8.58(s,1H),8.26–8.17(m,2H),7.59–7.47(m,2H),7.28 –7.14(m,2H),6.84(d,J=4.9Hz,1H),4.35(d,J=0.7Hz,2H),4.06(s,3H).LC / MS(ESI,m / z):[(M+1)] + =323.15.

[0290] Preparation of Compound I-15 in Examples 1-15

[0291] Figure 15 The synthetic scheme for compound I-15 is described. For example... Figure 15 As shown, the specific synthesis steps are as follows:

[0292] Step 1:

[0293] Methyl 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazine-2-carboxylate (100.00 mg, 0.285 mmol, 1.00 equivalence) and NH3·H2O (5.00 mL) were added to a 40 mL sealed tube, and the mixture was reacted at 80 °C for 16 h °C, then cooled to room temperature. The solution was concentrated under reduced pressure, and the residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient of 30% to 50% over 15 min; detector, UV 254 nm. This resulted in 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazine-2-carboxamide (15.4 mg, 16.09%) as a yellow solid. 1 H NMR (300MHz, chloroform-d) δ8.68(s,1H),8.55(s,1H),8.15(d,J=4.9Hz,1H),7.59–7.47(m,2H),7.23(s,1 H),7.21–7.09(m,2H),6.81(d,J=4.9Hz,1H),5.60(s,1H),4.09(s,3H).LC / MS(ESI,m / z):[(M+1)] + =337.1.

[0294] Preparation of Compound I-16 in Examples 1-16

[0295] Figure 16 The synthetic scheme for compound I-16 is described. For example... Figure 16 As shown, the specific synthesis steps are as follows:

[0296] Step 1:

[0297] Methyl 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazine-2-carboxylate (100.00 mg, 0.285 mmol, 1.00 equivalent) and methylamine THF solution (5 mL, 2 M) were added to a 40 mL sealed tube, and the solution was reacted at 100 °C for 16 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient of 40% to 60% over 15 min; detector, UV 254 nm. 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]-N-methylimidazo[1,2-b]pyridazine-2-carboxamide (25.7 mg, 25.77%) was given as a grayish-white solid. 1H NMR (300MHz, chloroform-d) δ8.65(s,1H),8.53(s,1H),8.15(d,J=4.9Hz,1H),7.58–7.47(m,2H),7.36(s,1H),7. 15(t,J=8.7Hz,2H),6.80(d,J=4.9Hz,1H),4.10(s,3H),3.11(d,J=5.1Hz,3H).LC / MS(ESI,m / z):[(M+1)] + =351.2.

[0298] Preparation of compound I-17 in Examples 1-17

[0299] Figure 17 The synthetic scheme for compound I-17 is described. For example... Figure 17 As shown, the specific synthesis steps are as follows:

[0300] Step 1:

[0301] A mixture of methyl 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]prop-2-carboxylate (100 mg, 0.285 mmol, 1.00 equivalence) and THF (10.00 mL) was stirred at 0 °C and in air. The reaction was carried out at room temperature for 1 h. The reaction was monitored by LCMS, then quenched with aqueous NH4Cl solution and concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 35% to 55% over 15 min; detector, UV 254 nm. This resulted in 2-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]prop-2-ol (29.5 mg, 29.50%) as a pale yellow solid. 1 ¹H NMR (300 MHz, chloroform-d) δ 8.80 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.53 (dd, J = 8.6, 5.4 Hz, 2H), 7.14 (t, J = 8.7 Hz, 2H), 6.76 (s, 1H), 4.08 (s, 3H), 1.74 (s, 6H). LC / MS (ESI, m / z): [(M+1)] + =352.2.

[0302] Preparation of Compound I-18 in Examples 1-18

[0303] Figure 18 The synthetic scheme for compound I-18 is described. For example... Figure 18 As shown, the specific synthesis steps are as follows:

[0304] Step 1: N-(4-bromo-6-chloropyridazine-3-yl)-4-methylbenzenesulfonamide

[0305] Under a nitrogen atmosphere and with stirring, 3.84 g of NaH (3.84 g of NaH, 96.009 mmol of NaH, 2.00 equivalent, 60%) was added in portions to a THF solution of 100.00 mL containing 10.00 g of 4-bromo-6-chloropyridazine-3-amine (47.975 mmol, 1.00 equivalent) under nitrogen atmosphere and incubation. The resulting mixture was stirred for 15 min at room temperature and under nitrogen atmosphere. A THF solution of 100.00 mL containing 10.98 g of p-toluenesulfonyl chloride (57.570 mmol, 1.20 equivalent) was added to the resulting mixture under nitrogen atmosphere and incubation, and the mixture was stirred for 2 h at room temperature and under nitrogen atmosphere. The desired product was detectable by LCMS. The reaction was quenched with 20 mL of H₂O at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (1:10) to give N-(4-bromo-6-chloropyridazine-3-yl)-4-methylbenzenesulfonamide (9.1 g, 52.31%) as a pale yellow solid. 1 ¹H NMR (300MHz, chloroform-d) δ 7.97 (s, 2H), 7.66 (s, 1H), 7.29 (s, 2H), 2.41 (s, 3H). LC / MS (ESI, m / z): [(M+1)] + =362.0, 364.0.

[0306] Step 2: 2-[(6Z)-5-bromo-3-chloro-6-[(4-methylbenzenesulfonyl)imino]pyridazin-1-yl]acetamide

[0307] N-(4-bromo-6-chloropyridazin-3-yl)-4-methylbenzenesulfonamide (100.00 mg, 0.276 mmol, 1.00 equivalent), DIEA (891.01 mg, 6.895 mmol, 5.00 equivalent), and bromoacetamide (190.23 mg, 1.380 mmol, 5.00 equivalent) were dissolved in DMF (5.00 mL) at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 4 hours under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (1:10) to give the crude product. The crude product was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; detector, UV 254nm / 220nm; mobile phase, acetonitrile aqueous solution (0.1% mol / L FA), over 30 minutes with a gradient of 20% to 50% to give 2,2-[(6Z)-5-bromo-3-chloro-6-[(4-methylbenzenesulfonyl)imino]pyridazin-1-yl]acetamide (100 mg, 17.28%), as a yellow solid. LC / MS (ESI, m / z): [(M+1)] + =419.1,421.1.

[0308] Step 3: N-[8-bromo-6-chloroimidozoprothiolane[1,2-b]pyridazin-2-yl]-2,2,2-trifluoroacetamide

[0309] Under a nitrogen atmosphere and with stirring, trifluoroacetic anhydride (2.1 mL) was added in portions to a solution of 2-[(6Z)-5-bromo-3-chloro-6-[(4-methylbenzenesulfonyl)imino]pyridazin-1-yl]acetamide (420.00 mg, 1.001 mmol, 1.00 equivalence) in DCM (8.00 mL). The resulting mixture was stirred at room temperature for 1 hour. The desired product was detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (1:10) to give N-[8-bromo-6-chloroimidazolo[1,2-b]pyridazin-2-yl]-2,2,2-trifluoroacetamide (285 mg, 82.91%) as a yellow oil. LC / MS (ESI, m / z): [(M+1)] + =342.9,344.9.

[0310] Step 4: N-[6-chloro-8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]-2,2,2-trifluoroacetamide

[0311] A mixture of N-[8-bromo-6-chloroimidazolo[1,2-b]pyridazin-2-yl]-2,2,2-trifluoroacetamide (500.00 mg, 1.456 mmol, 1.00 equivalent), 3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dimethylbenzyl-2-yl)pyrazole (439.84 mg, 1.456 mmol, 1.00 equivalent), Pd(dppf)Cl2CH2Cl2 (118.58 mg, 0.146 mmol, 0.10 equivalent), and Cs2CO3 (948.56 mg, 2.911 mmol, 2.00 equivalent) in DMF (15.00 mL) was stirred at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. LC / MS detected the desired product. The resulting mixture was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; detector, UV 254nm / 220nm; mobile phase, acetonitrile-water solution (0.1% mol / L formic acid), gradient of 40% to 80% over 40 minutes, to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with DCM / MeOH (1:10) to provide N-[6-chloro-8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazol[1,2-b]pyridazin-2-yl]-2,2,2-trifluoroacetamide (53 mg, 8.30%), as a yellow solid. LC / MS (ESI, m / z): [(M+1)] + =439.2.

[0312] Step 5:

[0313] Pd / C (12.85 mg, 0.012 mmol, 0.10 equivalence, 10%) was added to a stirred mixture of N-[6-chloro-8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]-2,2,2-trifluoroacetamide (53.00 mg, 0.121 mmol, 1.00 equivalence) in MeOH (2.00 mL) and EA (2.00 mL) at room temperature and under a hydrogen atmosphere. The resulting mixture was stirred at 50 °C for 12 hours under a H2 atmosphere. The desired product was detected by LCMS. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; detector, UV 254nm / 220nm; mobile phase, aqueous acetonitrile (0.1% mol / L FA), gradient from 30% to 60% over 30 minutes, to give 2,2,2-trifluoro-N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]acetamide (15 mg, 30.71%), as a pale yellow solid. 1¹H NMR (400MHz, chloroform-d) δ 8.94 (s, 1H), 8.49 (d, J = 4.7 Hz, 1H), 8.30 (s, 1H), 7.83 (dd, J = 8.8, 5.4 Hz, 2H), 7.16–7.08 (m, 4H), 4.10 (s, 3H). LC / MS (ESI, m / z): [(M+1)] + =405.1.

[0314] Preparation of Compound I-19 in Examples 1-19

[0315] Figure 19 The synthetic scheme for compound I-19 is described. For example... Figure 19 As shown, the specific synthesis steps are as follows:

[0316] Step 1: 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid

[0317] LiOH·H2O (348 mg, 8.3 mmol, 3.0 equivalent) was added to a stirred solution of methyl 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazine-2-carboxylate (970 mg, 2.8 mmol, 1.0 equivalent) in a mixture of MeOH (7 mL) / THF (7 mL) / H2O (7 mL). The resulting mixture was stirred at room temperature and under nitrogen atmosphere for 2 hours. The mixture was concentrated under reduced pressure. The residue was acidified to pH 4 with 3N HCl aqueous solution. The resulting mixture was extracted with CHCl3 / IPA (3 × 80 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM / MeOH (10:1) to give 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-carboxylic acid (280 mg, 30%) as a light brown solid. LC / MS (ESI, m / z): [(M+1)] + =338.

[0318] Step 2: N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]tert-butyl carbamate

[0319] DPPA (330 mg, 1.2 mmol, 1.5 equivalence) was added to a mixed solution of 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-carboxylic acid (270 mg, 0.8 mmol, 1.0 equivalence) and Et3N (162 mg, 1.6 mmol, 2.0 equivalence) in t-BuOH (15 mL) at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred for 10 min at room temperature and under a nitrogen atmosphere. Then, the temperature was raised to 100 °C under a nitrogen atmosphere and stirring was continued for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EA (30 mL). The mixture was neutralized to pH 8 with a saturated aqueous solution of NaHCO3. The resulting mixture was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]carbamate (150 mg, 46%), as a pale yellow solid. LC / MS (ESI, m / z): [(M+1)] + =409.

[0320] Step 3: N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]-N-methylcarbamate tert-butyl

[0321] Under a nitrogen atmosphere and with stirring, 70 mg (0.17 mmol, 2.0 equivalence) of N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]carbamate tert-butyl carbamate was added in portions to a 2 mL THF solution with NaH (14 mg, 0.34 mmol, 2.0 equivalence, 60%). The resulting mixture was stirred at 0 °C for 15 min under a nitrogen atmosphere. MeI (37 mg, 0.26 mmol, 1.5 equivalence) was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at room temperature for another 1 h. A saturated aqueous solution of NH4Cl (5 mL) was added at 0 °C. The resulting mixture was extracted with EA (3 × 15 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over a Na2SO4-free environment. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]-N-methylcarbamate (60 mg, 83%), as a pale yellow solid. LC / MS (ESI, m / z): [(M+1)] + =423.

[0322] Step 4:

[0323] N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]-N-methylcarbamate tert-butyl ester (60 mg, 0.14 mmol, 1.0 equivalence) was dissolved in HCl (5 mL, 4 M EA solution) and stirred for 1 h at room temperature and under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Select CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; mobile phase rate: 25 mL / min; gradient: from 18B to 48B, 254 / 220 nm over 7 min; RT1: 6.22 min; injection volume: 0.4 mL; number of runs: 8) to obtain N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]N-methylimidazo[1,2-b]pyridazine-2-amino (14.3 mg, 31%) as a yellow solid. 1 H NMR (300MHz, CDCl3) δ8.54 (s, 1H), 7.89 (d, J = 5.1Hz, 1H), 7.54-7.47 (m, 2H), 7.25 (s, 1H), 7. 13-7.03(m,2H),6.58(d,J=5.1Hz,1H),4.01(s,3H),2.94(s,3H).LC / MS(ESI,m / z):[(M+1)] + =323.

[0324] Preparation of Compound I-20 in Examples 1-20

[0325] Figure 20 The synthetic scheme for compound I-20 is described. For example... Figure 20 As shown, the specific synthesis steps are as follows:

[0326] Step 1:

[0327] Under a nitrogen atmosphere, 30 mg (30 mg, 0.1 mmol, 1.0 equivalence) and 30 mg (3.29 mmol, 3.0 equivalence) of 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-amine (30 mg, 0.02 mmol, 0.2 equivalence) and 3 mL of TEA (30 mg, 0.29 mmol, 3.0 equivalence) were added to a stirred solution in a DCM (3 mL) containing DMAP (2.4 mg, 0.02 mmol, 0.2 equivalence) and Ac2O (11 mg, 0.11 mmol, 1.1 equivalence). The resulting mixture was stirred for 3 hours under a nitrogen atmosphere at room temperature. The mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Select CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: from 18B to 48B, 254 / 220 nm over 7 min; RT1: 6.22 min; injection volume: 0.4 mL; number of runs: 8) to obtain N-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]acetamide (6.7 mg, 20%) as a grayish-white solid. 1 H NMR (300MHz, CDCl3) δ8.49 (s, 1H), 8.42 (s, 1H), 8.14 (br, 1H), 8.06 (d, J = 5.0Hz, 1H), 7.53-7.46 (m, 2H),7.14-7.06(m,2H),6.71(d,J=5.0Hz,1H),4.02(s,3H),2.23(s,3H).LC / MS(ESI,m / z):[(M+1)] + =351.

[0328] Preparation of compound I-21 in Examples 1-21

[0329] Figure 21 The synthetic scheme for compound I-21 is described. For example... Figure 21 As shown, the specific synthesis steps are as follows:

[0330] Step 1:

[0331] Acetyl chloride (14.61 mg, 0.186 mmol, 1.20 equivalence) was added dropwise to a stirred solution of 1-[8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methylamine (50.00 mg, 0.155 mmol, 1.00 equivalence) and TEA (23.54 mg, 0.233 mmol, 1.5 equivalence) in DCM (0.50 mL) under air atmosphere. The resulting mixture was stirred for 1 hour at room temperature and under air atmosphere. The reaction was monitored by LCMS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 10% to 50% over 20 minutes; detector, UV 254 nm, yielding N-([8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)acetamide (20 mg, 35.39%), as a grayish-white solid. 1 H NMR(300MHz, chloroform-d)δ8.69(s,1H),8.10(d,J=5.0Hz,1H),7.95(s,1H),7.57–7.47(m,2H),7.13(t,J=8.6Hz,2H), 6.76(d,J=4.9Hz,1H),6.25(s,1H),4.69(d,J=4.7Hz,2H),4.08(s,3H),2.09(s,3H).LC / MS(ESI,m / z):[(M+1)] + =365.1.

[0332] Preparation of compound I-22 in Examples 1-22

[0333] Figure 22 The synthetic scheme for compound I-22 is described. For example... Figure 22 As shown, the specific synthesis steps are as follows:

[0334] Step 1: N-([8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)-N-methylacetamide

[0335] Under a nitrogen atmosphere and with stirring, NaH (10.98 mg, 0.274 mmol, 2 equivalences, 60%) was added in portions to a solution of N-([8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)acetamide (50.00 mg, 0.137 mmol, 1.00 equivalence) in DMF (1.00 mL). The resulting mixture was stirred for 30 min at room temperature and under a nitrogen atmosphere. CH3I (38.95 mg, 0.274 mmol, 2 equivalences) was then added to the mixture. The mixture was stirred for another 16 h under a nitrogen atmosphere and at 80 °C. The reaction was monitored by LCMS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN containing 0.1% aqueous FA solution, gradient from 10% to 50% over 10 minutes; detector, UV 254 nm, yielding N-([8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)-N-methylacetamide (50 mg, 96.29%), as a yellow solid. LC / MS (ESI, m / z): [(M+1)] + =379.3.

[0336] Step 2:

[0337] At room temperature and under air atmosphere, 0.50 mL of 4 M NaOH aqueous solution was added dropwise to a solution of N-([8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)-N-methylacetamide (50.00 mg, 0.132 mmol, 1.00 equivalent) in EtOH (0.50 mL). The resulting mixture was stirred for 4 hours under air atmosphere and at 90 °C. The reaction was monitored by LCMS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 10% to 50% over 10 minutes; detector, UV 254 nm, yielding ([8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazin-2-yl]methyl)(methyl)amine (14 mg, 31.50%), as a white solid. 1 ¹H NMR (300MHz, chloroform-d) δ 8.91 (s, 1H), 8.53 (s, 1H), 8.05 (d, J = 5.3 Hz, 2H), 7.56–7.45 (m, 2H), 7.19–7.07 (m, 2H), 6.73 (d, J = 5.0 Hz, 1H), 4.25 (s, 2H), 4.07 (s, 3H), 2.69 (s, 3H). LC / MS (ESI, m / z): [(M+1)] +=337.15.

[0338] Preparation of compound I-23 in Examples 1-23

[0339] Figure 23 The synthetic scheme for compound I-23 is described. For example... Figure 23 As shown, the specific synthesis steps are as follows:

[0340] Step 1:

[0341] Under a nitrogen atmosphere and with stirring, NaH (10.98 mg, 0.274 mmol, 2 equivalences, 60%) was added in portions to a DMF (1.00 mL) solution of (8-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazol[1,2-b]pyridazin-2-yl)methylamine (44.11 mg, 0.137 mmol, 1.00 equivalences). The resulting mixture was stirred for 30 min at room temperature and under a nitrogen atmosphere. CH3I (38.95 mg, 0.274 mmol, 2 equivalences) was then added to the mixture. The mixture was further stirred for 16 h at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 10% to 50% over 10 min; detector, UV 254 nm, yielding 1-(8-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)-N,N-dimethylmethylamine (12 mg, 25%) as a yellow solid. LC / MS (ESI, m / z): [(M+1)] + =351.4.

[0342] Preparation of compound I-24 in Examples 1-24

[0343] Figure 24 The synthetic scheme for compound I-24 is described. For example... Figure 24 As shown, the specific synthesis steps are as follows:

[0344] Step 1:

[0345] Under a nitrogen atmosphere and with stirring, 1-[2-(4-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dimethylbenzyl-2-yl)-4H,6H,6H,7H-pyrazolo[1,5-a]pyrazin-5-yl]acetone (1000 mg, 2.5958 mmol) was dissolved in 1,4-dioxane / H₂O = 10:1 (30 mL), and 4-bromo-1H-pyrazolo[2,3-b]pyridine (767.18 mg, 3.8937 mmol), Na₂CO₃ (825.46 mg, 7.7874 mmol), and Pd(dppf)Cl₂ (379.51 mg, 0.5191 mmol) were added. The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The reaction was confirmed to be complete by LC-MS. The solution was filtered, and the filtrate was collected. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and eluted with DCM / MeOH (10:1). Chemical formula: (M+H) + C 21 H 18 The calculated value of FN5O:375.1 is 375.1, and the measured value is 376.0.

[0346] Preparation of Compound I-25 in Examples 1-25

[0347] Figure 25 The synthetic scheme for compound I-25 is described. For example... Figure 25 As shown, the specific synthesis steps are as follows:

[0348] Step 1: 8-Bromo-2-(Bromomethyl)-6-chloroimidazolo[1,2-b]pyridazine

[0349] To a stirred mixture of 4-bromo-6-chloropyridazin-3-amine (12.05 g, 57.810 mmol, 1.00 equivalence) in 100.00 mL DME, 2-propanone and 1,3-dibromo- (24.96 g, 115.624 mmol, 2.00 equivalence) were added. The solution was stirred at 90 °C for 2 h. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 8-bromo-2-(bromomethyl)-6-chloroimidazolo[1,2-b]pyridazine (7.4 g, 39.34%) as a white solid. LC / MS (ESI, m / z): [(M+1)] + =324.1.

[0350] Step 2: 2-([8-bromo-6-chloroimidozono[1,2-b]pyridazin-2-yl]methyl)isoindole-1,3-dione

[0351] At room temperature and in an air atmosphere, K₂CO₃ (11.30 g, 40.874 mmol, 1.00 equivalent) and phthalimide (6.62 g, 0.045 mmol, 1.10 equivalent) were added to a stirred solution of 8-bromo-2-(bromomethyl)-6-chloroimidazolo[1,2-b]pyridazine (13.30 g, 40.874 mmol, 1.00 equivalent) in dioxane (200.00 mL). The mixture was stirred at 80 °C for 1 h, and the reaction was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure. The residues were purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient of 30% to 50% over 20 min; detector, UV 254 nm. 2-([8-bromo-6-chloroimidazolo[1,2-b]pyridazin-2-yl]methyl)isoindol-1,3-dione (10 g, 62.47%) was given as a white solid. LC / MS (ESI, m / z): [(M+1)] + =393.1.

[0352] Step 3: 2-((8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazole[1,5-a]pyrazin-3-yl)-6-clomizol[1,2-b]pyridinazin-2-yl)methyl)isobutyl-1,3-dione

[0353] Under a nitrogen atmosphere at room temperature, 5.70 g (14.555 mmol, 1.00 equivalent) of 2-([8-bromo-6-chloroimidazolo[1,2-b]pyridazin-2-yl]methyl)isoindole-1,3-dione and 1-(2-(4-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-6,7-dihydropyrazolo[1, [5-a]pyrazin-5(4H)-yl)ethyl-1-one (8.85 g, 0.023 mmol, 1.50 equivalence) was added to a stirred solution of toluene (90.00 mL) with Pd(dppf)Cl2.CH2Cl2 (1.19 g, 1.456 mmol, 0.10 equivalence) and Cs2CO3 (14.23 g, 43.665 mmol, 3.00 equivalence). The resulting mixture was stirred at 100 °C for 2 h. The reaction was monitored by LCMS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 10% to 50% over 10 min; detector, UV 254 nm, yielding 2-((8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazole[1,5-a]pyrazin-3-yl)-6-chloroimidazole[1,2-b]pyridinazin-2-yl)methyl)isobutyl-1,3-dione (2.34 g, 28.22%) as a yellow solid. LC / MS (ESI, m / z): [(M+1)] + =570.9.

[0354] Step 4: 2-((8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)isoindoline-1,3-dione

[0355] Pd / C (437.14 mg, 0.411 mmol, 0.10 equivalence, 10%) was added to a solution of 2-((8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazole[1,5-a]pyrazin-3-yl)-6-chloroimidazole[1,2-b]pyridazin-2-yl)methyl)isobutyl-1,3-dione in EtOH (60.00 mL) under a nitrogen atmosphere and with stirring. The resulting mixture was stirred for 48 hours under a hydrogen atmosphere and at 50 °C. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 30 mL). The filtrate was concentrated under reduced pressure. 2-((8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)isoindoline-1,3-dione (1 g, 53.81%) was obtained as a yellow solid. The crude product was used directly in the next step without further purification. LC / MS (ESI, m / z): [(M+1)] + =536.5.

[0356] Step 5: 1-(3-(2-(aminomethyl)imidazo[1,2-b]pyridazin-8-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethyl-1-one

[0357] Under a stirring atmosphere and at room temperature, 1.00 mL of EtOH containing 2-((8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-yl)methyl)isoindoline-1,3-dione (118.00 mg, 0.221 mmol, 1.00 equivalent) was added to N2H4·H2O (66.39 mg, 1.326 mmol, 6 equivalent). The resulting mixture was stirred at 80 °C for 1 h. The reaction was monitored by LCMS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 10% to 50% over 25 minutes; detector, UV 254 nm, yielding 1-(3-(2-(aminomethyl)imidazo[1,2-b]pyridazin-8-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethyl-1-one (62.6 mg, 70%) as a grayish-white solid.

[0358] Step 6:

[0359] Under a nitrogen atmosphere and with stirring, a solution of 1-(3-(2-(aminomethyl)imidazo[1,2-b]pyridazin-8-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethyl-1-one (55.00 mg, 0.137 mmol, 1.00 equivalent) in DMF (1.00 mL) was mixed with NaH (10.98 mg, 0.274 mmol, 2 equivalents, 60%). The resulting mixture was stirred for 30 minutes under a nitrogen atmosphere at room temperature. CH3I (38.95 mg, 0.274 mmol, 2 equivalents) was then added to the mixture. The mixture was further stirred for 16 hours at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 10% to 50% over 10 min; detector, UV 254 nm, yielding 1-(3-(2-((dimethylamino)methyl)imidazo[1,2-b]pyrazin-8-yl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)ethyl-1-one (50 mg, 96.29%) as a yellow solid. LC / MS (ESI, m / z): [(M+1)] + =434.4.

[0360] Preparation of Compound I-26 in Examples 1-26

[0361] Figure 26 The synthetic scheme for compound I-26 is described. For example... Figure 26 As shown, the specific synthesis steps are as follows:

[0362] Step 1: Methyl 8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazole[1,5-a]pyrazin-3-yl)-6-cloimidazole[1,2-b]pyridazine-2-carboxylic acid ester

[0363] Under a nitrogen atmosphere, Cs₂CO₃ (2.3 g, 6.9 mmol, 2.0 equivalence) and Pd(dppf)Cl₂CH₂Cl₂ (280 mg, 0.34 mmol, 0.1 equivalence) were added to a stirred mixture of methyl 8-bromo-6-chloroimidazolo[1,2-b]pyrazine-2-carboxylic acid (1 g, 3.4 mmol, 1.0 equivalence) and 1-(2-(4-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)ethyl-1-one (1 g, 3.4 mmol, 1.0 equivalence) in toluene (15 mL) at room temperature. The resulting mixture was stirred for 2 hours at 100 °C under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2), to give methyl 8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazole[1,5-A]pyrazin-3-yl)-6-chloroimidozolo[1,2-b]pyridazine-2-carboxylic acid ester (490 mg, 29%), as a light brown solid.

[0364] Step 2: Methyl 8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-carboxylic acid ester

[0365] Under a nitrogen atmosphere, Pd / C (97 mg, 10%) was added to a solution of methyl 8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazole[1,5-a]pyrazin-3-yl)-6-chloroimidazolo[1,2-b]pyridazin-2-carboxylic acid ester (468 mg, 1.0 mmol, 1.0 equivalent) in EA (10 mL). The resulting mixture was hydrogenated at 50 °C for 16 hours under hydrogen protection using a hydrogen chamber. The mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Select CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; mobile phase rate: 25 mL / min; gradient: from 30B to 55B over 7 min, 254 / 220 nm; RT1: 6.47 min; injection volume: 0.4 mL; number of runs: 8) to give methyl 8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazine-2-carboxylate (295 mg, 68%) as a grayish-white solid.

[0366] Step 3:

[0367] At 0 °C and in an air atmosphere, MeMgBr (0.60 mL, 1.800 mmol, 6.32 mmol) was added dropwise to a THF (10.00 mL) solution of methyl 8-(5-acetyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazine-2-carboxylic acid ester (123 mg, 0.285 mmol, 1.00 equivalence). The reaction was stirred at room temperature for 1 h. The reaction was monitored by LCMS, then quenched with aqueous NH4Cl solution and concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 35% to 55% over 15 min; detector, UV 254 nm. 1-(2-(4-fluorophenyl)-3-(2-(2-hydroxypropane-2-yl)imidazo[1,2-b]pyridazin-8-yl)-6,7-dihydropyrazol[1,5-a]pyrazin-5(4H)-yl)ethyl-1-one (29.5 mg, 24.0%) was obtained as a pale yellow solid.

[0368] Preparation of Compound I-27 in Examples 1-27

[0369] Figure 27 The synthetic scheme for compound I-27 is described. For example... Figure 27 As shown, the specific synthesis steps are as follows:

[0370] Step 1: Methyl 6-chloro-8-(2-(4-fluorobenzene)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-carboxylic acid ester

[0371] Cs₂CO₃ (2.3 g g, 6.9 mmol, 2.0 equivalence) and Pd(dppf)Cl₂CH₂Cl₂ (280 mg, 0.34 mmol, 0.1 equivalence) were added to a stirred mixture of methyl 8-bromo-6-chloroimidazolo[1,2-b]pyridazin-2-carboxylate (1 g, 3.4 mmol, 1.0 equivalence) and 1-(2-(4-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-diaxopentaborane-2-yl)-6,7-dihydropyrazole[1,5-a]pyrazin-5(4H)-yl)ethyl-1-one (1.3 g, 3.4 mmol, 1.0 equivalence) in toluene (15 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 100 °C under a nitrogen atmosphere. The resulting mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1:2) to give methyl 6-chloro-8-(2-(4-fluorobenzene)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-carboxylic acid ester (460 mg, 28%) as a light brown solid.

[0372] Step 2: Methyl 8-(2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydropyrazole[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-carboxylic acid ester

[0373] Pd / C (97 mg, 10%) was added to a solution of methyl 6-chloro-8-(2-(4-fluorobenzene)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-carboxylic acid ester (440 mg, 1.0 mmol, 1.0 equivalent) in EA (10 mL). The mixture was hydrogenated at 50 °C for 16 h using a hydrogen tire under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (column: X Select CSH Prep C18 OBD column, 19*250 mm, 5 μm; mobile phase A: water (0.05% FA), mobile phase B: ACN; mobile phase rate: 25 mL / min; gradient: from 30B to 55B over 7 min, 254 / 220 nm; RT1: 6.47 min; injection volume: 0.4 mL; number of runs: 8) to give methyl 8-(2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydropyrazol[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazine-2-carboxylate (280 mg, 69%) as a grayish-white solid.

[0374] Step 3:

[0375] MeMgBr (0.60 mL, 1.800 mmol, 6.32 equivalence) was added dropwise to a THF (10.00 mL) solution of methyl 8-(2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydropyrazol[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-carboxylic acid ester (123 mg, 0.285 mmol, 1.00 equivalence) at 0 °C and in air. The reaction was allowed to proceed for 1 h at room temperature. The reaction was monitored by LCMS, quenched with aqueous NH4Cl solution, and concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 35% to 55% over 15 min; detector, UV 254 nm. 2-(8-(2-(4-fluorophenyl)-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazo[1,2-b]pyridazin-2-yl)prop-2-ol (29.5 mg, 24.0%) was prepared as a pale yellow solid.

[0376] Preparation of Compound I-28 in Examples 1-28

[0377] Figure 28 The synthetic scheme for compound I-28 is described. For example... Figure 28 As shown, the specific synthesis steps are as follows:

[0378] Step 1:

[0379] A solution of methyl 8-[3-(4-fluorophenyl)-1-methylpyrazol-4-yl]imidazo[1,2-b]pyridazine-2-carboxylate [100 mg, 0.2846 mmol] in THF [5 mL] was added, followed by the addition of LAH [32.44 mg, 0.8538 mmol]. The reaction mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS, then quenched by H2O and concentrated under reduced pressure. The residues were purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% formic acid (FA) aqueous solution, gradient from 35% to 55% over 15 min; detector, UV 254 nm. (8-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazol[1,2-B]pyridazin-2-yl)methanol (29.5 mg, 29.50%) was obtained as a pale yellow solid.

[0380] Preparation of Compound I-29 in Examples 1-29

[0381] Figure 29 The synthetic scheme for compound I-29 is described. For example... Figure 29 As shown, the specific synthesis steps are as follows:

[0382] Step 1: 8-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxaldehyde

[0383] 8-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (985 mg, 3.05 mmol), 4-methylmorpholine N-oxide (465 mg, 3.97 mmol) and Molecular sieves (600 mg) were dissolved in anhydrous dichloromethane (30 mL) under an argon atmosphere. Tetrapropylperruthenate ammonium (107 mg, 0.305 mmol) was added in portions as a solid to the above solution, and the resulting solution was stirred at 25 °C for 16 hours. The crude reaction mixture was filtered through a diatomaceous earth filter and concentrated under vacuum. The crude product was purified by silica gel chromatography (300 g hexane-ethyl acetate elution gradient of 15-75%) to provide 8-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxaldehyde as a colorless oil.

[0384] Step 2:

[0385] MeMgBr (0.60 mL, 1.800 mmol, 6.32 equivalence) was added dropwise to a solution of 8-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxaldehyde (100 mg, 0.311 mmol, 1.00 equivalence) in THF (10.00 mL) under air atmosphere. The reaction was allowed to proceed for 1 h at room temperature. The reaction was monitored by LCMS, quenched with aqueous NH4Cl solution, and concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, acetonitrile (ACN) containing 0.1% aqueous formic acid (FA) in a gradient of 35% to 55% over 15 min; detector, UV 254 nm. 1-(8-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)ethyl-1-ol (29.5 mg, 28%) was obtained as a pale yellow solid.

[0386] Preparation of compound I-30 in Examples 1-30

[0387] Figure 30a and Figure 30b The synthetic scheme for compound I-30 is described. For example... Figure 30a As shown, the specific synthesis steps are as follows:

[0388] Step 1: (E)-3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (2)

[0389] A solution of 1-(4-fluorophenyl)ethyl-1-one (5.00 g, 36.20 mmol, 1.0 equivalence) in DMF-DMA (20 mL) was stirred at 100 °C for 2 h. After the reaction was complete, (E)-3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (6.92 g, 35.81 mmol, 98.92%) was a yellow solid, which was used directly in the next step. Chemical formula: Calculated for (M+H) + C 11 H 12 FNO: 193.22, Measured value: 194.

[0390] Step 2: 3-(4-fluorophenyl)-1H-pyrazole (3)

[0391] At room temperature, 98% (2.29 g, 45.75 mmol, 1.3 equivalence) of hydrazine monohydrate was added to a 30 mL solution of (E)-3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (6.80 g, 35.19 mmol, 1.0 equivalence) in EtOH. After addition, the mixture was stirred at 85 °C for 12 h. LC-MS showed the starting material disappeared. The mixture was concentrated and purified by silica gel column chromatography to give 3-(4-fluorophenyl)-1H-pyrazole (4.57 g, 28.18 mmol, 80.08%) as a yellow solid. Chemical formula: Calculated value (M+H) + C9H7FN2: 162.17, measured value: 163.

[0392] Step 3: 4-Bromo-3-(4-fluorophenyl)-1H-pyrazole (4)

[0393] NBS (5.92 g, 33.30 mmol, 1.2 equivalence) was added to a solution of 3-(4-fluorophenyl)-1H-pyrazole (4.50 g, 27.75 mmol, 1.0 equivalence) in DMF (25 mL). After addition, the mixture was stirred at 60 °C for 12 h. LC-MS showed that the starting material disappeared. The mixture was poured into water (200 mL), extracted with EtOA (100 mL × 3 times), and the combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄, concentrated, and purified by silica gel column to give crude 4-bromo-3-(4-fluorophenyl)-1H-pyrazole (5.04 g, 20.91 mmol, 75.36%) as a yellow solid. Chemical formula: (M+H) + Calculated value of C9H6BrFN2: 241.06, measured value: 241, 243.

[0394] Step 4: 4-Bromo-3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazole (5)

[0395] At room temperature, iodomethane-d3 (3.24 g, 22.36 mmol, 1.1 equivalence) and Cs2CO3 (13.25 g, 40.66 mmol, 2.0 equivalence) were added to a DMF (50 mL) solution of 4-bromo-3-(4-fluorophenyl)-1H-pyrazole (4.90 g, 20.33 mmol, 1.0 equivalence). After addition, the mixture was stirred at 10 °C for 10 h. LCMS showed that the starting material disappeared. The mixture was poured into water (250.0 mL), extracted with EtOAc (100.0 mL × 3 times), and the combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to give 4-bromo-3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazole (3.95 g, 15.31 mmol, 75.33%). Chemical formula: (M+H) + C 10 Calculated value of H5D3BrFN2: 258.11, measured value: 258, 260.

[0396] Step 5: 3-(4-fluorophenyl)-1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)-1H-pyrazole (6)

[0397] At room temperature, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-diaxoxopentaborane) (4.49 g, 17.66 mmol, 1.2 equivalence), Pd(dppf)Cl2 (538.54 mg, 0.736 mmol) and KOAc (2.89 g, 29.44 mmol, 2.0 equivalence) were added to a solution of 4-bromo-3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazole (3.80 g, 14.72 mmol, 1.0 equivalence) in dioxane (38 mL), Pd(dppf)Cl2 (538.54 mg, 0.736 mmol) and KOAc (2.89 g, 29.44 mmol, 2.0 equivalence). After addition, the mixture was stirred at 100°C under N2 for 6 hours. The mixture was concentrated and purified by rapid column chromatography (petroleum ether:EtOAc = 60:40) to give 3-(4-fluorophenyl)-1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (3.75 g, 12.29 mmol, 83.49%) as a white solid. Chemical formula: (M+H) + C 16 H 17 The calculated value of D3BFN2O2 is 305.17, and the measured value is 306.

[0398] like Figure 30b As shown, the specific synthesis steps are as follows:

[0399] Step 1: Methyl 8-bromo-6-chloroimidozolo[1,2-b]pyridazine-2-carboxylate (8)

[0400] A solution of 4-bromo-6-chloropyridazin-3-amine (5.00 g, 23.99 mmol, 1.0 equivalence) and methyl 3-bromo-2-oxopropionate (17.37 g, 95.96 mmol, 4.0 equivalence) in DME (50 mL) was stirred at room temperature under air. The reaction was stirred at 90 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to give methyl 8-bromo-6-chloroimidazolo[1,2-b]pyridazin-2-carboxylate (5.73 g, 19.72 mmol, 82.20%) as a grayish-white solid. Chemical formula: (M+H) + Calculated value of C8H5BrClN3O2: 290.50, measured value: 290, 292.

[0401] Step 2: Methyl 6-chloro-8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylate (9)

[0402] Cs₂CO₃ (7.87 g, 24.14 mmol, 2.0 equivalent) and Pd(dppf)Cl₂CH₂Cl₂ (995 mg, 1.207 mmol, 0.1 equivalent) were added to a stirred mixture of methyl 8-bromo-6-chloroimidazolo[1,2-b]pyridazine-2-carboxylate (3.50 g, 12.07 mmol, 1.0 equivalent) and 3-(4-fluorophenyl)-1-(methyl-d3))-4-(4,4,5,5-tetramethyl-1,3,2-dihexylborane-2-yl)-1H-pyrazole (3.68 g, 12.07 mmol, 1.0 equivalent) in a mixture of DME (60 mL) and water (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 100 °C under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:2) to give methyl 6-chloro-8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylate (3.53 g, 9.08 mmol, 75.26%), as a light brown solid. Chemical formula: (M+H + C 18 H 10 Calculated value of D3ClFN5O2: 388.80, measured value: 389.

[0403] Step 3: methyl 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylate (10)

[0404] At room temperature and under a nitrogen atmosphere, 10% Pd / C (340 mg, 10% w / w) was added to a solution of methyl 6-chloro-8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylate (3.40 g, 8.74 mmol, 1.0 equivalence) in EA (35 mL). The mixture was stirred in hydrogen at 25 °C for 16 h. After the reaction was complete, the resulting mixture was filtered and the filter cake was washed with MeOH (50 mL x 3 times). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give methyl 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylate (2.75 g, 7.76 mmol, 88.78%) as a grayish-white solid. Chemical formula: (M+H) + C 18 H 11 Calculated value of D3FN5O2: 354.36, measured value: 355.

[0405] Step 4: 2-(8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)prop-2-ol (I-30)

[0406] Under a nitrogen atmosphere, methyl 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl carboxylate (500 mg, 1.41 mmol, 1.00 equivalence) in THF (10.00 mL) was added dropwise with MeMgBr (3.53 mL, 7.05 mmol, 5.0 equivalence). The reaction was allowed to proceed at room temperature for 1 h. The reaction was monitored by LCMS, quenched with aqueous NH4Cl solution, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give 2-(8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)prop-2-ol (344.22 mg, 0.96 mmol, 68.32%) as a pale yellow solid. Chemical formula: (M+H) + C 19 H 15 Calculated value of D3FN5O: 354.40, measured value: 355.

[0407] Preparation of compound I-31 in Examples 1-31

[0408] Figure 31 The synthetic scheme for compound I-31 is described. For example... Figure 31 As shown, the specific synthesis steps are as follows:

[0409] Step 1: (8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (I-31)

[0410] LiAlH4 (385.57 mg, 10.16 mmol, 2.0 equivalence) was added to a stirred mixture of methyl 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-carboxylate (1.80 g, 5.08 mmol, 1.00 equivalence) in THF (15.00 mL) under a nitrogen atmosphere. The reaction was allowed to proceed for 1 h at room temperature. The reaction was monitored by LCMS, quenched with aqueous NH4Cl solution, extracted with EtOAc (20.0 mL × 3 times), and the combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography to yield (8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (1.25 g, 3.83 mmol, 75.31%) as an oil. Chemical formula: (M+H + C 17 H 11 Calculated value of D3FN5O: 326.35, measured value: 327.

[0411] Preparation of compound I-32 in Examples 1-32

[0412] Figure 32 The synthetic scheme for compound I-32 is described. For example... Figure 32 As shown, the specific synthesis steps are as follows:

[0413] Step 1: (8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (I-31)

[0414] LiAlH4 (385.57 mg, 10.16 mmol, 2.0 equivalence) was added to a solution of methyl 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylate (1.80 g, 5.08 mmol, 1.00 equivalence) in THF (15.00 mL) under a nitrogen atmosphere. The reaction was allowed to proceed for 1 h at room temperature. The reaction was monitored by LCMS, quenched with aqueous NH4Cl solution, extracted with EtOAc (20.0 mL × 3 times), and the combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography to yield (8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (1.25 g, 3.83 mmol, 75.31%) as an oil. Chemical formula: (M+H + C 17 H 11 Calculated value of D3FN5O: 326.35, measured value: 327.

[0415] Step 2: (8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methylamine (I-32)

[0416] (8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (450 mg, 1.38 mmol, 1.00 equivalence) was dissolved in ammonia-methanol solution (10 mL). The mixture was reacted at 40 °C for 10 h, and the reaction was monitored by LCMS. The reaction system was concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography to obtain (8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methylamine (292.83 mg, 0.90 mmol, 65.26%) as an oil. Chemical formula: (M+H) + C 17 H 12 Calculated value of D3FN6: 325.37, measured value: 326.

[0417] Preparation of compound I-33 in Examples 1-33

[0418] Figure 33 The synthetic scheme for compound I-33 is described. For example... Figure 33 As shown, the specific synthesis steps are as follows:

[0419] Step 1: 1-(8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)-N-methylmethylamine (I-33)

[0420] (8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)methanol (450 mg, 1.38 mmol, 1.00 equivalence) was added to a solution of methylamine in MeOH (10 mL). The mixture was stirred at 40 °C for 10 h. The reaction was monitored by LCMS, and the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give 1-(8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)-N-methylmethylamine (329.21 mg, 0.97 mmol, 70.15%) as a white solid. Chemical formula: (M+H) + C 18 H 14 Calculated value of D3FN6: 339.39, measured value: 340.

[0421] Preparation of compound I-34 in Examples 1-34

[0422] Figure 34 The synthetic scheme for compound I-34 is described. For example... Figure 34 As shown, the specific synthesis steps are as follows:

[0423] Step 1: 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylic acid (15)

[0424] Methyl 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylate (450 mg, 1.27 mmol, 1.0 equivalence) was dissolved in a mixture of MeOH (10 mL) and water (5 mL), and LiOH·H2O (133.43 mg, 3.18 mmol, 2.5 equivalence) was added. The reaction was carried out at 35 °C for 4 h, and the reaction was monitored by LCMS. The pH of the reaction system was adjusted to 5–6, and the mixture was extracted with EtOAc (15.0 mL × 3 times). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography to provide 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-2-carboxylic acid (377.77 mg, 1.11 mmol, 87.20%) as an oil. Chemical formula: (M+H + C17 Calculated value of H9D3FN5O2: 340.33, measured value: 341.

[0425] Step 2: (8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)tert-butyl carbamate (16)

[0426] 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-carboxylic acid (350 mg, 1.03 mmol, 1.0 equivalence) was dissolved in t-BuOH (10 mL), and DPPA (341.25 mg, 1.24 mmol, 1.2 equivalence) and TEA (261.07 mg, 2.58 mmol, 2.5 equivalence) were added. The reaction was carried out at 85 °C for 4 h, and the reaction was monitored by LCMS. The reaction system was quenched with water and extracted with EtOAc (15.0 mL x 3 times). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried with Na2SO4, and the organic phases were combined and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography to give tert-butyl(8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)carbamate (308.60 mg, 0.75 mmol, 73.18%) as a white solid. Chemical formula: (M+H + C 21 H 18 Calculated value of D3FN6O2: 411.46, measured value: 412.

[0427] Step 3: 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-amine (I-34)

[0428] tert-butyl(8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-yl)carbamate (300 mg, 0.73 mmol, 1.0 equivalence) was dissolved in DCM (10 mL), and then TFA (0.5 mL) was added. The reaction was carried out at 25 °C for 4 h, and the reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography to give 8-(3-(4-fluorophenyl)-1-(methyl-d3)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-2-amine (155.67 mg, 0.50 mmol, 68.37%) as a white solid. Chemical formula: (M+H) + C 16 H 10Calculated value of D3FN6: 311.34, measured value: 312.

[0429] Example 2 Bioactivity Assay

[0430] CK1δ kinase activity was determined using a buffer (40 μL, pH 7.5) containing 50 mmol / L Tris (tris(hydroxymethyl)aminomethane), 10 mmol / L MgCl2, 1 mmol / L dithiothreitol, 100 μg / mL BSA (bovine serum albumin), 10 μg / mL ATP (adenosine triphosphate), 2 nanomol / L wild-type CK1δ, and 42 μmol / L peptide substrate PLSRTLpSVASLPGL (Flotow et al., 1990) in the presence of 1 μL CK1δ inhibitor (e.g., the compound of this application) or 4% DMSO (e.g., as a control). The reaction mixture was incubated at 25 °C for 85 min; Kinase-Glo assay (Promega) was performed as described above. The luminescence output was measured on a Perkin Elmer Envision plate reader (PerkinElmer, Waltham, MA).

[0431] Bmal1-dLuc or Per2-dLuc U2OS cells were suspended in DMEM culture medium (added with 10% fetal bovine serum, 0.29 mg / mL L-glutamine, 100 IU / mL penicillin, and 100 mg / mL streptomycin) and seeded into 96-well white solid plates at 200 μL per well (10,000 cells). After 2 days, 100 μL of ex vivo culture medium (DMEM supplemented with 2% B27, 10 mmol / L HEPES, 0.38 mg / mL sodium bicarbonate, 0.29 mg / mL L-glutamine, 100 IU / mL penicillin, 100 mg / mL streptomycin, 0.1 mg / mL gentamicin, and 1 mmol / L fluorescein, pH 7.2) was dispensed into each well, followed by 1 μL of the compound of this application (dissolved in DMSO; final DMSO concentration 0.7%). The plate was covered with an optically transparent membrane and placed in the microplate reader (Infinite M200, Tecan). Bioluminescence was recorded every hour for 3-4 days. The cycle parameters were obtained by fitting the bioluminescence rhythm using either CellulaRhythm or MultiCycle (Actimetrics) programs; the results from both programs were similar.

[0432] Table 2 summarizes the results of CK1δ inhibition (EC50).

[0433] Table 2

[0434]

[0435]

[0436] Example 3 Drug Transport Assay

[0437] 1. Preparation of Caco-2 cells

[0438] 1) Add 50 μL and 25 mL of cell culture medium to each well of the upper and lower chambers of the Transwell culture plate, respectively. Then, incubate the HTS transwell culture plate at 37°C and 5% CO2 for 1 hour before cell seeding.

[0439] 2) Dilute Caco-2 cells to 6.86 x 10⁻⁶ using culture medium. 5 Cells per mL: dispense 50 μL of cell suspension into the upper chamber of a 96-well HTS Transwell plate. Incubate cells at 37°C, 5% CO2, and 95% relative humidity for 14–18 days. Change the cell culture medium every other day, no later than 24 hours after initial plating.

[0440] 2. Preparation of stock solutions

[0441] A 10 mmol / L stock solution of the test compound was prepared in DMSO. A stock solution of the positive control was also prepared in DMSO at a concentration of 10 mmol / L. Digoxin and propranolol were used as control compounds in this assay.

[0442] 3. Assessment of cell monolayer integrity

[0443] 1) Remove the culture medium from the upper and lower chambers of each Transwell culture plate and replace it with preheated fresh culture medium.

[0444] 2) Transmembrane impedance (TEER) was measured using the Millicell Epithelial Volt-Ohm measurement system (Millipore, USA).

[0445] 3) After the measurement is completed, put the culture plate back into the incubator.

[0446] The TEER value is calculated using the following formula: TEER measurement (ohms) * membrane area (cm²) = TEER value (ohms·cm²). The TEER value should be greater than 230 ohms·cm², which indicates that the Caco-2 monolayer is qualified.

[0447] 4. Testing Procedure

[0448] 1) Remove the Caco-2 culture plate from the incubator, wash it twice with preheated HBSS (10 mmol / L HEPES, pH 7.4), and then incubate it at 37°C for 30 minutes.

[0449] 2) Dilute the stock solutions of the control and test compounds in DMSO to obtain a 1 mmol / L solution, then dilute with HBSS (10 mmol / L HEPES, pH 7.4) to obtain a 5 μmol / L working solution. The final concentration of DMSO in the incubation system is 0.5%.

[0450] 3) To determine the drug transport rate from the top to the outer side of the substrate, 125 μL of working solutions of the control and test compounds at 5 μmol / L were added to the top chamber of a Transwell plate, and 50 μL of sample (D0 sample) was immediately transferred from the top chamber to a new 96-well plate. 235 μL of HBSS (10 mmol / L HEPES, pH 7.4) was added to the bottom chamber (outer side of the substrate).

[0451] 4) To determine the drug transport rate from the outer substrate to the top, 285 μL of working solutions of the control compound and the test compound at 5 μmol / L were added to the lower chamber (outer substrate portion), and immediately 50 μL of sample (D0 sample) was transferred from the outer substrate chamber to a new 96-well plate. 75 μL of HBSS (10 mmol / L HEPES, pH 7.4) was added to the upper chamber (top portion) of the Transwell plate. This assay was performed in duplicate.

[0452] 5) Incubate the culture plate at 37°C for 2 hours.

[0453] 6) At the end of the incubation, 50 μL of sample from the donor side (Ap→Bl flowing towards the top and Bl→Ap flowing towards the outer side of the substrate) and from the receiver side (Ap→Bl flowing towards the outer side of the substrate and Bl→Ap flowing towards the top) were transferred to the wells of a new 96-well plate, and then 4 volumes of cold methanol containing an appropriate internal standard (IS) were added. The sample was vortexed for 5 minutes and then centrifuged at 3,220 g for 40 minutes. Before LC-MS / MS analysis, 100 μL aliquots of the supernatant were mixed with an appropriate amount of ultrapure water.

[0454] 7) To determine leakage of fluorescein during the 2-hour transport period, a fluorescein stock solution was prepared in water and diluted with HBSS (10 mmol / L HEPES, pH 7.4) to a final concentration of 100 μmol / L. 100 μL of the fluorescein solution was added to each Transwell plate chamber (top portion), followed by 300 μL of HBSS (10 mmol / L HEPES, pH 7.4) to the lower chamber (outer basal portion). The plates were incubated at 37°C for 30 minutes. 80 μL of sample was removed directly from both the upper and lower chambers (using the lower chamber wells) and transferred to the wells of a new 96-well plate. The fluorescence signal of the yellow fluorescence (to monitor the integrity of the monolayer cells) was measured using a fluorescein plate reader with excitation at 485 nm and emission at 530 nm.

[0455] 5. Data Analysis

[0456] Apparent permeability (Papp), measured in centimeters per second, can be calculated using the following formula for Caco-2 drug transport assays:

[0457] P app =(V A ×[Medication] 接收 ) / (Area × Time × [Drug] 初始，供体 )

[0458] Where V A The volume in the receiving aperture is in milliliters, the area is the surface area of ​​the membrane (0.143 square centimeters for the Transwell-96 permeable membrane), and the time is the total transport time in seconds.

[0459] The outflow rate will be determined using the following formula:

[0460] Outflow ratio = P app(B-A) / P app(A-B)

[0461] Where P app(B-A) P represents the apparent permeability coefficient from the outer side of the substrate to the top. app(A-B) It represents the apparent permeability coefficient in the direction from the top to the outer side of the substrate.

[0462] The recovery rate can be determined using the following formula:

[0463] Recovery rate % = (V A ×[Medication] 接收 +V D ×[Medication] 供体 ) / (V D ×[Medication] 初始，供体 )

[0464] Where V AThis refers to the volume in the receiving port (in milliliters) (0.235 ml for the Ap→Bl flow direction, and 0.075 ml for the Bl→Ap flow direction), V D This refers to the volume in the donor well (in milliliters) (0.075 ml for the Ap→Bl flow direction and 0.235 ml for the Bl→AP flow direction).

[0465] The leakage of fluorescent yellow, expressed as a percentage (%), can be calculated using the following formula:

[0466] %LY leakage = 100 × [LY] 接收 / ([LY] 供体 +[LY] 接收 )

[0467] <1% LY leakage is acceptable, indicating qualified Caco-2 monolayer cells.

[0468] P app(B-A) P app(A-B) The outflow and outflow ratios are summarized in Table 3.

[0469] Table 3

[0470]

[0471] Example 4: Determination of Intrinsic Scavenging Rate

[0472] 1. Prepare the mother liquor according to Table 4.

[0473] Table 4

[0474]

[0475]

[0476] 2. Three separate experiments were conducted as follows: a) With NADPH: 10 μL of 20 mg / mL liver microsomes and 40 μL of 10 mmol / L NADPH were added to the culture. The final concentrations of liver microsomes and NADPH were 0.5 mg / mL and 1 mmol / L, respectively. b) Without NADPH: 10 μL of 20 mg / mL liver microsomes and 40 μL of ultrapure water were added to the culture. The final concentration of liver microsomes was 0.5 mg / mL. c) Without NADPH, heat-inactivated microsomes: 10 μL of 20 mg / mL heat-inactivated liver microsomes and 40 μL of ultrapure water were added to the culture. The final concentration of microsomes was 0.5 mg / mL.

[0477] 3. Start the reaction by adding 4 μL of 200 μmol / L test compound solution or control compound solution at 37°C, with a final concentration of 2 μmol / L.

[0478] 4. Remove 50 μL aliquots of the sample from the reaction solution at 0, 15, 30, 45, and 60 minutes. Terminate the reaction by adding 4 volumes of cold acetonitrile containing internal standards IS (100 nmol / L alprazolam, 200 nmol / L labetalol, 200 nmol / L caffeine, and 2 μM / L ketoprofen). Centrifuge the sample at 3,220 g (3,220 times the acceleration due to gravity) for 40 minutes. Mix 100 μL of the supernatant with 100 μL of ultrapure water and then perform LC-MS / MS analysis.

[0479] 5. Data Analysis

[0480] All calculations were performed using Microsoft Excel.

[0481] Peak area was determined by the extracted ion chromatogram. Slope value k was determined by linear regression of the remaining percentage of parent drug versus the natural logarithm of the incubation time curve.

[0482] In vitro half-life (in vitro t) 1 / 2 Determined by the slope value:

[0483] In vitro t 1 / 2 =-(0.693 / k)

[0484] The in vitro t-values ​​were calculated using the following formula (average of repeated measurements). 1 / 2 (minutes) converted to in vitro intrinsic clearance rate (in vitro CL) int (Unit: μL / min / mg protein):

[0485] In vitro CL int = (0.693 * incubation volume (µL)) / (in vitro t) 1 / 2 *Protein content (mg))

[0486] The in vitro t-values ​​were calculated using the following formula (average of repeated measurements). 1 / 2 (minutes) converted to amplified non-binding intrinsic clearance rate (amplified CL) int (in milliliters / minutes / kilograms):

[0487] Table 5 summarizes the proportional factors for predicting the intrinsic clearance rate in liver microsomes.

[0488] Table 5

[0489]

[0490] a. Iwatsubo et al., Davies and Morris, 1993, 10(7), pp. 1093-1095.

[0491] b. Barter et al., 2007, Curr Drug Metab, 8(1), pp. 33-45; Iwatsubo et al., 1997, JPET,

[0492] 283 Pages 462-469.

[0493] Table 6 summarizes the data on the in vitro intrinsic clearance rate of liver microsomes.

[0494] Table 6

[0495]

[0496] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. The invention is not limited to the specific examples within the specification. Although the invention has been described with reference to the foregoing description, the description and illustrations of the embodiments herein are not intended to be limiting. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it should be understood that all aspects of the invention are not limited to the specific descriptions, structures, or relative proportions depending on various conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. Therefore, the invention is also intended to cover any such substitutions, modifications, variations, or equivalents. The appended claims are intended to define the scope of the invention, and the methods and structures within the scope of these claims and their equivalents are thereby covered.

Claims

1. A compound selected from: ， ， ， ， ， ， ， ， ， ， ， ， or a pharmaceutically acceptable salt.

2. A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

3. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and / or treatment of a disease or disorder.

4. Use according to claim 3, characterized in that, The disease or disorder is selected from the group consisting of neurological and psychiatric diseases.

5. Use according to claim 3, characterized in that, The disease or disorder is selected from the group consisting of mood disorders, sleep disorders, and circadian rhythm disorders.

6. Use according to any one of claims 3 to 5, wherein the compound is of formula (I) ###00001### (I) or a pharmaceutically acceptable salt thereof. The disease or disorder is selected from the group consisting of depression and bipolar disorder.

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