Pyrrolo[2,1-f][1,2,4]triazine derivatives and their applications

Abstract

The present invention provides a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I). The compound of the present invention has a strong inhibitory activity against TTK and is used as a novel TTK inhibitor for the treatment of tumors. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to pyrrolo[2,1-f][1,2,4]triazine derivatives and applications thereof. Background Art

[0002] The spindle assembly checkpoint (SAC) is one of the main checkpoints in the cell cycle. SAC monitors the arrangement of chromosomes at the equatorial plate and their separation to the two poles of the spindle, ensuring the adhesion of kinetochore-microtubules and the integrity of mitosis, so that all chromosomes are placed at the equatorial plate and enter the late stage after bipolar orientation, ensuring that chromosomes are accurately distributed to daughter cells during mitosis. When spindle microtubules are incorrectly connected to chromosomes or errors occur in spindle assembly, the spindle checkpoint is activated and the cell cycle process is inhibited. There have been reports of overexpression or non-expression of SAC members in various types of cancer. In most cases, the expression status of SAC members is associated with high proliferation activity and poor prognosis of tumors.

[0003] Threonine and Tyrosine Kinase (TTK), also known as Mps1 (Monopolar Spindle 1), is a key kinase for the activation and maintenance of SAC function. TTK is almost undetectable in normal tissues except for testis and placenta. However, TTK mRNA levels are elevated in many human cancers, including papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer and lung cancer. Inhibition of TTK can cause SAC function deficiency, leading to premature exit from mitosis and severe chromosome missegregation, ultimately leading to cancer cell death.

[0004] Therefore, TTK inhibitors have great potential for treating tumors. Summary of the invention

[0005] The present invention relates to a class of pyrrolo[2,1-f][1,2,4]triazine derivatives, which, through in vitro biological activity tests, show strong inhibitory activity on TTK and have the potential to be used as a class of novel TTK inhibitors for the treatment of tumors.

[0006] The present invention provides a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I),

[0007]

[0008] Among them, R 1 , R 2 , R 3, R 4 , R 5 , R 6 , L 2 , R′ and m have the same definitions as described in the present invention.

[0009] In other embodiments, L 2 is a key or O;

[0010] R 1 , R 2 , R 4 , R 5 Each independently represents H, F, Cl, Br, CN, NO 2 、-OR b 、-NR c R d , C 1-6 alkyl;

[0011] R 3 -C(=O)R a 、-C(=O)OR b 、-S(=O) 2 R b 、-C(=O)NR c R d 、-OR b 、-NR c R d , R b OC 1-4 Alkylene, R d R c NC 1-4 Alkylene, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-10 atoms or (heteroaryl composed of 5-10 atoms)-C 1-4 Alkylene, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl consisting of 5-10 atoms and (heteroaryl consisting of 5-10 atoms)-C 1-4 Each alkylene group is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene;

[0012] R 6 H or

[0013] Among them, L 1 N or O;

[0014] A 1 and A 2 Each is independent of H and C 1-6 Alkyl, C 3-12 Carbocyclic group, C 3-12 Carbocyclyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms, (heteroaryl composed of 5-14 atoms)-C 1-4 Alkylene, or A 1 , A 2 and the L connected to them 1 Together, they form a heterocyclic ring consisting of 3 to 6 atoms, wherein the C 1-6 Alkyl, C 3-12 Carbocyclic group, C 3-12 Carbocyclyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms, (heteroaryl composed of 5-14 atoms)-C 1-4Alkylene, or A 1 , A 2 and the L connected to them 1 together, form a heterocyclic ring of 3 to 6 atoms, each independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R', provided that A 1 and A 2 Not at the same time H;

[0015] Each R' is independently H, F, Cl, Br, CN, NO 2 ,=O,-OR b 、-NR c R d 、-S(=O) 2 R b , C 1-6 Alkyl|、C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms, wherein the C 3-8 Cycloalkyl, heterocyclic group consisting of 3-12 atoms, C 6-10 The aryl or heteroaryl consisting of 5-10 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene;

[0016] m is 0, 1, 2 or 3;

[0017] The condition is that when R 6 When H, m is not 0, and at least one R' is C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms, wherein the C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, C 6-10 The aryl or heteroaryl consisting of 5-10 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from F, Cl, Br, CN, =O, -ORb 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene;

[0018] R a , R b , R c , R d Each independently is H, C 1-6 Alkyl, C 1-6 Haloalkyl, heterocyclic group consisting of 3-6 atoms or R c , R d Together with the nitrogen atom to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms, wherein the C 1-6 The alkyl group and the heterocyclic ring composed of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, wherein the substituents are independently selected from F, Cl, CN, OH, NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Alkylamino.

[0019] In other embodiments, the present invention relates to a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (II).

[0020]

[0021] Among them, R 1 , R 3 , L 2 , R′ and m have the same definitions as described in the present invention.

[0022] In other embodiments, X is the following sub-structure:

[0023]

[0024] Ring W is C 3-8 Cycloalkyl, heterocyclic ring composed of 3-8 atoms, benzene or heteroaromatic ring composed of 5-6 atoms; each R w H, F, Cl, Br, CN, NO independently 2 ,=O,-OR b 、-NRc R d 、-S(=O) 2 R b , C 1-6 Alkyl or C 1-6 Haloalkyl; R 6 , R 7 Each independently is H, C 1-6 Alkyl; s is 0, 1, 2 or 3.

[0025] In other embodiments, the present invention relates to a compound of formula (III) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (III).

[0026]

[0027] Among them, R 1 , R 3 , L 2 , Y, R Y and q have the definitions as described in the present invention.

[0028] In other embodiments, ring Y is C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, a heterocyclic ring composed of 3-8 atoms, benzene or a heteroaromatic ring composed of 5-6 atoms; each R Y H, F, Cl, Br, CN, NO independently 2 ,=O,-OR b 、-NR c R d 、-S(=O) 2 R b , C 1-6 Alkyl or C 1-6 haloalkyl; q is 0, 1, 2 or 3.

[0029] In other embodiments, the R 2 , R 4 , R 5 Each is independently H.

[0030] In other embodiments, the R 3 -C(=O)NR c R d , OR b 、-NR c R d 、-S(=O) 2 R b , heterocyclic group consisting of 3-6 atoms, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C6-9 Aryl, C 6-9 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-9 atoms or (heteroaryl composed of 5-9 atoms)-C 1-4 Alkylene.

[0031] In other embodiments, the A 1 and A 2 Each is independent of H and C 1-6 Alkyl, C 3-6 Carbocyclic group, C 3-6 Carbocyclyl-C 1-4 Alkylene, heterocyclic group consisting of 3-6 atoms, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C 6-8 Aryl, C 6-8 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-8 atoms, (heteroaryl composed of 5-8 atoms)-C 1-4 Alkylene, or A 1 , A 2 and the L connected to them 1 Together, they form a heterocyclic ring consisting of 3 to 6 atoms.

[0032] In other embodiments, each R′ is independently H, F, Cl, Br, CN, NO 2 ,=O,-OR b 、-NR c R d 、-S(=O)OR b , C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-8 Aryl or heteroaryl consisting of 5 to 8 atoms, wherein the C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-8 The aryl or 5-8-atom heteroaryl is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene.

[0033] In other embodiments, the R a , R b , R c , R d are independently H, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, C 1-3 Haloalkyl, heterocyclic group consisting of 3-6 atoms or R c , R d Together with the nitrogen atoms to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms.

[0034] In other embodiments, the A 1 and A 2 Each is independent of H and C 1-6 Alkyl, C 3-6 Carbocyclic group, heterocyclic group composed of 3-6 atoms, C 6-8 Aryl, heteroaryl composed of 5-8 atoms.

[0035] In other embodiments, the R 3 -C(=O)NR c R d , OR b 、-NR c R d 、-S(=O) 2 R b , heterocyclic radical composed of 3-6 atoms, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiyl, wherein the heterocyclic radical composed of 3-6 atoms, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents, and the substituents are independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene.

[0036] In other embodiments, the ring W is C 3-6Cycloalkyl, heterocyclic group composed of 3-6 atoms, phenyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl.

[0037] In other embodiments, the R w H, F, Cl, Br, CN, NO independently 2 ,=O,-OR b 、-NR c R d 、-S(=O) 2 R b , methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl or C 1-6 Halogenated alkyl.

[0038] In other embodiments, the ring Y is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, a heterocyclic group consisting of 3 to 6 atoms, phenyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, 3,6-dihydro-2H-pyran or tetrahydro-2H-pyran.

[0039] In other embodiments, the R Y H, F, Cl, Br, CN, NO independently 2 ,=O,-OR b 、-NR c R d 、-S(=O) 2 R b , methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl or C 1-6 Halogenated alkyl.

[0040] In other embodiments, the present invention relates to a compound represented by formula (IV) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (IV).

[0041]

[0042] Among them, ring V, ring W, R 1 , L 2 , R', R w , R V , s, p, and m have the definitions described in the present invention.

[0043] In other embodiments, the present invention relates to a compound represented by formula (V) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (V),

[0044]

[0045] Among them, ring V, R 1 , L 2 , R', R w , R V , s, p, and m have the definitions as described in the present invention.

[0046] In other embodiments, the present invention relates to a compound of formula (VI) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (VI).

[0047]

[0048] Among them, ring V, ring Y, R 1 , L 2 , R V , R V , p, q have the definitions as described in the present invention.

[0049] In other embodiments, the present invention relates to a structure represented by formula (VII) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (VII).

[0050]

[0051] Among them, ring W, R 1 , R a , R b , L 2 , R', R w , s, and m have the definitions described in the present invention.

[0052] In other embodiments, the present invention relates to a compound represented by formula (VIII) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (VIII).

[0053]

[0054] Among them, ring W, R 1 , R b , L 2 , R', R w, s, and m have the definitions described in the present invention.

[0055] In other embodiments, the present invention relates to a structure represented by formula (VIIII) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (VIIII).

[0056]

[0057] Among them, ring W, R 1 , R b , L 2 , R', R w , s, and m have the definitions described in the present invention.

[0058] In other embodiments, ring V is C 3-8 Cycloalkyl, heterocyclic ring composed of 3-8 atoms, benzene or heteroaromatic ring composed of 5-6 atoms; R V F, Cl, Br, CN, -OH, =O, C 1-6 Alkyl or C 1-6 p is 0, 1, 2 or 3.

[0059] In other embodiments, the present invention relates to a compound having one of the following structures, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof having the structure shown below.

[0060]

[0061] In other embodiments, the present invention relates to a pharmaceutical composition comprising an effective amount of the aforementioned compound.

[0062] In some other embodiments, the pharmaceutical composition further comprises: a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

[0063] In other embodiments, the pharmaceutical composition further comprises one or more therapeutic agents, wherein the therapeutic agents are selected from other anti-tumor drugs.

[0064] In other embodiments, the therapeutic agent is an anti-mitotic drug, an alkylating agent, an antimetabolite drug, a topoisomerase inhibitor, an estrogen receptor modulator, an androgen receptor modulator, a small molecule inhibitor targeting protein kinase, or an antibody drug targeting protein kinase.

[0065] In some other embodiments, the anti-mitotic drug is paclitaxel or vincristine.

[0066] In other embodiments, the alkylating agent is cisplatin, oxaliplatin, carboplatin, or cyclophosphamide.

[0067] In other embodiments, the antimetabolite drug is gemcitabine, 5-fluorouracil, or methotrexate.

[0068] In other embodiments, the topoisomerase inhibitor is epipodophyllotoxin, etoposide, topotecan, or camptothecin.

[0069] In other embodiments, the estrogen receptor modulator is tamoxifen or fulvestrant.

[0070] In other embodiments, the androgen receptor modulator is bicalutamide.

[0071] In some other embodiments, the small molecule inhibitor targeting protein kinase is dasatinib, bosutinib, gefitinib, erlotinib, lapatinib, imatinib, nilotinib, sorafenib, tipifarnib, sunitinib, or axitinib.

[0072] In some other embodiments, the antibody drug targeting protein kinase is trastuzumab, panitumumab, or cetuximab.

[0073] In other embodiments, the present invention relates to the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to prevent, manage, treat or alleviate a disease associated with TTK overexpression or overactivity in a patient.

[0074] In some other embodiments, the disease associated with TTK overexpression is a tumor.

[0075] In other embodiments, the tumor is papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial carcinoma or lung cancer.

[0076] In other embodiments, the present invention relates to the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to inhibit TTK.

[0077] Unless otherwise stated, the present invention includes all stereoisomers, geometric isomers, tautomers, solvates, hydrates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention.

[0078] In some embodiments, the salts are pharmaceutically acceptable salts.The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0079] The compounds of the present invention also include salt forms thereof, which are not necessarily pharmaceutically acceptable salts but are intermediates useful for preparing and / or purifying the compounds of the present invention and / or for separating the enantiomers of the compounds of the present invention.

[0080] The compounds of the present invention, including their salts, may also be obtained in the form of their hydrates, or include other solvents for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention also includes their solvated and unsolvated forms.

[0081] On the other hand, the compounds of the invention may contain several asymmetric centers or may be in the form of racemic mixtures as generally described herein. The invention further encompasses racemic mixtures, partially racemic mixtures, and isolated enantiomers and diastereomers.

[0082] The compounds of the present invention may exist in the form of one of possible isomers, rotational isomers, atropisomers, tautomers or mixtures thereof. The present invention may further include mixtures of isomers, rotational isomers, atropisomers and tautomers of the compounds of the present invention, or partial mixtures of isomers, rotational isomers, atropisomers and tautomers or separated isomers, rotational isomers, atropisomers and tautomers.

[0083] On the other hand, the compounds of the present invention include compounds defined in the present invention which are labeled with various isotopes, for example, wherein a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 Compounds of C.

[0084] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I).

[0085] The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and complete below.

[0086] Definitions and general terms

[0087] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formula and chemical formula. The present invention is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included in the scope of the present invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described in the present invention can be used to practice the present invention. The present invention is by no means limited to the methods and materials described in the present invention. In the event that one or more of the combined documents, patents and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0088] It should be further appreciated that certain features of the invention, which for clarity are described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in a single embodiment, may also be provided separately or in any suitable sub-combination.

[0089] Unless otherwise noted, technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs. Unless otherwise noted, all patent publications cited in the entire disclosure of the present invention are incorporated herein by reference in their entirety.

[0090] The following definitions shall apply to the present invention unless otherwise indicated. For the purposes of this invention, the chemical elements are those according to the Periodic Table of the Elements, CAS version and the Handbook of Chemicals, 75, th Ed, 1994. In addition, the general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, and all contents of the present invention are incorporated by reference.

[0091] The term "subject" as used in the present invention refers to an animal. Typically, the animal is a mammal. Subjects also refer to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0092] The terms "subject" and "patient" used in the present invention are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails or turkeys or mammals), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs and mice) and primates (e.g., monkeys, chimpanzees and humans), more particularly humans. In one embodiment, the subject is a non-human animal, such as livestock (e.g., horses, cows, pigs or sheep) or a pet (e.g., dogs, cats, guinea pigs or rabbits). In other embodiments, "patient" refers to humans.

[0093] The present invention also includes isotopically labeled compounds of the present invention which are identical to those described herein except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 Oh, 17 Oh, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0094] Compounds of the invention containing the aforementioned isotopes and / or other isotopes of other atoms and pharmaceutically acceptable salts of the compounds are included within the scope of the invention. Isotopically labeled compounds of the invention, for example radioactive isotopes, such as 3 H and 14 C incorporation into the compounds of the present invention can be used for drug and / or substrate tissue distribution analysis. Due to the ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, heavy isotopes, such as deuterium, 2 H substitution may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0095] The stereochemical definitions and conventions used herein are generally in accordance with SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes d and l or (+) and (–) are the signs used to designate the rotation of plane polarized light caused by a compound, where (–) or l indicates that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0096] Depending on the choice of starting materials and processes, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as isomer mixtures, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)-isomers may be prepared using chiral synthons or chiral agents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis- or trans- configuration.

[0097] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0098] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomers, diastereomeric atropisomers, and geometric (or conformational)) forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric isomer (or conformational) mixtures of the compounds of the invention are within the scope of the invention.

[0099] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4 (1H)-one tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0100] As used herein, "nitrogen oxide" means that when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA).

[0101] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0102] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0103] The "pharmaceutically acceptable salt" used in the present invention refers to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a group of N. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0104] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0105] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the invention may exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents on atoms with unsaturated double bonds may exist in cis-(Z)- or trans-(E)-form, if possible.

[0106] Therefore, as described herein, the compounds of the present invention may exist in the form of one or a mixture of possible isomers, rotamers, atropisomers, tautomers, for example, in the form of substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0107] Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the components into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0108] Any resulting racemate of the final product or intermediate can be separated into the optical antipodes by known methods by methods familiar to those skilled in the art, for example, by separation of the diastereomeric salts thereof obtained. The racemic products can also be separated by chiral chromatography, for example, by high pressure liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0109] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in the embodiments. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". The term "optionally", "optional" or "optionally" means that the event or situation described below may but may not occur, and the description includes situations in which the event or situation occurs, as well as situations in which the event or situation does not occur. In general, the term "optionally", whether or not it is preceded by the term "substituted", means that one or more hydrogen atoms in the given structure are replaced by the specified substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted with one or more substituents selected from the specific group, the substituents can be substituted at each position the same or different. The substituents described can be, but are not limited to, F, Cl, Br, CN, N 3 ,OH,NH 2 , NO 2 , oxo(=O), -C(=O)R a , -C(=O)OR b , -S(=O) 2 R b 、-C(=O)NR c R d , OR b , -NR c R d , R b OC 1-4 Alkylene, R d R c NC 1-4 Alkylene, C 1-6 Alkyl, C 1-6 Aliphatic, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms or (heteroaryl composed of 5-14 atoms)-C 1-4 Alkylene, wherein the Ra , R b , R c , R d Has the definition as described in the present invention.

[0110] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0111] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" refers specifically to methyl, ethyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 alkyl.

[0112] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0113] The term "alkyl" or "alkyl group" used in the present invention refers to a saturated straight or branched monovalent hydrocarbon radical containing 1 to 20 carbon atoms. Unless otherwise specified, the alkyl group contains 1 to 20 carbon atoms, some embodiments of which are 1 to 10 carbon atoms, and other embodiments of which are 1 to 9 carbon atoms; other embodiments of which are 1 to 8 carbon atoms, other embodiments of which are 1 to 6 carbon atoms, other embodiments of which are 1 to 4 carbon atoms, and other embodiments of which are 1 to 3 carbon atoms.

[0114] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3)(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and the like, wherein the alkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0115] As used herein, the term "alkyl" and its prefix "alkane" include both straight and branched saturated carbon chains.

[0116] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a straight or branched saturated hydrocarbon group. Unless otherwise specified, an alkylene group contains 1-10 carbon atoms, in some other embodiments, an alkylene group contains 1-6 carbon atoms, in some other embodiments, an alkylene group contains 1-4 carbon atoms, and in some other embodiments, an alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene (-CH(CH 3 )CH 2-), etc., wherein the alkylene groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0117] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position CC is sp 2 The double bond unsaturation state, wherein the alkenyl group can be independently unsubstituted or substituted with one or more substituents described in the present invention, including groups with "cis", "trans" or "Z" "E" orientation, wherein specific examples include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 )etc.

[0118] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position CC is an unsaturated sp triple bond, wherein the alkynyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention, specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH 2 C≡CH), 1-propynyl (-C≡C-CH 3 )etc.

[0119] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-20 carbon atoms, in some embodiments, the alkoxy group contains 1-10 carbon atoms, in other embodiments, the alkoxy group contains 1-8 carbon atoms, in other embodiments, the alkoxy group contains 1-6 carbon atoms, in other embodiments, the alkoxy group contains 1-4 carbon atoms, and in other embodiments, the alkoxy group contains 1-3 carbon atoms.

[0120] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy(i-PrO,i-propoxy,-OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butyloxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy(s-BuO,s-butoxy,-OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy(t-BuO,t-butyloxy,-OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy(-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy(-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy(-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy(-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ), etc., wherein the alkoxy groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0121] The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy and the like.

[0122] The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein and all refer to non-aromatic carbocyclic ring systems that are saturated or contain one or more unsaturated units and contain 3-14 ring carbon atoms. In some embodiments, the number of carbon atoms is 3-12; in other embodiments, the number of carbon atoms is 3-10; in other embodiments, the number of carbon atoms is 3-8; in other embodiments, the number of carbon atoms is 5-6; in other embodiments, the number of carbon atoms is 6-8. This "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems, and also includes polycyclic ring systems in which the carbocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the carbocyclic ring. Bicyclic carbocyclyls include bridged bicyclic carbocyclyls, fused bicyclic carbocyclyls and spiro bicyclic carbocyclyls, and "fused" bicyclic ring systems contain two rings that share 2 adjacent ring atoms. The bridged bicyclic group includes two rings sharing 3 or 4 adjacent ring atoms. The spirocyclic ring system shares 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of carbocyclic groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Bridged carbocyclic groups include, but are not limited to, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, etc.

[0123] The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms, having one or more points of attachment to the rest of the molecule. In some embodiments, the cycloalkyl group is a ring system containing 3-10 ring carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 3-8 ring carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 3-6 ring carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 5-6 ring carbon atoms; and the cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0124] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring system has one or more points of attachment to the rest of the molecule. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems, and also includes polycyclic ring systems in which the heterocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the heterocyclic ring. Bicyclic heterocyclyl includes bridged bicyclic heterocyclyl, fused bicyclic heterocyclyl and spiro bicyclic heterocyclyl. Unless otherwise specified, heterocyclyl may be carbonyl or nitrogenyl, and -CH 2 -groups may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to an S-oxide. The nitrogen atom of the ring may be optionally oxidized to an N-oxide. In some embodiments, the heterocyclyl is a monocyclic or bicyclic heterocyclyl consisting of 3-8 atoms; in other embodiments, the heterocyclyl is a monocyclic or bicyclic heterocyclyl consisting of 3-6 atoms; in other embodiments, the heterocyclyl is a monocyclic or bicyclic heterocyclyl consisting of 6-8 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 5-6 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 4 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 5 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 6 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 7 atoms; in other embodiments, the heterocyclyl is a heterocyclyl consisting of 8 atoms.

[0125] Examples of heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin yl, indolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. -CH 2Examples of -groups substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, pyrimidinedione. Examples of heterocyclic groups where the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. Bridged heterocyclic groups include, but are not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and the like. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0126] The term "bridge" refers to a bond, an atom, or an unbranched chain of atoms that connects two different parts of a molecule. Two atoms (usually, but not always, two tertiary carbon atoms) connected by a bridge are denoted "bridgeheads."

[0127] The term "spiro" refers to a ring system having one atom (usually a quaternary carbon atom) as the only common atom between two rings.

[0128] The term "n-atom-consisting", where n is an integer, typically describes the number of ring-forming atoms in a molecule, where the number of ring-forming atoms is n. For example, piperidinyl is a 6-atom heterocyclyl, while 1,2,3,4-tetrahydronaphthyl is a 10-atom carbocyclyl group.

[0129] The term "heteroatom" refers to O, S, N, P and Si, including N, S and P in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form of a nitrogen atom in a heterocyclic ring in which the hydrogen is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl).

[0130] The term "halogen" refers to F, Cl, Br or I.

[0131] The term "N 3 " represents an azide structure. This group can be connected to other groups, for example, it can be connected to a methyl group to form azidomethane (MeN 3 ), or connected to a phenyl group to form phenylazide (PhN 3 ).

[0132] The term "aryl" may be used alone or as a part of "aralkyl", "aralkyloxy" or "aryloxyalkyl" to refer to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring", such as aromatic rings may include phenyl, naphthyl and anthracenyl. The aryl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0133] The term "heteroaryl" may be used alone or as a large part of "heteroarylalkyl" or "heteroarylalkoxy" to refer to monocyclic, bicyclic, and tricyclic ring systems containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein each ring system contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. Unless otherwise specified, heteroaryl can be carbon or nitrogen radical, and -CH 2 -group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to S-oxide. The nitrogen atom of the ring can be optionally oxidized to N-oxygen compound. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-12 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, the heteroaryl group is a 6-atom heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0134] In some other embodiments, the heteroaryl group includes the following monocyclic groups, but is not limited to these monocyclic groups: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl) , 1,2,3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl , pyrazinyl, 1,3,5-triazinyl; also include the following bicyclic groups, but are by no means limited to these bicyclic groups: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), oxathiol, The heteroaryl group is optionally substituted with one or more substituents described herein.

[0135] The term "carboxyl", whether used alone or in combination with other terms, such as "carboxyalkyl", refers to -CO 2 H; The term "carbonyl", whether used alone or in combination with other terms, such as "aminocarbonyl" or "acyloxy", means -(C=O)-.

[0136] The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are independently substituted with one or two alkyl groups. In some embodiments, the alkylamino group is one or two C 1-6 The alkyl group is a lower alkylamino group attached to the nitrogen atom. In some other embodiments, the alkylamino group is C 1-3 Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.

[0137] The term "arylamino" means an amino group substituted by one or two aryl groups, such examples include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group may be further substituted.

[0138] The term "aminoalkyl" includes C 1-10 In some embodiments, aminoalkyl is a C substituted with one or more amino groups. 1-6 Examples of "lower aminoalkyl" include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.

[0139] As described in the present invention, a substituent is connected to a central ring by a bond to form a ring system, which means that the substituent can be substituted at any substitutable position on the ring. The ring system includes a monocyclic, bicyclic or polycyclic system.

[0140] As used herein, the term "unsaturated" means that the group contains one or more degrees of unsaturation.

[0141] The term “comprise” or “include” is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0142] As described in the present invention, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizer, adhesive, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or a combination thereof, which are known to those skilled in the art (such as Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except for the case where any conventional carrier is incompatible with the active ingredient, its use in treatment or pharmaceutical composition is covered.

[0143] The term "inhibiting TTK" as used herein includes reducing the expression or activity of TTK (e.g., reducing by at least 10%) and completely inhibiting the expression or activity of TTK (i.e., 100% inhibition of the expression or activity of TTK). In some embodiments, the expression or activity of TTK is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90% or at least 95%.

[0144] The term "effective amount" of a compound of the invention refers to an amount that causes a desired biological response. In the present invention, the desired biological response is to inhibit TTK, prevent the recurrence, evolution, onset or progression of symptoms associated with TTK overexpression, or enhance or improve the preventive or therapeutic effect of another anti-tumor therapy used. The exact amount of the compound administered to the subject will depend on the mode of administration and the severity and characteristics of the subject, such as health status, age, sex, weight and tolerance to drugs. The technician will be able to determine the appropriate dose based on these and other factors. When administered in combination with other anti-tumor agents, such as anti-mitotic drugs, the "effective amount" of the second agent will depend on the type of drug used. Suitable doses of approved agents are known and can be adjusted by the technician according to the condition of the subject, the type of condition being treated and the amount of the compound of the invention used. In the absence of an explicit indication of an amount, an effective amount should be taken. For example, the compound of the invention may be administered to a subject in a dosage range of about 0.01-100 mg / body weight / day for therapeutic or preventive treatment.

[0145] As used herein, the term "treatment" refers to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes reducing or ameliorating the progression, severity and / or duration of a TTK overexpression-mediated or overactive condition, or ameliorating one or more symptoms (particularly, one or more discernible symptoms) of a TTK overexpression-mediated or overactive condition due to administration of one or more therapies (e.g., one or more therapeutic agents (e.g., compounds and compositions of the present invention)). In certain embodiments, therapeutic treatment includes ameliorating at least one measurable physical parameter of a TTK overexpression-mediated or overactive condition. In other embodiments, therapeutic treatment includes inhibiting the progression of a TTK overexpression-mediated or overactive condition, for example, by stabilizing a discernible symptom physically or by stabilizing a physical parameter physiologically, for example, or both. In other embodiments, therapeutic treatment includes alleviating or stabilizing a TTK overexpression-mediated or overactive disease, such as papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer, or lung cancer.

[0146] The term "protecting group" or "PG" refers to a substituent that reacts with other functional groups, usually to block or protect a specific functionality. For example, an "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a substituent of the hydroxy group used to block or protect the functionality of the hydroxy group. Suitable protecting groups include acetyl and silyl. A "carboxyl protecting group" refers to a substituent of the carboxyl group used to block or protect the functionality of the carboxyl group. Typical carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl, etc. For a general description of protecting groups, reference may be made to: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P J Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

[0147] Description of the compounds of the present invention

[0148] The present invention proposes a class of pyrrolo[2,1-f][1,2,4]triazine derivatives, which show strong inhibitory activity on TTK and have the potential to be used as a class of novel TTK inhibitors for the treatment of tumors.

[0149] The present invention provides a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I),

[0150]

[0151] Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , R′ and m have the same definitions as described in the present invention.

[0152] In other embodiments, L2 is a key or O;

[0153] R 1 , R 2 , R 4 , R 5 Each independently represents H, F, Cl, Br, CN, NO 2 、-OR b 、-NR c R d , C 1-6 alkyl;

[0154] R 3 -C(=O)R a 、-C(=O)OR b 、-S(=O) 2 R b 、-C(=O)NR c R d 、-OR b 、-NR c R d , R b OC 1-4 Alkylene, R d R c NC 1-4 Alkylene, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-10 atoms or (heteroaryl composed of 5-10 atoms)-C 1-4 Alkylene, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl consisting of 5-10 atoms and (heteroaryl consisting of 5-10 atoms)-C 1-4Each alkylene group is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene;

[0155] R 6 H or

[0156] Among them, L 1 N or O;

[0157] A 1 and A 2 Each is independent of H and C 1-6 Alkyl, C 3-12 Carbocyclic group, C 3-12 Carbocyclyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms, (heteroaryl composed of 5-14 atoms)-C 1-4 Alkylene, or A 1 , A 2 and the L connected to them 1 Together, they form a heterocyclic ring consisting of 3 to 6 atoms, wherein the C 1-6 Alkyl, C 3-12 Carbocyclic group, C 3-12 Carbocyclyl-C 1-4 Alkylene, heterocyclic group consisting of 3-12 atoms, (heterocyclic group consisting of 3-12 atoms)-C 1-4 Alkylene, C 6-10 Aryl, C 6-10 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-14 atoms, (heteroaryl composed of 5-14 atoms)-C 1-4 Alkylene, or A 1 , A 2 and the L connected to them 1 together, form a heterocyclic ring of 3 to 6 atoms, each independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R', provided that A1 and A 2 Not at the same time H;

[0158] Each R' is independently H, F, Cl, Br, CN, NO 2 ,=O,-OR b 、-NR c R d 、-S(=O) 2 R b , C 1-6 Alkyl|、C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms, wherein the C 3-8 Cycloalkyl, heterocyclic group consisting of 3-12 atoms, C 6-10 The aryl or heteroaryl consisting of 5-10 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene;

[0159] m is 0, 1, 2 or 3;

[0160] The condition is that when R 6 When H, m is not 0, and at least one R' is C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms, wherein the C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, C 6-10 The aryl or heteroaryl consisting of 5-10 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC1-4 Alkylene or R d R c NC 1-4 Alkylene;

[0161] R a , R b , R c , R d Each independently is H, C 1-6 Alkyl, C 1-6 Haloalkyl, heterocyclic group consisting of 3-6 atoms or R c , R d Together with the nitrogen atom to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms, wherein the C 1-6 The alkyl group and the heterocyclic ring composed of 3-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, wherein the substituents are independently selected from F, Cl, CN, OH, NH 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Alkylamino.

[0162] In other embodiments, the present invention relates to a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (II).

[0163]

[0164] Among them, R 1 , R 3 , L 2 , R′, X and m have the same definitions as described in the present invention.

[0165] In other embodiments, X is the following sub-structure:

[0166]

[0167] Ring W is C 3-8 Cycloalkyl, heterocyclic ring composed of 3-8 atoms, benzene or heteroaromatic ring composed of 5-6 atoms; each R w H, F, Cl, Br, CN, NO independently 2 ,=O,-OR b 、-NR c R d 、-S(=O) 2 R b , C 1-6 Alkyl or C 1-6 Haloalkyl; R6 , R 7 Each independently is H, C 1-6 Alkyl; s is 0, 1, 2 or 3.

[0168] In other embodiments, the present invention relates to a compound of formula (III) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (III).

[0169]

[0170] Among them, R 1 , R 3 , L 2 , Ring Y, R Y and q have the definitions as described in the present invention.

[0171] In other embodiments, ring Y is C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, a heterocyclic ring composed of 3-8 atoms, benzene or a heteroaromatic ring composed of 5-6 atoms; each R Y H, F, Cl, Br, CN, NO independently 2 ,=O,-OR b 、-NR c R d 、-S(=O) 2 R b , C 1-6 Alkyl or C 1-6 haloalkyl; q is 0, 1, 2 or 3.

[0172] In other embodiments, L 1 is N;

[0173] In other embodiments, L 1 is O;

[0174] In other embodiments, L 2 is the key;

[0175] In other embodiments, L 2 is O;

[0176] In other embodiments, the R 2 , R 4 , R 5 Each is independently H.

[0177] In other embodiments, the R 3 -C(=O)NR c R d , ORb 、-NR c R d 、-S(=O) 2 R b , heterocyclic group consisting of 3-6 atoms, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C 6-9 Aryl, C 6-9 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-9 atoms or (heteroaryl composed of 5-9 atoms)-C 1-4 Alkylene.

[0178] In other embodiments, R 6 is H, then m is not 0, and at least one R' is C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, C 6-10 Aryl or heteroaryl consisting of 5 to 10 atoms, wherein the C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-12 atoms, C 6-10 The aryl or heteroaryl consisting of 5-10 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, and the substituents are independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene.

[0179] In other embodiments, R 6 for

[0180] In other embodiments, the A 1 and A 2 Each is independent of H and C 1-6 Alkyl, C 3-6 Carbocyclic group, C 3-6 Carbocyclyl-C 1-4 Alkylene, heterocyclic group consisting of 3-6 atoms, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C 6-8 Aryl, C 6-8 Aryl-C 1-4Alkylene, heteroaryl composed of 5-8 atoms, (heteroaryl composed of 5-8 atoms)-C 1-4 Alkylene, or A 1 , A 2 and the L connected to them 1 Together, they form a heterocyclic ring consisting of 3 to 6 atoms.

[0181] In other embodiments, the A 1 and A 2 Each is independent of H and C 1-6 Alkyl, provided that A 1 and A 2 Not H at the same time.

[0182] In other embodiments, the A 1 and A 2 Each is independent of H and C 3-6 Carbocyclic group, C 3-6 Carbocyclyl-C 1-4 Alkylene, heterocyclic group consisting of 3-6 atoms, (heterocyclic group consisting of 3-6 atoms)-C 1-4 Alkylene, C 6-8 Aryl, C 6-8 Aryl-C 1-4 Alkylene, heteroaryl composed of 5-8 atoms, (heteroaryl composed of 5-8 atoms)-C 1-4 Alkylene, provided that A 1 and A 2 Not H at the same time.

[0183] In other embodiments, A 1 , A 2 and the L connected to them 1 Together, they form a heterocyclic ring consisting of 3 to 6 atoms.

[0184] In other embodiments, each R′ is independently H, F, Cl, Br, CN, NO 2 ,=O,-OR b 、-NR c R d 、-S(=O)OR b , C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-8 Aryl or heteroaryl consisting of 5 to 8 atoms, wherein the C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, C 6-8The aryl or 5-8-atom heteroaryl is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene.

[0185] In other embodiments, each R' is independently H.

[0186] In other embodiments, each R' is independently F, Cl, Br.

[0187] In other embodiments, each R' is independently CN.

[0188] In other embodiments, R 6 for m is 0, 1, 2 or 3.

[0189] In other embodiments, the R a , R b , R c , R d are independently H, methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, C 1-3 Haloalkyl, heterocyclic group consisting of 3-6 atoms or R c , R d Together with the nitrogen atoms to which they are attached, they form a heterocyclic ring consisting of 3 to 6 atoms.

[0190] In other embodiments, the A 1 and A 2 Each is independent of H and C 1-6 Alkyl, C 3-6 Carbocyclic group, heterocyclic group composed of 3-6 atoms, C 6-8 Aryl, heteroaryl composed of 5-8 atoms.

[0191] In other embodiments, the R 3 -C(=O)NR c R d , OR b 、-NR c R d 、-S(=O) 2 R b, heterocyclic radical composed of 3-6 atoms, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiyl, wherein the heterocyclic radical composed of 3-6 atoms, phenyl, naphthyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolyl, isoquinolyl, phenoxathiyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents, and the substituents are independently selected from F, Cl, Br, CN, =O, -OR b 、-NR c R d , C 1-6 Alkyl, C 1-6 Haloalkyl, R b OC 1-4 Alkylene or R d R c NC 1-4 Alkylene.

[0192] In other embodiments, the R 3 -C(=O)NR c R d .

[0193] In other embodiments, the R 3 OR b .

[0194] In other embodiments, the R 3 For-NR c R d .

[0195] In other embodiments, the R 3 -S(=O) 2 R b .

[0196] In other embodiments, the R 3 It is a heterocyclic group consisting of 3 to 6 atoms.

[0197] In other embodiments, the R 3 It is phenyl.

[0198] In other embodiments, the R 3 It is naphthyl.

[0199] In other embodiments, the R 3 It is pyrrolyl.

[0200] In other embodiments, the R 3 It is pyridyl.

[0201] In other embodiments, the R 3 It is pyrazolyl.

[0202] In other embodiments, the R 3 It is an imidazolyl group.

[0203] In other embodiments, the R 3 It is a triazole group.

[0204] In other embodiments, the R 3 It is a tetrazolyl group.

[0205] In other embodiments, the R 3 It is oxazolyl.

[0206] In other embodiments, the R 3 It is oxadiazolyl.

[0207] In other embodiments, the R 3 It is 1,3,5-triazine.

[0208] In other embodiments, the R 3 It is thiazolyl.

[0209] In other embodiments, the R 3 It is a thienyl group.

[0210] In other embodiments, the R 3 It is pyrazinyl.

[0211] In other embodiments, the R 3 It is a pyridazinyl group.

[0212] In other embodiments, the R 3 It is pyrimidinyl.

[0213] In other embodiments, the R 3 Indolyl.

[0214] In other embodiments, the R 3 It is a purine group.

[0215] In other embodiments, the R 3 It is quinolinyl.

[0216] In other embodiments, the R 3 It is isoquinolinyl.

[0217] In other embodiments, the R 3 It is phenoxathiol.

[0218] In other embodiments, the ring W is C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, phenyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl.

[0219] In other embodiments, the ring W is C 3-6 Cycloalkyl.

[0220] In other embodiments, the ring W is a heterocyclic group consisting of 3-6 atoms.

[0221] In other embodiments, the ring W is phenyl.

[0222] In other embodiments, the ring W is C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, phenyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl.

[0223] In other embodiments, the ring W is a heterocyclic group consisting of 3-6 atoms.

[0224] In other embodiments, the ring W is C 3-6 Cycloalkyl.

[0225] In other embodiments, the ring W is phenyl.

[0226] In other embodiments, the ring W is pyrrolyl.

[0227] In other embodiments, the ring W is pyridinyl.

[0228] In other embodiments, the ring W is pyrazolyl.

[0229] In other embodiments, the ring W is imidazolyl.

[0230] In other embodiments, the ring W is triazolyl.

[0231] In other embodiments, the ring W is tetrazolyl.

[0232] In other embodiments, the ring W is oxazolyl.

[0233] In other embodiments, the ring W is oxazolyl.

[0234] In other embodiments, the ring W is oxadiazolyl.

[0235] In other embodiments, the ring W is 1,3,5-triazinyl.

[0236] In other embodiments, the ring W is thiazolyl.

[0237] In other embodiments, the ring W is thienyl.

[0238] In other embodiments, the ring W is pyrazinyl.

[0239] In other embodiments, the ring W is thienyl.

[0240] In other embodiments, the ring W is pyrazinyl.

[0241] In other embodiments, the ring W is pyridazinyl.

[0242] In other embodiments, the ring W is pyrimidinyl.

[0243] In other embodiments, the R w H, F, Cl, Br, CN, NO independently 2 ,=O,-OR b 、-NR c R d 、-S(=O) 2 R b , methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl or C 1-6 Halogenated alkyl.

[0244] In other embodiments, the ring Y is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, a heterocyclic group consisting of 3 to 6 atoms, phenyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, 3,6-dihydro-2H-pyran or tetrahydro-2H-pyran.

[0245] In other embodiments, the ring Y is C 3-6 Cycloalkyl.

[0246] In other embodiments, the ring Y is C 3-6 Cycloalkenyl.

[0247] In other embodiments, the ring Y is a heterocyclic group consisting of 3-6 atoms.

[0248] In other embodiments, the ring Y is phenyl.

[0249] In other embodiments, the ring Y is pyrrolyl.

[0250] In other embodiments, the ring Y is pyridinyl.

[0251] In other embodiments, the ring Y is pyrazolyl.

[0252] In other embodiments, the ring Y is imidazolyl.

[0253] In other embodiments, the ring Y is triazolyl.

[0254] In other embodiments, the ring Y is tetrazolyl.

[0255] In other embodiments, the ring Y is oxazolyl.

[0256] In other embodiments, the ring Y is oxadiazolyl.

[0257] In other embodiments, the ring Y is 1,3,5-triazinyl.

[0258] In other embodiments, the ring Y is thiazolyl.

[0259] In other embodiments, the ring Y is thienyl.

[0260] In other embodiments, the ring Y is pyrazinyl.

[0261] In other embodiments, the ring Y is pyridazinyl.

[0262] In other embodiments, the ring Y is pyrimidinyl.

[0263] In other embodiments, the ring Y is 3,6-dihydro-2H-pyran or tetrahydro-2H-pyran.

[0264] In other embodiments, the R Y H, F, Cl, Br, CN, NO independently 2 ,=O,-OR b 、-NR c R d 、-S(=O) 2 R b , methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl or C 1-6 Halogenated alkyl.

[0265] In other embodiments, the present invention relates to a compound represented by formula (IV) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (IV).

[0266]

[0267] Among them, ring V, ring W, R 1 , L 2 , R', R w , R V , s, p, and m have the definitions as described in the present invention.

[0268] In other embodiments, the present invention relates to a compound represented by formula (V) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (V),

[0269]

[0270] Among them, ring V, R 1 , L 2 , R', R w , R V , s, p, and m have the definitions as described in the present invention.

[0271] In other embodiments, the present invention relates to a compound of formula (VI) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (VI).

[0272]

[0273] Among them, ring V, ring Y, R 1 , L 2 , R V , R V , p, q have the definitions as described in the present invention.

[0274] In other embodiments, the present invention relates to a structure represented by formula (VII) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (VII).

[0275]

[0276] Among them, ring W, R 1 , R a , R b , L 2, R', R w , s, and m have the definitions described in the present invention.

[0277] In other embodiments, the present invention relates to a compound represented by formula (VIII) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (VIII).

[0278]

[0279] Among them, ring W, R 1 , R b , L 2 , R', R w , s, and m have the definitions described in the present invention.

[0280] In other embodiments, the present invention relates to a structure represented by formula (VIIII) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound represented by formula (VIIII).

[0281]

[0282] Among them, ring W, R 1 , R b , L 2 , R', R w , s, and m have the definitions described in the present invention.

[0283] In other embodiments, ring V is C 3-8 Cycloalkyl, heterocyclic ring composed of 3-8 atoms, benzene or heteroaromatic ring composed of 5-6 atoms; R V F, Cl, Br, CN, -OH, =O, C 1-6 Alkyl or C 1-6 p is 0, 1, 2 or 3.

[0284] In other embodiments, ring V is C 3-8 Cycloalkyl

[0285] In other embodiments, the ring V is phenyl.

[0286] In other embodiments, the ring V is naphthyl.

[0287] In other embodiments, the ring V is pyrrolyl.

[0288] In other embodiments, the ring V is pyridinyl.

[0289] In other embodiments, the ring V is pyrazolyl.

[0290] In other embodiments, the ring V is imidazolyl.

[0291] In other embodiments, the ring V is triazolyl.

[0292] In other embodiments, the ring V is tetrazolyl.

[0293] In other embodiments, the ring V is oxazolyl.

[0294] In other embodiments, the ring V is oxadiazolyl.

[0295] In other embodiments, the ring V is 1,3,5-triazinyl.

[0296] In other embodiments, the ring V is thiazolyl.

[0297] In other embodiments, the ring V is thienyl.

[0298] In other embodiments, the ring V is pyrazinyl.

[0299] In other embodiments, the ring V is pyridazinyl.

[0300] In other embodiments, the ring V is pyrimidinyl.

[0301] In other embodiments, the ring V is indolyl.

[0302] In other embodiments, the ring V is a purinyl group.

[0303] In other embodiments, the ring V is quinolinyl.

[0304] In other embodiments, the ring V is isoquinolinyl.

[0305] In other embodiments, the ring V is phenoxathiyl.

[0306] In one aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention.

[0307] In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

[0308] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more therapeutic agents.

[0309] In some embodiments, the therapeutic agent is an anti-mitotic drug, an alkylating agent, an antimetabolite, a topoisomerase inhibitor, an estrogen receptor modulator, an androgen receptor modulator, a small molecule inhibitor targeting protein kinase, or an antibody drug targeting protein kinase.

[0310] In some embodiments, the anti-mitotic drug is paclitaxel or vincristine.

[0311] In some embodiments, the alkylating agent is cisplatin, oxaliplatin, carboplatin, or cyclophosphamide.

[0312] In some embodiments, the topoisomerase inhibitor is epipodophyllotoxin, etoposide, topotecan, or camptothecin.

[0313] In some embodiments, the estrogen receptor modulator is tamoxifen or fulvestrant.

[0314] In some embodiments, the androgen receptor modulator is bicalutamide.

[0315] In some embodiments, the small molecule inhibitor targeting protein kinase is dasatinib, bosutinib, gefitinib, erlotinib, lapatinib, imatinib, nilotinib, sorafenib, tipifarnib, sunitinib, axitinib.

[0316] In some embodiments, the antibody drug targeting protein kinase is trastuzumab, panitumumab, or cetuximab.

[0317] In other embodiments, the pharmaceutical composition may be in liquid, solid, semisolid, gel or spray form.

[0318] In other embodiments, the present invention relates to the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to prevent, manage, treat or alleviate a disease associated with TTK overexpression or overactivity in a patient.

[0319] In some other embodiments, the disease associated with TTK overexpression is a tumor.

[0320] In other embodiments, the tumor is papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial carcinoma or lung cancer.

[0321] In other embodiments, the present invention relates to the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to inhibit TTK.

[0322] In some embodiments, the salts are pharmaceutically acceptable salts.The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal to be treated therewith.

[0323] The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts and can be used as intermediates for preparing and / or purifying the compounds of the present invention and / or for separating the enantiomers of the compounds of the present invention.

[0324] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlorophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalactonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate and trifluoroacetate.

[0325] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0326] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

[0327] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0328] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0329] Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0330] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, the basic or acidic part by conventional chemical methods. In general, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) can be found in some other suitable salt lists.

[0331] Moreover, the compounds of the present invention, including their salts, may also be obtained in the form of their hydrates, or include other solvents for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include solvated and unsolvated forms.

[0332] Any structural formula given herein is also intended to represent unlabeled forms of these compounds as well as isotopically labeled forms. Isotopically labeled compounds have structures depicted by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 36 S, 37 Cl or 125 I.

[0333] On the other hand, the compounds of the present invention include compounds defined in the present invention which are labeled with various isotopes, for example, wherein a radioactive isotope is present, such as3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and 13 C. This type of isotope-labeled compound can be used for metabolic studies (using 14 C), reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiation therapy of the patient. 18 F-labeled compounds are particularly ideal for PET or SPECT studies. Isotope-labeled compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparations of the present invention using appropriate isotope-labeled reagents in place of the unlabeled reagents originally used.

[0334] In addition, heavier isotopes, especially deuterium (i.e. 2 H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, increased half-life in vivo or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in this context is regarded as a substituent of the compound of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the solvent of crystallization may be isotopically substituted, such as D 2 O, acetone-d 6 , or DMSO-d 6 Those solvates.

[0335] Compositions, formulations and administration of compounds of the invention

[0336] The present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention or a stereoisomer thereof. According to a specific embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle, and optionally, other therapeutic and / or preventive ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.

[0337] The pharmaceutically acceptable carrier may contain inert ingredients that do not excessively inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or have no other adverse reactions or side effects once administered to a patient. Standard pharmaceutical techniques can be used.

[0338] As described in the present invention, the pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant or excipient, such as the one used in the present invention, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc. suitable for the specific target dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York discloses various carriers used in the preparation of pharmaceutically acceptable compositions and their known preparation methods. In addition to conventional carrier media that are incompatible with the compounds of the present invention, such as those that produce adverse biological effects or have harmful interactions with any other components in the pharmaceutically acceptable composition, any other conventional carrier media and their uses are also within the scope of the present invention.

[0339] Some examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80, phosphates, glycine, sorbic acid or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropyl methylcellulose, lanolin, sugars (e.g., lactose, glucose and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose , ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl dodecanoate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffers and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and, according to the judgment of the formulator, coloring agents, anti-adherents, coating agents, sweetening and flavoring agents, preservatives and antioxidants may also be present in the composition.

[0340] The compounds or compositions of the present invention can be administered by any suitable means, and can be administered to humans or other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (such as by powders, ointments or drops), orally as an oral or nasal spray, etc., depending on the severity of the disease being treated.

[0341] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and flavor enhancers.

[0342] Injectable preparations can be prepared according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable water or oil suspensions. Sterile injectable preparations may also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are used as solvents or suspension media as a rule. For this reason, any tasteless fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used to prepare injections.

[0343] For example, the injectable formulation can be sterilized by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0344] In order to prolong the effect of the compound or composition of the present invention, it is often desirable to slow down the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystal or amorphous substance. Then, the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. An injectable storage form is prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The compound release rate can be controlled according to the ratio of the compound to the polymer and the properties of the special polymer used. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable storage preparations can also be prepared by trapping the compound in a liposome or microemulsion compatible with body tissues.

[0345] Compositions for rectal or vaginal administration are particularly suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0346] Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or expanders such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarder such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0347] Also can use the solid composition of similar type as the filler in soft and hard gel capsules with excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Available coating and shell, for example enteric coating and other well-known coatings in the pharmaceutical field prepare the solid dosage form of tablets, lozenges, capsules, pills and particles. They can optionally contain an emulsifier and can also have the property of the composition, so that optionally only release active ingredients in a delayed manner, or preferably, release in a certain part of the intestinal tract. The example of the embedding composition that can be used includes polymers and waxes. Also can use the solid composition of similar type as the filler in soft and hard gel capsules with excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0348] The active compound may also be in a micro-sealed form with one or more of the above-mentioned excipients. Available coatings and shells, such as enteric coatings, controlled release coatings and other well-known coatings in the pharmaceutical field, can be prepared into solid dosage forms of tablets, lozenges, capsules, pills and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Generally, such dosage forms may also include other substances except the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffer. They may optionally contain an emulsifier and may also have the properties of the composition, so that the active ingredient is optionally released only in a delayed manner, or preferably, released in a certain part of the intestinal tract. Examples of usable embedded compositions include polymers and waxes.

[0349] The topical or transdermal dosage forms of the compounds of the present invention include ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic preparations, ear drops and eye drops are also considered within the scope of the present invention. In addition, the present invention contemplates the use of skin patches with the additional advantage of providing controlled compound delivery to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0350] The compositions of the present invention may also be administered orally, parenterally, topically, rectally, nasally, buccally, vaginally, or by implanted kits via inhalation sprays. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In particular, the compositions may be administered orally, intraperitoneally, or intravenously.

[0351] The sterile injectable form of the composition of the present invention may be an aqueous or oil suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution may be used. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any odorless fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form, fatty acids such as octadecenoic acid and its glyceride derivatives are used to prepare injections. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0352] The pharmaceutical composition of the present invention can be taken orally in any oral acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, common carriers include but are not limited to lactose and starch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. If necessary, certain sweeteners, flavor enhancers or coloring agents may also be added.

[0353] Alternatively, the pharmaceutical compositions of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions may be prepared by mixing reagents and non-irritating excipients that are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0354] The pharmaceutical compositions of the present invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0355] Topical application to the lower intestinal tract may be accomplished in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical skin patches may also be used.

[0356] For topical drip application, the pharmaceutical composition can be formulated as a suitable ointment containing an active component suspended or dissolved in one or more carriers. Carriers suitable for topical drip application of the compound of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0357] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic pH adjusted sterile saline, or particularly as a solution in isotonic pH adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

[0358] The pharmaceutical composition may also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0359] The compounds used in the methods of the present invention can be formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for subjects, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect, optionally in combination with a suitable pharmaceutical carrier. The unit dosage form can be a single daily dose or one of multiple daily doses (e.g., about 1-4 times or more per day). When multiple daily doses are used, the unit dosage form for each dose can be the same or different.

[0360] Uses of the compounds and compositions of the present invention

[0361] The above-mentioned compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicines for preventing, treating or alleviating TTK overexpression or overactivity-related diseases in patients. Preferably, the TTK overexpression or overactivity-related diseases are tumors, for example, the tumors are papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer or lung cancer.

[0362] The present invention also provides use of the above compound or its pharmaceutical composition in preparing a drug for inhibiting TTK.

[0363] The present invention provides a method for treating, preventing or delaying a disease caused by overexpression or overactivity of TTK, the method comprising administering a therapeutically effective amount of the above-mentioned compound or its pharmaceutical composition to a patient in need of treatment. The disease caused by overexpression or overactivity of TTK is a tumor, such as papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer or lung cancer. In addition, the above-mentioned compound or its pharmaceutical composition provided by the present invention can be co-administered with other therapies or therapeutic agents. The administration method can be simultaneous, sequential or at a certain time interval.

[0364] The dosage of the compound or pharmaceutical composition required for the treatment, prevention or delay of the effect usually depends on the specific compound, patient, specific disease or condition and its severity, administration route and frequency, etc., and needs to be determined by the attending physician according to the specific circumstances. For example, when the compound or pharmaceutical composition provided by the present invention is administered by intravenous route, it can be administered once a week or even at longer intervals.

[0365] In summary, the present invention provides a novel compound, which can be used as a TTK inhibitor. The compound of the present invention is suitable for preparing drugs in various dosage forms and can be widely used in treating tumors, such as papillary thyroid cancer, breast cancer, gastric cancer, bronchial cancer or lung cancer.

[0366] The compounds and pharmaceutical compositions of the present invention are useful for human treatment and can also be used in veterinary treatment of pets, introduced species of animals and mammals in farm animals. Other examples of animals include horses, dogs and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0367] General synthesis process

[0368] To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0369] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following reaction schemes and examples are provided to further illustrate the present invention.

[0370] Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of the non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art by modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0371] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Solvents used in the present invention are commercially available. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, ArcoChemical Company and Alfa Chemical Company, J&K Scientific Ltd. and were used without further purification unless otherwise indicated.

[0372] The LCMS model used for detection in the following examples is Agilent Technologies 6110, and the NMR model is Avance III 400 MHz.

[0373] The present invention uses the following abbreviations: DIPEA represents N-diisopropylethylamine; HOAT represents 1-hydroxy-7-azobenzotriazole; DMF represents N,N-dimethylacetamide; EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DCE represents 1,2-dichloroethane; BINAP represents 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; NMP represents N-methylpyrrolidone; and m-CPBA represents meta-chloroperbenzoic acid.

[0374] The compounds were named according to conventional naming conventions in the art or using ChemDraw software.

[0375] The following synthesis scheme lists the experimental steps for preparing the compounds disclosed in the present invention. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L 2 , R′, m, X, ring Y, ring V, ring W, R Y , R w , R V , q, s, and p have the definitions described in the present invention,

[0376] Synthesis Scheme 1

[0377] Compound II-a reacts with a nucleophilic reagent XH in the presence of a base through a nucleophilic substitution reaction to prepare compound II-b, and compound II-b reacts with a corresponding aniline compound through a metal-catalyzed coupling reaction to prepare a compound of formula II.

[0378]

[0379] Synthesis Scheme 2

[0380] Compound III-a is oxidized by m-CPBA to obtain compound III-b, III-b undergoes a nucleophilic substitution reaction with a corresponding formamide compound in the presence of a base, and is further hydrolyzed by an alkaline to obtain compound III-c, and compound III-c undergoes a coupling reaction with a corresponding boric acid or boric ester compound in the presence of a metal to obtain a compound of formula III.

[0381] DETAILED DESCRIPTION

[0382] The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention.

[0383] Preparation Example

[0384] In the following preparation examples, the inventors describe in detail the preparation process of the compounds of the present invention by taking some of the compounds of the present invention as examples.

[0385] Intermediate A

[0386]

[0387] first step

[0388] Compound 1-A (5.3 g, 28.7 mmol) was dissolved in EtOH (50 mL), and EtONa (4.7 g, 68.8 mmol) was added to the reaction system. The reaction mixture was heated to reflux for 2 h. After the reaction system was diluted with water, 2N HCl was added until a large amount of solid precipitated. The filter cake was filtered and washed with water (3*40 mL), and dried to obtain a yellow solid compound 1-B. LCMS (M+H) + =212.1.

[0389] Step 2

[0390] Compound 1-B (5.9 g, 28 mmol), DIPEA (18 g, 140 mmol), methylamine hydrochloride (5.7 g, 84 mmol) and HOAT (4.5 g, 34 mmol) were dissolved in DMF (60 mL). EDCI (6.4 g, 34 mmol) was added to the reaction system at room temperature and reacted at 50 °C for 18 h under nitrogen protection. 1N NaOH (80 mL) solution was added to the reaction system, extracted with dichloromethane (3*60 mL), dried over anhydrous sodium sulfate, spin-dried, and column chromatography (PE:EA=5:1) was performed to obtain a yellow solid compound 1-C. LCMS (M+H) + =225.0.

[0391] Step 3

[0392] Compound 1-C (0.7 g, 3.1 mmol) was dissolved in DCE (20 mL) and SOCl 2 (2.1g, 15.6mmol) was added to the reaction system at room temperature. The reaction mixture was heated to 85℃ and microwaved for 2h. The reaction mixture was evaporated to dryness under reduced pressure and dissolved in DMF (15mL), and then formic hydrazide (281mg, 4.7mmol) was added to the reaction system. The reaction mixture was heated to 110℃ and reacted for 1h. The reaction solution was cooled to room temperature. A large amount of solid was precipitated when saturated brine was added to the reaction system. The filter cake was washed with a small amount of water and dried to obtain a yellow solid compound 1-D. LCMS (M+H) + =249.0.

[0393] Step 4

[0394] Compound 1-D (300 mg, 1.2 mmol) was dissolved in EtOH (15 mL) / MeOH (5 mL), and 10% Pd / C (130 mg) was added to the reaction system. The reaction mixture was heated to 70°C under hydrogen conditions and reacted for 12 h. The filter cake was washed and the filtrate was dried to obtain intermediate A. LCMS (M+H) + =219.0. 1 H NMR (400MHz, DMSO) δ8.53–8.35(m,1H),7.11(d,J=1.7Hz,1H),7.04(dd,J=8.1,1.7Hz,1H),6 .72(t,J=9.4Hz,1H),5.16(s,2H),4.14–3.95(m,2H),3.76–3.63(m,3H),1.47–1.23(m,3H).

[0395] Intermediate B

[0396]

[0397] first step

[0398] Compound 2-A (200 mg, 0.9 mmol) was dissolved in formic acid (10 mL), and solid sodium formate (1.2 g, 18 mmol) was added. The reaction solution was heated to 70°C and stirred for 1 h. Most of the formic acid was removed by concentration under reduced pressure, and the residue was adjusted to pH 9-10 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (3*40 mL), dried over anhydrous sodium sulfate, and dried by spin drying. Yellow solid compound intermediate B was prepared by column chromatography (PE:EA=2:1). LCMS: (M+H) + =247.0.

[0399] Intermediate C

[0400]

[0401] first step

[0402] Compound 3-A (200 mg, 0.8 mmol) was dissolved in tetrahydrofuran (5 mL), and m-chloroperbenzoic acid (987 mg, 5.7 mmol) was added in batches under ice bath, and the reaction solution was heated to 50 ° C and stirred for 2 h. Under ice water bath conditions, m-chloroperbenzoic acid (100 mg, 0.57 mmol) was added in batches again, and the reaction was continued for 2 h. Concentrate to remove the solvent, dilute with ethyl acetate (30 mL), wash with sodium bicarbonate aqueous solution, wash with saturated brine, dry the organic phase over anhydrous sodium sulfate, concentrate, and purify the crude product by column chromatography (PE: EA = 3: 7) to obtain yellow solid compound 3-B. LCMS (M + H) + =276.0.

[0403] Step 2

[0404] Dissolve intermediate B (50 mg, 0.2 mmol) in THF (5 mL), add NaH (20 mg, 0.8 mmol) in batches under ice-water bath conditions, heat the reaction solution to 50 ° C, stir for 1 hour, cool to room temperature, add compound 3-B (56 mg, 0.2 mmol) in batches, and continue to react at 50 ° C for 12 hours. Cool to room temperature, add 2N sodium hydroxide aqueous solution (0.5 mL) and methanol (0.5 mL), and react at room temperature for 1 hour. After the reaction solution is concentrated, the crude product is separated by HPLC to obtain intermediate C. LCMS: (M+H) + =414.0. 1 H NMR(400MHz,DMSO)δ8.97(s,1H),8.58(d,J=11.3Hz,2H),8.04(s,1H),7.45–7.31(m,2H) ,7.01(dd,J=20.9,4.6Hz,2H),4.25(q,J=7.0Hz,2H),3.79(s,3H),1.44(t,J=6.9Hz,3H).

[0405] Example 1

[0406]

[0407] first step

[0408] Compound 4-A (200 mg, 1 mmol), DIPEA (332 mg, 2.6 mmol) and 2,2-methylpropane-1-amine (112 mg, 1.3 mmol) were dissolved in acetonitrile (5 mL), and the reaction solution was heated to 60°C for 12 h. The reaction solution was directly concentrated to a yellow oil, and the crude product was purified by column chromatography (PE:EA=1:1) to obtain a yellow oil compound 1-1. LCMS: (M+H) + =239.0.

[0409] Step 2

[0410] Compound 1-1 (98 mg, 0.4 mmol), intermediate A (60 mg, 0.275 mmol), BINAP (34 mg, 0.055 mmol), Cs 2 CO 3 (224 mg, 0.688 mmol) and palladium acetate (6.0 mg, 0.028 mmol) were dissolved in dioxane (10 mL) and the reaction mixture was heated to 100 ° C and reacted for 12 h under nitrogen protection. After the reaction solution was concentrated, the crude product was separated by HPLC to obtain compound 1. LCMS: (M+H) + =421.0. 1H NMR (400MHz, DMSO) δ8.59–8.48(m,2H),8.08(t,J=6.2Hz,1H),7.55–7.47(m,1H),7.37–7.27(m,2H),7.19(s,1H),6.97(dd,J=4.4, 1.6Hz, 1H), 6.48 (dd, J=4.3, 2.5Hz, 1H), 4.24 (q, J=6.9Hz, 2H), 3.76 (s, 3H), 3.47–3.26 (m, 4H), 1.44 (t, J=6.9Hz, 3H), 0.97 (s, 9H).

[0411] Example 2

[0412]

[0413] first step

[0414] Compound 4-A (250 mg, 1.3 mmol) was dissolved in acetonitrile (5 mL), cyclohexylamine (160 mg, 1.6 mmol) and DIPEA were added to the reaction system, the mixture was heated to 60°C, reacted for 16 hours, concentrated to remove the solvent, and the crude product was purified by column chromatography (PE:EA=1:1) to obtain yellow solid compound 2-1. LCMS (M+H) + =251.0.

[0415] Step 2

[0416] Compound 2-1 (172 mg, 0.7 mmol), intermediate A (100 mg, 0.5 mmol), BINAP (57 mg, 0.09 mmol), Cs 2 CO 3 (374 mg, 1.1 mmol) and palladium acetate (10 mg, 0.05 mmol) were dissolved in dioxane (10 mL), the reaction mixture was heated to 100 ° C, and the reaction was carried out under nitrogen protection for 12 hours. The reaction solution was concentrated, and the crude product was separated by HPLC to obtain compound 2. LCMS: (M+H) + =433.0.

[0417] 1H NMR(400MHz,DMSO)δ8.61–8.48(m,2H),7.97(d,J=7.8Hz,1H),7.49(s,1H),7 .37–7.27(m,2H),7.21(s,1H),6.89(d,J=2.8Hz,1H),6.46(dd,J=4.3,2.5Hz ,1H),4.24(q,J=7.0Hz,2H),4.08(m,1H),3.77(m,3H),1.99(m,2H),1.79(m, 2H),1.67(d,J=14.4Hz,1H),1.45(t,J=6.9Hz,3H),1.38(m,4H),1.20(m,1H).

[0418] Example 3

[0419]

[0420] first step

[0421] Compound 4-A (500 mg, 2.7 mmol) was dissolved in NMP (5 mL), and DIPEA (690 mg, 5.3 mmol) and cyclopentylamine (455 mg, 5.3 mmol) were added to the reaction system. The reaction solution was heated to 120 ° C and stirred for 1 h. The reaction system was restored to room temperature, water was added to quench the reaction, and ethyl acetate (3*40 mL) was extracted and washed with saturated brine. Drying over anhydrous sodium sulfate, spin drying, and the crude product was purified by column chromatography (PE: EA = 1: 1) to obtain a yellow solid compound 3-1. LCMS (M+H) + =237.1.

[0422] Step 2

[0423] Compound 3-1 (100 mg, 0.4 mmol), intermediate A (139 mg, 0.6 mmol), BINAP (53 mg, 0.09 mmol) and Cs 2 CO 3 (346 mg, 1 mmol) was dissolved in dioxane (10 mL), and palladium acetate (10 mg, 0.04 mmol) was added to the reaction system at room temperature, and the reaction was carried out at 110°C for 18 h under nitrogen protection. The solvent was removed by concentration, and the crude product was purified by high performance liquid chromatography to obtain compound 3. LCMS (M+H) + =419.0. 1H NMR (400MHz, DMSO) δ8.54(t,J=4.1Hz,2H),8.02(d,J=7.3Hz,1H),7.50(s,1H),7.31 (dd,J=12.5,4.1Hz,2H),7.20(s,1H),6.90(dd,J=4.3,1.3Hz,1H),6.46(dd,J=4.1,2 .6Hz,1H),4.53(dd,J=13.8,7.0Hz,1H),4.25(q,J=6.9Hz,2H),3.78(d,J=11.1Hz,3H ), 2.03 (d, J = 2.6Hz, 2H), 1.76 (s, 2H), 1.63 (d, J = 19.8Hz, 4H), 1.44 (t, J = 6.9Hz, 3H).

[0424] Example 4

[0425]

[0426] first step

[0427] Compound 4-A (500 mg, 2.7 mmol) was dissolved in NMP (5 mL), and DIPEA (690 mg, 5.3 mmol) and tetrahydro-2H-pyran-4-amine (540 mg, 5.3 mmol) were added to the reaction system. The reaction solution was heated to 120 ° C and stirred for 1 h. The reaction system was restored to room temperature, water was added to quench the reaction, and ethyl acetate (3*40 mL) was extracted and washed with saturated brine. Drying over anhydrous sodium sulfate, spin drying, and the crude product was purified by column chromatography (PE: EA = 1: 1) to obtain yellow solid compound 4-1. LCMS (M+H) + =253.0.

[0428] Step 2

[0429] Compound 4-1 (100 mg, 0.4 mmol), intermediate A (130 mg, 0.6 mmol), BINAP (50 mg, 0.08 mmol) and Cs 2 CO 3 (324 mg, 1 mmol) was dissolved in dioxane (10 mL). Palladium acetate (9 mg, 0.04 mmol) was added to the reaction system at room temperature and reacted at 110°C for 18 h under nitrogen protection. The solvent was removed by concentration and the crude product was purified by high performance liquid chromatography to obtain compound 4. LCMS (M+H) + =435.0. 1H NMR(400MHz,DMSO)δ8.59–8.44(m,2H),8.04(d,J=7.7Hz,1H),7.51(s,1H),7.39–7 .29(m,2H),7.24(s,1H),6.89(d,J=4.2Hz,1H),6.54–6.41(m,1H),4.41–4.29(m,1H ),4.24(q,J=6.9Hz,2H),3.94(d,J=8.1Hz,2H),3.80–3.73(m,3H),3.46(t,J=11.6H z,2H),1.92(d,J=10.9Hz,2H),1.63(qd,J=12.3,4.5Hz,2H),1.44(t,J=6.9Hz,3H).

[0430] Example 5

[0431]

[0432] first step

[0433] Compound 4-A (300 mg, 1.6 mmol) was dissolved in NMP (5 mL), and DIPEA (414 mg, 3.2 mmol) and 4-methoxycyclohexane-1-amine (414 mg, 3.2 mmol) were added to the reaction system. The reaction solution was heated to 120 ° C and stirred for 1 h. The reaction system was restored to room temperature, water was added to quench the reaction, and ethyl acetate (3*40 mL) was extracted and washed with saturated brine. Drying over anhydrous sodium sulfate, spin drying, and the crude product was purified by column chromatography (PE: EA = 1: 1) to obtain a yellow solid compound 5-1. LCMS (M+H) + =281.0.

[0434] Step 2

[0435] Compound 5-1 (120 mg, 0.4 mmol), intermediate A (139 mg, 0.6 mmol), BINAP (53 mg, 0.09 mmol) and Cs 2 CO 3 (346 mg, 1 mmol) was dissolved in dioxane (10 mL), and palladium acetate (10 mg, 0.04 mmol) was added to the reaction system at room temperature, and the reaction was carried out at 110°C for 18 h under nitrogen protection. The solvent was removed by concentration, and the crude product was purified by high performance liquid chromatography to obtain compound 5. LCMS (M+H) + =463.0. 1H NMR (400MHz, DMSO) δ8.58–8.46 (m, 2H), 7.98 (d, J = 7.8Hz, 1H), 7.52–7.46 (m, 1H), 7.35–7. 26(m,2H),7.23(s,1H),6.88(dd,J=4.4,1.6Hz,1H),6.46(dd,J=4.3,2.5Hz,1H),4.24(q,J =6.9Hz,2H),4.17–4.00(m,1H),3.78(d,J=10.3Hz,3H),3.25(d,J=11.5Hz,3H),3.22–3.0 7(m,1H),2.05(dd,J=29.4,10.0Hz,4H),1.51–1.37(m,5H),1.28(dd,J=23.0,10.2Hz,2H).

[0436] Example 6

[0437]

[0438] first step

[0439] Compound 4-A (100 mg, 0.8 mmol) was dissolved in NMP (5 mL), and DIPEA (200 mg, 1.5 mmol) and compound 6-1 (160 mg, 0.85 mmol) were added to the reaction system. The reaction solution was heated to 120 ° C and stirred for 1 h. The reaction system was restored to room temperature, water was added to quench the reaction, and ethyl acetate (3*30 mL) was extracted and washed with saturated brine. Drying over anhydrous sodium sulfate, spin drying, and the crude product was purified by column chromatography (PE: EA = 1: 1) to obtain yellow solid compound 6-2. LCMS (M+H) + =281.1.

[0440] Step 2

[0441] Compound 6-2 (70 mg, 0.25 mmol), intermediate A (55 mg, 0.25 mmol), BINAP (31 mg, 0.05 mmol) and Cs 2 CO 3 (204 mg, 0.6 mmol) was dissolved in dioxane (10 mL), and palladium acetate (6 mg, 0.03 mmol) was added to the reaction system at room temperature, and the reaction was carried out at 110°C for 18 h under nitrogen protection. The solvent was removed by concentration, and the crude product was purified by high performance liquid chromatography to obtain compound 6. LCMS (M+H) + =463.0. 1H NMR (400MHz, DMSO) δ8.59–8.48(m,2H),8.00(d,J=8.0Hz,1H),7.52–7.45(m ,1H),7.39–7.25(m,2H),7.20(s,1H),6.92(dd,J=4.3,1.5Hz,1H),6.45(dd, J=4.3,2.5Hz,1H),4.24(q,J=6.9Hz,2H),4.14(s,1H),4.10–4.00(m,1H),3. 75(d,J=11.9Hz,3H),1.87–1.58(m,6H),1.43(q,J=6.9Hz,5H),1.15(s,3H).

[0442] Example 7

[0443]

[0444] first step

[0445] Compound 4-A (20 mg, 0.16 mmol) was dissolved in NMP (3 mL), and DIPEA (40 mg, 0.3 mmol) and compound 7-1 (32 mg, 0.17 mmol) were added to the reaction system. The reaction solution was heated to 120 ° C and stirred for 1 h. The reaction system was restored to room temperature, water was added to quench the reaction, and ethyl acetate (3*30 mL) was extracted and washed with saturated brine. Drying over anhydrous sodium sulfate, spin drying, and the crude product was purified by column chromatography (PE: EA = 1: 1) to obtain yellow solid compound 7-2. LCMS (M+H) + =281.1.

[0446] Step 2

[0447] Compound 7-2 (28 mg, 0.1 mmol), intermediate A (33 mg, 0.15 mmol), BINAP (13 mg, 0.02 mmol) and Cs 2 CO 3 (82 mg, 0.25 mmol) was dissolved in dioxane (10 mL), and palladium acetate (3 mg, 0.01 mmol) was added to the reaction system at room temperature, and the reaction was carried out at 110°C for 18 h under nitrogen protection. The solvent was removed by concentration, and the crude product was purified by high performance liquid chromatography to obtain compound 7. LCMS (M+H) + =463.0. 1H NMR (400MHz, DMSO) δ8.52(d,J=9.5Hz,2H),7.91(d,J=7.8Hz,1H),7.49(s,1H),7.37–7.2 7(m,2H),7.21(s,1H),6.88(dd,J=4.3,1.5Hz,1H),6.47(dd,J=4.3,2.5Hz,1H),4.38(s,1 H),4.24(q,J=7.0Hz,2H),4.11(s,1H),3.77(s,3H),3.32(s,2H),1.90(s,2H),1.65(d,J =4.4Hz,2H),1.55(dd,J=19.1,11.2Hz,4H),1.45(t,J=6.9Hz,3H),1.19(d,J=7.6Hz,3H).

[0448] Example 8

[0449]

[0450] first step

[0451] Compound 4-A (300 mg, 1.6 mmol) was dissolved in NMP (5 mL), and DIPEA (414 mg, 3.2 mmol) and piperidine (389 mg, 3.2 mmol) were added to the reaction system. The reaction solution was heated to 120°C and stirred for 1 h. The reaction system was restored to room temperature, water was added to quench the reaction, and ethyl acetate (3*30 mL) was extracted and washed with saturated brine. Drying over anhydrous sodium sulfate, spin drying, and the crude product was purified by column chromatography (PE:EA=2:1) ​​to obtain yellow solid compound 8-1. LCMS (M+H) + =237.0.

[0452] Step 2

[0453] Compound 8-1 (100 mg, 0.4 mmol), intermediate A (139 mg, 0.6 mmol), BINAP (53 mg, 0.09 mmol) and Cs 2 CO 3 (346 mg, 1 mmol) was dissolved in dioxane (10 mL), and palladium acetate (10 mg, 0.04 mmol) was added to the reaction system at room temperature, and the reaction was carried out at 110°C for 18 h under nitrogen protection. The solvent was removed by concentration, and the crude product was purified by high performance liquid chromatography to obtain compound 8. LCMS (M+H) + =419.0. 1H NMR (400MHz, DMSO) δ8.58–8.44(m,2H),7.62(dd,J=2.5,1.5Hz,1H),7.37–7.27(m,2H),7.20(s,1H),6.87(dd,J=4.6,1.5Hz,1H), 6.56(dd,J=4.6,2.6Hz,1H),4.24(q,J=6.9Hz,2H),3.95(d,J=5.1Hz,4H),3.77(s,3H),1.78–1.59(m,6H),1.44(t,J=6.9Hz,3H).

[0454] Example 9

[0455]

[0456] first step

[0457] Compound 2-1 (50 mg, 0.2 mmol) was dissolved in acetonitrile (5 mL), and NCS (45.5 mg, 0.3 mmol) was added in batches. The reaction solution was heated to 70°C and stirred for 12 h, and concentrated under reduced pressure. The crude product was purified by HPLC to obtain white solid compound 9-1. LCMS (M+H) + =285.0. 1 H NMR (400MHz, DMSO) δ8.62(d,J=8.0Hz,1H),7.12(d,J=4.7Hz,1H),6.72(d,J=4.6Hz,1H),4.04(s,1H),2.0 8(s,1H),1.92(s,2H),1.76(s,2H),1.64(d,J=12.2Hz,1H),1.35(t,J=9.8Hz,3H),1.16(d,J=12.3Hz,1H).

[0458] Step 2

[0459] Compound 9-1 (15 mg, 0.05 mmol), BINAP (12 mg, 0.05 mmol), intermediate A (12 mg, 0.05 mmol) and cesium carbonate (43 mg, 0.13 mmol) were dissolved in dioxane (5 mL), palladium acetate (1 mg, 0.005 mmol) was added under nitrogen protection, the reaction system was heated to 100 ° C, and reacted under nitrogen protection for 12 hours. The solvent was removed by concentration under reduced pressure, and the crude product was purified by high performance liquid chromatography to obtain compound 9. LCMS (M+H) + =467.0. 1H NMR (400MHz, DMSO) δ8.61(d,J=8.4Hz,1H),8.53(s,1H),8.10(d,J=8.1Hz,1H),7.33(dd,J=12.6,7.6Hz,3H),7.00(d,J=4.6Hz,1H),6.56(d,J=4.6Hz,1 H),4.26(q,J=6.8Hz,2H),4.09(m,1H),3.77(m,3H),1.99(m,2H),1.79(m,2 H),1.67(d,J=12.7Hz,1H),1.46(d,J=6.9Hz,3H),1.37(m,3H),1.23(m,2H).

[0460] Example 10

[0461]

[0462] first step

[0463] Compound 2-1 (50 mg, 0.2 mmol) was dissolved in acetonitrile (5 mL), and NCS (45.5 mg, 0.3 mmol) was added in batches. The reaction solution was heated to 70°C, stirred for 12 h, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC to obtain a white solid compound 10-1. LCMS (M+H) + =285.0. 1 H NMR (400MHz, DMSO) δ7.73(d,J=2.9Hz,1H),7.00(d,J=8.1Hz,1H),6.75(d,J=2.9Hz,1H),4.17–3.98(m,1H),1.90(dd,J=12.3,3.3Hz ,2H),1.72(dd,J=9.2,3.9Hz,2H),1.64–1.55(m,1H),1.54–1.45(m,2H),1.36(td,J=12.0,3.3Hz,2H),1.20(td,J=11.9,3.4Hz,1H).

[0464] Step 2

[0465] Compound 10-1 (15 mg, 0.05 mmol), BINAP (6 mg, 0.01 mmol), intermediate A (12 mg, 0.05 mmol), cesium carbonate (43 mg, 0.13 mmol) were dissolved in dioxane (5 mL), palladium acetate (1 mg, 0.005 mmol) was added, the reaction solution was heated to 100 ° C, and reacted under nitrogen protection for 12 hours. The solvent was removed by concentration under reduced pressure, and the crude product was purified by high performance liquid chromatography to obtain compound 10. LCMS (M+H) +=467.0. 1 H NMR (400MHz, DMSO) δ8.52(d,J=15.9Hz,1H),8.41(d,J=8.4Hz,1H),7.58(d,J=2.8Hz,1H),7.40–7.24(m,3H),6.66–6.54(m,2H),4.24(q,J=7.0Hz,2 H),4.13(s,1H),3.76(m,3H),1.97(m,2H),1.73(m,2H),1.60(m,1H),1.50 (d,J=12.2Hz,2H),1.43(t,J=6.9Hz,3H),1.41–1.35(m,1H),1.23(m,2H).

[0466] Embodiment 11

[0467]

[0468] first step

[0469] Compound 2 (40 mg, 0.09 mmol) was dissolved in acetonitrile (3 mL), and NBS (16.5 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL), and then slowly added dropwise to the reaction system under an ice-water bath. The reaction solution was reacted at room temperature for 1 h. The solvent was removed by concentration, and the crude product was purified by HPLC to obtain compound 11. LCMS (M+H) + =511.0. 1 H NMR (400MHz, DMSO) δ8.66(d,J=8.4Hz,1H),8.54(s,1H),8.08(d,J=7.9Hz,1H ),7.37(m,3H),7.03(d,J=4.6Hz,1H),6.62(d,J=4.6Hz,1H),4.26(q,J=6.9H z,2H),4.09(s,1H),3.79(d,J=10.6Hz,3H),1.99(m,2H),1.79(m,2H),1.67( d,J=11.6Hz,1H),1.45(t,J=6.9Hz,3H),1.38(d,J=5.1Hz,4H),1.19(m,1H).

[0470] Example 12

[0471]

[0472] first step

[0473] Intermediate C (15 mg, 0.04 mmol) was dissolved in a mixed solution of dioxane (2 mL) and water (0.5 mL), and compound 12-1 (14 mg, 0.07 mmol), potassium carbonate (10 mg, 0.07 mmol) and Pd(dppf)Cl were added. 2 (3 mg, 0.004 mmol). The reaction solution was heated to 100°C and reacted for 2 h under nitrogen protection. The crude product was concentrated and separated by HPLC to obtain compound 12. LCMS: (M+H) + =402.0. 1 H NMR (400MHz, DMSO) δ8.98(s,1H),8.67(s,1H),8.36–8.29(m,1H),7.99(s,1H),7.38(dd,J=10.3,1.9Hz,2H),6.99(s,1H),6.93(d,J=4.7Hz,1 H),6.85(d,J=4.7Hz,1H),4.22(q,J=6.9Hz,2H),3.80(s,3H),2.83(s,2H),2.65(d,J=16.7Hz,2H),2.03–1.88(m,2H),1.42(t,J=6.9Hz,3H).

[0474] Embodiment 13

[0475]

[0476] first step

[0477] Compound 12 (15 mg, 0.04 mmol) was dissolved in ethyl acetate (3 mL), and 10% palladium on carbon (10 mg) was added. The mixture was stirred at room temperature for 5 h under hydrogen. After dilution with ethyl acetate, the residue was washed with ethyl acetate for 3 times. The filtrates were combined and concentrated, and the crude product was separated by HPLC to obtain compound 13. LCMS: (M+H) + =404.0. 1 H NMR (400MHz, DMSO) δ8.89(s,1H),8.61–8.40(m,2H),7.77(m,1H),7.44–7.30(m,2H),6.86(d,J=4.6Hz,1H),6.72(d,J=4.6Hz,1 H),4.24(q,J=6.9Hz,2H),3.78(s,3H),3.57(d,J=7.5Hz,1H),2.17(d,J=8.0Hz,2H),1.86–1.64(m,6H),1.45(t,J=6.9Hz,3H).

[0478] Embodiment 14

[0479]

[0480] first step

[0481] Intermediate C (28 mg, 0.07 mmol) and compound 14-1 (28 mg, 0.14 mmol) were dissolved in a mixed solution of dioxane (2 mL) and water (0.5 mL). Potassium carbonate (19 mg, 0.14 mmol) and Pd(dppf)Cl 2 (10 mg, 0.014 mmol) was added to the reaction system, the reaction solution was heated to 90°C, and the reaction was carried out under nitrogen protection for 18 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography to obtain compound 14. LCMS (M+H) + =416.0. 1 H NMR (400MHz, DMSO) δ8.94(s,1H),8.57(s,1H),8.35(m,1H),7.87(m,1H),7.37(d,J=10.7Hz,2H),7.12(m,1H),6 .89(d,J=17.5Hz,2H),4.24(m,2H),3.78(s,3H),2.01(m,1H),1.73(d,J=39.1Hz,5H),1.43(m,3H),1.24(m,2H).

[0482] Embodiment 15

[0483]

[0484] first step

[0485] Compound 14 (23 mg, 0.05 mmol) was dissolved in a mixture of MeOH (1 mL) and ethyl acetate (1 mL), and the reaction system was reacted at room temperature for 2 h under a hydrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 15. LCMS: (M+H) + =418.0. 1 H NMR (400MHz, DMSO) δ8.89(s,1H),8.50(m,2H),7.78(s,1H),7.36(m,2H),6.86(d,J=4.6Hz,1H),6.67(d,J=4.6Hz,1H),4.25(q,J =6.9Hz,2H),3.78(s,3H),3.15(m,1H),2.09(m,2H),1.86(m,2H),1.52(m,2H),1.44(d,J=6.9Hz,3H),1.30(m,2H),1.23(m,2H).

[0486] Example 16

[0487]

[0488] first step

[0489] Intermediate C (80 mg, 0.19 mmol), compound 16-1 (80 mg, 0.38 mmol), Pd(dppf)Cl 2 (15 mg, 0.02 mmol) and K 2 CO 3 (52 mg, 0.38 mmol) was dissolved in dioxane (6 mL) and H 2 O (1 mL), the reaction system was heated to 110 ° C, and the reaction was carried out under nitrogen protection for 8 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography to obtain compound 16. LCMS: (M+H) + =418.0. 1 H NMR (400MHz, DMSO) δ8.98(s,1H),8.56(s,1H),8.26(d,J=8.1Hz,1H),7.95(s,1H),7.38(m,2H),7.19(m,1H),6.92(dd,J=10.1,4 .8Hz,2H),4.37(d,J=2.6Hz,2H),4.22(q,J=6.9Hz,2H),3.88(t,J=5.4Hz,2H),3.78(s,3H),2.59(m,2H),1.42(t,J=6.9Hz,3H).

[0490] Embodiment 17

[0491]

[0492] first step

[0493] Compound 16 (20 mg, 0.05 mmol) was dissolved in MeOH (1 mL) and ethyl acetate (1 mL), and the reaction system was reacted at room temperature for 2 h under a hydrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 17. LCMS: (M+H) + =420.0. 1H NMR(400MHz,DMSO)δ8.92(s,1H),8.55(s,1H),8.49(d,J=8.8Hz,1H),7.81(s,1 H),7.37(m,2H),6.88(d,J=4.6Hz,1H),6.71(d,J=4.6Hz,1H),4.24(q,J=7.0Hz ,2H),4.00(dd,J=11.1,3.0Hz,2H),3.78(s,3H),3.60(dd,J=11.7,9.9Hz,2H), 3.45(m,1H),2.01(d,J=14.9Hz,2H),1.78(dd,J=12.5,3.9Hz,2H),1.45(m,3H).

[0494] Embodiment 18

[0495]

[0496] first step

[0497] Intermediate C (20 mg, 0.05 mmol) and compound 18-1 (20 mg, 0.10 mmol) were dissolved in a mixed solution of dioxane (2 mL) and water (0.4 mL). Potassium carbonate (14 mg, 0.1 mmol) and Pd(dppf)Cl 2 (5 mg, 0.005 mmol)) was added to the reaction system. The reaction system was heated to 90°C and reacted for 18 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain compound 18. LCMS (M+H) + =416.0. 1 H NMR (400MHz, DMSO) δ8.92(s,1H),8.57(s,1H),8.44(s,1H),8.31(d,J=8.1Hz,1H),8.16(s,1H),8.00(s,1H),7.40(m,2H ),7.12(d,J=4.7Hz,1H),6.98(d,J=4.7Hz,1H),4.23(q,J=6.9Hz,2H),3.96(s,3H),3.79(s,3H),1.41(t,J=6.9Hz,3H).s

[0498] Activity Test Example

[0499] In the following examples, the inventors took some compounds of the present invention as examples to detect the TTK inhibitory activity and pharmacokinetic properties of the compounds of the present invention.

[0500] Example A: TTK Inhibitory Activity

[0501] The purpose of this experiment is to detect the in vitro inhibitory activity of compounds on TTK.

[0502] Experimental steps and methods:

[0503] The TTK kinase reaction system was 10 μL, which included 0.5 nM TTK, a concentration gradient of the test compound, and 10 mM MgCl. 2 , 2mM DTT, 7uM ATP, 0.2uM Fluorescein-PolyGT (Fluorescein-Poly Glu: Tyr (4: 1)), 0.01% Triton X-100, 0.01% BSA and 50mM HEPES at pH 7.5. The enzyme and test compound were added to a 384-well plate, and then the substrate and ATP were added. The plate was incubated at 28°C. The reaction started. After 30 minutes, 10μL of the corresponding antibody and EDTA mixture was added to terminate the reaction. The plate was incubated at 28°C for 60 minutes. The Envision instrument read the data, and a curve was drawn with the Log concentration of the inhibitor as the X-axis and the inhibition rate as the Y-axis. According to the formula Y=Bottom+(Top-Bottom) / (1+(IC 50 / X)^HillSlope) to get IC 50 .

[0504] Table 1 shows the experimental data of the TTK inhibitory activity of some compounds of the present invention.

[0505] Table 1:

[0506] Compound No. <![CDATA[TTK IC 50 (nM)]]> Compound 1 27.0 Compound 2 1.9 Compound 3 8.9 Compound 4 4.0 Compound 5 1.7 Compound 6 3.0 Compound 7 1.1 Compound 10 5.5 Compound 12 8.7 Compound 13 7.1 Compound 14 2.4 Compound 15 4.2 Compound 16 2.0 Compound 17 6.3 Compound 18 2.1

[0507] The experimental results show that the compound of the present invention has good TTK inhibitory activity.

[0508] Example B: Pharmacokinetic evaluation of the compound of the invention after intravenous or oral administration to mice

[0509] The purpose of this experiment is to test the pharmacokinetic properties of the compound in mice

[0510] Experimental steps and methods:

[0511] The test compound was dissolved in 10% DMSO / 45% PEG400 / 45% water, vortexed and sonicated to prepare a clear solution of the corresponding concentration, which was filtered through a microporous membrane for later use. 18 to 20 grams of Balb / c female mice were selected and intravenously injected with the test compound solution at a dose of 1 mg / kg. The test compound was dissolved in 10% NMP / 10% polyethylene glycol-15-hydroxystearate / 80% water, vortexed and sonicated to prepare a clear solution of the corresponding concentration, which was filtered through a microporous membrane for later use. 18 to 20 grams of Balb / c female mice were selected and orally administered with the test compound solution at a dose of 10 mg / kg. Whole blood was collected at a certain time point to prepare plasma, and the drug concentration was analyzed by LC-MS / MS method, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software.

[0512] The experimental results show that the compound of the present invention has a large exposure amount in the test animals, is well absorbed, and has significant advantages in its pharmacokinetic properties.

[0513] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0514] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula (I) or a pharmaceutically acceptable salt of a compound represented by formula (I), (I)， in, L2-R1 is -OC 1-6 alkyl; R2, R4, and R5 are each independently H, F, Cl, or Br; R3 is triazole; wherein the triazole is unsubstituted or substituted with 1 C 1-6 Alkyl substituted; R6 is H, m is 1, and R' is C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, heterocyclic group consisting of 3-8 atoms, or heteroaryl consisting of 5-8 atoms, wherein the C 3-8 Cycloalkyl, C 3-8 The cycloalkenyl, heterocyclic group consisting of 3-8 atoms, or heteroaryl consisting of 5-8 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, wherein the substituents are independently selected from F, Cl, Br, C 1-6 Alkyl, C 1-6 haloalkyl; or m is 0, R6 is ,in, L1 is N, A1 is H, A2 is C 1-6 Alkyl, C 3-8 A carbocyclic group, a heterocyclic group consisting of 3 to 8 atoms, wherein the C 3-8 The carbocyclic group and the heterocyclic group composed of 3-8 atoms are unsubstituted or substituted by 1, 2, 3, 4 or 5 groups, each of which is independently F, Cl, Br, -OR b , C 1-6 Alkyl; or A1, A2 and the L1 to which they are connected together form a heterocyclic ring consisting of 3 to 6 atoms; R b H or C 1-6 alkyl.

2. The compound according to claim 1, having a structure shown in formula (II): (II), in, X is the following substructure: (X-1-1)、 (X-2-1); Ring W is C 3-8 Cycloalkyl, heterocyclic ring composed of 3-8 atoms, s is 0, 1, 2 or 3, each R w1 are independently H, F, Cl, Br, -OH, -OC 1-6 Alkyl, or C 1-6 alkyl; R6 and R7 are H, R w2 C 1-6 alkyl.

3. The compound according to claim 1, having a structure shown in formula (III): (III), in, Ring Y is C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, a heterocyclic ring consisting of 3-8 atoms or a heteroaromatic ring consisting of 5-6 atoms; Each R Y are independently H, F, Cl, Br, C 1-6 Alkyl or C 1-6 Haloalkyl; q is 0, 1, 2, or 3.

4. The compound according to claim 1, wherein R2, R4, and R5 are each independently H.

5. The compound according to claim 1, wherein L1 is N, A1 is H, and A2 is C 1-6 Alkyl, C 3-6 Carbocyclic group, heterocyclic group composed of 3-6 atoms, wherein The C 1-6 Alkyl, C 3-6 The carbocyclic group and the heterocyclic group composed of 3-6 atoms are each independently unsubstituted or substituted by 1 or 2 groups, each of which is independently F, Cl, Br, -OH, -OC 1-3 Alkyl, C 1-3 Alkyl; or A1, A2 and L1 connected to them together form a heterocyclic ring consisting of 6 atoms.

6. The compound according to any one of claims 1 to 3, wherein R6 is H, m is 1, and R′ is C 3-6 Cycloalkenyl, heterocyclic group consisting of 3-6 atoms, or heteroaryl consisting of 5-8 atoms, wherein the C 3-6 Cycloalkyl, C 3-6 The cycloalkenyl, heterocyclic group consisting of 3-6 atoms, or heteroaryl consisting of 5-8 atoms are each independently unsubstituted or substituted by 1 or 2 substituents, wherein the substituents are independently selected from F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

7. The compound according to any one of claims 1 to 3, wherein R6 is H, m is 1, and R′ is C 3-6 Cycloalkenyl, heterocyclic group consisting of 3 to 6 atoms, or heteroaryl consisting of 5 to 8 atoms, wherein the heteroaryl consisting of 5 to 8 atoms is separated by 1 or 2 C 1-6 Alkyl substituted.

8. The compound according to claim 1, wherein L1 is N, A1 is H, and A2 is C 1-6 Alkyl, C 3-6 Carbocyclic group, heterocyclic group composed of 3-6 atoms, wherein The C 3-6 The carbocyclic group is unsubstituted or substituted with 1 or 2 -OH, -OC 1-3 Alkyl, or C 1-3 alkyl.

9. The compound according to claim 2, wherein the ring W is C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms.

10. The compound according to claim 2, wherein R w1 are independently H, -OH, -O-CH3, methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl.

11. The compound according to claim 3, wherein the ring Y is C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, or a heterocyclic group consisting of 3 to 6 atoms.

12. The compound according to claim 3, wherein R Y is independently methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl.

13. The compound according to claim 2, having a structure shown in formula (IV): (IV), in, Ring V is a triazole group; R V C 1-6 alkyl; p is 1.

14. The compound according to claim 2, having a structure shown in formula (V): （V）， in, Ring V is a triazole group; R V C 1-6 alkyl; p is 1.

15. The compound according to claim 3, having a structure shown in formula (VI): (WE), in, Ring V is a triazole group; R V C 1-6 alkyl; p is 1.

16. A compound having one of the following structures: ， or pharmaceutically acceptable salts thereof.

17. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 16.

18. The pharmaceutical composition according to claim 17, further comprising: a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

19. The pharmaceutical composition according to claim 17 or 18, further comprising one or more therapeutic agents, wherein the therapeutic agents are selected from other anti-tumor drugs.

20. The pharmaceutical composition according to claim 19, wherein the therapeutic agent is an anti-mitotic drug, an alkylating agent, an antimetabolite drug, a topoisomerase inhibitor, an estrogen receptor modulator, an androgen receptor modulator, a small molecule inhibitor targeting protein kinase, or an antibody drug targeting protein kinase.

21. The pharmaceutical composition according to claim 20, wherein the antimitotic drug is paclitaxel or vincristine.

22. The pharmaceutical composition according to claim 20, wherein the alkylating agent is cisplatin, oxaliplatin, carboplatin or cyclophosphamide.

23. The pharmaceutical composition of claim 20, wherein the antimetabolite is gemcitabine, 5-fluorouracil or methotrexate.

24. The pharmaceutical composition according to claim 20, wherein the topoisomerase inhibitor is epipodophyllotoxin, etoposide, topotecan or camptothecin.

25. The pharmaceutical composition according to claim 20, wherein the estrogen receptor modulator is tamoxifen or fulvestrant.

26. The pharmaceutical composition of claim 20, wherein the androgen receptor modulator is bicalutamide.

27. The pharmaceutical composition according to claim 20, wherein the small molecule inhibitor targeting protein kinase is dasatinib, bosutinib, gefitinib, erlotinib, lapatinib, imatinib, nilotinib, sorafenib, tipifarnib, sunitinib, axitinib.

28. The pharmaceutical composition according to claim 20, wherein the antibody drug targeting protein kinase is trastuzumab, panitumumab, or cetuximab.

29. Use of the compound according to any one of claims 1 to 16 or the pharmaceutical composition according to any one of claims 17 to 28 in the preparation of a medicament, wherein the medicament is used to prevent, treat, cure or alleviate a disease associated with TTK overexpression or overactivity in a patient.

30. The use according to claim 29, wherein the disease associated with TTK overexpression is a tumor.

31. The use according to claim 30, wherein the tumor is papillary thyroid carcinoma, breast cancer, gastric cancer, bronchial cancer or lung cancer.

32. Use of the compound of any one of claims 1 to 16 or the pharmaceutical composition of any one of claims 17 to 28 in the preparation of a medicament, wherein the medicament is used to inhibit TTK.

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