Ttk kinase inhibitors and methods of use

Abstract

This document discloses novel compounds as Mps1 / TTK inhibitors. It also discloses compositions comprising said compounds and methods of using said compounds to treat various diseases in patients. In some embodiments, some of these compounds, compositions, and uses thereof can be used to treat cancer. In some implementations, said cancer is brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, gastric or stomach cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, lymphoma, thyroid cancer, mesothelioma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, or endometrial cancer.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 621,789, filed January 17, 2024, and U.S. Provisional Patent Application No. 63 / 664,986, filed June 27, 2024, each of which is incorporated herein by reference in its entirety.

[0002] Statement on Federally Funded Research This invention was completed with government support, and the grant / contract number issued by the National Institutes of Health is P30CA016058. The government holds certain rights to this invention.

[0003] field This disclosure generally pertains to the field of anticancer treatment, and more specifically, to the field of Mps1 / TTK kinase inhibitors for the treatment of cancer.

[0004] background Cancer is a significant public health burden, being the second leading cause of death in the United States, causing 10 million deaths in 2020. Cancer treatments are diverse. Current cancer treatments include surgery, radiation therapy, and chemotherapy, either alone or in combination.

[0005] Current cancer treatments have numerous drawbacks, including limitations in application and severe side effects. For example, surgery (which typically involves removing all or part of a tumor from the body) is generally most effective for treating early-stage cancers, but its application is limited to areas with easy access to the tumor. Furthermore, regarding radiation, it is usually applied to a defined area of ​​the patient's body containing cancerous tissue to maximize the amount of radiation absorbed by the cancerous tissue and minimize the amount absorbed by "normal" or non-cancerous tissue. However, it is difficult to selectively apply radiation only to cancerous tissue without exposing "normal" or non-cancerous tissue. In addition, chemotherapy (which involves using drugs or therapeutic agents to slow or stop the growth of cancer cells) often has severe side effects that impact the patient's quality of life, such as vomiting, weight loss, hair loss, and low white blood cell counts. These severe side effects may cause patients to discontinue treatment. Furthermore, drug resistance to chemotherapy and metastasis can also occur. Therefore, given the numerous shortcomings of current cancer treatments, improved anticancer therapies are needed.

[0006] Overview This document discloses Mps1 / TTK kinase inhibitory compounds, compositions, and their uses. In some embodiments, some of these compounds, compositions, and their uses can be used to treat cancer.

[0007] In one aspect, compositions comprising compounds are provided. In some embodiments, a composition comprising a compound of formula I is provided herein: (Formula I), Or its tautomers, pharmaceutically acceptable salts and / or solvates in R 1 It is H; R 2 It is H; R 3 Not H; R 4 Selected from -ZR 15 or -ZR 19 ,in Z is NH, N-methyl, or O; R 15 It is a six-membered ring with the following structure ,in R 16 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(S)NR 20 R 21 -NR 23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R 21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR 23 -S(O)2NR 20 R 21 -CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 18 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(O)NR 20 R 21 -C(S)NR 20 R 21 -NR23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R 21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR 23 -S(O)2NR 20 R 21 -CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 19 Selected from linear C1-C 16 Alkyl, branched C1-C 16 Alkyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, cyclobutyl, and cyclopentyl; R 20 R 21 and R 23 Each is independently hydrogen or a C1-C6 alkyl group; and R 22 It is a C1-C6 alkyl group; R 5 Selected from C1-C4 alkyl groups, substituted or unsubstituted 4- to 7-membered heterocycles, sulfoxides, sulfonamides, and fused or bridged spirocyclic heterocycles, E3-ligase-binding moieties, and -NHR. 24 and -NR 24 R 31 , R 24 Selected from C1-C4 alkyl halides, -R 25 -OR 26 -R 27 -C(O)NH-R 28 -R 29 NHC(O)-R 30 Substituted or unsubstituted 4-membered heterocycles and substituted or unsubstituted cyclobutanes, R 25 It is a C1-C4 alkyl group. R 26 It is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide. R 27 and R 28 Each is independently a C1-C4 alkyl group. R29 and R 30 Each is independently a C1-C4 alkyl group, and R 31 It is a C1-C4 alkyl or a C1-C4 alkyl halide; R 6 It is hydrogen, methyl, -CN, -S-methyl or -XR 8 Where X is O, S or SO2 and R 8 It is a C1-C3 alkyl or a C1-C3 haloalkyl; R 7 It is H, CN, OCH3, or F; Y is CH, N, CF, or C-CH3; and Indicates a single bond or a double bond.

[0008] In some cases, R 3 It includes C1-C4 alkyl, C3-C4 cycloalkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-isopropyl, -C(O)O-butyl, -CH2OH, -C(O)N-methyl, -C(O)O-cycloalkyl, -C(O)OH, -CN, alkyl nitrile, imidazole, pyrazole, triazole, tetrazolium, oxazole, isoxazole, thiazole, -C(O)R 9 or -C(O)NHR 9 ;where R 9 It is an H or C1-C4 alkyl group. In some cases, -C(O)O-cycloalkyl includes -C(O)O-cyclopropyl, -C(O)O-cyclobutyl, -C(O)O-cyclopentyl or -C(O)O-cyclohexyl.

[0009] In some implementations of the compositions described herein, R 5 It is caused by one or two oxygen atoms and / or R 17 The replaced 5- to 7-membered heterocycles, Where R 17 Independently selected from -OR 10 -NR 10 C(O)R 12 -C(O)OR 10 -NR 10 R 11 -C(O)NR 10 R 11 -C(S)NR 10 R 11 -NR 13 C(O)NR 10 R 11 -NR 13 C(S)NR 10 R11 -OC(O)NR 10 R 11 -S(O)2NR 10 R 11 -OS(O)2NR 10 R 11 -NR 13 -S(O)NR 10 R 11 CN, halogens, NO and -S(O)-R 12 , Where R 10 R 11 and R 13 Each is independently hydrogen or a C1-C6 alkyl group; and Where R 12 Independently, it is a C1-C6 alkyl group. In other cases, R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidinone, oxazolidinone, morpholine, thiomorpholine dioxide, tetrahydrothiophene dioxide, thiacyclohexane dioxide, thiazolidinone, thiadiazolone, sulfoxide, or sulfonamide.

[0010] In other cases, compounds of other formulas are provided herein. For example, compounds of formula II are provided herein: (Formula II) Or its tautomers, pharmaceutically acceptable salts and / or solvates Where R 3 R 5 R 6 and R 7 Defined as described above.

[0011] Furthermore, in some embodiments, compounds of formula III are provided herein: (Formula III) Or its tautomers, pharmaceutically acceptable salts and / or solvates Among them, R 3 R 5 and R 7 Defined as described above.

[0012] In another aspect, pharmaceutical compositions are provided comprising the compositions or compounds described herein and a carrier, optionally a pharmaceutically acceptable carrier. Such compositions may comprise any of the compounds and / or compositions described herein.

[0013] Furthermore, in another aspect, this document provides a method for treating a disease in a patient with this need, wherein the method comprises administering to the patient a therapeutically effective amount of the composition described herein, and wherein the disease is cancer. Such a composition may comprise any of the compounds and / or compositions described herein.

[0014] Furthermore, in yet another aspect, a method is provided for treating a patient requiring an Mps1 / TTK inhibitor, wherein the method comprises determining the levels of Mps1 / TTK protein and / or Mps1 / TTK mRNA in the patient's cells, and, if the presence of Mps1 / TTK protein and / or Mps1 / TTK mRNA is detected, administering to the patient a therapeutically effective amount of the composition described herein. In some cases, the patient is a cancer patient. Such a composition may comprise any of the compounds described herein.

[0015] Detailed description The embodiments described herein can be more readily understood by referring to the following detailed description and examples, as well as the preceding and following descriptions therebefore and after them. However, the elements and methods described herein are not limited to the specific embodiments presented in the detailed description and examples. It should be recognized that these embodiments are merely examples of the principles of the invention. Many modifications and adjustments will be readily apparent to those skilled in the art without departing from the spirit and scope of the invention.

[0016] Furthermore, all ranges disclosed herein should be understood to include any and all subranges contained therein. For example, the specified range “1.0 to 10.0” should be considered to include any and all subranges that begin with a minimum value of 1.0 or greater and end with a maximum value of 10.0 or less, such as 1.0 to 5.3, or 4.7 to 10.0, or 3.6 to 7.9.

[0017] When a range of integers is given, the range includes any number falling within that range as well as the numbers that define the endpoints of the range. For example, when the term "integers from 1 to 20" is used, the range includes integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., up to and including 20. Unless otherwise explicitly stated, all ranges disclosed herein should also be considered to include the endpoints of the range. For example, the range "between 5 and 10" should generally be considered to include the endpoints 5 and 10.

[0018] Furthermore, when the phrase "until" is used in conjunction with a quantity or amount, it should be understood that the quantity is at least a detectable quantity or amount. For example, a substance that exists in a specific amount "until" can exist in a quantity that is detectable up to and includes that specific amount.

[0019] Furthermore, as used herein, the terms “substantially,” “about,” and “approximately” when referring to measurable values ​​(e.g., the amount, dosage, time, temperature, etc. of the compounds or reagents of the present invention) are intended to include variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount. The term “substantially constitutes” (and grammatical variations) shall be given in its ordinary sense and shall also imply that the composition or method referred to may contain additional components, provided that said additional components do not materially alter the composition or method. The term “consisting of” (and grammatical variations) shall be given in its ordinary sense and shall also imply that the composition or method referred to does not contain additional components. The term “comprising” (and grammatical variations) shall be given in its ordinary sense and shall also imply that the composition or method referred to may contain additional components.

[0020] It should also be understood that, unless the context of a particular application requires otherwise, the article “a” or “an” means “at least one / a kind”.

[0021] As used in this article, “and / or” refers to and covers any and all possible combinations of one or more of the related listed items, as well as the lack of combinations when interpreted in an alternative manner (“or”).

[0022] This disclosure discloses compounds, pharmaceutical compositions comprising said compounds, methods of preparation, and uses thereof. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter pertains. The terminology used herein to describe the subject matter is for the purpose of describing particular embodiments only and is not intended to limit the subject matter. This disclosure will be better understood with reference to the following definitions.

[0023] definition As used herein, the term “effective amount” refers broadly to the amount of the listed compounds that are effective in treating, preventing, or reducing the severity or progression of a disorder in a subject (e.g., a human subject). This includes improving a subject’s condition (e.g., one or more symptoms), delaying or reducing the progression of a disease and / or disorder, preventing or delaying the onset of a disorder, and / or altering clinical parameters, diseases, or ailments, as is well known in the art.

[0024] For example, an effective amount can represent the amount of a composition, compound, or reagent that improves the condition of a subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%.

[0025] The term "pharmaceutically acceptable salt" is used throughout this specification to describe any pharmaceutically acceptable form, such as an ester, that provides the compound upon administration to a patient. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals (e.g., potassium and sodium) and alkaline earth metals (e.g., calcium and magnesium), in addition to the many other acids well known in the pharmaceutical industry.

[0026] As used herein, the terms “treatment,” “manipulation,” etc., are used to indicate the attainment of desired pharmacological and / or physiological effects. These effects may be preventative, i.e., complete or partial prevention of the disorder or its signs or symptoms, and / or therapeutic, i.e., partial or complete cure of the disorder and / or adverse effects caused by it, or relief or elimination of its symptoms. Therefore, treatment includes prevention or protection from disease or disorder, i.e., prevention of the onset of clinical symptoms; and / or inhibition of disease or disorder, i.e., prevention or suppression of the development of clinical symptoms; and / or relief of disease or disorder, i.e., remission of clinical symptoms; and / or reduction of metastasis of the primary tumor or cancer.

[0027] The term “Mps1 / TTK kinase inhibitor compound” or “Mps1 / TTK kinase inhibitor” refers to substances and / or molecules that inhibit the activity of Mps1 / TTK kinases.

[0028] As disclosed herein, the “patient” or “subject” of treatment is a human patient in some embodiments; however, it should be understood that the principles of the currently disclosed subject matter indicate that it is effective for all vertebrate species, including mammals, and is intended to be included in the terms “subject” and “patient.” Suitable subjects are typically mammalian subjects. The subject matter described herein can be used for research as well as in veterinary and medical applications. As used herein, the term “mammal” includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats or mice), monkeys, etc. Human subjects include newborns, infants, adolescents, adults, and elderly subjects. Subjects who “need” the methods disclosed herein may be subjects experiencing and / or expecting to experience a disease state, and who use the methods and compositions of the invention for therapeutic treatment and / or preventative treatment.

[0029] For the general chemical formulas provided herein, unless otherwise specified, those skilled in the art will understand that the substituent is hydrogen. Unattached bonds indicate that the position of such substituents is variable. A zigzag, wavy, or double-wavy line drawn across a bond or at the end of a bond indicates that some additional structure is attached at that position. Furthermore, if the stereochemistry of a compound having one or more chiral centers is not specified, all enantiomers and diastereomers are included. Similarly, the enumeration of aliphatic or alkyl groups includes all their structural isomers. Unless otherwise stated, they are shown as R1 to R2 in the general formulas provided herein. n And the group referred to herein as an alkyl group is independently selected from alkyl or aliphatic groups, particularly alkyl groups having 20 or fewer carbon atoms, and even more generally lower alkyl groups having 10 or fewer atoms, such as methyl, ethyl, propyl, isopropyl, and butyl. The alkyl group may optionally be substituted (e.g., substituted or unsubstituted, as disclosed elsewhere herein). The alkyl group may be a substituted alkyl group, such as an alkyl halide (e.g., —CX3, where X is a halogen and combinations thereof, either in the chain or bonded thereto), an alcohol (e.g., an aliphatic or alkyl hydroxyl group, particularly a lower alkyl hydroxyl group), or other similarly substituted moieties such as amino-, amino acid-, aryl-, alkylaryl-, alkyl ester-, ether-, ketone-, nitro-, mercapto-, sulfonyl-, or sulfoxide-modified alkyl groups.

[0030] The terms "amino" and "amine" refer to nitrogen-containing groups such as NR3, NH3, NHR2, and NH2R, where R can be as described elsewhere herein. Thus, "amino" as used herein can refer to a primary, secondary, or tertiary amine. In some embodiments, one of the R groups of the amino group can be an azomonium glycol salt (e.g., NONO).

[0031] Whenever a group is described as “optionally substituted”, the group may be unsubstituted or substituted with one or more specified substituents. Similarly, when a group is described as “unsubstituted or substituted” (or “substituted or unsubstituted”), if substituted, the substituent may be selected from one or more specified substituents. If no substituent is specified, the specified “optionally substituted” or “substituted” group may be substituted by one or more groups individually and independently selected from the following: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aryl (alkyl), cycloalkyl (alkyl), heteroaryl (alkyl), heterocyclic (alkyl), hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, amino, monosubstituted amino, disubstituted amino, monosubstituted amine (alkyl), disubstituted amine (alkyl), diamino-group, polyamino, diether-group and polyether-group.

[0032] As used in this article, "C" a To C b The designation "a" or "Cb" (where "a" and "b" are integers) indicates the number of carbon atoms in the group. The specified group may contain "a" to "b" (including terminal values) carbon atoms. Thus, for example, "C1 to C4 alkyl" or "C1-C4 alkyl" or "C1 to C4 alkyl" or "C1-C4 alkyl" groups refer to all alkyl groups having 1 to 4 carbon atoms, namely CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If "a" and "b" are not specified, the broadest range described in these definitions should be assumed.

[0033] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety can be branched or straight-chain. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, tert-butyl, etc. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc. The alkyl group can have 1 to 30 carbon atoms. Whenever it appears herein, a numerical range, such as "1 to 30," refers to each integer within a given range; for example, "1 to 30 carbon atoms" means that the alkyl group can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, although this definition also covers the occurrence of the term "alkyl" where no numerical range is specified. The "alkyl" group can also be a medium-sized alkyl group having 1 to 12 carbon atoms. The "alkyl" group can also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group can be substituted or unsubstituted. By way of example only, "C1-C5 alkyl" indicates that there are 1 to 5 carbon atoms in the alkyl chain, for example, the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight), etc. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0034] As used herein, the term "alkylene" refers to a divalent, fully saturated, straight-chain aliphatic hydrocarbon group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, and octylene. Alkylene groups can be derived from... The symbol is followed by the number of carbon atoms, and then an asterisk (*). For example, ethylene can be represented as: The alkylene group may have 1 to 30 carbon atoms. Whenever it appears herein, the numerical range, such as “1 to 30”, refers generally to each integer within the given range; for example, “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although this definition also covers the occurrence of the term “alkylene” where no numerical range is specified. The alkylene group may also be a medium-sized alkyl group having 1 to 12 carbon atoms. The alkylene group may also be a lower alkyl group having 1 to 6 carbon atoms. The alkylene group may be substituted or unsubstituted. For example, by replacing one or more hydrogens of the lower alkylene group, and / or by using C… 3-6 Monocyclic cycloalkyl groups replace two hydrogen atoms on the same carbon atom (e.g., ), which can replace lower alkylene groups.

[0035] As used herein, the term "alkenyl" refers to a monovalent straight-chain or branched residue consisting of two to twenty carbon atoms containing a carbon double bond, including but not limited to 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, etc. Alkenyl groups may be unsubstituted or substituted.

[0036] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched residue consisting of two to twenty carbon atoms containing a triple carbon bond, including but not limited to 1-propynyl, 1-butynyl, 2-butynyl, etc. The alkynyl group may be unsubstituted or substituted.

[0037] As used herein, “cycloalkyl” refers to a fully saturated (without double or triple bonds) monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring system. When composed of two or more rings, the rings may be connected together in a fused, bridged, or spiro fashion. As used herein, the term “fused” refers to two rings sharing two atoms and one bond. As used herein, the term “bridged cycloalkyl” refers to a compound in which the cycloalkyl group contains a link of one or more atoms that are not adjacent to each other. As used herein, the term “spiro” refers to two rings sharing one atom and not connected by a bridge. Cycloalkyl groups may contain 3 to 30 atoms, 3 to 20 atoms, 3 to 10 atoms, 3 to 8 atoms, or 3 to 6 atoms in the ring. Cycloalkyl groups may be unsubstituted or substituted. Examples of monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthyl, dodecahydro-1H-finalenyl, and tetrahydroanthrayl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantyl, and norbornyl; and examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0038] As used herein, “cycloalkenyl” refers to a monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring system containing one or more double bonds in at least one ring; although if more than one is present, the double bonds cannot form a fully delocalized π-electron system in all rings (otherwise the group would be “aryl,” as defined herein). A cycloalkenyl group may contain 3 to 10 atoms, 3 to 8 atoms, or 3 to 6 atoms in the ring. When composed of two or more rings, the rings may be fused, bridged, or spirolinked together. The cycloalkenyl group may be unsubstituted or substituted.

[0039] As used herein, "aryl" refers to a carbocyclic (all-carbon), monocyclic, or polycyclic (e.g., bicyclic) aromatic ring system (including fused ring systems where two carbon rings share a single chemical bond), in which all rings possess a fully delocalized π-electron system. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be C6-C. 14 aryl group, C6-C 10 An aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azurite. Aryl groups can be substituted or unsubstituted. As used herein, “heteroaryl” refers to a monocyclic or polycyclic (e.g., bicyclic) aromatic ring system (a ring system with a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring of a heteroaryl group can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring, such as 9 carbon atoms and 1 heteroatom; 8 carbon atoms and 2 heteroatoms; 7 carbon atoms and 3 heteroatoms; 8 carbon atoms and 1 heteroatom; 7 carbon atoms and 2 heteroatoms; 6 carbon atoms and 3 heteroatoms; 5 carbon atoms and 4 heteroatoms; 5 carbon atoms and 1 heteroatom; 4 carbon atoms and 2 heteroatoms; 3 carbon atoms and 3 heteroatoms; 4 carbon atoms and 1 heteroatom; 3 carbon atoms and 2 heteroatoms; or 2 carbon atoms and 3 heteroatoms. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings (e.g., at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings) share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazolidone, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazolium, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, and triazine. The heteroaryl group may be substituted or unsubstituted.

[0040] As used herein, "heterocyclic group" or "heterocyclic ring group" refers to monocyclic, bicyclic, and tricyclic ring systems of ternary, quaternary, pentaneous, hexacyclic, heptacyclic, octaneous, nonacyclic, decacyclic, up to 18-membered structures, wherein a carbon atom is present along with one to five heteroatoms. A heterocycle may optionally contain one or more unsaturated bonds, but the positions of these unsaturated bonds ensure that a fully delocalized π-electron system is not present in all rings. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functional groups, thereby including oxo- and thio-systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be connected together in a fused, bridged, or spiro fashion. As used herein, the term "fused" refers to two rings sharing two atoms and one bond. As used herein, the terms "bridged heterocyclic group" or "bridged alicyclic group" refer to compounds in which the heterocyclic group or alicyclic group contains a link of one or more atoms that are not adjacent to each other. As used herein, the term "spiral" refers to two rings that share a single atom and are not connected by a bridge. Heterocyclic and alicyclic groups may contain 3 to 30 atoms, 3 to 20 atoms, 3 to 10 atoms, 3 to 8 atoms, or 3 to 6 atoms in the ring. For example, 5 carbon atoms and 1 heteroatom; 4 carbon atoms and 2 heteroatoms; 3 carbon atoms and 3 heteroatoms; 4 carbon atoms and 1 heteroatom; 3 carbon atoms and 2 heteroatoms; 2 carbon atoms and 3 heteroatoms; 1 carbon atom and 4 heteroatoms; 3 carbon atoms and 1 heteroatom; or 2 carbon atoms and 1 heteroatom. Furthermore, any nitrogen in the alicyclic group may be quaternized. Heterocyclic or alicyclic groups can be unsubstituted or substituted.Examples of such "heterocyclic" or "heterocyclic" groups include, but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxane, 1,3-dioxane, 1,4-dioxane, 1,3-oxathionecyclohexane, 1,4-oxathionecyclohexadiene, 1,3-oxathionecyclohexadiene, 1,3-dithionecyclohexadiene, 1,3-dithionecyclohexane, 1,4-oxathionecyclohexane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, etc. Hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazoline, isoxazoline, isoxazoline, oxazoline, oxazolidinone, oxazolidinone, thiazoline, thiazoline, morpholine, oxazolidinone, piperidine N-oxide, piperidine, piperazine, pyrrolidine, aziridine heptane, pyrrolidone, pyrrolidone, 4-piperidinone, pyrazoline, pyrrolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiaran, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone and their benzo[a]-fused analogues (e.g., benzimidazolinone, tetrahydroquinoline and / or 3,4-methylenedioxyphenyl). Examples of spirochetal groups include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.

[0041] As used herein, "aralkyl" and "aryl (alkyl)" refer to an aryl group linked by a lower alkylene group as a substituent. The lower alkylene group and aryl group of an aralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0042] As used herein, “cycloalkyl” refers to a cycloalkyl group linked by a lower alkylene group as a substituent. The lower alkylene group and the cycloalkyl group in a cycloalkyl group may be substituted or unsubstituted.

[0043] As used herein, “heteroarylalkyl” and “heteroaryl(alkyl)” refer to heteroaryl groups linked by a lower alkylene group as a substituent. The lower alkylene group and heteroaryl group of a heteroarylalkyl group may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furanylalkyl, thienylalkyl, pyrroliylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and their benzofused analogues.

[0044] "Heterocyclic (alkyl)" and "heterocyclic (alkyl)" refer to heterocyclic or heterocyclic groups linked by a lower alkylene group as a substituent. The lower alkylene group and heterocyclic group of the (heterocyclic)alkyl group can be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiaran-4-yl (methyl), and 1,3-thiazin-4-yl (methyl).

[0045] As used in this article, the term "hydroxyl group" refers to the -OH group in general.

[0046] As used herein, “alkoxy” refers to the formula -OR, where R is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl) group as defined herein. A non-limiting list of alkoxy groups includes methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoyloxy. Alkoxy groups may be substituted or unsubstituted.

[0047] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, aryl(alkyl), heteroaryl(alkyl), and heterocyclic(alkyl) group connected by a carbonyl group as a substituent. Examples include formyl, acetyl, propionyl, benzoyl, and propenyl. The acyl group may be substituted or unsubstituted.

[0048] As used in this article, the "cyano" group refers to the "-CN" group in general.

[0049] As used in this article, “halogen atom” or “halogen” refers to any of the radioactive stable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine, and iodine.

[0050] The term "thiocarbonyl" generally refers to the "-C(=S)R" group, where R can be the same as the definition for an O-carboxyl group. The thiocarbonyl group can be substituted or unsubstituted. The "O-carbamoyl" group represents "-OC(=O)N(R)". A R B )" group, wherein R A and R B It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The O-carbamoyl group can be substituted or unsubstituted.

[0051] The "N-carbamoyl" group generally refers to "ROC(=O)N(R A)-” groups, wherein R and R A It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The N-carbamoyl group can be substituted or unsubstituted.

[0052] The "O-thiocarbamoyl" group generally refers to "-OC(=S)-N(R)". A R B )" group, wherein R A and R B It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The O-thiocarbamoyl group can be substituted or unsubstituted.

[0053] The "N-thiocarbamoyl" group generally refers to "ROC(=S)N(R A )-” groups, wherein R and R A It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The N-thiocarbamoyl group can be substituted or unsubstituted.

[0054] The "C-amide" group generally refers to "-C(=O)N(R"). A R B )" group, wherein R A and R B It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The C-amide can be substituted or unsubstituted.

[0055] The "N-acylamino" group generally refers to "RC(=O)N(R A )-” groups, wherein R and R A It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The N-amide can be substituted or unsubstituted.

[0056] The "S-sulfonamide" group generally refers to "-SO2N(R)". A R B )" group, wherein R A and R BIt can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). S-sulfonamide can be substituted or unsubstituted.

[0057] The "N-sulfonamide" group generally refers to "RSO2N(R A )-” groups, wherein R and R A It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). N-sulfonamide can be substituted or unsubstituted.

[0058] The term "O-carboxyl" generally refers to the "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl), as defined herein. The O-carboxyl group can be substituted or unsubstituted.

[0059] The terms "ester" and "C-carboxyl" refer generally to the "-C(=O)OR" group, where R can be the same as defined for the O-carboxyl group. Esters and C-carboxyl groups can be substituted or unsubstituted.

[0060] The term "nitro" generally refers to the "-NO2" group.

[0061] The term "sulfenyl" generally refers to the "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl). The sulfenyl group can be substituted or unsubstituted.

[0062] The term "sulfinyl" generally refers to the "-S(=O)-R" group, where R can be the same as defined for sulfinyl groups. The sulfinyl group can be substituted or unsubstituted.

[0063] The term "sulfonyl" generally refers to the "SO2R" group, where R can be the same as defined for a sulfenyl group. The sulfonyl group can be substituted or unsubstituted.

[0064] As used herein, “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl groups may be substituted or unsubstituted.

[0065] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. The haloalkoxy group may be substituted or unsubstituted.

[0066] As used in this article, the terms "amino" and "unsubstituted amino" refer to the -NH2 group in general.

[0067] The term "monosubstituted amine" generally refers to "-NHR". A "group, wherein R A It can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl), as defined herein. A It can be substituted or unsubstituted. Monosubstituted amino groups can include, for example, mono-alkylamino, mono-C1-C6 alkylamino, mono-arylamino, mono-C6-C... 10 Arylamines, etc. Examples of monosubstituted amine groups include, but are not limited to, −NH (methyl), −NH (phenyl), etc.

[0068] The term "disubstituted amine" generally refers to "-NR". A R B "group, wherein R A and R B It can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl), as defined herein. R A and R B It can be substituted or unsubstituted independently. The disubstituted amino group can include, for example, di-alkylamino, di-C1-C6 alkylamino, di-arylamino, di-C6-C... 10 Arylamine groups, etc. Examples of disubstituted amine groups include, but are not limited to, −N(methyl)2, −N(phenyl)(methyl), −N(ethyl)(methyl), etc.

[0069] The term "monosubstituted amine (alkyl)" generally refers to the monosubstituted amines described herein linked by a lower alkylene group as a substituent. The monosubstituted amine (alkyl) can be substituted or unsubstituted. Monosubstituted amine (alkyl) groups can include, for example, mono-alkylamine (alkyl) groups, mono-C1-C6 alkylamine (C1-C6 alkyl) groups, mono-arylamine (alkyl) groups, mono-C6-C... 10Arylamine (C1-C6 alkyl) groups, etc. Examples of monosubstituted amine (alkyl) groups include, but are not limited to, −CH2NH (methyl), −CH2NH (phenyl), −CH2CH2NH (methyl), −CH2CH2NH (phenyl), etc.

[0070] The term "disubstituted amine (alkyl)" generally refers to the disubstituted amines described herein linked by a lower alkylene group as a substituent. The disubstituted amine (alkyl) can be substituted or unsubstituted. The disubstituted amine (alkyl) group can include, for example, dialkylamine (alkyl) groups, di-C1-C6 alkylamine (C1-C6 alkyl) groups, di-arylamine (alkyl) groups, di-C6-C... 10 Arylamine (C1-C6 alkyl) groups, etc. Examples of disubstituted amine (alkyl) groups include, but are not limited to, −CH2N(methyl)2, −CH2N(phenyl)(methyl), −CH2N(ethyl)(methyl), −CH2CH2N(methyl)2, −CH2CH2N(phenyl)(methyl), −NCH2CH2(ethyl)(methyl), etc.

[0071] As used herein, the term "diamino-" means "-N(R)". A )R B -N(R C (R) D )" group, wherein R A R C and R D It can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl), as defined herein, and wherein R B Connecting two "N" groups can be (independent of R) A R C and R D ) Substituted or unsubstituted alkylene groups. R A、 R B R C and R D It can be further replaced independently or not replaced.

[0072] As used herein, the term "polyamino" means "-(N(R)" A )R B -) n -N(R C (R) D For illustrative purposes, the term polyamino can include -N(R) A )alkyl-N(R A )alkyl-N(R A )alkyl-N(RA )alkyl-H. In some embodiments, the alkyl group of the polyamino group is as disclosed elsewhere herein. Although this example has only 4 repeating units, the term "polyamino" can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeating units. R A R C and R D It can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl), as defined herein, and wherein R B Connecting two "N" groups can be (independent of R) A R C and R D ) Substituted or unsubstituted alkylene groups. R A、 R C and R D It may be further substituted or not substituted independently. As noted here, polyamino comprises an amino group having spaced alkyl groups, wherein the alkyl group is defined elsewhere herein.

[0073] As used herein, the term "diether-" means "-OR". B OR A "group, wherein R A It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl), as defined herein, and wherein R B It connects two "O" groups and can be substituted or unsubstituted alkylene groups. R A It can be further replaced independently or not replaced.

[0074] As used herein, the term "polyether" indicates a repeated -(OR) B -) n OR A Group. For illustrative purposes, the term polyether may include -Oalkyl-Oalkyl-Oalkyl-Oalkyl-OR A In some embodiments, the alkyl group of the polyether is as disclosed elsewhere herein. Although this example has only four repeating units, the term "polyether" can consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeating units. A It can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl (alkyl), aryl (alkyl), heteroaryl (alkyl), or heterocyclic (alkyl), as defined herein. B It can be a substituted or unsubstituted alkylene group. RA It may be further substituted independently or not substituted. As noted herein, polyethers comprise ether groups having spaced alkyl groups, wherein the alkyl groups are as defined elsewhere herein and may optionally be substituted.

[0075] Where the number of substituents (e.g., haloalkyl) is not specified, one or more substituents may be present. For example, "haloalkyl" can include one or more of the same or different halogens. As another example, "C1-C3 alkoxyphenyl" can include one or more of the same or different alkoxy groups containing one, two, or three atoms. As used herein, a residue indicates a substance having a single unpaired electron, such that a substance containing that residue can covalently bond with another substance. Therefore, in this context, a residue is not necessarily a free radical. Instead, a residue indicates a specific part of a larger molecule. The term "residue" may be used interchangeably with the term "group." The term "part" may also be used to refer to a portion or functional group of a larger molecule or substance.

[0076] The subject matter of this disclosure will now be described in more full below. However, those skilled in the art to which this subject matter pertains, having benefited from the teachings presented in the foregoing description, will conceive of numerous modifications and other embodiments of the subject matter described herein. Therefore, it should be understood that the subject matter of this disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein encompasses all alternatives, modifications, and equivalents. If one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terms, usage of terms, described techniques, etc.), this application shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety.

[0077] This article presents Mps1 / TTK kinase inhibitory compounds that can be used to treat cancer. The dual-specificity protein kinase Mps1 (also known as TTK or Mps1 / TTK) is essential for centrosome replication and spindle assembly checkpoints. Phosphotyrosine-selective threonine kinase / threonine and tyrosine kinase (PYT / TTK) is a dual-specificity protein kinase. Mps1 / TTK regulates centrosome replication and spindle checkpoints. Its substrates include the centriole protein Centrin 2, and its centrosome levels are controlled by proteasome-mediated degradation. Inhibition of this degradation is sufficient to cause centrosome repetition, and defects in this control are associated with centrosome expansion and tumorigenesis. Furthermore, Mps1 / TTK directly phosphorylates Chk2 in vitro. In addition, the mRNA and protein levels of Mps1 / TTK are readily detectable in all proliferating cells and tissues, but are significantly reduced or absent in quiescent cells and tissues with low proliferation indices. Mps1 / TTK regulates cell cycle progression, and alterations to Mps1 / TTK have been associated with cell transformation and chromosomal instability in various tumor models. Furthermore, it has been reported that silencing Mps1 / TTK, which plays a dual role in checkpoint activation and chromosome alignment, can sensitize cancer cells to sublethal doses of paclitaxel, while non-tumor cells remain unsensitized. Other reports indicate that inhibition of Mps1 / TTK leads to chromosome segregation errors and the formation of cytoplasmic micronuclei, resulting in cytoplasmic dsDNA and / or dsRNA, which can act as sensors for immune responses via the STING and MAVS signaling pathways, respectively. Additional reports have confirmed that the mutant BRAF V600E directly phosphorylates and stabilizes Mps1 / TTK, thereby preventing its ubiquitination and degradation, suggesting that the BRAF V600E mutation may be a biomarker for cancers sensitive to Mps1 / TTK inhibitor therapy.

[0078] I. Compounds In one aspect, compositions comprising compounds are provided. In some cases, a composition comprising a compound of formula I is provided herein: (Formula I), Or its tautomers, pharmaceutically acceptable salts and / or solvates in R 1 It is H; R 2 It is H; R 3 Not H; R 4 Selected from -ZR 15 or -ZR 19 ,in Z is NH, N-methyl, or O; R 15 It is a 6-membered ring with the following structure ,in R 16 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(S)NR 20 R 21 -NR 23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R 21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR 23 -S(O)2NR 20 R 21 -CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 18 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(O)NR 20 R 21 -C(S)NR 20 R 21 -NR 23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R 21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR 23 -S(O)2NR 20 R 21-CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 19 Selected from linear C1-C 16 Alkyl, branched C1-C 16 Alkyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, cyclobutyl, and cyclopentyl; R 20 R 21 and R 23 Each is independently hydrogen or a C1-C6 alkyl group; and R 22 It is a C1-C6 alkyl group; R 5 Selected from C1-C4 alkyl groups, substituted or unsubstituted 4- to 7-membered heterocycles, sulfoxides, sulfonamides, and fused or bridged spirocyclic heterocycles, E3-ligase-binding moieties, and -NHR. 24 and -NR 24 R 31 , R 24 Selected from C1-C4 alkyl halides, -R 25 -OR 26 -R 27 -C(O)NH-R 28 -R 29 NHC(O)-R 30 Substituted or unsubstituted 4-membered heterocycles and substituted or unsubstituted cyclobutanes, R 25 It is a C1-C4 alkyl group. R 26 It is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide. R 27 and R 28 Each is independently a C1-C4 alkyl group. R 29 and R 30 Each is independently a C1-C4 alkyl group, and R 31 It is a C1-C4 alkyl or a C1-C4 alkyl halide; R 6 It is hydrogen, methyl, -CN, -S-methyl or -XR 8 Where X is O, S or SO2 and R 8 It is a C1-C3 alkyl or a C1-C3 haloalkyl; R 7 It is H, CN, OCH3, or F; Y is CH, N, CF, or C-CH3; and Indicates a single bond or a double bond.

[0079] This document also provides compositions comprising compounds of other formulas. For example, in some embodiments, compounds of formula II are provided herein: (Formula II) Or its tautomers, pharmaceutically acceptable salts and / or solvates Where R 3 R 5 R 6 and R 7 As defined above.

[0080] Furthermore, in some implementations, this paper provides compounds of formula III: (Formula III) Or its tautomers, pharmaceutically acceptable salts and / or solvates Where R 3 R 5 and R 7 As defined above.

[0081] It should be understood that in some cases of the compositions described herein, R 3 Not H. R could be considered. 3 Several parts. For example, in some implementations, R 3 It is a C1-C4 alkyl group. In some implementations, R 3 It is a C3-C4 cycloalkyl group. Furthermore, in some cases, R... 3 It is -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-isopropyl, -C(O)O-butyl, -CH2OH, or -C(O)NH-methyl. Furthermore, in some cases, R... 3 It is -C(O)O-cycloalkyl. In some embodiments, -C(O)O-cycloalkyl includes -C(O)O-cyclopropyl, -C(O)O-cyclobutyl, -C(O)O-cyclopentyl, or -C(O)O-cyclohexyl. In some cases, R 3 It is -C(O)OH. In some implementations, R 3 Yes -CN. In some implementations, R 3 It is an alkyl nitrile. For example, in some such cases, R 3 It is -CH2CN or -CH2CH2CN.

[0082] Furthermore, in some implementation schemes, R 3It is an imidazole. An imidazole can be any imidazole component that does not conflict with the technical objectives of this disclosure. The following shows non-limiting examples of imidazoles.

[0083] In some cases, imidazoles may be unsubstituted or substituted. For example, in some cases, imidazoles may be C1-C3 alkyl-substituted imidazoles or N-alkylimidazoles. Non-limiting examples of N-alkylimidazoles are shown below.

[0084] In some implementations, R 3 It is pyrazole. In R 3 The pyrazole at the position can be any pyrazole moiety that does not conflict with the technical objectives of this disclosure. For example, in some implementations, the pyrazole can be a 1,2-diazole. Furthermore, in some cases, the pyrazole can be unsubstituted or substituted. In some cases, the substituted pyrazole can be a C1-C3 alkyl-substituted pyrazole or an N-alkylpyrazole. Non-limiting examples of pyrazoles and N-alkylpyrazoles are shown below.

[0085] In some cases, R 3 It's triazole. In R 3 The triazole at a position can be any triazole portion that does not conflict with the technical objectives of this disclosure. In some embodiments, the triazole can be 1,2,3-triazole, 1,2,4-triazole, or 1,3,4-triazole. Non-limiting examples of triazoles are shown below.

[0086] Furthermore, in some cases, the triazole may be unsubstituted or substituted. For example, in some embodiments, in R... 3 The substituted triazole at a position can be a C1-C3 alkyl-substituted triazole or an N-alkyltriazole. Non-limiting examples of N-alkyltriazoles are shown below.

[0087] In some cases, R 3 It's tetrazolium. In R... 3 The tetrazolium at the position can be any tetrazolium portion that does not conflict with the technical objectives of this disclosure. In some embodiments, the tetrazolium can be 1,2,3,4-tetrazolium or 1,2,4,5-tetrazolium. Non-limiting examples of tetrazolium are shown below.

[0088] Additionally, in some cases, the tetrazolium can be unsubstituted or substituted. For example, in some implementations, the tetrazolium can be alkylated such that it is a C1-C3 alkyl-substituted tetrazolium. In some embodiments, the tetrazolium is an N-alkyltetrazole. Non-limiting examples of N-alkyltetrazoles are shown below.

[0089] In some implementations, R 3 It is an oxazole. An oxazole can be any oxazole moiety that does not conflict with the objectives of this disclosure. For example, in some cases, an oxazole can be 1,3-oxazole. In some cases, an oxazole can be unsubstituted or substituted. For example, in some implementations, the oxazole is alkyl-substituted. In some embodiments, the alkyl-substituted oxazole is a C1-C3 alkyl-substituted oxazole. Non-limiting examples of oxazoles are shown below.

[0090] In some implementation schemes, R 3 It is isoxazole. The isoxazole part used herein can be any isoxazole part that does not conflict with the technical objectives of this disclosure. Non-limiting examples of isoxazole are shown below.

[0091] In some cases, the isoxazole moiety can be unsubstituted or substituted. For example, in some implementations, the isoxazole is alkyl-substituted. In some implementations, the alkyl-substituted isoxazole is a C1-C3 alkyl-substituted isoxazole. Non-limiting examples of alkyl-substituted isoxazoles are shown below.

[0092] Furthermore, in some cases of the compounds and / or compositions described herein, R 3 It is a thiazole. The thiazole part used herein can be any thiazole part that does not conflict with the technical objectives of this disclosure. In some cases, the thiazole can be an isothiazole. The following shows non-limiting examples of thiazoles (including isothiazoles).

[0093] Additionally, in some cases, the thiazole moiety can be unsubstituted or substituted. For example, in some implementations, the thiazole is alkyl-substituted. In some implementations, the alkyl-substituted thiazole is a C1-C3 alkyl-substituted thiazole. Non-limiting examples of alkyl-substituted thiazoles and isothiazoles are shown below.

[0094] Go to R 3In some cases, R is an alternative implementation scheme. 3 It is -C(O)R 9 or -C(O)NHR 9 In some such implementations, R 9 It is an H or C1-C4 alkyl group. It should also be understood that in some other cases of the compounds and / or compositions described herein, R... 3 It's H.

[0095] Regarding other locations of the compounds and / or compositions described herein, in some cases described herein, R may be considered. 5 Several parts. For example, in some implementations, R... 5 It is a substituted or unsubstituted 4-membered heterocycle. In some embodiments, one or more carbon atoms may be replaced by a nitrogen atom, an oxygen atom, a sulfoxide group, or a thioyl group. In some embodiments, the 4-membered heterocycle may be alkyl-substituted or substituted with a halogenated group. Non-limiting examples of 4-membered heterocycles are shown below.

[0096] In addition, in some cases, R 5 It is caused by one or two oxygen atoms and / or R 17 The replaced 5- to 7-membered heterocycles, Where R 17 Independently selected from -OR 10 -NR 10 C(O)R 12 -C(O)OR 10 -NR 10 R 11 -C(O)NR 10 R 11 -C(S)NR 10 R 11 -NR 13 C(O)NR 10 R 11 -NR 13 C(S)NR 10 R 11 -OC(O)NR 10 R 11 -S(O)2NR 10 R 11 -OS(O)2NR 10 R 11 -NR 13 -S(O)NR 10 R 11 CN, halogens, NO and -S(O)-R 12 , Where R10 R 11 and R 13 Each is independently hydrogen or a C1-C6 alkyl group; and Where R 12 It is independently a C1-C6 alkyl group.

[0097] In some implementation schemes, R 5 It's imidazole. In R 5 The imidazole in the position can be any imidazole portion that does not conflict with the technical objectives of this disclosure. The following shows non-limiting examples of imidazoles.

[0098] In some cases, imidazoles may be unsubstituted or substituted. For example, imidazoles may be N-alkylimidazolium or dimethylimidazolium. Non-limiting examples of N-alkylimidazolium and dimethylimidazolium are shown below.

[0099] In some cases, R 5 It is pyrazole. In R 5 The pyrazole at the position can be any pyrazole moiety that does not conflict with the technical objectives of this disclosure. For example, in some implementations, the pyrazole can be unsubstituted or substituted. In some embodiments, the pyrazole is a C1-C3 alkyl-substituted pyrazole, such as 1-methylpyrazole. In other embodiments, the pyrazole is a C1-C3 haloalkyl-substituted pyrazole. The following shows the pyrazole at position R 5 Non-limiting examples of pyrazoles at a given position.

[0100] In some implementation schemes, R 5 It's triazole. In R 5 The triazole in the position can be any triazole portion that does not conflict with the technical objectives of this disclosure. In some implementations, the triazole is 1,2,3-triazole or 1,3,4-triazole. Non-limiting examples of triazoles are shown below.

[0101] In some cases, the triazole may be unsubstituted or substituted. For example, in some embodiments, in R... 5 The triazole substituted at that position is an N-alkyltriazole. Non-limiting examples of N-alkyltriazoles are shown below. In some embodiments, the N-alkyltriazole is 4-methyl-1,2,4-triazole, 4-ethyl-1,2,4-triazole, 4-n-propyl-1,2,4-triazole, and 4-isopropyl-1,2,4-triazole.

[0102] In some implementation schemes, R 5 It's tetrazolium. In R... 5 The tetrazolium at the position can be any tetrazolium portion that does not conflict with the technical objectives of this disclosure. In some implementations, the tetrazolium is 1,2,3,4-tetrazolium or 1,2,4,5-tetrazolium. Non-limiting examples of tetrazolium are shown below.

[0103] In some cases, the tetrazolium can be unsubstituted or substituted. For example, in some implementations, the tetrazolium is an N-alkyltetrazole. Non-limiting examples of N-alkyltetrazoles are shown below.

[0104] In some cases, R 5 It is a pyrazolone, such as 3-pyrazolone. The pyrazolone can be any pyrazolone moiety that does not conflict with the technical objectives of this disclosure. In some embodiments, the pyrazolone can be unsubstituted or substituted. For example, in some implementations, the pyrazolone can be alkylated. Non-limiting examples of pyrazolone are shown below.

[0105] In some implementations, R 5 It is an oxazolidinone. An oxazolidinone can be any oxazolidinone portion that does not conflict with the technical objectives of this disclosure. In some embodiments, the oxazolidinone can be unsubstituted or substituted. In some such implementations, the oxazolidinone can be alkylated, hydroxylated, or both. Non-limiting examples of oxazolidinones are shown below.

[0106] In some implementation schemes, R 5 It is morpholine. Morpholine can be any morpholine moiety that does not conflict with the technical objectives of this disclosure. In some embodiments, morpholine can be unsubstituted or substituted. In some such implementations, morpholine can be alkylated. Non-limiting examples of morpholine are shown below.

[0107] In other implementation schemes, R 5 It is a thiomorpholine dioxide. The thiomorpholine dioxide can be any thiomorpholine dioxide moiety that does not conflict with the technical objectives of this disclosure. In some embodiments, the thiomorpholine dioxide can be unsubstituted or substituted. In some such implementations, the thiomorpholine dioxide moiety can be alkylated. Non-limiting examples of thiomorpholine dioxide are shown below.

[0108] In some implementations, R 5 It is tetrahydrothiophene dioxide. Tetrahydrothiophene dioxide can be any tetrahydrothiophene dioxide portion that does not conflict with the technical objectives of this disclosure. In some embodiments, tetrahydrothiophene dioxide can be unsubstituted or substituted. In some such cases, tetrahydrothiophene dioxide can be alkylated. Non-limiting examples of tetrahydrothiophene dioxide are shown below.

[0109] In some cases, R 5 It is a thiocyclohexane dioxide. The thiocyclohexane dioxide can be any thiocyclohexane dioxide portion that does not conflict with the technical objectives of this disclosure. In some embodiments, the thiocyclohexane dioxide can be unsubstituted or substituted. In some such implementations, the thiocyclohexane dioxide can be alkylated. Non-limiting examples of thiocyclohexane dioxide are shown below.

[0110] In other implementations, R 5 It is a thiazolidinedion. The thiazolidinedion can be any thiazolidinedion portion that does not conflict with the technical objectives of this disclosure. For example, in some cases, the thiazolidinedion can be an isothiazolidine. Furthermore, in some embodiments, the thiazolidinedion can be unsubstituted or substituted. For example, in some implementations, the thiazolidinedion can be alkyl-substituted. Non-limiting examples of thiazolidinediones are shown below.

[0111] Additionally, in some implementations, R5 is a thiadiazolidine. The thiadiazolidine can be any thiadiazolidine moiety that does not conflict with the technical objectives of this disclosure. Furthermore, in some embodiments, the thiadiazolidine can be unsubstituted or substituted. For example, in some implementations, the thiadiazolidine can be alkyl-substituted, N-alkyl-substituted, or substituted with a sulfonyl group. Non-limiting examples of thiadiazolidines are shown below.

[0112] In some cases, alternative implementations of the replaced 4- to 7-membered heterocycles can be considered. For example, in some cases, R... 5 It has the following structure: (Formula IV).

[0113] In some implementations, R 5 It can also have the following structure: (Form V).

[0114] In some implementation schemes, R 5 It can be one of the following: (Form VI) (Form VII) (Formula VIII) (Form IX) (Formula X) (Formula XI) (Form XII), or (Formula XIII).

[0115] In some implementation schemes, R 5 It is sulfoxide imine. The following are non-limiting examples of sulfoxide imine.

[0116] In other implementation schemes, R 5 It is a sulfonamide. The following are non-limiting examples of N-sulfonamides.

[0117] In some cases, R 5 It is a fused or bridged spirocyclic heterocycle. The following shows non-limiting examples of spirocyclic heterocycles.

[0118] In some implementations, R 5 Yes - NHR 24 or -NR 24 R 31 In some cases, R 24 Selected from C1-C4 alkyl halides, -R 25 -OR 26 -R 27 -C(O)NH-R 28 -R 29 NHC(O)-R 30 Substituted or unsubstituted 4-membered heterocycles and substituted or unsubstituted cyclobutanes, R 25 It is a C1-C4 alkyl group. R 26 It is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide. R 27 and R 28Each is independently a C1-C4 alkyl group. R 29 and R 30 Each is independently a C1-C4 alkyl group, and R 31 It is a C1-C4 alkyl or a C1-C4 alkyl halide.

[0119] In some implementations, R 24 It is a substituted or unsubstituted 4-membered heterocycle. In some embodiments, one or more carbons of the heterocycle may be replaced by a nitrogen atom, an oxygen atom, a sulfoxide group, or a thioyl group. The following shows R... 5 Group, wherein R 24 It is a non-restrictive example of a 4-membered heterocycle.

[0120] In some implementations, R 24 It is a substituted or unsubstituted cyclobutane. In some cases, the cyclobutane is alkylated, hydroxylated, or both. In some embodiments, the cyclobutane is substituted with an ether group. The following shows R... 5 Group, wherein R 24 It is a non-limiting example of cyclobutane.

[0121] In addition, switch to R 5 In some cases, R is an alternative implementation scheme. 5 This is the E3-ligase-binding moiety. It should be understood that, in some cases, for the purposes of this document, the E3-ligase-binding moiety can be any part capable of binding E3-ligase. It should also be understood that, in some cases, binding to E3-ligase can be through non-covalent or covalent interactions.

[0122] The E3-ligase binding moiety described herein can bind any E3-ligase that does not conflict with the technical objectives of this disclosure. For example, in some embodiments, the E3-ligase may be a HECT-type E3-ligase. In some cases, the E3-ligase may be a U-box-type E3-ligase. In some cases, the E3-ligase may be a ring-finger-type E3-ligase. In some cases, the E3-ligase may be an RBR-type E3-ligase.

[0123] Furthermore, any E3-ligase binding moiety that does not conflict with the technical objectives of this disclosure may be used. In some cases, the E3-ligase binding moiety comprises a linker portion covalently bound to the terminal portion: , Wherein L contains the linker portion and T contains the terminal portion. It should be understood that, for the purposes of this document, the linker portion functions to bind and / or connect the terminal portion to the core structure of the TTK inhibitory compound. Furthermore, for the purposes of this document, the terminal portion binds to the E3-ligase. In some cases, the terminal portion itself is primarily responsible for the binding and / or recruitment of the E3-ligase. However, in some implementations, both the linker portion and the terminal portion are responsible for the binding and / or recruitment of the E3-ligase. In other words, in some embodiments, both the linker portion and the terminal portion can bind to and / or interact with the E3-ligase.

[0124] The identity of L is not necessarily limited. For example, L can contain any linking portion contemplated by those skilled in the art. In some cases, L can contain an alkyl group. In some embodiments, the alkyl group can have 20 or fewer carbon atoms. Furthermore, in some cases, the alkyl group can be substituted, for example, by an alkyl group modified with a halide or other moiety such as amino-, amino acid-, aryl-, alkylaryl-, alkyl ester-, ether-, ketone-, nitro-, mercapto-, sulfonyl-, or sulfoxide-. Furthermore, in some embodiments, L can contain an alkylene group or an alkylene chain. In some cases, the alkylene group can have 1 to 30 carbon atoms. Furthermore, in some cases, the alkylene group can be unsubstituted or substituted. In some implementations, L can contain a cycloalkyl group. For example, in some embodiments, L can contain a fused or bridged ring system. Furthermore, in some cases, L can contain a cycloalkenyl group. In some implementations, the cycloalkenyl group can be unsubstituted or substituted. In some embodiments, L can contain an aryl group. The number of carbon atoms in the aryl group can vary. For example, the aryl group can be C6-C. 14 aryl group, C6-C 10 An aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azurite. The aryl group may be substituted or unsubstituted. Additionally, the aryl group may be a heteroaryl group. The number of atoms in the ring of the heteroaryl group can vary. Furthermore, in some embodiments, L may comprise a heterocycle. Any heterocycle that does not conflict with the technical objectives of this disclosure may be used as L. Furthermore, in some implementations, L may comprise an ether. In some embodiments, the ether may be a diether or a polyether. In some cases, L may comprise an amino group. For example, in some embodiments, the amino group may comprise a diamino group or a polyamino group. Furthermore, L may comprise a polyethylene glycol chain.

[0125] Furthermore, the identity of T is not necessarily limited. For example, T can be any known part that binds and / or recruits E3-ligases. Non-limiting examples of parts that bind and / or recruit E3-ligase molecules are provided in the following literature: Sasso, et al., Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic, Biochemistry 202362 (3), 601-623; Toriki, et al., Rational ChemicalDesign of Molecular Glue Degraders, ACS Central Science 2023 9 (5), 915-926; Cowan, et al., Driving E3 Ligase Substrate Specificity for Targeted ProteinDegradation: Lessons from Nature and the Laboratory, Annual Review of Biochemistry 2022 91, 295-319; Simonetta, et al., Prospective discovery of smallmolecule enhancers of an E3 ligase-substrate interaction Nat Commun 10, 1402 (2019); and Bricelj, et al., E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points, Front Chem. July 5, 2021; 9:707317, which are incorporated herein by reference.

[0126] It should be understood that the compounds described in Part I can be synthesized and / or prepared in any manner that does not conflict with the technical objectives of this disclosure. For example, in some embodiments, the compounds described herein can be synthesized and / or prepared using the methods or similar methods described in the Examples section below, with modifications known to those skilled in the art.

[0127] II. Pharmaceutical Compositions In another aspect, compositions are provided comprising compounds described herein, such as compounds of formula I, II, or III. The compositions and / or compounds used in the pharmaceutical compositions described herein may be any compositions and / or compounds described in Part I. Generally, the compounds described herein are mixed with a suitable carrier or excipient in a therapeutically effective amount. "Therapeutically effective amount," "therapeuticly effective quantity," or interchangeably "pharmacologically acceptable amount" or "pharmacologically acceptable quantity" means that a sufficient amount of the compound and a pharmaceutically acceptable carrier are present to achieve the desired result, for example, treatment of a disease at least partially mediated by Mps1 / TTK kinases (as further described herein).

[0128] Generally, the compounds described herein are administered in a therapeutically effective amount via any accepted mode of administration. The actual amount of the compound (i.e., the active ingredient) depends on many factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors. The compound may be administered according to any suitable dosage regimen, such as once, twice, three or four times daily, or as needed. All these factors are within the skill of the attending clinician. In some embodiments, the compound is administered once or more times within a treatment cycle. In other embodiments, the treatment cycle is 21 days. In other embodiments, the treatment cycle is 28 days. In some embodiments, the compound is administered once or more times within a treatment cycle up to four treatment cycles.

[0129] The therapeutically effective dose of the compound can range from about 0.03 to 50 mg / kg of recipient body weight / day; for example, about 0.1-25 mg / kg / day, or about 0.5 to 10 mg / kg / day. Therefore, for a person weighing 70 kg, the dose range could be about 1-3,500 mg per day.

[0130] In some embodiments of the technology described herein, pharmaceutical compositions are packaged in unit dose form. Unit dose form can effectively treat diseases and / or disorders. Typically, the unit dose of compounds comprising this technology varies based on patient considerations. Such considerations include, for example, age, regimen, condition, sex, disease severity, contraindications, concomitant therapies, etc. Those skilled in the art can also adjust or modify exemplary unit doses based on these considerations. For example, for a patient, the unit dose of a compound comprising this technology can range from 3 x 10 -5 g / kg to 1 g / kg, preferably lx 10 -3The dosage of the compound can vary from g / kg to 1.0 g / kg. The dosage of the compound in this technology can also vary from 0.01 mg / kg to 100 mg / kg or preferably from 0.1 mg / kg to 10 mg / kg.

[0131] In some embodiments, the unit dose comprises 0.01 mg / kg to 0.5 g / kg. In some embodiments, the unit dose comprises 0.01 mg / kg to 100 mg / kg. In some embodiments, the unit dose comprises 0.01 mg / kg to 50 mg / kg. In some embodiments, the unit dose comprises 0.01 mg / kg to 10 mg / kg. In some embodiments, the unit dose comprises 0.01 mg / kg to 5 mg / kg. In some embodiments, the unit dose comprises 0.1 mg / kg to 0.5 g / kg. In some embodiments, the unit dose comprises 0.1 mg / kg to 100 mg / kg. In some embodiments, the unit dose comprises 0.1 mg / kg to 50 mg / kg. In some embodiments, the unit dose comprises 0.01 mg / kg to 10 mg / kg. In some embodiments, the unit dose comprises 0.1 mg / kg to 5 mg / kg.

[0132] Generally, the compounds described herein will be administered as pharmaceutical compositions via any of the following routes: oral, transdermal, intranasal, suppository, parenteral (e.g., intramuscular, intravenous, or subcutaneous), or intrathecal administration. The compositions may be in the form of tablets, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition. The choice of formulation depends on a number of factors, such as the mode of drug administration and the bioavailability of the pharmaceutical substance.

[0133] Another way to administer a compound is by inhalation. This is an efficient method of delivering a therapeutic agent directly to the respiratory tract (see U.S. Patent No. 5,607,915). For delivery by inhalation, the compound can be formulated as a liquid solution, suspension, aerosol propellant, or dry powder and dispensed into a suitable dispenser. There are several types of drug inhalation devices: nebulizer inhalers, metered-dose inhalers (MDIs), and dry powder inhalers (DPIs). Nebulizer devices generate a high-speed airflow that causes the therapeutic agent (formulated in liquid form) to be expelled as a mist, which is carried into the patient's respiratory tract. MDIs are typically formulations packaged with compressed gas. Upon activation, the device expels a measured amount of the therapeutic agent via compressed gas, thus providing a reliable method of administering a set dose of the drug. DPIs dispense the therapeutic agent as a free-flowing powder, which can be dispersed into the patient's inspiratory airflow as the patient breathes. To obtain a free-flowing powder, the therapeutic agent is formulated with an excipient (e.g., lactose). The measured amount of the therapeutic agent is stored in capsule form and dispensed with each activation.

[0134] In some embodiments, the pharmaceutical compositions described herein typically comprise the compound described herein with at least one pharmaceutically acceptable excipient. In some cases, the acceptable excipient is non-toxic, facilitates administration, and does not adversely affect the therapeutic benefit of the compound. Such excipients can be any solid, liquid, semi-solid excipient commonly available to those skilled in the art, or, in the case of aerosol compositions, a gaseous excipient.

[0135] Solid pharmaceutical excipients include, but are not limited to, starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, and skim milk powder. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Preferred liquid carriers, especially for injectable solutions, include water, saline, phosphate-buffered saline, citrate buffer, glucose aqueous solution, and ethylene glycol.

[0136] The amount of the compounds described herein in a pharmaceutical formulation or composition can vary within the full range employed by those skilled in the art. In some embodiments, the formulation contains about 0.01-99.99 wt% of the active ingredient compound (based on the total weight of the formulation), with the balance being one or more suitable pharmaceutical excipients. Preferably, in some cases, the compounds described herein are present at a level of about 1-80 wt%.

[0137] The pharmaceutical compositions described herein can be prepared in any manner that does not conflict with the technical objectives of this disclosure. For example, in some embodiments, the compound can be mixed with one or more additional components (e.g., using a high-shear mixer) to form the pharmaceutical compositions described herein.

[0138] III. Combination Therapy In some embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents to treat a subject in need. The compounds used in the combination therapy may include any of the compounds described herein in Part I. In some embodiments, the one or more additional therapeutic agents are selected from anticancer compounds. When using the combination therapy, the one or more additional therapeutic agents may be administered sequentially or simultaneously with the compounds described herein. In some embodiments, one or more additional therapeutic agents are administered before the administration of the compounds described herein. In some embodiments, one or more additional therapeutic agents are administered after the administration of the compounds described herein. In some embodiments, one or more additional therapeutic agents are administered in parallel with the administration of the compounds described herein.

[0139] In some embodiments, the one or more additional therapeutic agents are anti-angiogenic agents (e.g., agents that prevent tumors from forming new blood vessels). Non-limiting examples of anti-angiogenic agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKC-β inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (α-v / β-3), MMP-2 (matrix metalloproteinase-2) inhibitors, and MMP-9 (matrix metalloproteinase-9) inhibitors. Some preferred anti-angiogenic agents include sunitinib (Sutent®), bevacizumab (Avastin®), axitinib (AG13736), SU14813 (Pfizer), and AG13958 (Pfizer).

[0140] Other anti-angiogenic agents include vatalani (CGP79787), sorafenib (Nexavar®), pilgatanib octasodium (Macugen®), vandetanib (Zactima®), PF-0337210 (Pfizer), SU14843 (Pfizer), AZD2171 (AstraZeneca), ranibizumab (Lucentis®), neovastatin® (AE941), tetrathiomolybdate (Coprexa®), AMG706 (Amgen), VEGF Trap (AVE0005), CEP7055 (Sanofi-Aventis), XL880 (Exelixis), tellatinib (BAY57-9352), and CP-868,596 (Pfizer).

[0141] Other anti-angiogenic agents include enzatolin (LY317615), midotolin (CGP41251), perifolfen (KRX0401), teprenone (Selbex®), and UCN01 (Kyowa Hakka).

[0142] Other examples of antiangiogenic agents that can be used in combination with the compounds disclosed herein include celecoxib (Celebrex®), parecoxib (Dynastat®), delacoxib (SC59046), romecoxib (Preige®), vardicoxib (Bextra®), rofecoxib (Vioxx®), ellamod (Careram®), IP751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia®).

[0143] Other anti-angiogenic agents include Aptosyn®, Amigesic®, Dolobid®, Motrin®, Orudis®, Relaxon®, Feldene®, Naproxen®, Voltaren®, Indomethacin®, Clinoril®, Toletin®, Lodine®, Toradol®, and Daypro®.

[0144] Other anti-angiogenic agents include ABT510 (Abbott), areolaxetine (TMI005), AZD8955 (AstraZeneca), incyclinide (Metastat®), and PCK3145 (Procyon).

[0145] Other anti-angiogenic agents include retinoic acid (Neotigason®), aplidine®, silengitide (EMD 45 121974), cobustatin A4 (CA4P), fenritinib (4HPR), tempostatin®, panzem® (2-methoxyestradiol), PF-03446962 (Pfizer), remadustat (BMS 275291), caputoxumab®, lenalidomide (Revlimid®), squalene (EVIZON®), thalidomide (Thalomid®), Ukrain® (NSC631570), Vitaxin® (MEDI 522), and zoledronic acid (Zetan®).

[0146] In some embodiments, the anticancer agent is a so-called "signal transduction inhibitor" (e.g., inhibiting the way regulatory molecules controlling essential processes such as cell growth, differentiation, and survival communicate within the cell). In some cases, signal transduction inhibitors include small molecules, antibodies, and antisense molecules. In some embodiments, signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, in some implementations, signal transduction inhibitors include, for example, ALK inhibitors, ROSI inhibitors, TrkA inhibitors, TrkB inhibitors, TrkC inhibitors, farnesyltransferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan-erb, IGF IR inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, WNT pathway inhibitors, and so-called multi-target kinase inhibitors.

[0147] Some preferred signal transduction inhibitors include gefitinib (Iressa®), cetuximab (Erbitux®), erlotinib (Tarceva®), trastuzumab (Herceptin®), sunitinib (Sutent®), imatinib (Gleevec®), PD325901 (Pfizer®), (Tafinlar®), vemurafenib (Zelboraf®), trametinib (Mekinist®), bimetinib (Mektovi®), selumetinib (Koselugo®), and cobimetinib (Cotellic®).

[0148] Other examples of signal transduction inhibitors include BMS 214662 (Bristol-Myers Squibb), lonafab (Sarasar®), piritraxo (AG2037), mateuzumab (EMD 7200), nimotuzumab (TheraCIMh-R3®), panitumumab (Vectibix®), vandetanib (Zactima®), pazopanib (SB 786034), ALT110 (Alteris Therapeutics), BIBW2992 (Boehringer Ingelheim), and Cervene® (TP38).

[0149] Other examples of signal transduction inhibitors include PF-2341066 (Pfizer), PF-299804 (Pfizer), cannatinib (CI1033), pertuzumab (Omnitarg®), lapatinib (Tycerb®), pelitinib (EKB 569), miltefosin®, BMS 599626 (Bristol-Myers Squibb), lapuleucel-T (Neuvenge®), NeuVax® (E75 cancer vaccine), Osidem® (IDM1), lilotinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix®), lapatinib (Tycerb®), PF-299804 (Pfizer), and pertuzumab (Onmitarg®).

[0150] Other examples of signal transduction inhibitors include ARRY142886 (ArrayBiopharm), everolimus (Certican®), zotaolimus (Endeavor®), tamsulosinic acid (Torisel®), AP23573 (ARIAD), and VX680 (Vertex).

[0151] Other signal transduction inhibitors include XL647 (Exelixis), sorafenib (Nexavar®), LE-AON (Georgetown University), and GI-4000 (GlobeImmune).

[0152] Other signal transduction inhibitors include ABT751 (Abbott), avozidil ​​(vrapindo), BMS387032 (Bristol Myers), EM1421 (Erimos), indisulam (E7070), celecoxib (CYC200), BIO112 (OneBio), BMS387032 (Bristol-Myers Squibb), PD0332991 (Pfizer), AG024322 (Pfizer), 35LOXO-101 (Loxo Oncology), crizotinib, and ceritinib.

[0153] In some embodiments, the compounds disclosed herein are used in conjunction with classical antitumor agents. Classical antitumor agents include, but are not limited to, hormone modulators such as hormones, antihormones, androgen agonists, androgen antagonists and antiestrogens, histone deacetylase (HDAC) inhibitors, gene silencers or gene activators, ribonucleases, proteasomes, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-I (PARP-1) inhibitors, tubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins.

[0154] Examples of classic antitumor agents used in combination therapy with the compounds disclosed herein (optionally with one or more other agents) include, but are not limited to, glucocorticoids such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, and progestins such as medroxyprogesterone acetate, megestrol acetate (Megsi), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; such as tamoxifen, raloxifene, lasoxifene, afoxifene, azoxifen, bardoxifene, fepemifen, olmexifen, opemifen, telmilifen, toremifene, tralostertan, and CHF4227 (Cheisi)), and selective estrogen receptor downregulators (SEMs). RD; such as fulvestrant), exemestane (Arnex), anastrozole (Renard), atamitan, fazodazole, letrozole (Furron), gonadotropin-releasing hormone (GnRH; also commonly known as luteinizing hormone-releasing hormone (LHRH)) agonists such as suprefact, goserelin (Norlad), leuprorelin and triptorelin (Trelstar), abaricicliz (Plenaxis), bicalutamide (Constate), cyproterone acetate, flutamide (Eulexin), medroxyprogesterone acetate, nilandron and ozatalon, dutasteride, iridarone, finasteride, saw palmetto ( Serenoa repens), PHL 00801, abaricicli, goserelin, leuprorelin, triptorelin, bicalutamide, tamoxifen, exemestane, anastrozole, fazodazole, formexetine, letrozole and combinations thereof.

[0155] Other examples of classic antitumor agents used in combination with the compounds disclosed herein include, but are not limited to, succinyl aniline hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), peptides (FR901228 or FK228), G2M-777, MS-275, neopentyloxymethyl butyrate and PXD-101, Onconase, PS-341 (MLN-341), bortezomib, 9-aminocamptothecin, belotecone, BN-80915 (Roche), camptothecin, diflutamide, and edotecarin. ), Daiichi, Gematometazone, 10-Hydroxycamptothecin, Irinotecan Hydrochloride (Camptosar), Letopecan, Orathecin (Rubitecan, Supergen), Topotecan, Camptothecin, 10-Hydroxycamptothecin, 9-Aminocamptothecin, Irinotecan, SN-38, Aetcarin, Ararubicin, Doxorubicin, Aminofibrate, Ammoniac, Daunorubicin, Doxorubicin, Exalucin, Epirubicin, Exalucin ... Topposide, Idarubicin, Galorubicin, Hydroxyurea, Nemorubicin, Noscholine (Mitoxantrone), Pirarubicin, Pifenamic acid, Procarbazine, Butylmycin, Sobuzosen, Tafluposide, Pentorubicin, Dexrazoxane (Dexrazoxane), Nitrogen Mustard N-oxide, Cyclophosphamide, AMD-473, Hexamethylmelamine, AP-5280, Apatziquinone, Brostallicin, Bendamustine, Busulfan, Carboquinone, Carmustine, Chlorobenzine Dacarbazine, estradiol, formustine, glucosamine, ifosfamide, KW-2170, lomustine, malphosphamide, dichloromethyldiethylamine, melphalan, dibromomannitol, dibromoeusine, mitomycin C, mitoxantrone, nimustine, ramustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds such as cisplatin, carboplatin, epplatin, lobaplatin, nedaplatin, oxaliplatin (Sanofi), levozocin, saxaplatin, and combinations thereof.

[0156] In some embodiments, the compounds disclosed herein are used in combination with dihydrofolate reductase inhibitors (e.g., methotrexate and NeuTrexin (trimethotraxa glucuronide)), purine antagonists (e.g., 6-mercaptopurine nucleoside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nerabine, and raltitrexed), pyrimidine antagonists, alimta (pemetrexed disodium, LY231514, MTA), capecitabine (Xeloda®), cytosine cytarabine, gemcitabine® (EliLilly), and tegafur (UFT). Orzel or Uforal, and including TS-1, a combination of tegafur, germectin, and otostat), deoxyfluorouridine, carmoflu, cytarabine (including ocfosfate, phosphate, stearate, sustained-release, and liposomal forms), enoxabin, 5-azacitidine (Vidaza), decitabine, ethinylcytidine, and other antimetabolites such as efornithine, hydroxyurea, leucovorin, noratrexate (Thymitaq), triapine, trimethoprim, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thienocarboxyl)-L-glutamic acid, AG-01469 (Pfizer Inc.), ABT-47 (Abbott Laboratories), INO-100 (Inotek Pharmaceuticals), KU-0687 (KuDOS) Pharmaceuticals) and GPI18180 (Guilford Pharm Inc.) and their combinations.

[0157] Other examples of classic antitumor cytotoxic agents used in combination therapy with the compounds disclosed herein (optionally with one or more other agents) include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), Butabulin (Amgen), EPO906 (Novartis), Vinpocetine (Bristol-Myers Squibb Company), Actinomycin D, Bleomycin, Mitomycin C, Neocarcinomacin (Netsistatin), Vincristine, Vincristine, Vincristine, Vinorelbine (Noviben), Docetaxel (Tasocide), Oxaliplatin, Paclitaxel (including docosahexaenoic acid paclitaxel, a DHA / paclitaxel conjugate), Cisplatin, Carboplatin, Nedaplatin, Eloxatin, Saplatin, Camptosar, Capecitabine (Xeloda), Eloxatin, Taxocide, Alivitaic Acid, and Telfamine (Telc). YTA®, DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar®), ethproxyn® (radiation therapy), targretin®, telmilipin (DPPE, which enhances the potency of cytotoxic agents), Theratope® (Biomira), retinoic acid (Vesanoid®), trizaone®, xylazofenectomycin (Xcytrin®), Cotara® (mAb), and NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax®), and combinations thereof.

[0158] Other examples of classic antitumor agents used in combination therapy with the compounds disclosed herein (optionally with one or more other agents) include, but are not limited to, Advexin (ING201), TNFerade (GeneVec, one or more compounds that express TNFα in response to radiotherapy), and RB94 (Baylor College of...). Medicine), Genasense (Olimmersen sodium, Genta), Comparetin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Pravastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, Astra-Zeneca), Lovastatin, Nicotinic acid (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, Tocherp and combinations thereof.

[0159] In some embodiments, the compounds disclosed herein are used in conjunction with immune checkpoint inhibitors. Immune checkpoint inhibitors include, but are not limited to, PD-1 inhibitors such as pembrolizumab, nivolumab, and cimiprimab; PD-L1 inhibitors such as atezolizumab, avelumab, and durvalumab; CTLA-4 inhibitors such as ipilimumab and trimemumab; and LAG-3 inhibitors such as renalidomab; and combinations thereof.

[0160] In some cases, the compounds disclosed herein are used in conjunction with CDK4 / 6 inhibitors. In some embodiments, CDK4 / 6 inhibitors include, but are not limited to, palbociclib (Ibrance®), reboxiclib (Kisqali®), abecilibi (Verzenio®), and combinations thereof. In some cases, the one or more additional therapeutic agents are interferon gene stimulators (STING) agonists. STING agonists include, but are not limited to, CDK-002 (Codiak Biosciences, Inc.), SB-11285 (F-starTherapeutics, Inc.), ulevostinag (Merck & Co. Inc.), BI-1387446 (Boehringer Ingelheim International GmbH), BMS-986301 (Bristol-Myers Squibb), DN-015089 (Shanghai De Novo Pharmatech Co. Ltd.), E-7766 (Eisai Co. Ltd.), GSK3745417 (GSKplc), HG-381 (HitGen Inc.), MK-2118 (Merck & Co., Inc.), ONO-7914 (Ono Pharmaceutical Co. Ltd.), SNX-281 (Stingthera Inc.), SYNB-1891 (Synlogic Inc.), and TAK-500 (Takeda Pharmaceutical Co.). Ltd.), TAK-676 (Takeda Pharmaceutical Co. Ltd.), HH-18202 (Shanghai Haihe Biopharma Co. Ltd.), A-296 (KLUS Pharma Inc.), ALG-031048 (AligosTherapeutics Inc.), BI-09 (Wistar Institute), c-Di-GMP (Hokkaido University), CRD-5500 (Takeda Pharmaceutical Co. Ltd.), NZ-IO-STING (Lidds AB; Stipe Therapeutics ApS; CS-Bay Therapeutics Inc.), GSK-532 (GSK plc), IMGS-203 (Immunogenesis Inc.), IMSA-201 (ImmuneSensor Therapeutics Inc.), JNJ-4412 (Johnson&Johnson), JNJ-6196 (Johnson&Johnson; F-star Therapeutics Inc.), ONM-501 (OncoNano Medicine, Inc.QHL-816 (Shanghai Affinity Biomedical Technology Co., Ltd.), RVU-24024 (RyvuTherapeutics SA; University of Pennsylvania; Tsinghua University; Inimmune Corp.), and combinations thereof.

[0161] Other examples of STING agonists used in combination therapy with the compounds disclosed herein (optionally with one or more other agents) include, but are not limited to, STI-001 (Stimunity SAS), STIM1 (Stimunity SAS), STING STANDALONE (BioNTech SE), VB-85247 (Venenum Biodesign LLC), XMT-2068 (Mersana Therapeutics Inc.), XMT-2175 (Mersana Therapeutics Inc.), BJY-806 (Eight Plus One Pharmaceutical Co. Ltd.), IMGS-501 (Immunogenesis Inc.), Immunosynthen (Merck KGaA), JABBX-400 (Jacobio Pharmaceuticals Group Co. Ltd., Mersana Therapeutics Inc.), SA-001 (StingInn LLC; Eternity Bioscience Inc.; Lupin Ltd.; F-star Therapeutics Inc.), STI-002 (Stimunity SAS), and STI-002 (Stimunity SAS). SAS), ACU-0943 (Aculeus Therapeutics Pty Ltd.; Exelixis Inc.), AVA-VP (Avammune Therapeutics Inc., Repertoire Immune Medicines Inc.), AVA-NP (Avammune Therapeutics Inc., Repertoire Immune Medicines Inc.), OS-101 (OncoSTING LLC), PG-10 (Genochem) SAS), SB-11325 (F-star Therapeutics Inc.), SB-11345 (F-star Therapeutics Inc.), SB-11396 (F-star Therapeutics Inc.), SITX-799 (Silicon Therapeutics LLC; ArcusBiosciences Inc.; HitGen Inc.; Nimbus Therapeutics LLC; Bicycle Therapeutics), TTI-10001 (Trillium Therapeutics Inc.), XMT-2056 (Mersana Therapeutics Inc.) and ADUS-100 (Chinook Therapeutics Inc.). . In some embodiments, the compounds described herein are used in conjunction with colorectal cancer therapies. In some cases, the compounds are used in conjunction with fluoropyrimidine-based therapeutic agents. In some cases, for example, fluoropyrimidine-based therapeutic agents include, but are not limited to, capecitabine, fluorouracil (5-FU), FOLFOX (a combination of leucovorin, 5-FU, and oxaliplatin), FOLFIRI (a combination of leucovorin, 5-FU, and irinotecan), CAPOX (a combination of capecitabine and oxaliplatin), fluorouridine, irinotecan, and combinations thereof. In other implementations, the compounds described herein are used in conjunction with other known therapeutic agents for colorectal cancer, including but not limited to bevacizumab, cetuximab, permumab, pembrolizumab, nivolumab, trastuzumab combined with pertuzumab and lapatinib, regorafenib, trifluralin, tilpyrimidine, ipilimumab, trastuzumab, aflibercept, ramucirumab, cannefenib, or combinations thereof. In some cases, the compounds disclosed herein are used in conjunction with compounds used to treat glioblastoma multiforme. In some cases, compounds used in conjunction with the compounds disclosed herein for the treatment of glioblastoma multiforme include, but are not limited to, procarbazine, lomustine, vincristine, temozolomide, bevacizumab, selmetinib, compounds used to treat NTRK gene fusion tumors (e.g., larotrectinib and entrectinib), or combinations thereof. In some embodiments, the compounds disclosed herein are used in conjunction with one or more BRAF inhibitors. In some cases, the BRAF inhibitor is an inhibitor of a mutant BRAF (e.g., a mutation at BRAF V600). However, the BRAF mutation is not necessarily limited. In some embodiments, the BRAF mutation may be BRAF V600E, BRAF V600K, BRAF V600R, BRAF V600L, or BRAF V600D. Furthermore, the identity of the BRAF inhibitor is not necessarily limited. In some cases, the BRAF inhibitor includes, but is not limited to, dabrafenib, cannefenib, and vemurafenib. In some embodiments, one or more BRAF inhibitors may be used in combination with one or more MEK inhibitors. The identity of the MEK inhibitor is not necessarily limited. For example, in some cases, non-limiting examples of MEK inhibitors include, but are not limited to, cobimetinib and trametinib. Additionally, the combination of the compounds disclosed herein and a BRAF inhibitor, or the combination of the compounds disclosed herein, a BRAF inhibitor, and a MEK inhibitor, can be used to treat diseases without limitation. For example, in some embodiments, such combination therapy can be used to treat glioblastoma multiforme, melanoma, or colorectal cancer. In some cases, the compounds disclosed herein are used in combination with compounds used to treat various metastatic cancers, said cancers having metastasized to the brain, central nervous system, or bone, and characterized by molecular markers. In some cases, for example, if the metastatic cancer is NTRK gene positive, NTRK gene fusion tumor therapeutics (e.g., larotrectinib and entrectinib) may be used in combination with the compounds described herein. In other cases, if the metastatic cancer is PD-1 / PD-L1 positive, pembrolizumab or nivolumab or other anti-PD1 / PD-L1 antibodies may be used in combination with the compounds described herein. In still other cases, if the metastatic cancer is ALK rearrangement positive or ROS1 positive, crizotinib may be used in combination with the compounds described herein. In some other cases, if breast cancer metastasis has occurred and it is HER2-positive, trastuzumab-drug conjugates, combinations of capecitabine and lapatinib or neratinib, combinations of paclitaxel and neratinib, combinations of tucatinib and trastuzumab and capecitabine, detrastuzumab, pertuzumab, or high-dose trastuzumab may be used with the compounds described herein. In some embodiments, if the breast cancer metastasis is HER2-nonspecific, capecitabine, cisplatin, etoposide, combinations of cisplatin and etoposide, or high-dose methotrexate may be used with the compounds described herein. In some embodiments, if melanoma metastasis has occurred and the metastatic melanoma is BRAF V600E-positive, combinations of dabrafenib and trametinib or vemurafenib and cobimetinib may be used with the compounds described herein. In other embodiments, if the melanoma is BRAF nonspecific, a combination of ipilimumab and nivolumab, ipilimumab, nivolumab, or pembrolizumab may be used in conjunction with the compounds described herein. In some cases, if small cell lung cancer metastasis has occurred, topotecan is used in conjunction with the compounds described herein. In some other cases, if lung cancer metastasis has occurred, for example, metastatic non-small cell lung cancer (NSCLC), and the metastatic NSCLC is EGFR-sensitized mutation positive, osimertinib, erlotinib, afatinib, or gefitinib is used in conjunction with the compounds described herein. In other embodiments, if the metastatic NSCLC has a MET exon 14 mutation, carmatinib is used in conjunction with the compounds described herein. In some other embodiments, if the metastatic NSCLC is RET fusion positive, serpatinib is used in conjunction with the compounds described herein. In other embodiments, if the metastatic NSCLC is ALK rearrangement positive, brigatinib, lorlatinib, alectinib, ceritinib, or crizotinib are used in conjunction with the compounds described herein.In some other embodiments, if the metastatic NSCLC is ROS1 positive, crizotinib is used in conjunction with the compounds described herein. In other embodiments, if lymphoma metastasis has already occurred, high-dose methotrexate is used in conjunction with the compounds described herein.

[0162] Furthermore, in some embodiments, the compounds disclosed herein are used in conjunction with compounds for the treatment of melanoma. In some embodiments, the compounds for the treatment of melanoma used in conjunction with the compounds disclosed herein include, but are not limited to, trametinib, dabrafenib, ipilimumab, vemurafenib, pembrolizumab, nivolumab, combinations of nivolumab and renalalimumab, bimetinib, cannefenib, talimogene laherparepvec, or combinations thereof.

[0163] Additionally, in some embodiments, the compounds disclosed herein are used in conjunction with compounds for the treatment of pancreatic cancer. In some embodiments, the compounds used in conjunction with the compounds disclosed herein for the treatment of pancreatic cancer include, but are not limited to, FOLFIRINOX (a combination of leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin), a combination of gemcitabine and albumin-bound paclitaxel (with or without subsequent chemoradiotherapy), a combination of gemcitabine and cisplatin followed by chemoradiotherapy, a combination of irinotecan liposomes with fluorouracil and leucovorin, carboplatin, mitomycin C, olaparib, rucapaparib, or combinations thereof. Furthermore, in some embodiments, the compounds disclosed herein are used in conjunction with compounds used to treat bladder cancer. In some embodiments, compounds used in conjunction with the compounds disclosed herein for the treatment of bladder cancer include, but are not limited to, mitomycin, epirubicin, pirarubicin, gemcitabine, avelumab, carboplatin, atezolizumab, pembrolizumab, paclitaxel, gemcitabine, vinblastine, granulocyte colony-stimulating factor (G-CSF), enrofloxacin, DDMVAC (high-dose methotrexate, vinblastine, doxorubicin, and cisplatin) or combinations thereof. In some other embodiments, the compounds disclosed herein are used in conjunction with intravesical immunotherapy and BCG (Bacillus Calmette-Guérin).

[0164] In some cases, the compounds disclosed herein are used in conjunction with compounds used to treat the stomach or gastric cancer. In some cases, compounds used in conjunction with the compounds disclosed herein for the treatment of the stomach or gastric cancer include, but are not limited to, FLOT (a combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel), capecitabine, cisplatin, irinotecan, trastuzumab, nivolumab, pembrolizumab, ramucirumab, paclitaxel, trifluralin, and tipyrimidine, or combinations thereof.

[0165] Furthermore, in some cases, the compounds disclosed herein are used in conjunction with compounds used to treat renal cell carcinoma or renal cell carcinoma. In some embodiments, compounds used in conjunction with the compounds disclosed herein for the treatment of renal cell carcinoma or renal cell carcinoma include, but are not limited to, IL-2, interferon-alpha, sunitinib, a combination of bevacizumab and interferon, pazopanib, tamsurolimus, everolimus, a combination of lenvatinib and everolimus, nivolumab, a combination of nivolumab and ipilimumab or cabozantinib, a combination of avelumab and axitinib, cabozantinib, sorafenib, axitinib, avelumab, pembrolizumab, fluorouracil (FUDR), 5-FU, vincristine, paclitaxel, carboplatin, ifosfamide, gemcitabine, doxorubicin, or combinations thereof.

[0166] Furthermore, in some cases, the compounds disclosed herein are used in combination with compounds used to treat ovarian cancer. In some cases, for example, compounds used with the compounds disclosed herein for the treatment of ovarian cancer include, but are not limited to, combinations of cyclophosphamide and bevacizumab, docetaxel, etoposide, gemcitabine, doxorubicin liposomes alone or in combination with bevacizumab, paclitaxel alone or in combination with bevacizumab, topotecan alone or in combination with bevacizumab, carboplatin, olaparib, niraparib, rucaparib, aromatase inhibitors such as leuprorelin, megestrol acetate, or tamoxifen or combinations thereof.

[0167] In some embodiments, the compounds disclosed herein are used in conjunction with therapies for the treatment of endometrial cancer. In some cases, for example, the compounds for the treatment of endometrial cancer include, but are not limited to, cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel (Abraxane), doxorubicin, doxorubicin liposomes, docetaxel, ifosfamide, topotecan, trastuzumab, bevacizumab, pembrolizumab, lenvatinib, tamoxifen, letrozole, medroxyprogesterone acetate, levonorgestrel, or combinations thereof.

[0168] Additionally, in some cases, the compounds disclosed herein are used in combination with compounds used to treat head and neck cancer. In some cases, for example, compounds used to treat head and neck cancer include, but are not limited to, cisplatin, cetuximab, paclitaxel, 5-FU, carboplatin, pembrolizumab, methotrexate, docetaxel, capecitabine, afatinib, nivolumab, pembrolizumab, gemcitabine, or combinations thereof. In some cases, the compounds disclosed herein are used in combination with compounds used to treat breast cancer. In some cases, for example, compounds used to treat breast cancer include, but are not limited to, carboplatin, cyclophosphamide, doxorubicin, epirubicin, capecitabine, gemcitabine, methotrexate, vinorelbine, trastuzumab-drug conjugates, denosumab, trastuzumab, pertuzumab, combinations of trastuzumab and hyaluronidase, detrastuzumab, goxatuzumab, combinations of pertuzumab with trastuzumab and hyaluronidase, lapatinib, neratinib, tucatinib, eribulin, docetaxel, paclitaxel, ixaprilone, anastrozole, letrozole, exemestane, palbociclib, reboxil, abeciclib, olaparib, talapanib, tamoxifen, raloxifene, toremifene, ellastrantraniliprole, atezolimus, apeliximab, or combinations thereof.

[0169] Some implementations relate to methods for treating cancer in subjects who require such treatment, the methods comprising administering to the subject a quantity of the compounds disclosed herein and one or more (preferably 1 to 3) anticancer agents selected from: trastuzumab, tamoxifen, docetaxel, paclitaxel, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, and anastrozole.

[0170] Combination therapies comprising the compounds described herein and one or more additional therapeutic agents can be carried out in any manner not contrary to the technical objectives of this disclosure. For example, in some embodiments, the compounds described herein and one or more additional therapeutic agents can be mixed (e.g., using a high-shear mixer) to form a pharmaceutical composition.

[0171] Furthermore, in some embodiments, the compounds described herein can be used in conjunction with different types of therapies. For example, in some cases, the compounds disclosed herein are used in combination with radiotherapy. In other cases, the compounds disclosed herein are used in combination with alternating electric field therapy. In some specific cases, the compounds disclosed herein are used in combination with tumor therapeutic field therapy. IV. Treatment of the disease In some embodiments, a method for inhibiting Mps1 / TTK kinase is provided, the method comprising, consisting of, or substantially consisting of the following steps: contacting Mps1 / TTK with a compound, pharmaceutical composition, or combination therapy described herein. The compound can be any compound described in Part I. In some embodiments, the compound comprises a compound of Formula I: (Formula I), Or its tautomers, pharmaceutically acceptable salts and / or solvates in R 1 It is H; R 2 It is H; R 3 Not H; R 4 Selected from -ZR 15 or -ZR 19 ,in Z is NH, N-methyl, or O; R 15 It is a 6-membered ring with the following structure ,in R 16 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(S)NR 20 R 21 -NR 23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R 21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR 23 -S(O)2NR 20 R 21 -CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 18 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(O)NR 20 R 21 -C(S)NR 20 R 21 -NR 23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR 23 -S(O)2NR 20 R 21 -CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 19 Selected from linear C1-C 16 Alkyl, branched C1-C 16 Alkyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, cyclobutyl, and cyclopentyl; R 20 R 21 and R 23 Each is independently hydrogen or a C1-C6 alkyl group; and R 22 It is a C1-C6 alkyl group; R 5 Selected from C1-C4 alkyl groups, substituted or unsubstituted 4- to 7-membered heterocycles, sulfoxides, sulfonamides, and fused or bridged spirocyclic heterocycles, E3-ligase-binding moieties, and -NHR. 24 and -NR 24 R 31 , R 24 Selected from C1-C4 alkyl halides, -R 25 -OR 26 -R 27 -C(O)NH-R 28 -R 29 NHC(O)-R 30 Substituted or unsubstituted 4-membered heterocycles and substituted or unsubstituted cyclobutanes, R 25 It is a C1-C4 alkyl group. R 26 It is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide. R 27 and R 28 Each is independently a C1-C4 alkyl group. R 29 and R 30 Each is independently a C1-C4 alkyl group, and R 31 It is a C1-C4 alkyl or a C1-C4 alkyl halide; R 6It is hydrogen, methyl, -CN, -S-methyl or -XR 8 Where X is O, S or SO2 and R 8 It is a C1-C3 alkyl or a C1-C3 haloalkyl; R 7 It is H, CN, OCH3, or F; Y is CH, N, CF, or C-CH3; and Indicates a single bond or a double bond.

[0172] In some embodiments, a method for inhibiting Mps1 / TTK kinase is provided, the method comprising, consisting of, or substantially consisting of the following steps: contacting Mps1 / TTK with a compound of formula II or its tautomer, a pharmaceutically acceptable salt, and / or a solvate: (Formula II); Where R 3 R 5 R 6 and R 7 As defined above.

[0173] In some embodiments, a method for inhibiting Mps1 / TTK kinase is provided, the method comprising, consisting of, or substantially consisting of the following steps: contacting Mps1 / TTK with a compound of formula III or its tautomer, a pharmaceutically acceptable salt, and / or a solvate: (Formula III); Where R 3 R 5 and R 7 As defined above.

[0174] In some other embodiments, a method for treating a disease is provided, the method comprising, consisting of, or substantially consisting of the following steps: administering to a patient in need a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, II, or III) or its tautomers, pharmaceutically acceptable salts, and / or solvates (including, if desired, as part of a pharmaceutical composition or combination therapy described herein). The compound may be any compound described in Part I. In some cases, the disease is cancer. In some embodiments, the disease is associated with a biomarker sensitive to Mps1 / TTK inhibition. In some implementations, the biomarker may be a negative or positive selection biomarker, wherein the presence / increase or absence / decrease of the biomarker relative to a normal sample indicates, respectively, that the disease is sensitive to Mps1 / TTK inhibition. For example, in some cases, the biomarker may be characterized by the presence of cells overexpressing the protein kinase Mps1 / TTK, for example, Mps1 / TTK expression levels being at least 120%, 150%, or 200% of normal Mps1 / TTK expression levels. Normal Mps1 / TTK expression levels can be determined by measuring Mps1 / TTK expression levels in healthy individuals or cells using methods known in the art. In some embodiments, the biomarker is associated with the status of the STING and / or MAVS signaling pathways. For example, in some cases, the STING and / or MAVS signaling pathways are reduced or suppressed in disease, for example, through epigenetic methylation. However, in some cases, the STING and / or MAVS signaling pathways remain active even in the presence of such reduction and / or suppression. In some cases, the STING and / or MAVS pathways are not reduced or suppressed. In some cases, the biomarker is a KRAS, LKB1, and / or BRAF mutation.

[0175] Furthermore, in another embodiment, a method is provided for treating a disease at least partially mediated by protein kinase Mps1 in a patient with this need, the method comprising administering to the patient a therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt and / or solvate thereof (or a pharmaceutical composition or combination therapy comprising the compound). The compound may be any compound described in Part I. In some cases, the disease is cancer. In some implementations, the disease is brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, stomach or gastric cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, lymphoma, thyroid cancer, mesothelioma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, or endometrial cancer. Furthermore, in some cases, the cancer is not necessarily defined by its tissue of origin, but by a biomarker sensitive to Mps1 / TTK inhibition, as described above. For example, in some cases, the cancer comprises, is composed of, or is substantially composed of specific cells that overexpress the protein kinase Mps1 / TTK, such that the expression level of Mps1 / TTK is at least 120%, 150%, or 200% of the normal Mps1 / TTK expression level. Normal Mps1 / TTK expression levels can be determined by measuring the Mps1 / TTK expression level in healthy individuals or healthy cells using methods known in the art. In some cases, the cancer comprises cells with fully functional STING and / or MAVS signaling pathways. In some embodiments, the cancer comprises cells with mutated KRAS, LKB1, and / or BRAF.

[0176] In addition, in some cases, compounds for treating cancer are provided. The compound can be any compound described in Part I. In some embodiments, the compound is a compound of Formula I, II, or III, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the cancer is brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, stomach or gastric cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, lymphoma, thyroid cancer, mesothelioma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, or endometrial cancer. In some cases, the cancer is not defined by its tissue of origin, but by a biomarker sensitive to Mps1 / TTK inhibition. For example, in some cases, the cancer comprises, is composed of, or is substantially composed of specific cells that overexpress the protein kinase Mps1 / TTK, for example, at a level of Mps1 / TTK that is at least 120%, 150%, or 200% of the normal Mps1 / TTK expression level. Normal Mps1 / TTK expression levels can be determined by measuring Mps1 / TTK expression levels in healthy individuals using methods known in the art. In some cases, the cancer comprises cells with fully functional STING and / or MAVS signaling pathways. In some cases, the cancer comprises cells with mutated KRAS, LKB1, and / or BRAF.

[0177] In another embodiment, the use of the compounds described herein in the preparation of a medicament for the treatment of cancer is provided. In some embodiments, the cancer is brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, stomach or gastric cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, lymphoma, thyroid cancer, mesothelioma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, or endometrial cancer. The compound can be any compound described in Part I. In some embodiments, the compound is a compound of Formula I, II, or III or a pharmaceutically acceptable salt and / or solvate thereof. In other embodiments, the cancer is brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, stomach or gastric cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, lymphoma, thyroid cancer, mesothelioma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, or endometrial cancer. In some implementations, cancer is not defined by its tissue of origin, but by a biomarker sensitive to Mps1 / TTK inhibition, as described above. In some embodiments, the cancer comprises, is composed of, or is substantially composed of specific cells that overexpress the protein kinase Mps1 / TTK, for example, at a level of at least 120%, 150%, or 200% of normal Mps1 / TTK expression. Normal Mps1 / TTK expression levels can be determined by measuring Mps1 / TTK expression levels in healthy individuals using methods known in the art. In some cases, the cancer comprises cells with fully functional STING and / or MAVS signaling pathways. In some embodiments, the cancer comprises cells with mutated KRAS, LKB1, and / or BRAF.

[0178] In some implementations, the compounds described herein are provided for use in the treatment of cancer. The compounds may be any compounds described in Part I. In some embodiments, the compounds are compounds of Formula I, II, or III, or pharmaceutically acceptable salts and / or solvates thereof. In some embodiments, the cancer is brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, stomach or gastric cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, lymphoma, thyroid cancer, mesothelioma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, or endometrial cancer. In some cases, the cancer is not defined by its tissue of origin, but by a biomarker sensitive to Mps1 / TTK inhibition. For example, in some cases, the cancer comprises, is composed of, or is substantially composed of specific cells that overexpress the protein kinase Mps1 / TTK, for example, at a level of Mps1 / TTK that is at least 120%, 150%, or 200% of the normal Mps1 / TTK expression level. Normal Mps1 / TTK expression levels can be determined by measuring Mps1 / TTK expression levels in healthy individuals using methods known in the art. In some cases, the cancer comprises cells with fully functional STING and / or MAVS signaling pathways. In some cases, the cancer comprises cells with mutated KRAS, LKB1, and / or BRAF.

[0179] Methods for determining the presence and levels of Mps1 / TTK proteins and / or mRNA are known in the art, such as those described in the following literature: Kasbek C, et al. 2010. Antizyme Restrains Centrosome Amplification by Regulating the Accumulation of Mps1 at Centrosomes; Molecular Biology of the Cell21:3879-89; and Mills GB, et al. 1992. Expression of TTK, a Novel Human Protein-Kinase, Is Associated with Cell-Proliferation. Journal of Biological Chemistry 267:16000-6. Methods for determining the status and / or capacity of the STING and MAVS pathways are known in the art, such as those described in the following literature: Kitajima S, et al. 2019. Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer. Cancer Discov Jan;9(1):34-45; Kitajima S, et al. 2022. MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer. Cancer Cell. October 10, 2022;40(10):1128-1144.e8; and Sasaki et al., RNA sensing induced by chromosome missegregationaugments anti-tumor immunity, Molecular Cell (2024).

[0180] In another instance, a method for treating a patient requiring a protein kinase Mps1 / TTK inhibitor is provided, the method comprising, consisting of, or substantially consisting of the following steps: determining the level of Mps1 / TTK protein and / or mRNA in the patient's cells (e.g., cancer cells), and, if the presence of Mps1 / TTK protein and / or mRNA is detected, administering to the patient a therapeutically effective amount of the compound described herein or its tautomers and / or pharmaceutically acceptable salts and / or solvates.

[0181] In some implementations, the compound described herein is administered to the patient after Mps1 / TTK overexpression is detected in the patient's cells (e.g., Mps1 / TTK expression is at least 120%, 150%, or 200% of the normal Mps1 / TTK expression level). In some aspects, the patient is a cancer patient. In some cases, the patient is a patient with brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, stomach or gastric cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, lymphoma, thyroid cancer, mesothelioma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, or endometrial cancer. Furthermore, in some implementations, methods for treating patients requiring Mps1 / TTK inhibitors are provided. In some embodiments, such methods comprise, consist of, or substantially consist of the following steps: determining the level of sensitivity to Mps1 / TTK protein inhibition in the patient's cells (e.g., cancer cells), and, if sensitivity to Mps1 / TTK protein inhibition is detected, administering to the patient a therapeutically effective amount of the compound described herein or its tautomers and / or pharmaceutically acceptable salts and / or solvates. The level of sensitivity can be determined based on the evaluation of biomarkers, as described above.

[0182] In some embodiments, the compound described herein is administered to the patient after a biomarker sensitive to Mps1 / TTK inhibition is detected. In some cases, the biomarker is overexpression of Mps1 / TTK in the patient's cells, for example, Mps1 / TTK expression is at least 120%, 150%, or 200% of the normal Mps1 / TTK expression level. In some cases, the biomarker may be an indicator of a functional STING and / or MAVS signaling pathway. In some cases, the biomarker is a mutated KRAS, LKB1, and / or BRAF gene or protein. In some aspects, the patient is a cancer patient. In some cases, the patient has brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, gastric or stomach cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, or endometrial cancer. In other cases, the patient is a patient whose disease is characterized by a biomarker sensitive to Mps1 / TTK inhibition.

[0183] In another instance, a method for treating a patient requiring a protein kinase Mps1 / TTK inhibitor is provided, the method comprising, consisting of, or substantially consisting of the following steps: determining a triple-negative status in the patient's cancer cells; and, if the cancer cells are triple-negative, administering to the patient a therapeutically effective amount of the compound described herein or its tautomers and / or pharmaceutically acceptable salts and / or solvates. The compound can be any compound described in Part I. In some embodiments, the compound is a compound of Formula I or its tautomers and / or pharmaceutically acceptable salts and / or solvates. In some embodiments, the compound is a compound of Formula II or its tautomers and / or pharmaceutically acceptable salts and / or solvates. In some other embodiments, the compound is a compound of Formula III or its tautomers and / or pharmaceutically acceptable salts and / or solvates.

[0184] In any embodiment of the method described herein, the method may involve administering a pharmaceutical composition, wherein the pharmaceutical composition comprises a compound of any embodiment of the present technology or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0185] In any embodiment of the method described herein, the method may involve administering a pharmaceutical composition comprising an effective amount of a compound of any embodiment of the present technology or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In some embodiments, the effective amount is about 0.01 μg to about 900 mg of compound / g of composition. In some embodiments, the effective amount is about 0.01 μg to about 800 mg of compound / g of composition. In some cases, the effective amount is about 0.01 μg to about 700 mg of compound / g of composition. In some cases, the effective amount is about 0.01 μg to about 600 mg of compound / g of composition. In some embodiments, the effective amount is about 0.01 μg to about 500 mg of compound / g of composition. In some embodiments, the effective amount is about 0.01 μg to about 400 mg of compound / g of composition. In some implementations, the effective amount is about 0.01 μg to about 300 mg of compound / g of composition. In some embodiments, the effective amount is about 0.01 μg to about 200 mg of compound / g of composition. In some cases, the effective amount is from about 0.01 μg to about 100 mg of compound per gram of composition. In some embodiments, the effective amount is from about 0.1 μg to about 500 μg of compound per gram of composition.

[0186] In some embodiments, the effective amount of the compound is 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 mg or more, including increments thereto. In some embodiments, the effective amount of the compound is from about 10 mg to about 500 mg. In some embodiments, each unit dose of the composition contains about 0.1% to about 99% of the compound. In some embodiments, each unit dose of the composition contains about 10% to about 60% of the compound.

[0187] In some aspects, kits are provided that comprise, consist substantially of, or are composed of the following: an effective amount of the compound described herein and optional instructions for use. The compound can be any compound described in Part I, such as compounds of Formula I, II, or III. In some aspects, the instructions for use contain, consist substantially of, or are composed of the treatment methods described herein.

[0188] The following non-limiting examples further illustrate some implementation methods. Example

[0189] The following examples describe the synthesis and assays of various novel small molecule Mps1 / TTK inhibitors as targeted cancer therapies. Mps1 / TTK inhibitors were synthesized according to instructions. The activity of the compounds against Mps1 / TTK was evaluated, and assays were performed using an antiproliferative assay. The assay data indicated that the synthesized compounds were active against Mps1 / TTK and possessed antiproliferative potential in cancer cell lines.

[0190] Compound Synthesis As shown in Tables 1 and 2 respectively, through R 1 R 2 R 3 R 4 R 5 R 6 R 7 Modifications were made at position Y according to formula I to synthesize Mps1 / TTK inhibitor compounds and comparative compounds.

[0191] Table 1. Structures of Mps1 / TTK inhibitor compounds. .

[0192] Table 2. Comparison of the structures of the compounds. .

[0193] This paper describes the synthesis of compounds 1, 2, 4, 6, 9, 33, 40, 43, 45, 49, 53, 54, 56, 67, and 68. Other compounds shown in Tables 1 and 2 were synthesized in a similar manner to those described herein.

[0194] Preparation of Compound 1 Step 1. Synthesis of compound B.

[0195] NBS (94.7 g, 532 mmol, 1.00 equivalent) was added to a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (compound A) (100 g, 532 mmol, 1.00 equivalent) in DCM (700 mL). The mixture was stirred at 25 °C for 4 hours. LC-MS showed the desired mass was detected. Two batches were completed and combined. The reactants were diluted with H2O (350 mL) and extracted three times with ethyl acetate (300 mL each time). The organic layer was separated, washed twice with aqueous NaHCO3 solution (400 mL each time), washed twice with brine (400 mL each time), dried over Na2SO4, and concentrated under reduced pressure to produce the residue. The crude product was milled with MeCN at 25 °C for 12 hours. 5-Bromo-2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (compound B) was given as a brown solid (250 g, 937 mmol, 88.1% yield).

[0196] Step 2. Synthesis of compound C.

[0197] At -70°C, 5-bromo-2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (compound B) (50.0 g, 187 mmol, 1.00 equivalent) was slowly added dropwise to a solution of 5-bromo-2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine in 600 mL of THF. n-BuLi (2.50 M, 299 mL, 4.00 equivalents). After stirring the reaction mixture at -70 °C for 1.5 h, CH3I (79.8 g, 562 mmol, 35.0 mL, 3.00 equivalents) was added. The reaction mixture was stirred at -70 °C for 1.5 h. LC-MS showed the desired mass was detected. The reaction mixture was quenched with an aqueous solution of NH4Cl (800 mL) at 10 °C. The mixture was extracted three times with ethyl acetate (500 mL each time). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was milled with ethyl acetate at 25 °C for 12 h. 2,4-Dichloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine (compound C) (32.0 g, 158 mmol, 84.6% yield) as a brown solid.

[0198] Step 3. Synthesis of compound D.

[0199] TsCl (29.7 g, 156 mmol, 1.05 equivalent), DMAP (1.81 g, 14.8 mmol, 14.0 mL, 0.10 equivalent), and DIPEA (21.1 g, 163 mmol, 1.10 equivalent) were added to a solution of 2,4-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine (compound C) (30.0 g, 148 mmol, 1.00 equivalent) in DCM (180 mL) under N2 conditions. The mixture was stirred at 20 °C for 1 hour. LC-MS indicated the desired mass. The reactants were quenched with H2O and diluted with ethyl acetate. The organic layer was washed with 1 M HCl. The pH was adjusted to 7 with NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was milled with ethyl acetate at 25 °C for 12 hours. 2,4-Dichloro-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (compound D) was given as a white solid (40.0 g, 112 mmol, 75.6% yield).

[0200] Step 4. Synthesis of compound E.

[0201] To a solution of 2,4-dichloro-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (compound D) (35.0 g, 98.2 mmol, 1.00 equivalent) in DMF (175 mL), dioxane (175 mL), DIPE (50.8 g, 393 mmol, 68.4 mL, 4.00 equivalent), and cyclohexylamine (19.5 g, 196 mmol, 2.00 equivalent) were added. The mixture was stirred at 25 °C for 12 hours. LC-MS showed detection of the desired compound. The reaction mixture was quenched at 25 °C by adding H₂O (200 mL) and then extracted with DCM (400 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The crude product was milled with ethyl acetate at 25 °C for 12 hours. Compound E was given as a white solid (30.0 g, 71.6 mmol, 72.9% yield).

[0202] Step 5. Synthesis of compound F.

[0203] To a solution of compound E (8.00 g, 19.1 mmol, 1.00 equivalent) in DMF (80.0 mL), 2-methoxy-4-(4-morpholino)aniline (4.77 g, 22.9 mmol, 1.20 equivalent), Cs₂CO₃ (12.4 g, 38.2 mmol, 2.00 equivalent), and XPos (1.82 g, 3.82 mmol, 0.20 equivalent) were added. The mixture was degassed and purified three times with N₂. Then, Pd₂(dba)₃ (1.75 g, 1.91 mmol, 0.10 equivalent) was added. The mixture was stirred at 120 °C for 12 h. LC-MS showed detection of the desired compound. The reaction mixture was filtered, and the filtrate was diluted with 240 mL of H₂O and extracted three times with a total of 320 mL of DCM (extractions were performed with 160 mL, 100 mL, and 60.0 mL, respectively). The combined organic layers were washed twice with 20 mL of brine each time, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The crude product was ground with ethyl acetate at 25 °C for 2 hours to give compound F as a yellow solid (5.00 g, 8.46 mmol, 44.3% yield).

[0204] Step 6. Synthesis of Compound 1.

[0205] To a solution of compound F (5.00 g, 8.46 mmol, 1.00 equivalent) in methanol (50.0 mL) and THF (50.0 mL), NaOH (744 mg, 18.6 mmol, 2.20 equivalent) was added. The mixture was stirred at 70 °C for 12 hours. LC-MS showed detection of the desired compound. The reaction mixture was filtered. The filter cake was eluted with methanol (30.0 mL) and dried under vacuum to provide the product. Compound 1 (1.10 g, 2.52 mmol, 29.8% yield) was given as a grayish-white solid. 1 H NMR (400MHz, DMSO) δ 10.64 (s, 1H), 8.35 (d, J =8.8 Hz, 1H), 6.95 (s, 1H), 6.64 (d, J =2.4 Hz, 1H), 6.50 (d, J =16.0 Hz, 1H), 6.45-6.43 (m, 1H), 5.52 (d, J =8.0 Hz,1H), 4.04 (s, 1H), 3.86 (s, 3H), 3.75 (t, J =9.2 Hz, 4H), 3.05 (t, J =4.4 Hz,4H), 2.30 (s, 3H), 1.97 (d, J =2.4 Hz, 2H), 1.75-1.65 (m, 3H), 1.44-1.36 (m,4H), 1.20 (d, J =8.0 Hz, 1H). MS(ESI+) m / z:C 24 H 32 Calculation of N6O2 [M+H] + : 437.26; Actual measurement: 437.3.

[0206] Preparation of compound 2 Step 1. Synthesis of compound H.

[0207] Compound G (1.30 g, 2.96 mmol, 1.00 equivalent) and 2-methoxy-4-(4-morpholino)aniline (925.01 mg, 4.44 mmol, 1.50 equivalent) were subjected to oxidation at 20 °C. tPd2(dba)3 (271.16 mg, 296.11 μmol, 0.10 equivalent), XPhos (141.16 mg, 296.11 μmol, 0.10 equivalent) and [other substances] were added to the mixture in BuOH (10 mL). t -BuONa (569.13 mg, 5.92 mmol, 2.00 equivalents). The mixture was then stirred at 100 °C for 12 hours under N2. LC-MS indicated the end of the reaction. Compound G was depleted and the desired target mass was detected. H2O (10 mL) was added to the mixture, and the aqueous fraction was extracted three times with DCM (5 mL each time). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (plate 1: SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound H (1.20 g, 2.01 mmol, 67.91% yield) was given as a black solid.

[0208] Step 2. Synthesis of compound I.

[0209] HATU (286.71 mg, 754.03 μmol, 1.50 equivalent) and TEA (152.60 mg, 1.51 mmol, 209.90 μL, 3.00 equivalent) were added to a solution of compound H (300.00 mg, 502.69 μmol, 1.00 equivalent) in DMF (1 mL) at 20 °C. The solution was then stirred at 20 °C for 2 hours. LC-MS showed that compound H was depleted and the desired target mass was detected. The mixture was concentrated. H2O (10 mL) was added to the solution. The solution was then extracted three times with ethyl acetate (10 mL each time). The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 0:1). Compound I (274.00 mg, crude product) was obtained as a brown solid.

[0210] Step 3. Synthesis of compound J.

[0211] A solution of compound I (150.00 mg, 245.97 μmol, 1.00 equivalent) in TFA (1 mL) and DCM (1 mL) was stirred at 20 °C for 1 hour. LC-MS showed that compound I was depleted and the desired target mass was detected. The mixture was concentrated. Compound J (120.00 mg, crude, TFA) was obtained as a brown solid.

[0212] Step 4. Synthesis of compound 2.

[0213] NH4OH (4 mL) was added to a solution of compound J (120.00 mg, 192.42 μmol, 1.00 equivalent, TFA) in THF (1 mL) and methanol (1 mL) at 20 °C. The solution was then stirred at 20 °C for 12 hours. LC-MS showed that compound J was depleted and the desired target mass was detected. The mixture was concentrated. The crude product was purified by preparative HPLC. Compound 2 (26.5 mg, 54.72 μmol, 28.44% yield, 99.03% purity) was given as a white solid. 1 H NMR (DMSO- d 6400 MHz) δ =ppm 9.58 (br d, J =7.60 Hz, 1H) 8.28 (d, J =8.8 Hz, 1H) 8.14-8.21(m, 1H) 7.55 (d, J =2.2 Hz, 1H) 7.01 (s, H) 6.65 (d, J =2.4 Hz, 1H) 6.41-6.49 (m,1H) 3.9 -4.05 (m, 1H) 3.87 (s, 3H) 3.71-3.80 (m, 4H) 3.01-3.12 (m, 4H) 2.77(d, J =4.4 Hz, 3H) 1.89-2.02 (m, 2H) 1.71-1.82 (m, 2H) 1.55-1.64 (m, 1H) 1.23-1.50 (m, 5H). MS(ESI+) m / z:C 25 H 33 Calculation of N7O3 [M+H] + : 480.26; Actual measurement: 480.2.

[0214] Preparation of compound 4 Step 1. Synthesis of compound L.

[0215] SOCl2 (1.42 g, 11.89 mmol, 862.84 μL, 5.00 equivalent) was added to a solution of compound K (500.00 mg, 2.38 mmol, 1.00 equivalent) in DCE (8 mL) at 20 °C. The solution was then stirred at 90 °C for 2 h. The solution was then concentrated, and the residue was dissolved in DMF (4 mL). Formic acid hydrazide (285.72 mg, 4.76 mmol, 2.00 equivalent) was added to the solution, and the mixture was stirred at 100 °C for 12 h. LC-MS showed that compound K was depleted and the desired target mass was detected. A saturated aqueous solution of NH4Cl (5 mL) was added to the solution, and the mixture was extracted three times with ethyl acetate (10 mL each time). The combined organic layers were dried over Na2SO4 and then concentrated. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 5:1). Compound L (180.00 mg, crude product) was obtained as a white solid.

[0216] Step 2. Synthesis of compound M.

[0217] Fe (178.83 mg, 3.20 mmol, 5.00 equivalent) and NH4Cl (171.29 mg, 3.20 mmol, 5.00 equivalent) were added to a solution of compound L (150.00 mg, 640.45 μmol, 1.00 equivalent) in EtOH (2 mL) and H2O (0.40 mL) at 20 °C. The solution was then stirred at 80 °C for 12 h. LC-MS showed that compound L was synthesized and depleted and the desired target mass was detected. The mixture was filtered. The filtrate was concentrated to remove EtOH. H2O (15 mL) was added to the solution, and the solution was then extracted three times with ethyl acetate (15 mL each time). The organic layer was dried over Na2SO4 and then concentrated. Compound M (130.00 mg, 636.54 μmol, 99.39% yield) was given as a brown solid.

[0218] Step 3. Synthesis of compound 4.

[0219] Compound M (110.00 mg, 538.61 μmol, 1.00 equivalent) and compound N (171.12 mg, 646.34 μmol, 1.20 equivalent) were subjected to treatment at 20 °C. t Pd2(dba)3 (49.32 mg, 53.86 μmol, 0.10 equivalent), XPhos (25.68 mg, 53.86 μmol, 0.10 equivalent) and [other substances] were added to the solution of -BuOH (5 mL). t-BuONa (103.53 mg, 1.08 mmol, 2.00 equivalents). The solution was then stirred at 100 °C for 2 hours under N2. LC-MS showed that compound M was depleted and the desired target mass was detected. The mixture was concentrated. The residue was purified by preparative HPLC. Compound 4 was given as a white solid (34.50 mg, 69.49 μmol, 12.90% yield, 96.39% purity). 1 H NMR (DMSO- d 6400 MHz) δ =ppm10.63-10.93 (m, 1H), 8.70-8.79 (m, 1H), 8.46-8.52 (m, 1H), 8.13 (s, 0.2),7.19-7.34 (m, 3H), 6.49-6.61 (m, 1H), 5.61-5.72 (m, 1H), 3.99-4.11 (m, 1H),3.93 (s, 3H), 3.69 - 3.77 (m, 3H), 2.26-2.33 (m, 3H), 1.89-2.02 (m, 2H),1.67-1.80 (m, 2H), 1.56-1.66 (m, 1H), 1.29-1.47 (m, 4H), 1.09-1.25 (m, 1H). MS(ESI+) m / z:C3H 28 Calculation of N8O [M+H] + : 433.24; Actual measurement: 433.2.

[0220] Preparation of compound 6 Step 1. Synthesis of compound P.

[0221] Br2 (33.97 g, 212.55 mmol, 10.96 mL, 1.20 equivalent) was added to a solution of compound O (25.00 g, 177.13 mmol, 1.00 equivalent) in acetic acid (AcOH) (200 mL) at 20 °C. The solution was then stirred at 20 °C for 12 hours. LC-MS showed that compound O was depleted and the desired target mass was detected. H2O (200 mL) was added to the mixture, and the mixture was then extracted three times (200 mL) with ethyl acetate. The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to produce a residue. The residue was purified by MPLC (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound P (26.00 g, 118.16 mmol, 33.36% yield) was given as a yellow solid.

[0222] Step 2. Synthesis of compound Q.

[0223] TEA (4.60 g, 45.45 mmol, 6.33 mL, 2.00 equivalent) and Pd(dppf)Cl2 were added to a solution of compound P (5.00 g, 22.72 mmol, 1.00 equivalent) in methanol (20 mL). DCM (1.86 g, 2.27 mmol, 0.10 equivalent) was added at 20 °C, and the solution was stirred at 110 °C for 12 h under CO2. LC-MS indicated the end of the reaction. Compound P was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by MPLC (SiO2, petroleum ether:ethyl acetate = 1:0 to 0:1). Compound Q (1.00 g, 5.02 mmol, 22.09% yield) was given as a white solid.

[0224] Step 3. Synthesis of compound R.

[0225] NH₂ was added to a solution of compound Q (1.00 g, 5.02 mmol, 1.00 equivalence) in EtOH (10 mL). Then, H₂O (1.28 g, 25.10 mmol, 1.24 mL, 98% purity, 5.00 equivalence) was added at 20 °C, and the solution was stirred at 80 °C for 12 hours. LC-MS indicated the end of the reaction. Compound Q was depleted, and the desired target mass was detected. The mixture was concentrated. H₂O (20 mL) was added to the mixture, and the aqueous fraction was extracted three times with DCM (20 mL each time). The combined organic layers were dried over Na₂SO₄ and then concentrated under reduced pressure. The residue was purified by MPLC (SiO₂, ethyl acetate: methanol = 1:0 to 0:1). Compound R (500.00 mg, 2.51 mmol, 50.00% yield) was given as a yellow solid.

[0226] Step 4. Synthesis of compound S.

[0227] DMF-DMA (1.50 g, 12.55 mmol, 1.67 mL, 5.00 equivalent) was added to a solution of compound R (500.00 mg, 2.51 mmol, 1.00 equivalent) in MeCN (10 mL) at 20 °C. The solution was then stirred at 60 °C for 1 hour. LC-MS indicated the end of the reaction. Compound R was depleted, and the desired target mass was detected. The mixture was concentrated. Compound S (600.00 mg, crude product) was obtained as a yellow oil.

[0228] Step 5. Synthesis of compound T.

[0229] Compound S (600.00 mg, 2.36 mmol, 1.00 equivalent) and MeNH2 (318.66 mg, 4.72 mmol, 2.00 equivalent, HCl) in MeCN (10 mL) were added to AcOH (212.56 mg, 3.54 mmol, 202.64 μL, 1.50 equivalent) at 20 °C, and the solution was stirred at 80 °C for 12 h. LC-MS indicated the end of the reaction. Compound T was depleted, and the desired target mass was detected. H2O (20 mL) was added to the solution. The mixture was then concentrated to remove MeCN. The solution was extracted three times (15 mL) with ethyl acetate. The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by MPLC (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound T was given as a white solid (200.00 mg, 900.02 μmol, 38.14% yield).

[0230] Step 6. Synthesis of compound 6.

[0231] Compound T (107.96 mg, 485.81 μmol, 1.50 equivalent) and compound U (100.00 mg, 323.87 μmol, 1.00 equivalent) were subjected to treatment at 20 °C. t Pd₂(dba)₃ (29.66 mg, 32.39 μmol, 0.10 equivalent), XPhos (15.44 mg, 32.39 μmol, 0.10 equivalent), and K₂CO₃ (89.52 mg, 647.75 μmol, 2.00 equivalent) were added to a solution of -BuOH (10 mL). The solution was then stirred at 100 °C under N₂ for 12 hours. LC-MS indicated the end of the reaction. Compound T was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (75 mm x 30 mm, 3 μm; mobile phase: A: formic acid / H2O, B: MeCN; gradient: 5% - 45% B for 8 min). Compound 6 was given as a white solid (13.00 mg, 25.73 μmol, 7.94% yield, 97.88% purity). 1 H NMR (DMSO- d 6400 MHz) δ =ppm 12.09 (br s, 1H), 8.63 (s, 1H), 8.60-8.52 (m, 2H), 7.76 (s, 1H), 7.73 (d, J =2.4 Hz, 1H), 7.24 (t, J =8.2 Hz,1H), 4.14-4.04 (m, 1H), 3.99 (d, J =0.9 Hz, 3H), 3.83 (s, 3H), 3.61 (s, 3H), 2.08-1.98 (m, 2H), 1.76 (br dd, J =3.8, 9.3 Hz, 2H), 1.66 - 1.57 (m, 1H), 1.51 - 1.30 (m, 5H). MS(ESI+) m / z:C 24 H 27 [M+H] calculated from FN8O3 + : 495.22; Actual measurement: 495.2.

[0232] Preparation of compound 9 Step 1. Synthesis of compound W.

[0233] NaSMe (4.64 g, 66.20 mmol, 4.22 mL, 2.64 equivalent) was added to a mixture of compound V (5.00 g, 25.11 mmol, 1.00 equivalent) and pyridine (3.97 g, 50.22 mmol, 4.05 mL, 2.00 equivalent) in methanol (100 mL) at 0 °C. The mixture was then stirred at 20 °C for 12 h. TLC (SiO2, petroleum ether: ethyl acetate = 5:1) indicated that compound V was depleted and a spot was detected. The reaction mixture was quenched by adding 200 mL of saturated NH4Cl aqueous solution at 0 °C. The reaction mixture was then diluted with H2O (20 mL) and extracted three times with ethyl acetate (100 mL each time). The combined organic layers were washed three times with brine (100 mL each time), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound W (1.00 g, crude product) was given as a yellow solid.

[0234] Step 2. Synthesis of compound X.

[0235] LiOH was added to a mixture of compound W (1.00 g, 4.40 mmol, 1.00 equivalent) in methanol (20 mL) and H₂O (4 mL). H₂O (369.34 mg, 8.80 mmol, 2.00 equivalent) was added at 20 °C, and the mixture was stirred at 20 °C for 2 hours. LC-MS indicated the end of the reaction. Compound W was depleted, and the desired target mass was detected. The mixture was concentrated to remove methanol (20 mL). H₂O (20 mL) was then added to the mixture, followed by the addition of HCl (12 M) to adjust the pH to 3. The mixture was then filtered, and the filtrate was concentrated. Compound X (1.00 g, crude product) was given as a yellow solid.

[0236] Step 3. Synthesis of compound Y.

[0237] HATU (2.68 g, 7.04 mmol, 1.00 equivalent) and DIPEA (1.21 g, 9.38 mmol, 2.00 equivalent, HCl) were added to a mixture of compound X (1.00 g, 4.69 mmol, 1.00 equivalent) and MeNH2 (633.35 mg, 9.38 mmol, 2.00 equivalent, HCl) in DCM (50 mL) at 20 °C. The mixture was then stirred at 20 °C for 2 hours. LC-MS indicated the end of the reaction. Compound X was depleted, and the desired target mass was detected. H2O (500 mL) was added to the mixture, and the aqueous fraction was extracted three times with DCM (300 mL each time). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 3:1). Compound Y was given as a yellow solid (1.00 g, 4.42 mmol, 94.24% yield).

[0238] Step 4. Synthesis of compound Z.

[0239] NaN3 (0.58 g, 8.92 mmol, 2.02 equivalents) and POCl3 (3.39 g, 22.10 mmol, 2.05 mL, 5.00 equivalents) were added to a mixture of compound Y (1.00 g, 4.42 mmol, 1.00 equivalents) in MeCN (50 mL) at 0 °C. The mixture was then stirred at 80 °C under N2 for 12 h. LC-MS indicated the end of the reaction. Compound Y was depleted, and the desired target mass was detected. A saturated aqueous solution of NaHCO3 (100 mL) was added to the mixture to adjust the pH to 7. The mixture was then extracted three times (3 times each) with ethyl acetate. The combined organic layers were dried over Na2SO4 and then concentrated. The aqueous phase was quenched with NaClO (200 mL). The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 3:1). Compound Z was given as a yellow solid (490.00 mg, 1.95 mmol, 44.12% yield).

[0240] Step 5. Synthesis of compound AA.

[0241] Fe (533.41 mg, 9.55 mmol, 5.00 equivalent) and NH4Cl (510.93 mg, 9.55 mmol, 5.00 equivalent) were added to a mixture of compound Z (480.00 mg, 1.91 mmol, 1.00 equivalent) in EtOH (20 mL) and H2O (4 mL) at 20 °C. The mixture was then stirred at 80 °C for 2 hours. LC-MS indicated the end of the reaction. Compound Z was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. H2O (50 mL) was added to the mixture, and the aqueous solution was extracted three times with DCM (30 mL each time). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. Compound AA (400.00 mg, crude) was given as a yellow solid.

[0242] Step 6. Synthesis of compound 9.

[0243] Compound AA (86.28 mg, 389.89 μmol, 1.20 equivalent) and compound AS (100.00 mg, 324.91 μmol, 1.00 equivalent) were subjected to treatment at 20 °C. t Pd2(dba)3 (29.75 mg, 32.49 μmol, 0.10 equivalent), XPhos (15.49 mg, 32.49 μmol, 0.10 equivalent) and [other ingredients] were added to the mixture in BuOH (5 mL). t -BuONa (62.45 mg, 649.82 μmol, 2.00 equivalents). The mixture was then stirred at 100 °C for 12 hours. LC-MS indicated the end of the reaction. Compound AA was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC. Compound 9 was given as a white solid (21.10 mg, 41.85 μmol, 12.88% yield, 97.7% purity). 1 H NMR (DMSO- d 6400 MHz) δ =ppm 11.71-11.61 (m, 1H), 9.81-9.74 (m, 1H), 8.77-8.68 (m,1H), 8.3-8.23 (m, 1H), 7.93-7.91 (m, 1H), 7.91-7.89 (m, 1H), 7.74-7.70 (m,1H), 7.66 (d, J =2.9 Hz, 1H), 4.21 (s, 3H), 4.0-3.98 (m, 1H), 2.79 (d, J=4.5 Hz,3H), 2.50 (br s, 3H), 2.05-1.96 (m, 2H), 1.82-1.73 (m, 2H), 1.64-1.58 (m,1H), 1.48-1.30 (m, 5H). MS(ESI+) m / z:C 23 H 28 N 10 OS calculation [M+H] + : 493.22; Actual measurement: 493.2.

[0244] Preparation of compound 33 Step 1. Synthesis of compound AC.

[0245] DIPEA (4.92 g, 38.04 mmol, 6.63 mL, 1.50 equivalence) and HATU (12.54 g, 32.97 mmol, 1.30 equivalence) were added to a solution of compound AB (5.00 g, 25.36 mmol, 1.00 equivalence) and MeNH2 (1.58 g, 23.33 mmol, 0.92 equivalence, HCl) in THF (250 mL) at 20 °C. The solution was then stirred at 20 °C for 12 hours. LC-MS indicated the end of the reaction. Compound AB was depleted, and the desired target mass was detected. The mixture was concentrated to remove THF. H2O (150 mL) was then added to the solution. The solution was then extracted three times with ethyl acetate (200 mL each time), and the organic layer was dried over Na2SO4 and then concentrated. The residue was purified by MPLC (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound AC (4.10 g, crude product) was obtained as a yellow solid.

[0246] Step 2. Synthesis of compound AD.

[0247] Tf₂O (2.68 g, 9.52 mmol, 1.57 mL, 2.00 equivalent) was added to a mixture of compound AC (1.00 g, 4.76 mmol, 1.00 equivalent) and NaN₃ (1.180 g, 18.15 mmol, 3.82 equivalent) in MeCN (20 mL) at -10 °C. The mixture was then stirred at 20 °C for 3 hours. TLC (SiO₂, petroleum ether: ethyl acetate = 1:1) indicated that compound AC was depleted and a spot was detected. A saturated aqueous solution of NaHCO₃ was added to the mixture to adjust the pH to 7, and the mixture was then extracted three times with ethyl acetate (100 mL each time). The combined organic layers were dried over Na₂SO₄ and then concentrated. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 1:0 to 0:1). The compound AD was given as a yellow solid (540.00 mg, 1.95 mmol, 41.02% yield, 85% purity).

[0248] Step 3. Synthesis of compound AE.

[0249] 10% Pd / C (100.00 mg, 50% purity) was added to a mixture of compound AD (200.00 mg, 850.34 μmol, 1.00 equivalent) in methanol (3 mL) at 20 °C. The mixture was then stirred at 20 °C for 2 hours under H2 (15 psi). LC-MS indicated the end of the reaction. Compound AD was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. Compound AE (136.00 mg, crude product) was given as a white solid.

[0250] Step 4. Synthesis of compound 33.

[0251] Compound AE (136.00 mg, 662.72 μmol, 1.00 equivalent) and compound N (210.55 mg, 795.26 μmol, 1.20 equivalent) were subjected to treatment at 20 °C. t Pd2(dba)3 (60.69 mg, 66.27 μmol, 0.10 equivalent), XPhos (31.59 mg, 66.27 μmol, 0.10 equivalent) and [other ingredients] were added to the mixture in BuOH (5 mL). t-BuONa (127.38 mg, 1.33 mmol, 2.00 equivalents). The mixture was then stirred at 100 °C for 12 hours. LC-MS indicated the end of the reaction. Compound AE was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC. Compound 33 was given as a white solid (48.6 mg, 99.57 μmol, 15.03% yield, 98.25% purity). 1 HNMR (DMSO- d 6400 MHz) δ =ppm 10.97 - 10.81 (m, 1H), 8.89 (d, J =8.2 Hz, 1H),8.20-8.11 (m, 0.5H), 7.47-7.41 (m, 3H), 6.68-6.57 (m, 1H), 5.82-5.69 (m, 1H),4.24-4.21 (m, 3H), 4.10 (br dd, J =3.4, 5.0 Hz, 1H), 4.03-4.00 (m, 3H), 2.41-2.27 (m, 3H), 2.07 - 1.98 (m, 2H), 1.84 - 1.72 (m, 2H), 1.66 (br s, 1H),1.52-1.38 (m, 4H), 1.25 (br s, 1H). MS(ESI+) m / z: C 22 H 27 Calculation of N9O [M+H] + : 434.23; Actual measurement: 434.1.

[0252] Preparation of compound 40 Step 1. Synthesis of compound B.

[0253] NBS (94.7 g, 532 mmol, 1.00 equivalent) was added to a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (compound A) (100 g, 532 mmol, 1.00 equivalent) in DCM (700 mL). The mixture was stirred at 25 °C for 4 hours. LC-MS showed the desired mass was detected. Two batches were completed and combined. The reactants were diluted with H2O (350 mL) and extracted three times with ethyl acetate (300 mL each time). The organic layer was separated, washed twice with aqueous NaHCO3 solution (400 mL each time), washed twice with brine (400 mL each time), dried over Na2SO4, and concentrated under reduced pressure to produce the residue. The crude product was milled with MeCN at 25 °C for 12 hours. 5-Bromo-2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (compound B) was given as a brown solid (250 g, 937 mmol, 88.1% yield).

[0254] Step 2. Synthesis of compound C.

[0255] At -70°C, 5-bromo-2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (compound B) (50.0 g, 187 mmol, 1.00 equivalent) was slowly added dropwise to a solution of 5-bromo-2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine in 600 mL of THF. n -BuLi (2.50 M, 299 mL, 4.00 equivalents). After stirring the reaction mixture at -70 °C for 1.5 h, CH3I (79.8 g, 562 mmol, 35.0 mL, 3.00 equivalents) was added. The reaction mixture was stirred at -70 °C for 1.5 h. LC-MS showed the desired mass was detected. The reactants were quenched at 10 °C with 800 mL of aqueous NH4Cl solution. The mixture was extracted three times with ethyl acetate (500 mL each time). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was milled with ethyl acetate at 25 °C for 12 h. 2,4-Dichloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine (compound C) (32.0 g, 158 mmol, 84.6% yield) as a brown solid.

[0256] Step 3. Synthesis of compound D.

[0257] TsCl (29.7 g, 156 mmol, 1.05 equivalent), DMAP (1.81 g, 14.8 mmol, 14.0 mL, 0.10 equivalent), and DIPEA (21.1 g, 163 mmol, 1.10 equivalent) were added to a solution of 2,4-dichloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine (compound C) (30.0 g, 148 mmol, 1.00 equivalent) in DCM (180 mL) under N2 conditions. The mixture was stirred at 20 °C for 1 hour. LC-MS indicated the desired mass. The reaction mixture was quenched with H2O and diluted with ethyl acetate. The organic layer was washed with 1 M HCl. The pH was adjusted to 7 with NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was milled with ethyl acetate at 25 °C for 12 hours. 2,4-Dichloro-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (compound D) was given as a white solid (40.0 g, 112 mmol, 75.6% yield).

[0258] Step 4. Synthesis of compound E.

[0259] To a solution of 2,4-dichloro-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (compound D) (35.0 g, 98.2 mmol, 1.00 equivalent) in DMF (175 mL), dioxane (175 mL), DIPEA (50.8 g, 393 mmol, 68.4 mL, 4.00 equivalent), and cyclohexylamine (19.5 g, 196 mmol, 2.00 equivalent) were added. The mixture was stirred at 25 °C for 12 h. LC-MS showed detection of the desired compound. The reaction mixture was quenched by adding H2O (200 mL) at 25 °C and then extracted with DCM (400 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The crude product was milled with ethyl acetate at 25 °C for 12 h. Compound E was given as a white solid (30.0 g, 71.6 mmol, 72.9% yield).

[0260] Step 5. Synthesis of compound AG.

[0261] Compound AF (5.99 g, 28.6 mmol, 1.20 equivalent, prepared as described below), Cs₂CO₃ (11.7 g, 35.8 mmol, 1.50 equivalent), and XPhos (2.28 g, 4.77 mmol, 0.20 equivalent) were added to a solution of compound E (10.0 g, 23.8 mmol, 1.00 equivalent) in DMF (100 mL). The mixture was degassed and purified three times with N₂. Pd₂(dba)₃ (2.19 g, 2.39 mmol, 0.10 equivalent) was added. The mixture was degassed and purified three times with N₂. The mixture was then stirred at 130 °C for 12 hours. TLC (petroleum ether: ethyl acetate = 1:1, R f =0.41) indicates that compound E was completely exhausted. The reaction mixture was filtered, and the filtrate was diluted with H2O (200 mL) and extracted three times with DCM (80.0 mL, 60.0 mL, and 30.0 mL each time). The combined organic layers were washed twice with brine (50.0 mL each time), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 30:1 to 10:1). Compound AG was given as a yellow solid (8.50 g, 14.4 mmol, 60.2% yield).

[0262] Step 6. Synthesis of compound 40.

[0263] To a solution of compound AG (3.00 g, 5.07 mmol, 1.00 equivalent) in methanol (30.0 mL) and THF (30.0 mL), NaOH (446 mg, 11.1 mmol, 2.20 equivalent) was added. The mixture was stirred at 70 °C for 12 hours. LC-MS showed that the desired mass was detected. The reaction mixture was filtered, the filter cake was eluted with methanol (20.0 mL) and dried under vacuum to provide compound 40. Compound 40 was given as a grayish-white solid (1.00 g, 2.11 mmol, 41.6% yield, HCl). 1 ¹H NMR (methanol, 400 MHz) δ 8.01 (s, ¹H), 6.65 (s, ¹H), 6.46 (d, ¹H) J =8.4, 1H), 4.05(t, J =10.4, 1H), 3.96 (s, 3H), 3.85(t, J =4.8, 4H), 3.55 (t, J =5.2, 4H), 2.36 (s,3H), 2.04 (d, J=10.4, 2H), 1.82 (d, J =12.8, 2H), 1.72 (d, J =12.8, 1H), 1.52-1.29(m, 5H). MS (ESI+) m / z:C 23 H 31 Calculation of N7O2 [M+H] + : 438.25; Actual measurement: 438.3.

[0264] Preparation of compound 43 Step 1. Synthesis of compound AI.

[0265] Cs₂CO₃ (1.90 g, 5.84 mmol, 2.00 equivalent) was added to a mixture of compound AH (500.00 mg, 2.92 mmol, 1.00 equivalent) and 2-methylimidazole (359.84 mg, 4.38 mmol, 1.50 equivalent) in DMF (10 mL) at 20 °C. The mixture was then stirred at 80 °C for 2 hours. LC-MS indicated the end of the reaction. Compound AH was depleted, and the desired target mass was detected. H₂O (100 mL) was added to the mixture, and the aqueous fraction was extracted three times with DCM (30 mL each time). The combined organic layers were dried over Na₂SO₄ and then concentrated under reduced pressure. Compound AI (600.00 mg, crude) was given as a yellow solid.

[0266] Step 2. Synthesis of compound AJ.

[0267] 10% Pd / C (400.00 mg, 50% purity) was added to a mixture of compound AI (600.00 mg, 2.57 mmol, 1.00 equivalent) in methanol (20 mL) at 20 °C. The mixture was then stirred at 20 °C for 2 hours under H2 (15 psi). LC-MS indicated the end of the reaction. Compound AI was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. Compound AJ (660.00 mg, crude product) was obtained as a black oil.

[0268] Step 3. Synthesis of compound 43.

[0269] Compounds AJ (78.99 mg, 388.65 μmol, 1.20 equivalent) and U (100.00 mg, 323.87 μmol, 1.00 equivalent) were subjected to treatment at 20 °C. tPd2(dba)3 (29.66 mg, 32.39 μmol, 0.10 equivalent), XPhos (15.44 mg, 32.39 μmol, 0.10 equivalent) and [other ingredients] were added to the mixture in BuOH (5 mL). t -BuONa (62.25 mg, 647.75 μmol, 2.00 equivalents). The mixture was then stirred at 100 °C for 2 hours under N2. LC-MS indicated the end of the reaction. Compound AJ was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC. Compound 43 (51.2 mg, 96.88 μmol, 29.91% yield, 98.69% purity) was given as a white solid. 1 H NMR (DMSO- d 6, 400 MHz) δ =ppm 12.05 (br s, 1H), 8.66 (d, J =8.6 Hz, 1H), 8.49 (d, J =7.5 Hz, 1H), 8.17 (s, 0.1H), 7.69 (d, J =1.8 Hz, 1H), 7.42 (s, 1H),7.27 (d, J =1.2 Hz, 1H), 7.08 (d, J =2.3 Hz, 1H), 6.97 (dd, J =2.3, 8.6 Hz, 1H), 6.90 (d, J =1.2 Hz, 1H), 4.15 - 4.02 (m, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 2.30 (s, 3H), 2.07-1.96 (m, 2H), 1.75 (br dd, J =4.2, 8.8 Hz, 2H), 1.65-1.55 (m,1H), 1.52-1.27 (m, 5H). MS(ESI+) m / z:C 25 H 29 Calculation of N7O3 [M+H] + : 476.23; Actual measurement: 476.2.

[0270] Preparation of compound 45 Step 1. Synthesis of compound AC.

[0271] DIPEA (4.92 g, 38.04 mmol, 6.63 mL, 1.50 equivalent) and HATU (12.54 g, 32.97 mmol, 1.30 equivalent) were added to a solution of compound AB (5.00 g, 25.36 mmol, 1.00 equivalent) and MeNH2 (1.58 g, 23.33 mmol, 0.92 equivalent, HCl) in THF (250 mL) at 20 °C. The solution was then stirred at 20 °C for 12 h. LC-MS indicated the end of the reaction. Compound AB was depleted, and the desired target mass was detected. The mixture was concentrated to remove THF. H2O (150 mL) was added to the solution, and the solution was then extracted three times with ethyl acetate (200 mL each time). The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by MPLC (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound AC (4.10 g, crude product) was obtained as a yellow solid.

[0272] Step 2. Synthesis of compound AD.

[0273] Tf₂O (2.68 g, 9.52 mmol, 1.57 mL, 2.00 equivalent) was added to a mixture of compound AC (1.00 g, 4.76 mmol, 1.00 equivalent) and NaN₃ (1.180 g, 18.15 mmol, 3.82 equivalent) in MeCN (20 mL) at -10 °C. The mixture was then stirred at 20 °C for 3 hours. TLC (SiO₂, petroleum ether: ethyl acetate = 1:1) indicated that compound AC was depleted and a spot was detected. A saturated aqueous solution of NaHCO₃ was added to the mixture to adjust the pH to 7, and the mixture was then extracted three times with ethyl acetate (100 mL each time). The combined organic layers were dried over Na₂SO₄ and then concentrated. The residue was purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 1:0 to 0:1). The compound AD was given as a yellow solid (540.00 mg, 1.95 mmol, 41.02% yield, 85% purity).

[0274] Step 3. Synthesis of compound AE.

[0275] 10% Pd / C (100.00 mg, 50% purity) was added to a mixture of compound AD (200.00 mg, 850.34 μmol, 1.00 equivalent) in methanol (3 mL) at 20 °C. The mixture was then stirred at 20 °C for 2 hours under H2 (15 psi). LC-MS indicated the reaction was complete, compound AD was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. Compound AE (136.00 mg, crude product) was given as a white solid.

[0276] Step 4. Synthesis of compound 45.

[0277] Compound AE (100.00 mg, 487.29 μmol, 1.00 equivalent) and compound U (180.55 mg, 584.75 μmol, 1.20 equivalent) were subjected to treatment at 20 °C. t Pd₂(dba)₃ (44.62 mg, 48.73 μmol, 0.10 equivalence), XPhos (23.23 mg, 48.73 μmol, 0.10 equivalence), and K₂CO₃ (134.69 mg, 974.58 μmol, 2.00 equivalence) were added to the mixture in BuOH (5 mL). The mixture was then stirred at 100 °C under N₂ for 12 hours. LC-MS indicated that the reaction was complete, compound AE was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC. Compound 45 (7.10 mg, 14.87 μmol, 3.05% yield, 99.31% purity) was given as a white solid. 1 H NMR (DMSO- d 6, 400 MHz) δ =ppm 8.85 (d, J =8.2 Hz, 1H), 8.62-8.50 (m, 1H), 7.75 (s, 1H), 7.59 (s, 1H), 7.48-7.41 (m, 2H), 4.23 (s, 3H), 4.15-4.06 (m,1H), 4.06-3.99 (m, 3H), 3.88-3.77 (m, 3H), 2.10-2.00 (m, 2H), 1.82-1.72 (m,2H), 1.68-1.57 (m, 1H), 1.53-1.32 (m, 5H). MS(ESI+) m / z:C 23 H 27 Calculation of N9O3 [M+H] + : 478.22; Actual measurement: 478.2.

[0278] Preparation of compound 49 Step 1. Synthesis of compound AM.

[0279] H₂O (12 mL), Na₂CO₃ (1.48 g, 14.00 mmol, 1.00 equivalence), and Pd(dppf)Cl₂ (512.30 mg, 700.15 μmol, 0.10 equivalence) were added to a solution of compound AK (1.62 g, 7.00 mmol, 1.00 equivalence) and compound AL (1.90 g, 8.40 mmol, 1.20 equivalence) in dioxane (48 mL) at 20 °C. The solution was then stirred at 80 °C for 12 h. LC-MS indicated the end of the reaction. Compound AK was depleted, and the desired target mass was detected. H₂O (80 mL) was added to the solution. The solution was then extracted three times with ethyl acetate (80 mL each time). The organic layer was dried over Na₂SO₄ and then concentrated. The residue was purified by MPLC (SiO₂, petroleum ether: ethyl acetate = 0:1 to 1:0). Compound AM (2.65 g, crude product) was obtained as a yellow solid.

[0280] Step 2. Synthesis of compound AN.

[0281] Add to a solution of compound AM (1.95 g, 7.76 mmol, 1.00 equivalent) in DCM (30 mL) at 0 °C m -CPBA (4.73 g, 23.28 mmol, 85% purity, 3.00 equivalents). The mixture was stirred at 25 °C for 12 hours. LC-MS indicated the end of the reaction. Compound AM was depleted and the desired target mass was detected. The mixture was quenched with saturated Na2SO3 aqueous solution (20 mL), and then saturated Na2CO3 aqueous solution was added to adjust the pH to 7. H2O (50 mL) was added to the solution. The solution was then extracted three times with DCM (100 mL each time). The organic layer was dried with Na2SO4 and then concentrated. The solution was analyzed by column chromatography (plate 1: ethyl acetate: petroleum ether 3:1 (UV 254 nm), SiO2, petroleum ether: ethyl acetate = 99:1 to 10:1; R f =0.49) The residue was purified. Compound AN was given as a white solid (590.00 mg, 2.08 mmol, 26.84% yield).

[0282] Step 3. Synthesis of compound AO.

[0283] 10% Pd / C (100.00 mg, 50% purity) was added to a solution of compound AN (500.00 mg, 1.76 mmol, 1.00 equivalent) in methanol (10 mL) at 25 °C. The mixture was stirred at 25 °C for 12 hours under H2 (15 psi). LC-MS indicated the end of the reaction. Compound AN was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 3:1). Compound AO (420.00 mg, 1.64 mmol, 93.20% yield) was given as a black solid.

[0284] Step 4. Synthesis of compound 49.

[0285] Compound AO (100.00 mg, 391.65 μmol, 1.00 equivalent) was subjected to treatment at 25 °C. t XPhos (18.67 mg, 39.17 μmol, 0.10 equivalent), Pd2(dba)3 (35.86 mg, 39.17 μmol, 0.10 equivalent), K2CO3 (162.38 mg, 1.17 mmol, 3.00 equivalent), and compound U (120.93 mg, 391.65 μmol, 1.00 equivalent) were added to a solution of -BuOH (5 mL). The mixture was stirred at 100 °C for 12 hours. LC-MS indicated the end of the reaction. Compound AO was depleted, and the desired target mass was detected. H2O (5 mL) was added to the mixture, and the aqueous solution was extracted three times with ethyl acetate (5 mL each time). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by preparative HPLC. Compound 49 was given as a white solid (29.60 mg, 53.84 μmol, 13.75% yield, 95.98% purity). 1 H NMR (DMSO- d 6, 400 MHz) δ =ppm 11.97 (br s, 1H), 8.43 (br d, J =8.4 Hz, 2H), 8.32(s, 0.5 H), 7.66 (d, J =1.2 Hz, 1H), 7.27 (s, 1H), 6.88 (s, 1H), 6.79 (d, J =8.4Hz, 1H), 3.99-4.11 (m, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.29 (br s, 2H), 3.11(br d,J =11.8 Hz, 2H), 2.89 (td, J =10.07, 4.63 Hz, 1H), 2.08-2.19 (m, 4H), 2.02(br d, J =9.6 Hz, 2H), 1.76 (br dd, J =8.4, 3.94 Hz, 2H), 1.62 (br dd, J =9.19,3.19 Hz, 1H), 1.27 - 1.48 (m, 5H). MS(ESI+) m / z:C 26 H 33 Calculation of N5O5S [M+H] + : 528.22; Actual measurement: 528.2.

[0286] Preparation of compound 53 Step 1. Synthesis of compound AP.

[0287] NIS (13.16 g, 58.51 mmol, 1.10 equivalent) was added to a solution of compound A (10.00 g, 53.19 mmol, 1.00 equivalent) in DMF (80 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h. LC-MS showed that compound A was completely depleted and the desired mass was detected. The reaction mixture was added to ice water (1000 mL) and filtered, and the filter cake was dried under reduced pressure to produce a residue. Compound AP (14.00 g, crude product) was given as a yellow solid.

[0288] Step 2. Synthesis of compound AQ.

[0289] NaH (1.91 g, 47.78 mmol, 60% purity, 1.50 equivalent) was added to a mixture of compound AP (10.00 g, 31.86 mmol, 1.00 equivalent) in THF (150 mL) at 0 °C. The mixture was then stirred at 0 °C for 0.5 h. SEM-Cl (6.37 g, 38.23 mmol, 6.77 mL, 1.20 equivalent) was then added to the mixture at 20 °C. The mixture was then stirred at 20 °C for 12 h. LC-MS indicated the reaction was complete. H₂O (200 mL) was added to the mixture at 0 °C, and the aqueous fraction was extracted three times with DCM (100 mL each time). The combined organic layers were dried over Na₂SO₄ and then concentrated under reduced pressure. Multiple batches were prepared and combined. The residues were purified by column chromatography (SiO₂, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound AQ (24.00 g, crude product) was obtained as a yellow solid.

[0290] Step 3. Synthesis of compound AR.

[0291] TEA (2.28 g, 22.51 mmol, 3.13 mL, 2.00 equivalent) was added to a mixture of compound AQ (5.00 g, 11.26 mmol, 1.00 equivalent) and cyclohexylamine (1.12 g, 11.26 mmol, 1.29 mL, 1.00 equivalent) in MeCN (100 mL) at 20 °C. The mixture was then stirred at 60 °C for 12 hours. LC-MS indicated that the reaction was complete, compound AQ was depleted, and the desired target mass was detected. The mixture was concentrated, H2O (50 mL) was added to the mixture, and the aqueous fraction was extracted three times (20 mL) with DCM. The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound AR (5.00 g, crude) was given as a blue oil.

[0292] Step 4. Synthesis of compound G.

[0293] Pd(dppf)Cl2 (144.35 mg, 197.28 μmol, 0.10 equivalent) and TEA (399.26 mg, 3.95 mmol, 549.19 uL, 2.00 equivalent) were added to a mixture of compound AR (1.00 g, 1.97 mmol, 1.00 equivalent) in methanol (10 mL) at 20 °C. The mixture was then stirred at 70 °C for 2 h under CO (15 psi). LC-MS indicated that the reaction was complete, compound AR was depleted, and the desired target mass was detected. The mixture was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound G (500.00 mg, crude product) was given as a yellow oil.

[0294] Step 5. Synthesis of compound AT.

[0295] Compound G (130.00 mg, 296.11 μmol, 1.00 equivalent) and 2-methoxy-4-(4-morpholino)aniline (92.50 mg, 444.17 μmol, 1.50 equivalent) were subjected to oxidation at 20 °C. t Pd2(dba)3 (27.12 mg, 29.61 μmol, 0.10 equivalent), XPhos (14.12 mg, 29.61 μmol, 0.10 equivalent), and K2CO3 (81.85 mg, 592.22 μmol, 2.00 equivalent) were added to the mixture in BuOH (5 mL). The mixture was then stirred at 100 °C for 12 hours under N2. LC-MS indicated that the reaction was complete, compound G was depleted, and the desired target mass was detected. The mixture was concentrated. H2O (10 mL) was added to the mixture, and the aqueous solution was extracted three times (5 mL each time) with DCM. The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound AT (50.00 mg, crude) was given as a yellow solid.

[0296] Step 6. Synthesis of compound 53.

[0297] TFA (2 mL) was added to a mixture of compound AT (140.00 mg, 229.20 μmol, 1.00 equivalent) in DCM (2 mL) at 20 °C. The mixture was then stirred at 20 °C for 2 h. LC-MS showed that compound AT was not depleted, an intermediate was detected, and the desired target mass was not detected. The mixture was then concentrated to dryness under a stream of N2. K2CO3 (158.38 mg, 1.15 mmol, 5.00 equivalent) and methanol (4 mL) were added to the mixture. The mixture was then stirred at 60 °C for 12 h. LC-MS showed that the reaction was complete, compound AT was depleted, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC. Compound 53 (4.20 mg, 8.74 μmol, 3.81% yield, 100.00% purity) was given as a white solid. 1 H NMR (DMSO- d 6, 400 MHz) δ =11.91(br s, 1H), 8.40 (d, J =7.6 Hz, 1H), 8.22 (d, J =8.6 Hz, 1H), 7.63 (s, 1H), 7.14(s, 1H), 6.67 (d, J =2.2 Hz, 1H), 6.53-6.45 (m, 1H), 4.05 (br s, 1H), 3.88 (s,3H), 3.82 (s, 3H), 3.80-3.72 (m, 4H), 3.14 - 3.02 (m, 4H), 2.70 (s, 2H), 2.02(br d, J =11.4 Hz, 2H), 1.75 (br s, 2H), 1.62 (br s, 1H), 1.46 (br d, J =12.0 Hz,1H), 1.52-1.29 (m, 2H). MS(ESI+) m / z:C 25 H 32 Calculation of N6O4 [M+H] + : 481.25; Actual measurement: 481.1.

[0298] Preparation of compound 54 Step 1. Synthesis of compound AU.

[0299] K₂CO₃ (1.62 g, 11.69 mmol, 2.00 equivalent) was added to a solution of compound AH (1.00 g, 5.84 mmol, 1.00 equivalent) and imidazole (795.64 mg, 11.69 mmol, 2.00 equivalent) in MeCN (10 mL) at 20 °C. The solution was then stirred at 80 °C for 12 h. LC-MS indicated the end of the reaction. Compound AH was depleted, and the desired target mass was detected. The mixture was concentrated to remove the added MeCN, and then the solution was extracted three times with ethyl acetate (10 mL each time). The organic layer was dried over Na₂SO₄ and then concentrated. The residue was purified by preparative TLC (SiO₂, petroleum ether: ethyl acetate = 0:1). Compound AU (1.24 g, 5.66 mmol, 96.81% yield) was given as a white solid.

[0300] Step 2. Synthesis of compound AV.

[0301] Compound AU (500.00 mg, 2.28 mmol, 1.00 equivalent) was added to a solution of 10% Pd / C (250.00 mg, 50% purity, 1.00 equivalent) in methanol (10 mL) under a nitrogen atmosphere. The suspension was degassed and purified five times with H2. The mixture was stirred at 25 °C for 12 hours under H2 (15 psi). LC-MS indicated the end of the reaction. Compound AU was depleted, and the desired target mass was detected. The mixture was then filtered, and the filtrate was concentrated. Compound AV (120 mg, 634.20 μmol, 27.80% yield) was given as a pale yellow solid.

[0302] Step 3. Synthesis of compound AX.

[0303] Compound AV (129.30 mg, 683.34 μmol, 1.20 equivalent) and compound G (250 mg, 569.45 μmol, 1.00 equivalent) were subjected to treatment at 20 °C. tK₂CO₃ (157.40 mg, 1.14 mmol, 2.00 equivalents), Pd₂(dba)₃ (52.15 mg, 56.94 μmol, 0.10 equivalents), and XPhos (27.15 mg, 56.94 μmol, 0.10 equivalents) were added to a solution of -BuOH (4 mL). The solution was then stirred at 100 °C under N₂ for 12 hours. LC-MS indicated the end of the reaction. Compound AV was depleted, and the desired target mass was detected. H₂O (10 mL) was added to the solution, and the solution was then extracted three times (10 mL) with ethyl acetate. The organic layer was dried over Na₂SO₄ and then concentrated. The residue was purified by preparative TLC (SiO₂, ethyl acetate:methanol = 3:1). Compound AX (300.00 mg, 506.95 μmol, 89.02% yield) was given as a brown solid.

[0304] Step 4. Synthesis of compound AY.

[0305] A solution of compound AX (300.00 mg, 506.95 μmol, 1.00 equivalent) in TFA (5 mL) and DCM (2 mL) was stirred at 20 °C for 1 hour. LC-MS indicated the end of the reaction. Compound AX was depleted, and the desired target mass was detected. The mixture was concentrated. Compound AY (300.00 mg, 495.41 μmol, 97.72% yield) was given as a yellow oil.

[0306] Step 5. Synthesis of compound 53.

[0307] NH3 was added to a solution of compound AY (300.00 mg, 495.41 μmol, 1.00 equivalent) in methanol (1 mL) and THF (1 mL). H2O (3.82 mL, 25% purity) was added at 20 °C. The solution was then stirred at 20 °C for 12 hours. LC-MS indicated the end of the reaction. Compound AY was depleted, and the desired target mass was detected. The mixture was concentrated. The crude product was purified by preparative HPLC. Compound 53 (6.70 mg, 14.52 μmol, 2.93% yield, 100.00% purity) was given as a white solid. 1 H NMR (DMSO- d6, 400 MHz) δ =ppm 11.87-12.22 (m, 1H), 8.57-8.67(m, 1H), 8.44-8.54 (m, 1H), 8.17-8.26 (m, 1H), 7.64-7.78 (m, 2H), 7.33-7.43(m, 1H), 7.24-7.31 (m, 1H), 7.13-7.20 (m, 1H), 7.07-7.12 (m, 1H), 4.02-4.15(m, 1H), 3.97-4.02 (m, 3H), 3.77-3.87 (m, 3H), 1.94-2.10 (m, 2H), 1.67-1.83(m, 2H), 1.54-1.65(m, 1H), 1.23-1.52(m, 5H). MS(ESI+) m / z:C 24 H 27 Calculation of N7O3 [M+H] + : 462.22; Actual measurement: 462.2.

[0308] Preparation of compound 56 Step 1. Synthesis of compound BC.

[0309] XPhosPdG3 (166.99 mg, 197.28 μmol, 0.1 equivalent) and KOAc (387.24 mg, 3.95 mmol, 2 equivalent) were added to a solution of compound AR (1 g, 1.97 mmol, 1 equivalent) in dioxane (10 mL) and H2O (2.5 mL). The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that compound AR was completely depleted and the desired mass was detected. The mixture was diluted with 30 mL of H2O and extracted three times (90 mL) with 30 mL of ethyl acetate. The product was then dried over Na2SO4, filtered, and concentrated under reduced pressure to produce the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). Compound BC was obtained as a brown oil (240 mg, 520.52 μmol, 26.38% yield). MS (ESI+): m / z 461.3 [M+H].

[0310] Step 2. Synthesis of compound BE.

[0311] XPhos (11.37 mg, 238.57 μmol, 1 equivalent) was added to a solution of compound BC (110 mg, 238.57 μmol, 1 equivalent) and compound BD (49.68 mg, 238.57 μmol, 1 equivalent) in t-BuOH (2 mL), along with t-BuONa (45.86 mg, 477.15 μmol, 2 equivalent) and Pd2(dba)3 (21.85 mg, 23.86 μmol, 0.1 equivalent). The mixture was stirred at 80 °C for 2 hours under N2. LC-MS showed that compound BC was completely depleted and the desired mass was detected. The mixture was diluted with 5 mL H2O and extracted three times (15 mL) with 5 mL ethyl acetate. The product was then dried over Na2SO4, filtered, and concentrated under reduced pressure to produce the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 1:0 to 0:1). The compound BE (85 mg, 134.31 μmol, 56.30% yield) was obtained as a brown oil.

[0312] LCMS (ESI+): m / z 633.6 (M + H) Step 2. Synthesis of compound BF.

[0313] TFA (767.50 mg, 6.73 mmol, 0.5 mL, 50.12 equivalents) was added to a solution of compound BE (85 mg, 134.31 μmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at 20 °C for 2 hours. LC-MS showed that compound BE was completely depleted and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The crude product was used directly for the next step without purification. Compound BF was given as a black solid.

[0314] Step 2. Synthesis of compound 56.

[0315] NH3 / H2O (455.00 mg, 3.25 mmol, 0.5 mL, 25% purity, 20.34 equivalents) was added to a solution of compound BF (85 mg, 159.58 μmol, 1 equivalent) in THF (1.5 mL) and methanol (0.5 mL). The mixture was stirred at 20 °C for 12 h. LC-MS showed that compound BF was completely depleted and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC. Compound 56 (14.9 mg, 29.65 μmol, 18.58% yield) was given as a white solid. 1H NMR(400 MHz, DMSO-d6) δ ppm 1.18 - 1.27 (m, 3H)1.34 - 1.44 (m, 2H) 1.52 - 1.63 (m, 3H) 1.94 (br d, J =8.88 Hz, 2 H) 3.03 -3.08 (m, 4H) 3.73 - 3.76 (m, 4H) 3.86 (s, 3H) 3.89 (s, 3H) 3.95 - 4.02 (m,1H) 5.17 (d, J =8 Hz, 1H) 6.46 (dd, J =8.88, 2 Hz, 1H) 6.64 (d, J =2.4 Hz, 1H) 6.74(d, J =2 Hz, 1H) 7.02 (s, 1H) 7.51 (s, 1H) 7.80 (s, 1H) 8.29 (d, J =8.8 Hz, 1H)11.10 (s, 1H)MS(ESI+): m / z 503.3 [M + H].

[0316] Preparation of compound 67 Step 1. Synthesis of compound BG.

[0317] tert-butyl piperazine-1-carboxylate (21.60 g, 115.97 mmol, 1.10 equivalents) and compound AH (18 g, 105.19 mmol, 1 equivalent) were added to a solution of K₂CO₃ (14.54 g, 105.19 mmol, 1 equivalent) in DMF (80 mL). The mixture was stirred at 90 °C for 12 h. LC-MS showed that compound AH was completely depleted and the desired mass was detected. The mixture was added to H₂O (150 mL) at 20 °C. The solid was then filtered, washed three times with H₂O (50 mL each time), and dried under high vacuum. The crude product was milled twice in ethyl acetate (40 mL) at 20 °C for 20 min. The solid was filtered, and the filter cake was dried to yield a pure product. Compound BG (25 g, 74.10 mmol, 70.45% yield) was given as a yellow solid.

[0318] Step 2. Synthesis of compound BH.

[0319] Pd / C (946.32 mg, 4.45 mmol, 50% purity, 0.25 equivalents) was added to a solution of compound BG (6 g, 17.78 mmol, 1 equivalent) in methanol (200 mL) under N2. The suspension was degassed and purified three times with H2. The mixture was stirred at 20 °C for 12 h under H2 (35.85 mg, 17.78 mmol, 1 equivalent) (50 psi.). LC-MS showed that compound BG was completely consumed and the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under high vacuum. Compound BH (5 g, 16.27 mmol, 91.46% yield) was given as a pink solid.

[0320] Step 3. Synthesis of compound BI.

[0321] A mixture of compound BH, 2-chloro-N-cyclohexyl-5-(1-methylpyrazol-4-yl)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-amine (1.80 g, 3.90 mmol, 1 equivalent, compound BC), Cs₂CO₃ (2.54 g, 7.81 mmol, 2 equivalents), XPhos (372.21 mg, 780.77 μmol, 0.2 equivalents), and Pd₂(dba)₃ (357.48 mg, 390.39 μmol, 0.1 equivalents) in dioxane (50 mL) was degassed and purified three times with N₂. The mixture was then stirred at 90 °C for 4 hours under N₂ atmosphere. TLC indicated that compound BH was completely depleted and a new major spot was formed. The reaction mixture was partitioned three times (120 mL each) between H₂O (150 mL) and ethyl acetate, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography to give compound BI as a yellow solid (2 g, 2.73 mmol, 69.99% yield).

[0322] Step 4. Synthesis of compound BJ.

[0323] TBAF (1 M, 6.83 mL, 5 equivalents) was added to a solution of compound BI (1 g, 1.37 mmol, 1 equivalent) in THF (15 mL). The mixture was stirred at 70 °C for 12 hours. LC-MS showed that compound BI was completely depleted and the desired mass was detected. The reaction mixture was partitioned three times between H2O (60 mL) and ethyl acetate (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography. Compound BJ (500 mg, 830.92 μmol, 60.82% yield) was given as a yellow solid.

[0324] Step 5. Synthesis of compound BK.

[0325] A mixture of compound BJ (500 mg, 830.92 μmol, 1 equivalent) in HCl / ethyl acetate (4 M, 15 mL, 72.21 equivalents) was stirred at 20 °C for 1 hour. LC-MS showed that compound BJ was completely consumed and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. Compound BK (400 mg, crude, HCl) was given as a pink solid.

[0326] Step 6. Synthesis of compound 67.

[0327] Solution A was prepared by dropwise addition of DIEA (192.15 mg, 1.49 mmol, 258.96 μL, 2 equivalents) and T4P (1.07 g, 1.49 mmol, 50% purity, 2 equivalents) in 2-methyltetrahydrofuran (0.5 mL) to a solution of compound BK (400 mg, 743.38 μmol, 1 equivalent, HCl) in DMF (3 mL). Solution B was then prepared by adding DIEA (288.23 mg, 2.23 mmol, 388.45 μL, 3 equivalents) to a solution of compound BK (400 mg, 743.38 μmol, 1 equivalent, HCl) in DMF (3 mL). Solution B was then added to solution A. The mixture was stirred at 20 °C for 2 hours. LC-MS showed that compound BK was completely depleted and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC. Compound 67 was given as a yellow solid (126 mg, 167.87 μmol, 22.58% yield, 91.90% purity). It should be understood that in some cases, compounds with the same RK can be prepared in a similar manner. 5 Compounds with groups or having R similar to compound 675 Compounds containing functional groups. 1 H NMR (400 MHz, DMSO-d6) δ =11.24-11.08 (m, 1H), 8.29 (br d, J =8.8 Hz,1H), 8.13 (s, 1H), 8.10-8.02 (m, 2H), 7.86-7.77 (m, 2H), 7.52 (s, 1H), 7.49(s, 1H), 7.19-7.13 (m, 1H), 7.10 (d, J =9.2 Hz, 2H), 6.75 (d, J =1.6 Hz, 1H), 6.70 (d, J =2.4 Hz, 1H), 6.50 (dd, J =2.4, 8.8 Hz, 1H), 5.24 (br d, J =6.0 Hz, 1H),4.04-3.94 (m, 1H), 3.89 (s, 3H), 3.87 (s, 6H), 3.75 (br s, 4H), 3.13 (br s,4H), 1.94 (br d, J =10.0 Hz, 2H), 1.67-1.54 (m, 3H), 1.40 - 1.33 (m, 2H), 1.22(q, J =10.4 Hz, 3H), 0.89-0.83 (m, 1H). MS(ESI+): Measured m / z: 690.4 (M + H).

[0328] Preparation of compound 68 Step 1. Synthesis of compound 68.

[0329] Solution A was prepared by dropwise addition of DIEA (144.11 mg, 1.12 mmol, 194.22 μL, 2 equivalents) and T4P (803.42 mg, 1.12 mmol, 50% purity, 2 equivalents) in 2-methyltetrahydrofuran (0.5 mL) to a solution of 4-(4-methoxyphenyl)-4-oxo-butyric acid (92.87 mg, 446.03 μmol, 0.8 equivalents) in DMF (1 mL). Compound BK was synthesized as described with respect to compound 67. Solution B was prepared by adding DIEA (216.17 mg, 1.67 mmol, 291.33 μL, 3 equivalents) to a solution of compound BK (300 mg, 557.53 μmol, 1 equivalent, HCl) in DMF (2 mL). Solution B was then added to solution A. The mixture was stirred at 20 °C for 2 hours. LC-MS showed that compound BK was completely depleted and the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under high vacuum. The residue was purified by preparative HPLC. Compound 68 was given as a white solid (111 mg, 153.88 μmol, 27.60% yield, 95.91% purity). It should be understood that in some cases, compounds with the same RK can be prepared in a similar manner. 5 Compounds with groups or having R similar to compound 68 5 Compounds containing functional groups. 1 H NMR (400 MHz, DMSO-d6) δ =11.13 (d, J =1.6 Hz, 1H), 8.32 (d, J =8.8 Hz, 1H), 7.97 (d, J =8.8 Hz, 2H), 7.80 (s, 1H), 7.52 (s,1H), 7.14-6.96 (m, 3H), 6.80 - 6.64 (m, 2H), 6.49 (dd, J =2.4, 8.8 Hz, 1H), 5.18 (d, J =7.6 Hz, 1H), 4.00 (br dd, J =4.8, 8.7 Hz, 1H), 3.88 (d, J =6.4 Hz, 6H),3.84 (s, 3H), 3.72 - 3.54 (m, 4H), 3.20 (br t, J =6.0 Hz, 2H), 3.16 - 2.98 (m,4H), 2.74 (br t, J=6.0 Hz, 2H), 1.95 (br d, J =8.8 Hz, 2H), 1.68 - 1.50 (m, 3H), 1.48 - 1.31 (m, 2H), 1.31-1.13 (m, 3H). LCMS(ESI+): Measured m / z: 692.5 (M + H).

[0330] Preparation of compound AF Step 1. Synthesis of compound BA.

[0331] Morpholine (5.27 g, 60.4 mmol, 5.32 mL, 1.20 equivalent) and K₂CO₃ (13.9 g, 100 mmol, 2.00 equivalent) were added to a solution of 6-chloro-2-methoxy-3-nitropyridine (compound AZ) (9.50 g, 50.4 mmol, 1.00 equivalent) in MeCN (66.5 mL). The mixture was stirred at 70 °C for 12 hours. TLC (petroleum ether: ethyl acetate = 1:1, R f =0.38) indicates that compound AZ was completely depleted and a new spot was formed. The reaction mixture was diluted with 120 mL of H2O and extracted with DCM (three extractions of 100 mL, 50 mL, and 20 mL, respectively). The combined organic layers were washed twice with brine (100 mL each time), dried over Na2SO4, filtered, and concentrated under reduced pressure to produce a residue. The crude product was used for the next step without purification. Compound BA (9.50 g, crude product) was given as a yellow solid.

[0332] Step 2. Synthesis of compound AF.

[0333] Fe (6.65 g, 119 mmol, 3.00 equivalent) and NH4Cl (8.50 g, 159 mmol, 4.00 equivalent) were added to a solution of compound BA (9.50 g, 39.7 mmol, 1.00 equivalent) in EtOH (76.0 mL) and H2O (9.50 mL). The mixture was stirred at 80 °C for 12 hours. TLC (petroleum ether: ethyl acetate = 0:1, R f = 0.31) indicates that compound BA was completely depleted and formed numerous new spots. The mixture was filtered, and the filter cake was washed with EtOH (200 mL). The combined filtrates were concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 20:1 to 0:1). Compound AF (6.50 g, 78.0% yield) was given as a dark brown solid.1 H NMR (400 MHz, CDCl3) δ6.90 (d, J =8.0 Hz, 1H), 6.07 (d, J =8.0 Hz, 1H), 3.94 (s, 3H), 3.82-3.88 (m, 4H), 3.38 (s, 2H), 3.28-3.34 (m, 4H).

[0334] Mps1 / TTK measurement NanoBRET TTK Measurement HEK293 cells were cultured to 70-80% confluence, digested with trypsin, and collected. A 10 µg / mL DNA solution was prepared using serum-free OPTI-MEM without phenol red. 9.0 μg of transfection vector DNA and 1.0 μg of TTK-NanoLuc fusion vector DNA were mixed in 1 mL of medium. To form the lipid:DNA complex, 30 μL was added to 1 mL of the DNA mixture, and the mixture was inverted. To allow the complex to form, the mixture was incubated at ambient temperature for 20 minutes.

[0335] For transfection, the lipid:DNA complex mixture was diluted 20-fold with suspended HEK293 cells and mixed by gentle inversion in a sterile conical tube. The cell complex mixture was then aliquoted into sterile tissue culture dishes and incubated for 22–24 hours.

[0336] Each synthesized compound was applied to the wells of a 384-well white unbound surface plate using an Echo 550. Culture medium was removed from the culture dish containing transfected HEK293 cells by aspiration. Cells were digested with trypsin and detached from the culture dish. The trypsin was neutralized with serum-containing medium, and the cells were centrifuged at 200 x g for 5 min to pellet the cells. Cells were adjusted to 2 x 10⁻⁶ cells / mL in phenol red-free OPTI-MEM. 5 A density of cells / mL was determined. One complete 20X NanoBRET tracer K5 reagent was added to 20 cells in a test tube, and the cells and reagent were mixed by inverting.

[0337] The cell suspension was aliquoted into white 384 unbound surface plates containing the test compound, and the plates were incubated at 37°C and 5% CO2 for 1 hour. The final tracer K5 concentration in this mixture was 1 μM. Additionally, a set of samples without K5 tracer was prepared for the background correction step. After incubation, cell plates were removed from the incubator and equilibrated at room temperature for 15 minutes. Then, a 3X intact substrate plus inhibitor solution prepared on-prepared assay medium (OPTI-MEM I low-serum medium, phenol red-free) was added to each well, and the plates were incubated at room temperature for 2–3 minutes. Donor emission was then measured at 460 nm and acceptor emission at 600 nm using an Envison 2104 plate reader. To generate raw BRET ratio values, the acceptor emission value (600 nm) for each sample was divided by the donor emission value (460 nm), and to correct for background, the BRET ratio in the absence of a tracer (the average of the tracer-free control samples) was subtracted from the BRET ratio for each sample. The IC50 of the NanoBRET response of the compounds was plotted. 50 The curve was plotted, and the IC was calculated using the GraphPad Prism 4 program based on the sigmoid dose-response equation. 50 Values. Table 3 shows the results for the synthesized compounds, and Table 4 shows the results for the comparative compounds. “ND” indicates a result not determined.

[0338] TTK inhibition assay A basic reaction buffer was prepared containing 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO. TTK was added to the reaction mixture to achieve a final concentration in the range of 40–75 nM. The synthesized compound was delivered in nmL to the reaction mixture in 100% DMSO using an Echo 550. The mixture was incubated at room temperature for 20 minutes. 33 P-ATP was added to the reaction mixture to initiate the reaction. The reaction mixture was incubated for two hours. Kinase activity was detected using the P81 filter-binding assay. The kinetic constants and IC50 values ​​of the synthesized compound were plotted. 50 The curve was plotted, and the IC was calculated using the GraphPad Prism 4 program based on the sigmoid dose-response equation. 50 Values. Table 3 shows the results for the synthesized compounds, and Table 4 shows the results for the comparative compounds. “ND” indicates a result not determined.

[0339] Cancer cell line assay COLO205 Cell Titer-Glo Measurement The reference compound, asteroidin, was purchased from Sigma-Aldrich (Saint Louis, MI). The Cell Titer-Glo® 2.0 luminescent cell viability assay kit was purchased from Promega (Madison, WI). The COLO205 cell line was purchased from the American Type Culture Collection (Manassas, VA). COLO205 cells were cultured in RPMI medium supplemented with 10% FBS, 100 μg / mL penicillin, and 100 μg / mL streptomycin. Cultures were maintained at 37°C under humidified conditions of 5% CO2 and 95% atmospheric pressure. Add 25 μL of culture medium containing 2,000 COLO205 cells to each well of a cell culture plate. Incubate the cells statically for 24 hours to allow them to adhere. Dilute the compound and the reference compound asteroidin with RPMI containing 0.3% DMSO in 10-dose and 3-fold dilutions, starting at 30 μM (compound) and 60 μM (asteroidin) on source plates. Deliver 5 μL of either the compound or asteroidin in duplicate from the source plates to each well of a 384-well cell culture plate. Incubate the cells with the compound at 37°C and 5% CO2 for 120 hours. Add 30 μL of Cell Titer Glo 2.0 reagent to each well. Mix the contents on a track-controlled shaker for 2 min and incubate at room temperature for 15 min to stabilize the luminescence signal. Record the luminescence using an Envision 2104 multilabel reader (PerkinElmer, Santa Clara, CA). Determine the number of viable cells in the culture based on the quantification of ATP present in each well. Drawing the IC of the compound 50 The curve was plotted, and the IC was calculated using the GraphPad Prism 4 program based on the sigmoid dose-response equation. 50 Values. Table 3 shows the results for the synthesized compounds, and Table 4 shows the results for the comparative compounds. “ND” indicates a result not determined.

[0340] RPMI - 8226 MTS Measurement The reference compound, asteroidin, was purchased from Sigma-Aldrich (Saint Louis, MI). CellTiter 96 Aqueous single-solution reagent (MTS assay reagent) was purchased from Promega (Madison, WI). The RPMI-8226 cell line was purchased from the American Type Culture Collection (Manassas, VA). Cells were cultured in RPMI-1640 culture containing 10% FBS supplemented with 100 μg / mL penicillin and 100 μg / mL streptomycin. Cultures were maintained at 37°C in a humidified environment of 5% CO2 and 95% atmospheric pressure. Each compound and asteroidin was diluted in DMSO and subjected to 10-dose, 3-fold dilutions on source plates starting at 3.33 mM (test compound) and 1 mM (asteroidin). 25 nL of the compound or asteroidin was delivered from the source plates to each well of a 384-well cell culture plate using an Echo 550. 25 μL of culture medium containing 5,000 RPMI-8226 cells was delivered in duplicate to each well of the cell culture plate. The cells in the cell culture plate were incubated with the compound at 37°C and 5% CO2 for 96 hours. 5 μL of CellTiter 96® AQueous single-solution reagent (MTS assay reagent) was added to each well and incubated at 37°C and 5% CO2 for 6 hours. The absorbance at 492 nm was recorded using an Envision 2104 multilabel reader. The presence of viable cells in each well was determined using the colored formazan product. IC50 was plotted. 50 The curve was plotted, and the IC was calculated using the GraphPad Prism 4 program based on the sigmoid dose-response equation. 50 Values. Table 3 shows the results for the synthesized compounds, and Table 4 shows the results for the comparative compounds. “ND” indicates a result not determined.

[0341] A375 Cell Titer-Glo assay Bortezomib, the reference compound, was purchased from Selleckchem (Houston, TX). Astrococcus was purchased from Sigma-Aldrich (Saint Louis, MI). CellTiter-Glo® 2.0 Luminescent cell viability assay kit was purchased from Promega (Madison, WI). The A375 cell line was purchased from the American Type Culture Collection (Manassas, VA). A375 cells were cultured in DMEM containing 10% FBS, 100 μg / mL penicillin, and 100 μg / mL streptomycin. The culture was maintained at 37°C in a humidified environment of 5% CO2 and 95% atmospheric pressure.

[0342] 50 μL of culture medium containing 250 A375 cells was added to each well of several 384-well tissue culture plates using a Multidrop dispenser. The cells were incubated overnight at 37°C and 5% CO2. The next day, the compound, the reference compound bortezomib, and astrococcal were added to the tissue culture plates using a Tecan D300e digital dispenser. The test compound and bortezomib were added to the plates, and 8-fold, 3-fold dilutions were performed, starting at 3 μM (test compound) or 1 μM (bortezomib). Cells treated with 10 μM astrococcal were used as background. The cells and compound were incubated at 37°C and 5% CO2 for 72 hours.

[0343] Add 50 μL of CellTiter-Glo 2.0 reagent to each well. Mix the contents on a track-controlled shaker for 2 min and incubate at room temperature for 15 min to stabilize the luminescence signal. Record the luminescence using an Envision 2104 multilabel reader (PerkinElmer, Santa Clara, CA). Determine the number of viable cells in the culture based on the quantification of ATP present in each well. Plot the IC50. 50 The curve was plotted, and the IC was calculated using the GraphPad Prism 4 program based on the sigmoid dose-response equation. 50 Values. Table 3 shows the results for the synthesized compounds, and Table 4 shows the results for the comparative compounds. “ND” indicates a result not determined.

[0344] A375 Cell Titer-Glo serum transfer Measurement Repeat the A375 CTG assay as described above. However, modify the protocol by adding 4.5% human serum albumin (HSA) and 0.14% α-1-acid glycoprotein (AAG) to the culture medium during the 72-hour incubation period. Plot the IC50. 50 The curve was plotted, and the IC was calculated based on the sigmoid dose-response equation using the GraphPadPrism 4 program. 50 Value. The serum transfer fold is determined as follows: the IC50 value is determined in the presence of serum proteins. 50 Divide the value by the IC50 value determined in assays without supplementation of human serum protein. 50 Values. Table 3 shows the results for the synthesized compounds, and Table 4 shows the results for the comparative compounds. “ND” indicates a result not determined.

[0345] Table 3. IC50 of the synthesized compounds 50 result. serial number <![CDATA[NanoBRETIC 50 (nM)]]> <![CDATA[TTK IC 50 (nM)]]> <![CDATA[COLO205 CTGIC 50 (nM)]]> <![CDATA[RPMI-8226MTS IC 50 (nM)]]> <![CDATA[A375 CTGIC 50 (nM)]]> <![CDATA[A375 CTG IC 50 Serum transfer (nM) <![CDATA[A375 CTG IC 50 Serum transfer fold (nM) 1 <10 <10 82.0 148.4 55.7 2192.0 39 2 <10 <10 ND 30.5 12.1 129.2 11 3 <10 <10 ND 103.3 17.8 347.3 20 4 <10 <10 ND 41.3 ND ND ND 5 <10 <10 ND 318.8 ND ND ND 6 <10 <10 ND 86.6 8.2 140.6 17.1 7 <10 12.9 ND 704.7 ND ND ND 8 <10 <10 ND 1,354.0 ND ND ND 9 <10 <10 ND <10 ND ND ND 10 <10 <10 ND 429.9 ND ND ND 11 13 <10 ND 27.3 ND ND ND 12 <10 <10 ND 63.0 ND ND ND 13 <10 <10 ND 149.0 ND ND ND 14 <10 <10 ND <10 ND ND ND 15 <10 <10 ND 336.6 33.2 698.2 21.0 16 <10 <10 ND <10 16.0 478.6 37 17 <10 <10 ND 73.4 ND ND ND 18 <10 <10 ND 104.8 ND ND ND 19 <10 <10 ND <10 ND ND ND 20 <10 <10 ND 67.5 ND ND ND 21 <10 ND ND 119.2 36.8 362.4 10 22 <10 ND ND ND 17.6 132.6 9 23 <10 ND ND ND 115.2 ND ND 24 <10 ND ND ND <10 ND ND 25 <10 ND ND ND 68.5 1336.0 36 26 <10 ND ND ND 165.4 ND ND 27 <10 <10 ND 64.3 ND ND ND 28 <10 <10 ND 35.6 ND ND ND 29 14.9 <10 ND 339.2 ND ND ND 30 <10 <10 ND 469.4 ND ND ND 31 <10 <10 ND 181.4 ND ND ND 32 <10 <10 ND 606.8 ND ND ND 33 <10 <10 ND 119.9 ND ND ND 34 <10 <10 ND 73.8 ND ND ND 35 <10 15.0 ND 181.7 ND ND ND 36 <10 <10 ND 171.9 ND ND ND 37 <10 <10 119.2 41.3 ND ND ND 38 <10 <10 ND 69.3 ND ND ND 39 <10 <10 ND 268.5 ND ND ND 40 <10 <10 103.7 ND ND ND ND 41 <10 <10 ND <10 ND ND ND 42 <10 <10 ND 86.9 ND ND ND 43 <10 <10 ND <10 17.3 304.9 16 44 <10 <10 ND <10 10.0 124.0 11 45 <10 <10 ND 47.9 ND ND ND 46 <10 <10 ND 112.4 12.63 226.4 17.9 47 <10 <10 ND <10 13.8 127.8 9 48 <10 <10 ND 100.0 ND ND ND 49 <10 <10 ND 47.5 13.3 130.3 11 50 <10 ND ND ND 10.6 129.9 11 51 <10 ND ND ND <10 99.4 26 52 <10 <10 ND 518.7 ND ND ND 53 <10 <10 ND 43.2 10.6 164.5 14 54 <10 <10 ND 58.9 ND ND ND 55 <10 13.0 614.0 ND ND ND ND 56 <10 ND ND ND <10 49.3 6.4 57 <10 ND ND ND 16.9 241.6 14 58 <10 ND ND ND 36.1 333.0 9 59 <10 ND ND ND <10 36.6 15 60 <10 ND ND ND 11.6 264.8 23 61 <10 ND ND ND 18.1 253.1 14 62 ND ND ND ND 10.4 65.5 6 63 ND ND ND ND 18.1 169.9 9 64 ND ND ND ND 5.7 99.3 17 65 ND ND ND ND 4.7 69.2 14 66 ND ND ND ND 7.0 97.6 17 67 38.2 ND ND ND ND ND ND 68 11.5 ND ND ND ND ND ND .

[0346] Table 4. IC50 of the compounds for comparison 50 result. serial number <![CDATA[NanoBRETIC 50 (nM)]]> <![CDATA[TTK IC 50 (nM)]]> <![CDATA[COLO205 CTGIC 50 (nM)]]> <![CDATA[RPMI-8226MTS IC 50 (nM)]]> <![CDATA[A375 CTGIC 50 (nM)]]> <![CDATA[A375 CTG IC 50 Serum transfer (nM) <![CDATA[A375 CTG IC 50 Serum transfer fold (nM) 1 >1,000 82.4 >10,000 ND ND ND ND 2 >1,000 >5,000 >1,000 >3,000 ND ND ND 3 >1,000 289.5 >10,000 ND ND ND ND 4 <10 <10 206 728.8 167.2 >3,000 >17 5 >1,000 1,031 >10,000 ND ND ND ND 6 >1000 >5,000 ND >10,000 ND ND ND 7 >1,000 158.9 ND >10,000 ND ND ND 8 >1,000 <10 ND >10,000 ND ND ND 9 >1,000 54.9 ND >10,000 ND ND ND 10 460 <10 ND >10,000 ND ND ND 11 >1,000 <10 ND 739.4 ND ND ND 12 85.5 ND ND ND 746.8 >3000 >4 13 <10.0 ND ND ND ND ND ND 。

[0347] CYP inhibition assay The ability of selected compounds (including comparative compounds) to inhibit cytochrome P450 (CYP) isoforms was tested in vitro. Experiments were performed in plate form. Stock solutions of the selected compounds (0.005–5.0 mM) were prepared. Stock solutions of positive controls were prepared (100 μM α-naphthylflavonoid, 300 μM ticlopidine, 300 μM montelukast, 300 μM sulfadiazine, 100 μM (+)-N-3-benzylnivanol, 300 μM quinidine, and 300 μM ketoconazole). Human liver microsomes (HLMs) were prepared by dilution to 0.127 mg / mL in 100 mM potassium phosphate buffer.

[0348] Substrate stock solutions were prepared for various CYP isoforms. 75 μM phenacetin was prepared for CYP1A2. 80 μM bupropion was prepared for CYP2B6. 2 μM amodiaquine was prepared for CYP2C8. 10 μM diclofenac was prepared for CYP2C9. 20 μM S-mphentyxine was prepared for CYP2C19. 10 μM dextromethorphan was prepared for CYP2D6. 2 μM midazolam was prepared for CYP3A4-M. 40 μM testosterone was prepared for CYP3A4-T.

[0349] Add 20 μL of substrate stock solution to the corresponding well. Use 20 μL of 100 mM potassium phosphate buffer as a blank control. Add 2 μL of the selected compound (final concentration 0.05–50 μM) and positive control solution (final concentration 1–3 μM) to the corresponding well. Use 2 μL of solvent (DMSO or methanol) as an inhibitor-free well and add it to the blank well. Add 158 μL of HLM (final concentration in the reaction 0.1 mg / mL) to each well. Warm the plate at 37 °C for 10 min. Add 20 μL of 10 mM NADPH cofactor solution in 33 mM MgCl2 (final NADPH concentration in the reaction 1 mM) to each well. Mix the wells. Incubate the reaction mixture at 37 °C for 20 min (for CYP2C19 and CYP2D6), 3 min (for CYP3A4-M and CYP3A4-T), and 10 min (for the remaining CYP isoforms). The reaction was terminated using 400 μL of cold stop solution. The sample was centrifuged at 4000 rpm for 20 minutes to precipitate the protein. 200 μL of the supernatant was diluted with 100 μL of HPLC-grade water. The sample was shaken for 10 minutes. The sample was then analyzed by LC / MS / MS.

[0350] Use Microsoft Excel or SigmaPlot to plot the percentage of control compounds relative to the concentration of the test compound, and perform nonlinear regression analysis on the data. Determine the IC50 using a 3- or 4-parameter logistic equation. 50 Value. When the % inhibition is less than 50% at the highest concentration (50 μM), the IC50 value should be set. 50 The values ​​are reported as ">50 μM". Table 5 shows the IC50 values ​​for the variants CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4-M, and CYP3A4-T. 50 Results (in μM). In Table 5, "comparison" is an abbreviation for comparison.

[0351] Table 5. IC50 values ​​for CYP inhibition assays of selected compounds 50 result. compound CYP1A2 CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP3A4-M CYP3A4-T Compare compound 1 >50 >50 11.3 13.8 6.77 41.4 13.8 6.80 Compare compound 13 41.3 46.3 20.5 14.5 5.36 14.6 14.0 2.38 Compound 1 >50 >50 >50 >50 >50 >50 >50 >50 Compound 37 >50 >50 >50 >50 >50 >50 >50 >50 Compound 40 >50 >50 >50 >50 >50 >50 >50 2.96 Compound 53 >50 >50 >50 >50 >50 >50 >50 >50 。

[0352] in conclusion In light of the foregoing, the following are some non-limiting observations. Compared to previously described Mps1 / TTK inhibitors (e.g., comparative compound 4), the synthetic compounds described herein have the above formula I, where R... 3 The position is not a hydrogen atom. Compared to the comparison compounds, R is replaced with various parts. 3Position can improve the efficiency of the synthesized compound. For the synthesized compound, position R... 1 and R 2 It is a hydrogen atom. In comparing compounds (specifically compounds 1, 2, 3, 6, and 7), position R... 1 Or R 2 It contains methyl or Cl, and its potency is less than that of synthetic compounds that have hydrogen atoms at these positions.

[0353] The activity of the synthetic and comparative compounds against Mps1 / TTK was evaluated using an antiproliferative assay. Data showed that the synthetic compound was active against Mps1 / TTK at concentrations of 15 nM or lower compared to the comparative compound. The assay data also demonstrated the antiproliferative potential of the compound in cancer cell lines.

[0354] References 1. Winey M, Goetsch L, Baum P, Byers B. 1991. MPSl and MPS2: Novelyeast genes defining distinct steps of spindle pole body duplication. J. ofCell Biol. 114:745-54 2. Lindberg RA, Fischer WH, Hunter T. 1993. Characterization of ahuman protein threonine kinase isolated by screening an expression library with antibodies to phosphotyrosine. Oncogene 8:351-9 3. Mills GB, Schmandt R, McGill M, Amendola A, Hill M, et al. 1992. Expression of TTK, a novel human protein kinase, is associated with cellproliferation. J. Biol. Chem. 267:16000-6 4. Fisk HA, Mattison C P, Winey M. 2003. Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression. Proceedings of the National Academy of Sciences of the United States of America 100:14875-80 5. Yang C H, Kasbek C, Majumder S, Mohd Yusof A, Fisk H A. 2010. Mps1 phosphorylation sites regulate the function of Centrin 2 in centriole assembly. Molecular Biology of the Cell 21:4361-72 6. Liu J, Cheng X, Zhang Y, Li S, Cui H, et al. 2013. Phosphorylation of Mps1 by BRAF V600E prevents Mps1 degradation and contributes to chromosome instability in melanoma. Oncogene 32:713-23 7. Kasbek C, Yang, C.-H., and Fisk, H. A. 2009. Mps1 as a link between centrosomes and genetic instability. Environmental and Molecular Mutagenesis 50:654-65 8. Kasbek C, Yang C H, Fisk H A. 2010. Atizyme Restrains Centrosome Amplification by Regulating the Accumulation of Mps1 at Centrosomes. Molecular Biology of the Cell 21:3879-89 9. Kasbek C, Yang C H, Yusof A M, Chapman H M, Winey M, Fisk H A. 2007. Preventing the degradation of mps1 at centrosomes is sufficient to cause centrosome reduplication in human cells. Mol Biol Cell 18:4457-69 10. Wei J H, Chou Y F, Ou Y H, Yeh Y H, Tyan S W, et al. 2005. TTK / hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68. Journal of Biological Chemistry 280:7748-57 11. Mills G B, Schmandt R, Mcgill M, Amendola A, Hill M, et al. 1992. Expression of Ttk, a Novel Human Protein Kinase, Is Associated with Cell-Proliferation. Journal of Biological Chemistry 267: 16000-6 12. Schmandt R, Hill M, Amendola A, Mills G B, Hogg D. 1994. Il-2-Induced Expression of Ttk, a Serine, Threonine, Tyrosine Kinase, Correlates with Cell-Cycle Progression. Journal of Immunology 152:96-105 13. Saal L H, Gruvberger-Saal S K, Persson C, Lövgren K, Jumppanen M, et al. 2008. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nature Genetics 40: 102-7 14. Lingle W L, Barrett S L, Negron V C, D'Assoro A B, Boeneman K, et al. 2002. Centrosome amplification drives chromosomal instability in breast tumor development. Proceedings of the National Academy of Sciences of the United States of America 99: 1978-83 15. Lingle W L, Salisbury J L. 1999. Altered centrosome structure is associated with abnormal mitoses in human breast tumors. Am J Pathol 155: 1941-51. 16. Lingle W L, Lutz W H, Ingle J N, Maihle N J, Salisbury J L. 1998. Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity. Proceedings of the National Academy of Sciences of the United States of America 95: 2950-5 17. Hewitt L, Tighe A, Santaguida S, White AM, Jones C D, et al. 2010. Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex. Journal of Cell Biology 190:25-34 18. Kwiatkowski N, Jelluma N, Filippakopoulos P, Soundararajan M, Manak M S, et al. 2010. Small-molecule kinase inhibitors provide insight into Mps1 cell cycle function. Nature Chemical Biology 6:359-68 19. Santaguida S, Tighe A, D'Alise A M, Taylor S S, Musacchio A. 2010. Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine. Journal of Cell Biology 190:73-87 20. Tardif K D, Rogers A, Cassiano J, Roth BL, Cimbora D M, et al. 2011. Characterization of the Cellular and Antitumor Effects of MPI-0479605, a Small-Molecule Inhibitor of the Mitotic Kinase Mps 1. Molecular Cancer Therapeutics 10:2267-75 21. Tannous BA, Kerami M, Van der Stoop PM, Kwiatkowski N, Wang J, et al. 2013. Effects of the selective MPSl inhibitor MPSl-IN-3 on glioblastomasensitivity to antimitotic drugs. Journal of the National Cancer Institute105:1322-31 Another exemplary implementation considered in this paper is as follows: Implementation Scheme 1. A composition comprising a compound of Formula I: (Formula I), Or its tautomers, pharmaceutically acceptable salts and / or solvates in R 1 It is H; R 2 It is H; R 3 Not H; R 4 Selected from -ZR 15 or -ZR 19 ,in Z is NH, N-methyl, or O; R 15 It is a 6-membered ring with the following structure ,in R 16 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(S)NR 20 R 21 -NR 23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R 21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR23 -S(O)2NR 20 R 21 -CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 18 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(O)NR 20 R 21 -C(S)NR 20 R 21 -NR 23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R 21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR 23 -S(O)2NR 20 R 21 -CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 19 Selected from linear C1-C 16 Alkyl, branched C1-C 16 Alkyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, cyclobutyl, and cyclopentyl; R 20 R 21 and R 23 Each is independently hydrogen or a C1-C6 alkyl group; and R 22 It is a C1-C6 alkyl group; R 5 Selected from C1-C4 alkyl groups, substituted or unsubstituted 4- to 7-membered heterocycles, sulfoxides, sulfonamides, and fused or bridged spirocyclic heterocycles, E3-ligase-binding moieties, and -NHR. 24 and -NR 24 R 31 , R 24 Selected from C1-C4 alkyl halides, -R25 -OR 26 -R 27 -C(O)NH-R 28 -R 29 NHC(O)-R 30 Substituted or unsubstituted 4-membered heterocycles and substituted or unsubstituted cyclobutanes, R 25 It is a C1-C4 alkyl group. R 26 It is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide. R 27 and R 28 Each is independently a C1-C4 alkyl group. R 29 and R 30 Each is independently a C1-C4 alkyl group, and R 31 It is a C1-C4 alkyl or a C1-C4 alkyl halide; R 6 It is hydrogen, methyl, -CN, -S-methyl or -XR 8 Where X is O, S or SO2 and R 8 It is a C1-C3 alkyl or a C1-C3 haloalkyl; R 7 It is H, CN, OCH3, or F; Y is CH, N, CF, or C-CH3; and Indicates a single bond or a double bond.

[0355] Implementation Scheme 2. The composition of Implementation Scheme 1, wherein R 5 It is caused by one or two oxygen atoms and / or R 17 The replaced 5- to 7-membered heterocycles, Where R 17 Independently selected from -OR 10 -NR 10 C(O)R 12 -C(O)OR 10 -NR 10 R 11 -C(O)NR 10 R 11 -C(S)NR 10 R 11 -NR 13 C(O)NR 10 R 11 -NR 13 C(S)NR 10 R 11 -OC(O)NR10 R 11 -S(O)2NR 10 R 11 -OS(O)2NR 10 R 11 -NR 13 -S(O)NR 10 R 11 CN, halogens, NO and -S(O)-R 12 , Where R 10 R 11 and R 13 Each is independently hydrogen or a C1-C6 alkyl group; and Where R 12 It is independently a C1-C6 alkyl group.

[0356] Implementation Scheme 3. The composition of Implementation Scheme 1, wherein R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidinone, oxazolidinone, morpholine, thiomorpholine dioxide, tetrahydrothiophene dioxide, thiacyclohexane dioxide, thiazolidinone, thiadiazolone, sulfoxide, or sulfonamide.

[0357] Implementation Scheme 4. A composition of any one of Implementation Schemes 1-3, wherein: R 3 It includes C1-C4 alkyl, C3-C4 cycloalkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-butyl, C(O)O-propyl, -C(O)O-isopropyl, -C(O)O-butyl, -CH2OH, -C(O)NH-methyl, -C(O)O-cycloalkyl, -C(O)OH, -CN, alkyl nitrile, imidazole, pyrazole, triazole, tetrazolium, oxazole, isoxazole, thiazole, -C(O)R 9 or -C(O)NHR 9 ;and R 9 It is H or C1-C4 alkyl.

[0358] Implementation Scheme 5. The composition of Implementation Scheme 4, wherein R 3 It is C1-C4 alkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-butyl, -C(O)O-isopropyl, -C(O)O-butyl, imidazole, pyrazole, triazole, tetrazolium, oxazole, isoxazole, thiazole, or C(O)NHR 9 ;and R 9 It is H or C1-C4 alkyl.

[0359] Implementation Scheme 6. The composition of Implementation Scheme 1, wherein R 3 It is C1-C4 alkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-butyl, -C(O)O-isopropyl, imidazole, pyrazole, triazole, tetrazolium, oxazole, isoxazole, thiazole, or C(O)NHR 9 ; R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidineone, morpholine, thiomorpholine dioxide, tetrahydrothiophene dioxide, thiacyclohexane dioxide, thiazolidinyl ether, thiadiazolyl ether, sulfoxide, or sulfonamide; and R 9 It is H or C1-C4 alkyl.

[0360] Implementation Scheme 7. The composition of Implementation Scheme 6, wherein R 3 It is pyrazole or triazole; and R 5 It is morpholine or thiomorpholine dioxide.

[0361] Implementation Scheme 8. A composition of any one of Implementation Schemes 1-7, wherein said compound has Formula II: (Formula II).

[0362] Implementation Scheme 9. The composition of Implementation Scheme 8, wherein R 3 It is imidazole, pyrazole, triazole, tetraazole, oxazole, isoxazole, or thiazole.

[0363] Implementation Scheme 10. The composition of Implementation Scheme 8, wherein R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidinone, morpholine, thiomorpholine dioxide, or thiacyclohexane dioxide.

[0364] Implementation Scheme 11. The composition of Implementation Scheme 8, wherein R 3 It is imidazole, pyrazole, triazole, tetraazole, oxazole, isoxazole, or thiazole; and R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidinone, morpholine, thiomorpholine dioxide, or thiacyclohexane dioxide.

[0365] Implementation Scheme 12. The composition of Implementation Scheme 11, wherein R 3 It is pyrazole or triazole; and R 5It is morpholine or thiomorpholine dioxide.

[0366] Implementation Scheme 13. A composition of any one of Implementation Schemes 1-12, wherein said compound has Formula III: (Formula III).

[0367] Implementation Scheme 14. The composition of Implementation Scheme 13, wherein R 3 It is imidazole, pyrazole, triazole, tetraazole, oxazole, isoxazole, or thiazole.

[0368] Implementation Scheme 15. The composition of Implementation Scheme 13, wherein R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidinone, morpholine, thiomorpholine dioxide, or thiacyclohexane dioxide.

[0369] Implementation Scheme 16. The composition of Implementation Scheme 13, wherein R 3 It is imidazole, pyrazole, triazole, tetraazole, oxazole, isoxazole, or thiazole; and R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidinone, morpholine, thiomorpholine dioxide, or thiacyclohexane dioxide.

[0370] Implementation Scheme 17. The composition of Implementation Scheme 1, wherein R 5 It is a C1-C4 alkyl group.

[0371] Implementation Scheme 18. The composition of Implementation Scheme 1, wherein R 5 It's imidazole.

[0372] Implementation Scheme 19. The composition of Implementation Scheme 1, wherein R 5 It is pyrazole.

[0373] Implementation Scheme 20. The composition of Implementation Scheme 1, wherein R 5 It's triazole.

[0374] Implementation Scheme 21. The composition of Implementation Scheme 1, wherein R 5 It is tetrazolium.

[0375] Implementation Scheme 22. The composition of Implementation Scheme 1, wherein R 5 It is a pyrazolidine ketone.

[0376] Implementation Scheme 23. The composition of Implementation Scheme 1, wherein R 5 It is an oxazolidinone.

[0377] Implementation Scheme 24. The composition of Implementation Scheme 1, wherein R 5 It is morpholine.

[0378] Implementation Scheme 25. The composition of Implementation Scheme 1, wherein R 5 It is thiomorpholine dioxide.

[0379] Implementation Scheme 26. The composition of Implementation Scheme 1, wherein R 5 It is tetrahydrothiophene dioxide.

[0380] Implementation Scheme 27. The composition of Implementation Scheme 1, wherein R 5 It is a dioxide of thiocyclohexane.

[0381] Implementation Scheme 28. The composition of Implementation Scheme 1, wherein R 5 It is thiazolidinedione.

[0382] Implementation Scheme 29. The composition of Implementation Scheme 1, wherein R 5 It is thiadiazole.

[0383] Implementation Scheme 30. The composition of Implementation Scheme 1, wherein R 5 It is a 4- to 7-membered heterocyclic ring, either substituted or unsubstituted.

[0384] Implementation Scheme 31. The composition of Implementation Scheme 30, wherein R 5 It has the following structure: (Formula IV).

[0385] Implementation Scheme 32. The composition of Implementation Scheme 29, wherein R 5 It has the following structure: (Formula V).

[0386] Implementation Scheme 33. The composition of Implementation Scheme 30, wherein R 5 It has the following structure: (Form VI).

[0387] Implementation Scheme 34. The composition of Implementation Scheme 30, wherein R 5 It has the following structure: (Form VII).

[0388] Implementation Scheme 35. The composition of Implementation Scheme 30, wherein R 5 It has the following structure: (Formula VIII).

[0389] Implementation Scheme 36. The composition of Implementation Scheme 30, wherein R 5 It has the following structure: (Formula IX).

[0390] Implementation Scheme 37. The composition of Implementation Scheme 30, wherein R 5 It has the following structure: (Formula X).

[0391] Implementation Scheme 38. The composition of Implementation Scheme 30, wherein R 5 It has the following structure: (Formula XI).

[0392] Implementation Scheme 39. The composition of Implementation Scheme 30, wherein R 5 It has the following structure: (Formula XII).

[0393] Implementation Scheme 40. The composition of Implementation Scheme 30, wherein R 5 It has the following structure: (Formula XIII).

[0394] Implementation Scheme 41. The composition of Implementation Scheme 1, wherein R 5 It is sulfoxide imine.

[0395] Implementation Scheme 42. The composition of Implementation Scheme 1, wherein R 5 It is sulfonamide.

[0396] Implementation Scheme 43. The composition of Implementation Scheme 1, wherein R 5It is a fused or bridged helical heterocyclic ring.

[0397] Implementation Scheme 44. The composition of Implementation Scheme 1, wherein R 5 Yes - NHR 24 or -NR 24 R 31 , R 24 Selected from C1-C4 alkyl halides, -R 25 -OR 26 -R 27 -C(O)NH-R 28 -R 29 NHC(O)-R 30 Substituted or unsubstituted 4-membered heterocycles and substituted or unsubstituted cyclobutanes, R 25 It is a C1-C4 alkyl group. R 26 It is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide. R 27 and R 28 Each is independently a C1-C4 alkyl group. R 29 and R 30 Each is independently a C1-C4 alkyl group, and R 31 It is a C1-C4 alkyl or a C1-C4 alkyl halide.

[0398] Implementation Scheme 45. The composition of Implementation Scheme 43, wherein R 24 It is a substituted or unsubstituted 4-membered heterocycle.

[0399] Implementation Scheme 46. The composition of Implementation Scheme 1, wherein R 5 It is the E3-ligase binding site.

[0400] Implementation Scheme 47. The composition of Implementation Scheme 45, wherein The E3-ligase-binding moiety contains a linker portion that is covalently bound to the terminal portion: , Wherein L includes the connector portion and T includes the end portion.

[0401] Implementation Scheme 48. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is a C1-C4 alkyl group.

[0402] Implementation Scheme 49. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is a C3-C4 cycloalkyl group.

[0403] Implementation Scheme 50. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is -C(O)O-methyl.

[0404] Implementation Scheme 51. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is -C(O)O-ethyl.

[0405] Implementation Scheme 52. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is -C(O)O-propyl.

[0406] Implementation Scheme 53. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is -C(O)O-isopropyl.

[0407] Implementation Scheme 54. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is -C(O)O-butyl.

[0408] Implementation Scheme 55. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is -CH2OH.

[0409] Implementation Scheme 56. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is -C(O)N-methyl.

[0410] Implementation Scheme 57. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is -C(O)O-cycloalkyl.

[0411] Implementation Scheme 58. The composition of Implementation Scheme 57, wherein R 3 It is -C(O)O-cyclopropyl, -C(O)O-cyclobutyl, -C(O)O-cyclopentyl or -C(O)O-cyclohexyl.

[0412] Implementation Scheme 59. A composition of any one of Implementation Schemes 17-47, wherein R3 It is -C(O)OH.

[0413] Implementation Scheme 60. A composition of any one of Implementation Schemes 17-47, wherein R 3 Yes - CN.

[0414] Implementation Scheme 61. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is an alkyl nitrile.

[0415] Implementation Scheme 62. A composition of any one of Implementation Schemes 17-47, wherein R 3 It's imidazole.

[0416] Implementation Scheme 63. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is pyrazole.

[0417] Implementation Scheme 64. A composition of any one of Implementation Schemes 17-47, wherein R 3 It's triazole.

[0418] Implementation Scheme 65. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is tetrazolium.

[0419] Implementation Scheme 66. A composition of any one of Implementation Schemes 17-47, wherein R 3 It's oxazole.

[0420] Implementation Scheme 67. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is isoxazole.

[0421] Implementation Scheme 68. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is thiazole.

[0422] Implementation Scheme 69. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is -C(O)R 9 and R 9 It is H or C1-C4 alkyl.

[0423] Implementation Scheme 70. A composition of any one of Implementation Schemes 17-47, wherein R 3 It is C(O)NHR 9 and R 9 It is H or C1-C4 alkyl.

[0424] Implementation Scheme 71. A pharmaceutical composition comprising... Compositions of any one of embodiments 1-70; and Pharmaceutically acceptable carrier.

[0425] Implementation Scheme 72. A method for treating a disease in a patient who has this need, wherein the method comprises: Administering a therapeutically effective amount of the composition of any one of embodiments 1-70 to the patient; The disease mentioned is cancer.

[0426] Implementation Scheme 73. The method of Implementation Scheme 72, wherein the disease is characterized by a biomarker sensitive to Mps1 / TTK inhibition.

[0427] Implementation Scheme 74. A method for treating patients requiring a protein kinase Mps1 / TTK inhibitor, wherein the method comprises: Determine the levels of Mps1 / TTK protein and / or Mps1 / TTK mRNA in the patient's cells, and If the presence of Mps1 / TTK protein and / or Mps1 / TTK mRNA is detected, a therapeutically effective amount of any one of the compositions of embodiments 1-70 is administered to the patient. The patient in question is a cancer patient.

[0428] Implementation Scheme 75. The method of Implementation Scheme 74, wherein the patient is a patient with brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, stomach or gastric cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, lymphoma, thyroid cancer, mesothelioma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, or endometrial cancer.

[0429] All patent documents mentioned herein are incorporated herein by reference in their entirety. Various embodiments of the invention have been described to achieve its various objectives. It should be understood that these embodiments are merely examples of the principles of the invention. Many modifications and adjustments will be readily apparent to those skilled in the art without departing from the spirit and scope of the invention.

Claims

1. A composition comprising a compound of formula I: (Equation I), Or its tautomers, pharmaceutically acceptable salts and / or solvates in R 1 It is H; R 2 It is H; R 3 Not H; R 4 Selected from -ZR 15 or -ZR 19 ,in Z is NH, N-methyl, or O; R 15 It is a 6-membered ring with the following structure ,in R 16 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(S)NR 20 R 21 -NR 23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R 21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR 23 -S(O)2NR 20 R 21 -CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 18 Selected from hydrogen, halogens, -OR 20 -C(O)-R 20 -C(O)OR 20 -NR 20 R 21 -C(O)NR 20 R 21 -C(S)NR 20 R 21 -NR 23 C(O)NR 20 R 21 -NR 23 C(S)NR 20 R 21 -OC(O)NR 20 R 21 -S(O)2NR 20 R 21 -OS(O)2NR 20 R 21 -NR 23 -S(O)2NR 20 R 21 -CN, -NO2, C1-C6 alkyl groups and -S(O)2-R 22 ; R 19 Selected from linear C1-C 16 Alkyl, branched C1-C 16 Alkyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, sec-pentyl, tert-pentyl, neopentyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, cyclobutyl, and cyclopentyl; R 20 R 21 and R 23 Each is independently hydrogen or a C1-C6 alkyl group; and R 22 It is a C1-C6 alkyl group; R 5 Selected from C1-C4 alkyl groups, substituted or unsubstituted 4- to 7-membered heterocycles, sulfoxides, sulfonamides, and fused or bridged spirocyclic heterocycles, E3-ligase-binding moieties, and -NHR. 24 and -NR 24 R 31 , R 24 Selected from C1-C4 alkyl halides, -R 25 -OR 26 -R 27 -C(O)NH-R 28 -R 29 NHC(O)-R 30 Substituted or unsubstituted 4-membered heterocycles and substituted or unsubstituted cyclobutanes, R 25 It is a C1-C4 alkyl group. R 26 It is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide. R 27 and R 28 Each is independently a C1-C4 alkyl group. R 29 and R 30 Each is independently a C1-C4 alkyl group, and R 31 It is a C1-C4 alkyl or a C1-C4 alkyl halide; R 6 It is hydrogen, methyl, -CN, -S-methyl or -XR 8 Where X is O, S or SO2 and R 8 It is a C1-C3 alkyl or a C1-C3 haloalkyl; R 7 It is H, CN, OCH3, or F; Y is CH, N, CF, or C-CH3; and Indicates a single bond or a double bond.

2. The composition according to claim 1, wherein R 5 It is caused by one or two oxygen atoms and / or R 17 The replaced 5- to 7-membered heterocycles, Where R 17 Independently selected from -OR 10 -NR 10 C(O)R 12 -C(O)OR 10 -NR 10 R 11 -C(O)NR 10 R 11 -C(S)NR 10 R 11 -NR 13 C(O)NR 10 R 11 -NR 13 C(S)NR 10 R 11 -OC(O)NR 10 R 11 -S(O)2NR 10 R 11 -OS(O)2NR 10 R 11 -NR 13 -S(O)NR 10 R 11 CN, halogens, NO and -S(O)-R 12 , Where R 10 R 11 and R 13 Each is independently hydrogen or a C1-C6 alkyl group; and Where R 12 It is independently a C1-C6 alkyl group.

3. The composition according to claim 1, wherein R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidinone, oxazolidinone, morpholine, thiomorpholine dioxide, tetrahydrothiophene dioxide, thiacyclohexane dioxide, thiazolidinone, thiadiazolone, sulfoxide, or sulfonamide.

4. The composition according to claim 1, wherein: R 3 It includes C1-C4 alkyl, C3-C4 cycloalkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-isopropyl, -C(O)O-butyl, -CH2OH, -C(O)NH-methyl, -C(O)O-cycloalkyl, -C(O)OH, -CN, alkyl nitrile, imidazole, pyrazole, triazole, tetrazolium, oxazole, isoxazole, thiazole, -C(O)R 9 or -C(O)NHR 9 ;and R 9 It is H or C1-C4 alkyl.

5. The composition according to claim 4, wherein... R 3 It is a C1-C4 alkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-isopropyl, -C(O)O-butyl, imidazole, pyrazole, triazole, tetrazolium, oxazole, isoxazole, thiazole, or C(O)NHR 9 ;and R 9 It is H or C1-C4 alkyl.

6. The composition according to claim 1, wherein... R 3 It is a C1-C4 alkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-isopropyl, imidazole, pyrazole, triazole, tetrazolium, oxazole, isoxazole, thiazole, or C(O)NHR 9 ; R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidineone, morpholine, thiomorpholine dioxide, tetrahydrothiophene dioxide, thiacyclohexane dioxide, thiazolidinyl ether, thiadiazolyl ether, sulfoxide, or sulfonamide; and R 9 It is H or C1-C4 alkyl.

7. The composition according to claim 6, wherein R 3 It is pyrazole or triazole; and R 5 It is morpholine or thiomorpholine dioxide.

8. The composition according to claim 1, wherein the compound has formula II: (Formula II).

9. The composition according to claim 8, wherein... R 3 It is imidazole, pyrazole, triazole, tetraazole, oxazole, isoxazole, or thiazole.

10. The composition according to claim 8, wherein R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidinone, morpholine, thiomorpholine dioxide, or thiacyclohexane dioxide.

11. The composition according to claim 8, wherein R 3 It is imidazole, pyrazole, triazole, tetraazole, oxazole, isoxazole, or thiazole; and R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidinone, morpholine, thiomorpholine dioxide, or thiacyclohexane dioxide.

12. The composition according to claim 11, wherein R 3 It is pyrazole or triazole; and R 5 It is morpholine or thiomorpholine dioxide.

13. The composition according to claim 1, wherein the compound is of formula III: (Formula III).

14. The composition according to claim 13, wherein R 3 It is imidazole, pyrazole, triazole, tetraazole, oxazole, isoxazole, or thiazole.

15. The composition according to claim 13, wherein R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidinone, morpholine, thiomorpholine dioxide, or thiacyclohexane dioxide.

16. The composition according to claim 13, wherein R 3 It is imidazole, pyrazole, triazole, tetraazole, oxazole, isoxazole, or thiazole; and R 5 It is imidazole, pyrazole, triazole, tetraazole, pyrazolidineone, oxazolidinone, morpholine, thiomorpholine dioxide, or thiacyclohexane dioxide.

17. A pharmaceutical composition comprising The composition according to claim 1; and Pharmaceutically acceptable carrier.

18. A method for treating a disease in a patient who has this need, wherein the method comprises: Administer a therapeutically effective amount of the composition according to claim 1 to the patient; The disease mentioned is cancer.

19. The method of claim 18, wherein the disease is characterized by a biomarker sensitive to Mps1 / TTK inhibition.

20. A method of treating a patient requiring a protein kinase Mps1 / TTK inhibitor, wherein the method comprises: Determine the levels of Mps1 / TTK protein and / or Mps1 / TTK mRNA in the patient's cells, and If the presence of Mps1 / TTK protein and / or Mps1 / TTK mRNA is detected, a therapeutically effective amount of the composition according to claim 1 is administered to the patient; The patient in question is a cancer patient.

21. The method of claim 20, wherein the patient is a patient with brain cancer, glioblastoma multiforme, head and neck cancer, colorectal cancer, stomach or gastric cancer, pancreatic cancer, melanoma, bladder cancer, kidney cancer, renal cell carcinoma, breast cancer, ovarian cancer, lymphoma, thyroid cancer, mesothelioma, sarcoma, lung cancer, non-small cell lung cancer, small cell lung cancer, or endometrial cancer.

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