TTK kinase inhibitors and methods of use

Abstract

Disclosed herein are novel compounds that are Mpsl / TTK inhibitors. Also disclosed herein are compositions comprising the compounds and methods of using the compounds in treating various diseases in a patient. In some embodiments, some such compounds, compositions, and their uses may be useful for the treatment of cancer. In some implementations, the cancer is brain cancer, glioblastoma multiforme, head and neck cancers, 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.

Description

TTK KINASE INHIBITORS AND METHODS OF USECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Patent Application No. 63 / 621,789, filed January 17, 2024, and to U.S. Provisional Patent Application No. 63 / 664,986, filed June 27, 2024, each of which are hereby incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under grant / contract number P30CA016058 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD

[0003] This disclosure is generally in the area of anti -cancer treatments, and more specifically, in the area of Mpsl / TTK kinase inhibitors for use in the treatment of cancer.BACKGROUND

[0004] Cancer is a major public health burden that is the second leading cause of death in the United States, leading to 10 million deaths in 2020. The treatment of cancer is varied. Current cancer treatments include surgery, radiation, and chemotherapy, alone or in combination.

[0005] Current treatments for cancer have numerous shortcomings, including limitations for application and significant side effects. For example, generally, surgery, which typically involves removing all or part of a tumor from the body, is most effective for treating early stages of cancer, and its application is limited to areas where tumors are accessible. Moreover, regarding radiation, radiation is typically applied to a defined area of the patient’s body that contains the cancerous tissue in order 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 use radiation on only cancerous tissue without exposing “normal” or non- cancerous tissues. Additionally, chemotherapy, which involves the use of drugs or therapeuticsto slow or stop the growth of cancer cells, often has severe side effects that impact the quality of life of patients, such as vomiting, weight loss, hair loss, and low white blood cell count. These severe side effects can cause patients to discontinue treatment. Further, drug resistance to chemotherapies and metastasis may also occur. Thus, with the numerous shortcomings of current treatments for cancer, there is a need for improved anti-cancer therapies.SUMMARY

[0006] Disclosed herein are Mpsl / TTK kinase inhibitory compounds, compositions, and uses thereof. In some embodiments, some such compounds, compositions, and their uses may be useful for the treatment of cancer.

[0007] In one aspect, compositions comprising compounds are provided. In some embodiments, provided herein is a composition comprising a compound of Formula I:or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, whereinR1is H;R2is H;R3is not H;R4is selected from the group consisting of -ZR15or -ZR19, whereinZ is NH, N-methyl, or O;R15is a six-membered ring having the following structure, whereinR16is selected from the group consisting of hydrogen, halo, -O-R20, -C(O)-R20, -C(O)O- R20, -NR20R21, -C(S)NR20R21, -NR23C(O)NR20R21, -NR23C(S)NR20R21, -O-C(O)NR20R21, -S(O)2NR20R21, -O-S(O)2NR20R21, -NR23-S(O)2NR20R21, -CN, -NO2, C1-C6 alkyl, and - S(O)2-R22;R18is selected from the group consisting of hydrogen, halo, -O-R20, -C(O)-R20, -C(O)O- R20, -NR20R21, -C(O)NR20R21, -C(S)NR20R21, -NR23C(O)NR20R21, -NR23C(S)NR20R21, - O-C(O)NR20R21, -S(O)2NR20R21, -O-S(O)2NR20R21, -NR23-S(O)2NR20R21, -CN, -NO2, C1-C6 alkyl, and -S(O)2-R22;R19is selected from the group consisting of linear C1-C16 alkyl, branched C1-C16 alkyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, iso-hexyl, sec-hexyl, tert-hexyl, neo-hexyl, cyclo-butyl, and cyclo-pentyl;R20, R21, and R23are each independently hydrogen or Ci-Ce alkyl; andR22is Ci-Ce alkyl;R5is selected from the group consisting of C1-C4 alkyl, a substituted or unsubstituted 4- to 7- membered heterocycle, a sulfoximine, a sulfonamide, and a spirocyclic heterocycle that is fused or bridged, an E3-ligase binding moiety, -NHR24, and -NR24R31,R24is selected from the group consisting of C1-C4 alkyl halide, -R25-O-R26, -R27- C(O)NH-R28, -R29NHC(O)-R30, a substituted or unsubstituted 4-membered heterocycle, and a substituted or unsubstituted cyclobutane,R25is C1-C4 alkyl,R26is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide,R27and R28are each independently C1-C4 alkyl,R29and R30are each independently C1-C4 alkyl, andR31is C1-C4 alkyl or C1-C4 alkyl halide;R6is hydrogen, methyl, -CN, -S-methyl, or -XR8, wherein X is O, S, or SO2and R8is C1-C3 alkyl or C1-C3 haloalkyl;R7is H, CN, OCH3, or F;Y is CH, N, CF, or C-CH3; and- represents a single or double bond.

[0008] In some instances, R3is C1-C4 alkyl, C3-C4 cycloalkyl, -C(O)O-methyl, -C(O)O- ethyl, -C(O)O-propyl, -C(O)O-iso-propyl, -C(O)O-butyl, -CH2OH, -C(O)N-methyl, -C(O)O- cycloalkyl, -C(O)OH, -CN, an alkyl nitrile, an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, a thiazole, -C(O)R9, or -C(O)NHR9; wherein R9is H or C1-C4 alkyl. In some cases, -C(O)O-cycloalky comprises -C(O)O-cyclopropyl, -C(O)O-cyclobutyl, -C(O)O- cyclopentyl, or -C(O)O-cyclohexyl.

[0009] In some implementations of compositions described herein, R5is a 5- to 7-membered heterocycle substituted with one or two oxo and / or R17, wherein R17is independently selected from the group consisting of-O-R10, -wherein R10, R11, and R13are each independently hydrogen or Ci-Ce alkyl; and wherein R12is independently Ci-Ce alkyl. In other instances, R5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, a tetrahydrothiophene dioxide, a thiacyclohexane dioxide, a thiazolidine, a thiadiazolidine, a sulfoximine, or a sulfonamide.

[0010] In other instances, provided herein are compounds of other formulas. For example, provided herein is a compound of Formula II:or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, wherein R3, R5, R6, and R7are defined as stated above.

[0011] Moreover, in some embodiments, provided herein are compounds of Formula III:(Formula III), or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, wherein wherein R3, R5, and R7are defined as stated above.

[0012] Additionally, in another aspect, provided are pharmaceutical compositions comprising a composition or compound described herein and a carrier, optionally a pharmaceutically acceptable carrier. Such a composition may comprise any compound and / or composition described herein.

[0013] Further, in another aspect, provided herein is a method of treating a disease in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a composition described herein, and wherein the disease is cancer. Such a composition may comprise any compound and / or composition described herein.

[0014] Moreover, in yet another aspect, provided is a method of treating a patient in need of an inhibitor of protein kinase Mpsl / TTK, wherein the method comprises determining the level of Mpsl / TTK protein and / or Mpsl / TTK mRNA in a cell of the patient, and administering a therapeutically effective amount of the composition described herein to the patient if the presence of Mpsl / TTK protein and / or Mpsl / TTK mRNA is detected. In some cases, the patient is a cancer patient. Such a composition may comprise any compound described herein.DETAILED DESCRIPTION

[0015] Embodiments described herein can be understood more readily by reference to the following detailed description and examples and their previous and following descriptions. Elements and methods described herein, however, are not limited to the specific embodiments presented in the detailed description and examples. It should be recognized that these embodiments are merely illustrative of the principles of the present invention. Numerous modifications and adaptations will be readily apparent to those of skill in the art without departing from the spirit and scope of the invention.

[0016] In addition, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range of “1.0 to 10.0” should be considered to include any and all subranges beginning with a minimum value of 1.0 or more and ending with a maximum value of 10.0 or less, e.g., 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 the range and the numbers defining ends of the range. For example, when the terms “integer from 1 to 20” is used, the integers included in the range are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., up to and including 20. All ranges disclosed herein are also to be considered to include the end points of the range, unless expressly stated otherwise. For example, a range of “between 5 and 10” should generally be considered to include the end points 5 and 10.

[0018] Further, when the phrase “up to” is used in connection with an amount or quantity, it is to be understood that the amount is at least a detectable amount or quantity. For example, a material present in an amount “up to” a specified amount can be present from a detectable amount and up to and including the specified amount.

[0019] Furthermore, the terms “substantially,” “approximately,” and “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount. The term “consists essentially of’ (and grammatical variants) shall be given its ordinary meaning and shall also mean that the composition or method referred to can contain additional components as long as the additional components do not materially alter the composition or method. The term “consists of’ (and grammatical variants) shall be given its ordinary meaning and shall also mean that the composition or method referred to is closed to additional components. The term “comprising”(and grammatical variants) shall be given its ordinary meaning and shall also mean that the composition or method referred to is open to contain additional components.

[0020] It is also to be understood that the article “a” or “an” refers to “at least one,” unless the context of a particular use requires otherwise.

[0021] Also as used herein, “and / or” refers broadly to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0022] Compounds, pharmaceutical compositions including the compounds, and methods of preparation and uses thereof are disclosed. 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 belongs. The terminology used in the description of the subject matter herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the subject matter. The present disclosure will be better understood with reference to the following definitions.Definitions

[0023] The term “effective amount,” as used herein, refers broadly to that amount of a recited compound effective to treat, prevent, or reduce the severity or progression of a disorder in a subject, such as a human subject. This includes improving the subject’s condition (e g., in one or more symptoms), delaying or reducing the progression of the disease and / or disorder, preventing or delaying the onset of the disorder, and / or changing clinical parameters, disease or illness, etc., as would be well known in the art.

[0024] For example, an effective amount can refer to the amount of a composition, compound, or agent that improves a condition in 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 the specification to describe any pharmaceutically acceptable form, such as an ester, which, upon administration to a patient, provides the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts includethose derived from alkali metals such as potassium and sodium and alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.

[0026] As used herein, the terms “treating,” “treatment,” and the like are used to mean obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and / or may be therapeutic in terms of a partial or complete cure for a disorder and / or adverse effect attributable to the disorder, or the relief or elimination of a symptom thereof. Thus, treatment includes preventing or protecting against the disease or disorder, that is, causing the clinical symptoms not to develop; and / or inhibiting the disease or disorder, that is, arresting or suppressing the development of clinical symptoms; and / or relieving the disease or disorder that is, causing the regression of clinical symptoms; and / or reducing the metastasis of the primary tumor or cancer.

[0027] The terms “Mpsl / TTK kinase inhibitor compound” or “Mpsl / TTK kinase inhibitor” refer broadly to species and / or molecules that inhibit the activity of Mpsl / TTK kinase.

[0028] The “patient” or “subject” treated as disclosed herein is, in some embodiments, a human patient, although it is to be understood that the principles of the presently disclosed subject matter indicate that the presently disclosed subject matter is effective with respect to all vertebrate species, including mammals, which are intended to be included in the terms “subject” and “patient.” Suitable subjects are generally mammalian subjects. The subject matter described herein finds use in research as well as veterinary and medical applications. The term “mammal” as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats or mice), monkeys, etc. Human subjects include neonates, infants, juveniles, adults and geriatric subjects. The subject “in need of’ the methods disclosed herein can be a subject that is experiencing a disease state and / or is anticipated to experience a disease state, and the methods and compositions of the invention are used for therapeutic and / or prophylactic treatment.

[0029] For the general chemical formulas provided herein, if no substituent is indicated, a person of ordinary skill in the art will appreciate that the substituent is hydrogen. A bond that is not connected to an atom but is shown indicates that the position of such substituent is variable. A jagged line, wavy line, or two wavy lines drawn through a bond or at the end of a bond indicates that some additional structure is bonded to that position. Moreover, if no stereochemistry is indicated for compounds having one or more chiral centers, all enantiomersand diasteromers are included. Similarly, for a recitation of aliphatic or alkyl groups, all structural isomers thereof also are included. Unless otherwise stated, groups shown as Ri through Rn and referred to herein as an alkyl group, in the general formulas provided herein are independently selected from alkyl or aliphatic groups, particularly alkyl having 20 or fewer carbon atoms, and even more typically lower alkyl having 10 or fewer atoms, such as methyl, ethyl, propyl, isopropyl, and butyl. The alkyl may be optionally substituted (e.g., substituted or not substituted, as disclosed elsewhere herein). The alkyl may be a substituted alkyl group, such as alkyl halide (e.g. — CX3 where X is a halide, and combinations thereof, either in the chain or bonded thereto,), alcohols (e.g. aliphatic or alkyl hydroxyl, particularly lower alkyl hydroxyl) or other similarly substituted moieties such as amino-, amino acid-, aryl-, alkyl aryl-, alkyl ester-, ether-, keto-, nitro-, sulfhydryl-, sulfonyl-, or sulfoxide-modified- alkyl groups.

[0030] The term “amino” and “amine” refer to nitrogen-containing groups such as NR?, NH3, NHR2, and NH2R, wherein R can be as described elsewhere herein. Thus, “amino” as used herein can refer to a primary amine, a secondary amine, or a tertiary amine. In some embodiments, one R of an amino group can be a diazeniumdiolate (e.g., NONO).

[0031] Whenever a group is described as being “optionally substituted,” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” (or “substituted or unsubstituted”) if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl (alkyl), heteroaryl(alkyl), heterocyclyl (alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, an amino, a mono-substituted amine group, a di-substituted amine group, a mono- substituted amine(alkyl), a di-substituted amine(alkyl), a diamino-group, a polyamino, a diether-group, and a polyether-group.

[0032] As used herein, “Cato Cb” or “Ca to Cb” in which “a” and “b” are integers refer to the number of carbon atoms in a group. The indicated group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “Ci to C4 alkyl” or “C1-C4 alkyl” or “Cl to C4alkyl” or “C1-C4 alkyl” group refers broadly to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CFhhCH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.

[0033] As used herein, the term “alkyl” refers broadly to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms.Whenever it appears herein, a numerical range such as “1 to 30” refers broadly to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may 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 the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. The “alkyl” group may also be a medium size alkyl having 1 to 12 carbon atoms. The “alkyl” group could also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted. By way of example only, “C1-C5 alkyl” indicates that there are one to five carbon atoms in the alkyl chain, e.g., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), etc. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl.

[0034] As used herein, the term “alkylene” refers broadly to a bivalent 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. An alkylene group may be represented by followed by the number of carbon atoms, followed by a For example, ethylene can be represented as:

[0035] The alkylene group may have 1 to 30 carbon atoms. Whenever it appears herein, a numerical range such as “1 to 30” refers broadly to each integer in the given range; e.g., “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 the present definition alsocovers the occurrence of the term “alkylene” where no numerical range is designated. The alkylene group may also be a medium size alkyl having 1 to 12 carbon atoms. The alkylene group could also be a lower alkyl having 1 to 6 carbon atoms. An alkylene group may be substituted or un substituted. For example, a lower alkylene group can be substituted by replacing one or more hydrogens of the lower alkylene group and / or by substituting both hydrogens on the same carbon with a C3-6 monocyclic cycloalkyl group (e.g.,

[0036] The term “alkenyl” used herein refers broadly to a monovalent straight or branched chain radical from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2-butenyl, and the like. An alkenyl group may be unsubstituted or substituted.

[0037] The term “alkynyl” used herein refers broadly to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl, and the like. An alkynyl group may be unsubstituted or substituted.

[0038] As used herein, “cycloalkyl” refers broadly to a completely saturated (no double or triple bonds) mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or spiro fashion. As used herein, the term “fused” refers broadly to two rings which have two atoms and one bond in common. As used herein, the term “bridged cycloalkyl” refers broadly to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers broadly to two rings which have one atom in common and the two rings are not linked by a bridge. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Examples of monocycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthal enyl, dodecahydro- IH-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclofl.1.1 ]pentyl, adamantanyl, and norbomanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0039] As used herein, “cycloalkenyl” refers broadly to a mono- or multi- cyclic (such as bicyclic) hydrocarbon ring system that contains one or more double bonds in at least one ring; although if there is more than one, the double bonds cannot form a fully delocalized pi -electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged, or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted.

[0040] As used herein, “aryl” refers broadly to a carbocyclic (all carbon) monocyclic or multicyclic (such as bicyclic) aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a Ce-Ci4 aryl group, a Ce-Cio aryl group, or a CT aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. As used herein, “heteroaryl” refers to a monocyclic or multicyclic (such as bicyclic) aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as 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, furazan, 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,benzotri azole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. A heteroaryl group may be substituted or unsubstituted.

[0041] As used herein, “heterocyclyl” or “heteroalicyclyl” refers broadly to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems 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 joined together in a fused, bridged, or spiro fashion. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged heterocyclyl” or “bridged heteroalicyclyl” refers to compounds wherein the heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “spiro” refers to two rings which have one atom in common and the two rings are not linked by a bridge. Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.Examples of such “heterocyclyl” or “heteroalicyclyl” groups include but are not limited to, 1,3- dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-di oxolane, 1,3 -di oxolane, 1,4-di oxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1 ,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro- 1,4-thiazine, 2H-l,2-oxazine, mal eimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine,morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepane, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and / or 3,4-methylenedioxyphenyl). Examples of spiro heterocyclyl 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.

[0042] As used herein, “aralkyl” and “aryl(alkyl)” refer broadly to an aryl group connected as a substituent via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3- phenylalkyl, and naphthyl alkyl.

[0043] As used herein, “cycloalkyl(alkyl)” refers broadly to an cycloalkyl group connected as a substituent via a lower alkylene group. The lower alkylene and cycloalkyl group of a cycloalkyl(alkyl) may be substituted or unsubstituted.

[0044] As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer broadly to a heteroaryl group connected as a substituent via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3 -thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and their benzo-fused analogs.

[0045] A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer broadly to a heterocyclic or a heteroalicyclic group connected as a substituent via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4- yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and l,3-thiazinan-4-yl(methyl).

[0046] As used herein, the term “hydroxy” refers broadly to a -OH group.

[0047] As used herein, “alkoxy” refers broadly to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl (alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methyl ethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. An alkoxy may be substituted or unsubstituted.

[0048] As used herein, “acyl” refers broadly to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) connected as substituents via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.

[0049] As used herein, a “cyano” group refers broadly to a “-CN” group.

[0050] The term “halogen atom” or “halogen” as used herein means any one of the radiostable atoms of column 7 of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, and iodine.

[0051] A “thiocarbonyl” group refers broadly to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted. An “O-carbamyl” group refers to a “-OC(=O)N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

[0052] An “N-carbamyl” group refers broadly to an “R0C(=0)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

[0053] An “O-thiocarbamyl” group refers broadly to a “-OC(=S)-N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.

[0054] An “N-thiocarbamyl” group refers broadly to an “ROC(=S)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.

[0055] A “C-amido” group refers broadly to a “-C(=0)N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

[0056] An “N-amido” group refers broadly to a “RC(=O)N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

[0057] An “S-sulfonamido” group refers broadly to a “-SO2N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.

[0058] An “N-sulfonamido” group refers broadly to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.

[0059] An “O-carboxy” group refers broadly to a “RC(=O)O-” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl (alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl (alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted.

[0060] The terms “ester” and “C-carboxy” refer broadly to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0061] A “nitro” group refers broadly to an “-NO2” group.

[0062] A “sulfenyl” group refers broadly to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted.

[0063] A “sulfinyl” group refers broadly to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0064] A “sulfonyl” group refers broadly to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0065] As used herein, “haloalkyl” refers broadly to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl, tri-haloalkyl, and polyhaloalkyl). Such groups include but are not limited to chloromethyl, fluoromethyl,difluoromethyl, trifluoromethyl, l-chloro-2-fluorom ethyl, 2-fluoroisobutyl, and pentafluoroethyl. A haloalkyl may be substituted or unsubstituted.

[0066] As used herein, “haloalkoxy” refers broadly to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and trihaloalkoxy). Such groups include but are not limited to chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l-chloro-2-fluorom ethoxy, and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0067] The terms “amino” and “unsubstituted amino” as used herein refer broadly to a -NH2 group.

[0068] A “mono-substituted amine” group refers broadly to a “-NHRA” group in which RA can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl (alkyl), as defined herein. The RA may be substituted or unsubstituted. A mono-substituted amine group can include, for example, a mono-alkylamine group, a mono-Ci-Ce alkylamine group, a monoarylamine group, a mono-Cs-Cio arylamine group, and the like. Examples of mono- substituted amine groups include but are not limited to -NH(methyl), -NH(phenyl), and the like.

[0069] A “di -substituted amine” group refers broadly to a “-NRARB” group in which RA andRD can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. RA and RB can independently be substituted or unsubstituted. A di-substituted amine group can include, for example, a di-alkylamine group, a di-Ci-Ce alkylamine group, a diarylamine group, a di-Ce-Cio arylamine group, and the like. Examples of di-substituted amine groups include but are not limited to -N(methyl)2, -N(phenyl)(methyl), -N(ethyl)(methyl) and the like.

[0070] A “mono-substituted amine(alkyl)” group refers broadly to a mono-substituted amine as provided herein connected as a substituent via a lower alkylene group. A mono-substituted amine(alkyl) may be substituted or unsubstituted. A mono-substituted amine(alkyl) group can include, for example, a mono-alkylamine(alkyl) group, a mono-Ci-Ce alkylamine(Ci-C6 alkyl) group, a mono-arylamine(alkyl group), a mono-C6-Cio arylamine(Ci-Ce alkyl) group and the like. Examples of mono- substituted amine(alkyl) groups include but are not limited to -CH2NH(methyl), -CH2NH(phenyl), -CH2CH2NH(methyl), -CH2CH2NH(phenyl), and the like.

[0071] A “di -substituted amine(alkyl)” group refers broadly to a di-substituted amine as provided herein connected as a substituent via a lower alkylene group. A di-substituted amine(alkyl) may be substituted or unsubstituted. A di-substituted amine(alkyl) group can include, for example, a dialkylamine(alkyl) group, a di-Ci-Cs alkylamine(Ci-Ce alkyl) group, a di-arylamine(alkyl) group, a di-Ce-Cio arylamine(Ci-Ce alkyl) group, and the like. Examples of di-substituted 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), and the like.

[0072] As used herein, the term “diamino-” denotes a “-N(RA)RB-N(RC)(RD)” group in which RA, RC, and RD can be independently a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein, and wherein RB connects the two “N” groups and can be (independently of RA, RC, and RD) a substituted or unsubstituted alkylene group. RA, RB, RC, and RD can independently further be substituted or unsubstituted.

[0073] As used herein, the term “polyamino” denotes a “-(N(RA)RB-)n-N(Rc)(RD)”. For illustration, the term polyamino can comprise -N(RA)alkyl-N(RA)alkyl-N(RA)alkyl-N(RA)alkyl- H. In some embodiments, the alkyl of the polyamino is as disclosed elsewhere herein. While this example has only 4 repeat units, the term “polyamino” may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeat units. RA, Rc, and RD can be independently a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein, and wherein RB connects the two “N” groups and can be (independently of RA, RC, and RD) a substituted or unsubstituted alkylene group. RA, RC, and RD can independently further be substituted or unsubstituted. As noted here, the polyamino comprises amine groups with intervening alkyl groups, where alkyl is as defined elsewhere herein.

[0074] As used herein, the term “diether-” denotes an “-ORBO-RA” group in which RA can be a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein, and wherein RB connects the two “O” groups and can be a substituted or unsubstituted alkylene group. RA can independently further be substituted or unsubstituted.

[0075] As used herein, the term “poly ether” denotes a repeating -(ORB-)nORA group. For illustration, the term polyether can comprise -Oalkyl-Oalkyl-Oalkyl-Oalkyl-ORA. In some embodiments, the alkyl of the poly ether is as disclosed elsewhere herein. While this example has only 4 repeat units, the term “polyether” may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeat units. RA can be a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. RB can be a substituted or unsubstituted alkylene group. RA can independently further be substituted or unsubstituted. As noted here, the polyether comprises ether groups with intervening alkyl groups, where alkyl is as defined elsewhere herein and can be optionally substituted.

[0076] Where the number of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms. As used herein, a radical indicates a species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term “radical” can be used interchangeably with the term “group.” The term “moiety” can also be used to refer to a part or functional group of a larger molecule or species.

[0077] The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be 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 covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like this application controls. Unless otherwise defined, all technical andscientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0078] Provided herein are Mpsl / TTK kinase inhibitory compounds useful for the treatment of cancer. The dual specificity protein kinase Mpsl (also known as TTK or Mpsl / TTK) is required for centrosome duplication and the spindle assembly checkpoint. The phosphotyrosine- picked threonine kinase / threonine and tyrosine kinase (PYT / TTK) is a dual specificity protein kinase. Mpsl / TTK regulates centrosome duplication and the spindle checkpoint. Its substrates include the centriolar protein Centrin 2, and its centrosomal levels are controlled by proteasome- mediated degradation. Preventing this degradation is sufficient to cause centrosome reduplication, and defects in this control are correlated with centrosome amplification and tumorigenesis. Further, Mpsl / TTK directly phosphorylates Chk2 in vitro. In addition, both mRNA and protein levels of Mpsl / TTK are readily detectable in all proliferating cells and tissues but markedly reduced or absent in resting cells and tissues with a low proliferative index. Mpsl / TTK regulates cell cycle progression, and alterations to Mpsl / TTK have been associated with cell transformation and chromosome instability in different tumor models. Also, reports suggest that silencing Mpsl / TTK, which has dual roles in checkpoint activation and chromosome alignment, can sensitize cancer cells to sublethal doses of paclitaxel, whereas non-tumorigenic cells cannot be sensitized. Other reports suggest that inhibition of Mpsl / TTK results in chromosome mis segregation and cytosolic micronuclei formation, consequently generating cytoplasmic dsDNA and / or dsRNA, which can act as sensors for immune response via the STING and MAVS signalling pathways, respectively. Additional reports have demonstrated that mutant BRAF V600E directly phosphorylates and stabilizes Mpsl / TTK, preventing its ubiquitination and degradation, suggesting BRAF V600E mutation may be a biomarker for cancers that are sensitive to treatment with Mpsl / TTK inhibitors.I. Compounds

[0079] In one aspect, compositions comprising compounds are provided. In some instances, provided herein is a composition comprising a compound of Formula I:(Formula I), or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, whereinR1is H;R2is H;R3is not H;R4is selected from the group consisting of -ZR1?or -ZR19, whereinZ is NH, N-methyl, or O;R15is a six-membered ring having the following structure, whereinR16is selected from the group consisting of hydrogen, halo, -O-R20, -C(O)-R20, -C(O)O- R20, -NR20R21, -C(S)NR20R21, -NR23C(O)NR20R21, -NR23C(S)NR20R21, -O-C(O)NR20R21, -S(O)2NR20R21, -O-S(O)2NR20R21, -NR23-S(O)2NR20R21, -CN, -NO2, C1-C6 alkyl, and - S(O)2-R22;R18is selected from the group consisting of hydrogen, halo, -O-R20, -C(O)-R20, -C(O)O- R20, -NR20R21, -C(O)NR20R21, -C(S)NR20R21, -NR23C(O)NR20R21, -NR23C(S)NR20R21, - O-C(O)NR20R21, -S(O)2NR20R21, -O-S(O)2NR20R21, -NR23-S(O)2NR20R21, -CN, -NO2, C1-C6 alkyl, and -S(O)2-R22;R19is selected from the group consisting of linear C1-C16 alkyl, branched C1-C16 alkyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, iso-hexyl, sec-hexyl, tert-hexyl, neo-hexyl, cyclo-butyl, and cyclo-pentyl;R2°, R21ancj j^23are each independently hydrogen or Ci-Ce alkyl; andR22is Ci-Ce alkyl;R3is selected from the group consisting of C1-C4 alkyl, a substituted or unsubstituted 4- to 7- membered heterocycle, a sulfoximine, a sulfonamide, and a spirocyclic heterocycle that is fused or bridged, an E3-ligase binding moiety, -NHR24, and -NR24R31,R24is selected from the group consisting of C1-C4 alkyl halide, -R25-O-R26, -R27- C(O)NH-R28, -R29NHC(O)-R30, a substituted or unsubstituted 4-membered heterocycle, and a substituted or unsubstituted cyclobutane,R23is C1-C4 alkyl,R26is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide,R27and R28are each independently C1-C4 alkyl,R29and R30are each independently C1-C4 alkyl, andR31is C1-C4 alkyl or C1-C4 alkyl halide;R6is hydrogen, methyl, -CN, -S-methyl, or -XR8, wherein X is O, S, or SO2 and R8is C1-C3 alkyl or CI-C3 haloalkyl;R7is H, CN, OCH3, or F;Y is CH, N, CF, or C-CH3; and- represents a single or double bond.

[0080] Compositions comprising compounds of other formulas are also provided herein. For example, in some embodiments, provided herein are compounds of Formula II:(Formula II), or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, wherein R3, R5, R6, and R7are defined as above.

[0081] Moreover, in some implementations, provided herein are compounds of Formula III:(Formula III), or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, wherein R3, R5, and R7are defined as above.

[0082] It is to be understood that in some instances of compositions described herein, R3is not H. Several moieties for R3may be contemplated. For example, in some embodiments, R3is C1-C4 alkyl. In some implementations, R3is C3-C4 cycloalkyl. Moreover, in some instances, R3is -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-iso-propyl, -C(O)O-butyl, -CH2OH, or - C(O)NH-methyl. Further, in some cases, R3is -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 instances, R3is -C(O)OH. In some implementations, R3is -CN. Insome embodiments, R3is an alkyl nitrile. For example, in some such cases, R3is -CH2CN or - CH2CH2CN.

[0083] Further, in some embodiments, R3is an imidazole. An imidazole may be any imidazole moiety not inconsistent with technical objectives of the current disclosure. Nonlimiting examples of imidazoles are shown below.In some instances, an imidazole may be unsubstituted or substituted. For example, in some cases, an imidazole may be a C1-C3 alkyl substituted imidazole or an N-alkyl imidazole. Non-limiting examples of N-alkyl imidazoles are shown below.

[0084] In some implementations, R3is a pyrazole. A pyrazole in the R3position may be any pyrazole moiety not inconsistent with technical objectives of the current disclosure. For example, in some implementations, a pyrazole may be 1,2-diazole. Moreover, in some cases, the pyrazole may be unsubstituted or substituted. In some cases, a substituted pyrazole is may be a C1-C3 alkyl substituted pyrazole or an N-alkyl pyrazole. Non-limiting examples of pyrazoles and N- alkyl pyrazoles are shown below.

[0085] In some cases, R3is a triazole. A triazole in the R3position may be any triazole moiety not inconsistent with technical objectives of the current disclosure. In some embodiments, a triazole may be a 1,2, 3 -tri azole, a 1,2,4-triazole, or a 1,3,4-triazole. Non-limiting examples of triazoles are shown below.Further, in some instances, a triazole may be unsubstituted or substituted. For example, in some embodiments, a substituted triazole in the R3position may be a C1-C3 alkyl substituted triazole or a N-alkyl triazole. Non-limiting examples of N-alkyl triazoles are shown below.

[0086] In some cases, R3is a tetrazole. A tetrazole in the R3position may be any tetrazole moiety not inconsistent with technical objectives of the current disclosure. In some embodiments, a tetrazole may be a 1,2,3,4-tetrazole or a 1,2,4,5-tetrazole. Non-limiting examples of tetrazoles are shown below.Additionally, in some instances, a tetrazole may be unsubstituted or substituted. For example, in some implementations, a tetrazole may be alkylated such that a tetrazole is an C1-C3 alkylsubstituted tetrazole. In some embodiments, a tetrazole is a N-alkyl tetrazole. Non-limiting examples of N-alkyl tetrazoles are shown below.

[0087] In some implementations, R3is an oxazole. An oxazole may be any oxazole moiety not inconsistent with the objectives of the current disclosure. For example, in some cases, an oxazole may be 1,3-oxazole. In some instances, an oxazole may be unsubstituted or substituted. For example, in some implementations, an oxazole is alkyl-substituted. In some embodiments, the alkyl-substituted oxazole is an C1-C3 alkyl-substituted oxazole. Non-limiting examples of oxazoles are shown below.

[0088] In some embodiments, R3is an isoxazole. An isoxazole moiety used herein may be any isoxazole moiety not inconsistent with the technical objectives of the current disclosure.Non-limiting examples of isoxazoles are shown below.In some cases, an isoxazole moiety may be unsubstituted or substituted. For example, in some implementations, an isoxazole is alkyl-substituted. In some implementations, the alkyl-substituted isoxazole is an C1-C3 alkyl-substituted isoxazole. Non-limiting examples of alkylsubstituted isoxazoles are shown below.

[0089] Moreover, in some instances of compounds and / or compositions described herein, R3is a thiazole. A thiazole moiety used herein may be any thiazole moiety not inconsistent with the technical objectives of the current disclosure. In some cases, a thiazole may be an isothiazole.Non-limiting examples of thiazoles, including isothiazoles, are shown below.Additionally, in some instances, a thiazole moiety may be unsubstituted or substituted. For example, in some implementations, a thiazole is alkyl-substituted. In some implementations, an alkyl-substituted thiazole is an C1-C3 alkyl-substituted thiazole. Non-limiting examples of alkylsubstituted thiazoles and isothiazoles are shown below.

[0090] Turning to additional embodiments of R3, in some instances, R3is -C(O)R9or - C(0)NHR9. In some such embodiments, R9is H or C1-C4 alkyl. It is also to be understood that in some other instances of compounds and / or compositions described herein, R3is H.

[0091] Regarding additional positions of compounds and / or compositions described herein, in some instances described herein, several moi eties for R5may be contemplated. For example, in some implementations, R5is a substituted or unsubstituted 4-membered heterocycle. In some embodiments, one or more carbons may be replaced with a nitrogen atom, an oxygen atom, a sulfoxide group, or a sulfuryl group. In some embodiments, a 4-membered heterocycle may be alkyl-substituted or substituted with a halo group. Non-limiting examples of 4-membered heterocycles are shown below.

[0092] Moreover, in some cases, R is a 5- to 7-membered heterocycle substituted with one or two oxo and / or R17, wherein R17is independently selected from the group consisting of-O-R10, -wherein R10, R11, and R13are each independently hydrogen or Ci-Ce alkyl; and wherein R12is independently Ci-Ce alkyl.

[0093] In some embodiments, R5is an imidazole. An imidazole in the R5position may be any imidazole moiety not inconsistent with the technical objectives of the current disclosure.Non-limiting examples of imidazoles are shown below.In some instances, an imidazole may be unsubstituted or substituted. For example, an imidazole may be an N-alkyl imidazole or a dimethylimidazole. Non-limiting examples of N-alkyl imidazoles and dimethyl imidazoles are shown below.

[0094] In some instances, R5is a pyrazole. A pyrazole in the R position may be any pyrazole moiety not inconsistent with the technical objectives of the current disclosure. For example, in some implementations, the pyrazole may be unsubstituted or substituted. In some embodiments, a pyrazole is a C1-C3 alkyl-substituted pyrazole, such as a 1-methylpyrazole. In other embodiments, a pyrazole is a C1-C3 haloalkyl-substituted pyrazole. Non-limiting examples of pyrazoles in the R5position are shown below.

[0095] In some embodiments, R5is a triazole. A triazole in the R5position may be any triazole moiety not inconsistent with the technical objectives of the current disclosure. In some implementations, a triazole is a 1,2,3-triazole or a 1,3,4-triazole. Non-limiting examples of triazoles are shown below.In some instances, a triazole may be unsubstituted or substituted. For example, in some embodiments, a substituted triazole in the R5position is an N-alkyl triazole. Non-limiting examples of N-alkyl triazoles are shown below. In some embodiments, a N-alkyl triazole is 4- methyl-l,2,4-triazole, 4-ethyl-l,2,4-triazole, 4-n-propyl-l-2,4-triazole, and 4-iso-propyl- 1,2,4- triazole.

[0096] In some embodiments, R5is a tetrazole. A tetrazole in the R5position may be any tetrazole moiety not inconsistent with the technical objectives of the current disclosure. In some implementations, a tetrazole is a 1,2,3,4-tetrazole or a 1,2,4,5-tetrazole. Non-limiting examples of tetrazoles are shown below.In some instances, a tetrazole may be unsubstituted or substituted. For example, in some implementations, a tetrazole is an N-alkyl tetrazole. Non-limiting examples of N-alkyl tetrazoles are shown below.

[0097] In some cases, R is a pyrazolidinone, such as 3-pyrazolidinone. A pyrazolidinone may be any pyrazolidinone moiety not inconsistent with the technical objectives of the current disclosure. In some embodiments, the pyrazolidinone may be unsubstituted or substituted. For example, in some implementations, a pyrazolidinone may be alkylated. Non-limiting examples of pyrazolidinones are shown below.

[0098] In some implementations, R5is an oxazolidinone. An oxazolidinone may be any oxazolidinone moiety not inconsistent with the technical objectives of the current disclosure. In some embodiments, the oxazolidinone may be unsubstituted or substituted. In some such implementations, the oxazolidinone may be alkylated, hydroxylated, or both. Non-limiting examples of oxazolidinones are shown below.

[0099] In some embodiments, R5is a morpholine. A morpholine may be any morpholine moiety not inconsistent with the technical objectives of the current disclosure. In some embodiments, the morpholine may be unsubstituted or substituted. In some such implementations, the morpholine may be alkylated. A non-limiting example of a morpholine is shown below.

[0100] In other embodiments, R5is a thiomorpholine dioxide. A thiomorpholine dioxide may be any thiomorpholine dioxide moiety not inconsistent with the technical objectives of the current disclosure. In some embodiments, the thiomorpholine dioxide may be unsubstituted or substituted. In some such implementations, a thiomorpholine dioxide moiety may be alkylated. A non-limiting example of a thiomorpholine dioxide is shown below.

[0101] In some implementations, R5is a tetrahydrothiophene dioxide. A tetrahydrothiophene dioxide may be any tetrahydrothiophene dioxide moiety not inconsistent with the technical objectives of the current disclosure. In some embodiments, the tetrahydrothiophene dioxide may be unsubstituted or substituted. In some such cases, the tetrahydrothiophene dioxide may be alkylated. A non-limiting example of a tetrahydrothiophene dioxide is shown below.

[0102] In some instances, R is a thiacyclohexane dioxide. A thiacyclohexane dioxide may be any thiacyclohexane dioxide moiety not inconsistent with the technical objectives of the current disclosure. In some embodiments, the thiacyclohexane dioxide may be unsubstituted or substituted. In some such implementations, the thiacyclohexane dioxide may be alkylated. A non-limiting example of a thiacyclohexane dioxide is shown below.

[0103] In other implementations, R5is a thiazolidine. A thiazolidine may be any thiazolidine moiety not inconsistent with the technical objectives of the current disclosure. For example, in some cases, the thiazolidine may be an isothiazolidine. Moreover, in some embodiments, the thiazolidine may be unsubstituted or substituted. For example, in some implementations, the thiazolidine may be alkyl substituted. Non-limiting examples of thiazolidines are shown below.

[0104] Additionally, in some implementations, R5 is a thiadiazolidine. A thiadi azolidine may be any thiadiazolidine moiety not inconsistent with the technical objectives of the current disclosure. Moreover, in some embodiments, the thi di azolidine may be unsubstituted or substituted. For example, in some implementations, the thiadiazolidine may be alkyl substituted, N-alkyl substituted, or substituted with a sulfonyl group. Non-limiting examples of thiadi azolidines are shown below.

[0105] In some cases, other embodiments of substituted 4- to 7-membered heterocycles may be contemplated. For example, in some instances, R5has the following structure:(Formula IV).In some implementations, R5may also have the following structure:(Formula XIII).

[0106] In some embodiments, R5is a sulfoximine. Non-limiting examples of sulfoximines are shown below.

[0107] In other embodiments, R5is a sulfonamide. A non-limiting example of a N- sulfonamide is shown below.

[0108] In some instances, R5is a spirocyclic heterocycle that is fused or bridged. Nonlimiting examples of spirocyclic heterocycles are shown below.

[0109] In some implementations, R5is -NHR24or -NR24R31. In some cases, R24is selected from the group consisting of C1-C4 alkyl halide, -R25-O-R26, -R27-C(O)NH-R28, -R29NHC(O)- R30, a substituted or unsubstituted 4-membered heterocycle, and a substituted or unsubstituted cyclobutane,R25is C1-C4 alkyl,R26is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide,R27and R28are each independently C1-C4 alkyl,R29and R30are each independently C1-C4 alkyl, andR31is C1-C4 alkyl or C1-C4 alkyl halide.

[0110] In some implementations, R24is a substituted or unsubstituted 4-membered heterocycle. In some embodiments, one or more carbons of the heterocycle may be replaced with a nitrogen atom, an oxygen atom, a sulfoxide group, or a sulfuryl group. Non-limiting examples of R3groups wherein R24is a 4-membered heterocycle are shown below.

[0111] In some implementations, R24is 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. Non-limiting examples of R5groups wherein R24is a cyclobutane are shown below.

[0112] Moreover, turning to additional embodiments of R5, in some instances, R?is an E3- ligase binding moiety. It is to be understood that in some cases, for reference purposes herein, an E3-ligase binding moiety is any moiety that is capable of binding to an E3-ligase. It is also to be understood that in some cases, binding to an E3-ligase may be through a non-covalent interaction or a covalent interaction.

[0113] An E3-ligase binding moiety described herein may bind to any E3-ligase not inconsistent with the technical objectives of the present disclosure. For example, in some embodiments, an E3-ligase may be a HECT type E3-ligase. In some instances, an E3-ligase may be a U-box type E3-ligase. In some cases, an E3-ligase may be a RING-finger type E3-ligase. In some instances, an E3 -ligases may be a RBR-type E3 ligase.

[0114] Moreover, any E3-ligase binding moiety not inconsistent with the technical objectives of the present disclosure may be used. In some instances, an E3-ligase binding moiety comprises a linker moiety covalently bonded to a terminal moiety:wherein L comprises the linker moiety and T comprises the terminal moiety. It is to be understood that for reference purposes herein, the linker moiety acts to bind and / or link the terminal moiety to the core structure of the TTK inhibitory compound. Moreover, for reference purposes herein, the terminal moiety binds E3-ligase. In some instances, the terminal moiety alone is primarily responsible for the binding and / or recruitment of E3-ligase. However, in some implementations, both the linker moiety and terminal moiety are responsible for the binding and / or recruitment of E3-ligase. Stated differently, in some embodiments, both the linker moiety and terminal moiety may bind and / or interact with the E3 -ligase.

[0115] The identity of L is not necessarily limited. For example, L may comprise any linking moiety contemplated by one skilled in the art. In some cases, L may comprise an alkyl group. In some embodiments, the alkyl group may have 20 or fewer carbon atoms. Moreover, in some instances, the alkyl group may be substituted, such as with a halide or other moieties, such as amino-, amino acid-, aryl-, alkyl aryl-, alkyl ester-, ether-, keto-, nitro-, sulfhydryl-, sulfonyl-, or sulfoxide-modified-alkyl groups. Moreover, in some embodiments, L may comprise an alkylene group or alkylene chain. In some cases, the alkylene group may have 1 to 30 carbon atoms. Moreover, in some cases, the alkylene group may be unsubstituted or substituted. In someimplementations, L may comprise a cycloalkyl group. For example, in some embodiments, L may comprise a fused or bridged ring system. Further, in some instances, L may comprise a cycloalkenyl group. In some implementations, a cycloalkenyl group may be unsubstituted or substituted. In some embodiments, L may comprise an aryl group. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a Ce-Cio aryl group, or a Ce aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. Additionally, the aryl group may be a heteroaryl group. The number of atoms in the ring(s) of a heteroaryl group can vary. Further, in some embodiments, L may comprise a heterocycle. Any heterocycle not inconsistent with the technical objectives of the current disclosure may be used as L. Moreover, in some implementations, L may comprise an ether. In some embodiments, an ether may be a di ether or a polyether. In some cases, L may comprise an amino group. For example, in some embodiments, an amino group may comprise a diamino group or a polyamino group. Further, L may comprise a polyethylene glycol chain.

[0116] Additionally, the identity of T is not necessarily limited. For example, T may be any moiety known to bind and / or recruit an E3-ligase. Non-limiting examples of moieties that bind and / or recruit E3-ligase molecules are provided by Sasso, et al., Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic, Biochemistry 2023 62 (3), 601-623; Toriki, et al., Rational Chemical Design of Molecular Glue Degraders, ACS Central Science 2023 9 (5), 915-926; Cowan, et al., Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory, Annual Review of Biochemistry 2022 91, 295-319; Simonetta, et al., Prospective discovery of small molecule 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. 2021 Jul 5;9:707317, which are incorporated by reference herein.

[0117] It is to be understood that compounds described in Section I may be synthesized and / or made in any manner not inconsistent with the technical objectives of the current disclosure. For example, in some embodiments, compounds described herein may be synthesized and / or made using the methods described in the Examples section below or similar methods with modification known to one skilled in the art.II. Pharmaceutical Compositions

[0118] In another aspect, provided are compositions comprising a compound described herein, such as a compound of Formula I, Formula II, or Formula III. A composition and / or compound used in a pharmaceutical compositon described herein may be any composition and / or compound described in Section I. In general, a compound described herein is mixed with a suitable carrier or excipient in a therapeutically effective amount. By a “therapeutically effective dose”, “therapeutically effective amount”, or, interchangeably, “pharmacologically acceptable dose” or “pharmacologically acceptable amount”, it is meant that a sufficient amount of the compound and a pharmaceutically acceptable carrier, will be present in order to achieve a desired result, e.g., treating a disease mediated at least in part by Mpsl / TTK kinase (as further described herein).

[0119] In general, the compounds described herein will be administered in a therapeutically effective amount by any of the accepted modes of administration. The actual amount of the compound, i.e., the active ingredient, will depend upon numerous 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 can be administered according to any suitable dosage regimes, such as once, twice, three times, or four times, etc. a day, or as needed. All of these factors are within the skill of the attending clinician. In some embodiments, the compound is administered one or more times during a treatment cycle. In further embodiments, the treatment cycle is 21 days. In other embodiments, the treatment cycle is 28 days. In some embodiments, the compound is administered one or more times during a treatment cycle for up to four treatment cycles.

[0120] Therapeutically effective amounts of the compounds may range from approximately 0.03 to 50 mg per kilogram body weight of the recipient per day; for example, about 0.1-25 mg / kg / day, or from about 0.5 to 10 mg / kg / day. Thus, for administration to a 70 kg person, the dosage range can be about 1-3,500 mg per day.

[0121] In some of the embodiments of the technology described herein, the pharmaceutical compositions are packaged in unit dosage form. The unit dosage form is effective in treating a disease and / or disorder. Generally, a unit dosage including a compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitanttherapies, and the like. An exemplary unit dosage based on these considerations can also be adjusted or modified by a physician skilled in the art. For example, a unit dosage for a patient comprising a compound of the present technology can vary from 3 x IO’5g / kg to 1 g / kg, preferably, 1 x IO"3g / kg to 1.0 g / kg. Dosage of a compound of the present technology can also vary from 0.01 mg / kg to 100 mg / kg or, preferably, from 0.1 mg / kg to 10 mg / kg.

[0122] In some embodiments, the unit dosage comprises 0.01 mg / kg to 0.5 g / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 100 mg / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 50 mg / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 10 mg / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 5 mg / kg. In some embodiments, the unit dosage comprises 0.1 mg / kg to 0.5 g / kg. In some embodiments, the unit dosage comprises 0.1 mg / kg to 100 mg / kg. In some embodiments, the unit dosage comprises 0.1 mg / kg to 50 mg / kg. In some embodiments, the unit dosage comprises 0.01 mg / kg to 10 mg / kg. In some embodiments, the unit dosage comprises 0.1 mg / kg to 5 mg / kg.

[0123] In general, compounds described herein will be administered as pharmaceutical compositions by any one of the following routes: oral, transdermal, intranasal, by suppository, parenteral (e.g., intramuscular, intravenous or subcutaneous), or intrathecal administration. Compositions can take the form of tablets, pills, capsules, semi solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.

[0124] Another manner for administering compounds is inhalation. This is an effective method for delivering a therapeutic agent directly to the respiratory tract (see U.S. Pat. No. 5,607,915). For delivery via inhalation, the compound can be formulated as liquid solutions, suspensions, aerosol propellants, or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices: nebulizer inhalers, metered dose inhalers (MDI), and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient’s respiratory tract. MDIs typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPIs dispense therapeutic agents in the form of a freeflowing powder that can be dispersed in the patient's inspiratory airstream during breathing by the device. In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.

[0125] In some embodiments, pharmaceutical compositions described herein are comprised of, in general, a compound described herein in combination with at least one pharmaceutically acceptable excipient. In some instances, acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0126] 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, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, phosphate buffered saline, citrate buffer, aqueous dextrose, glycols, etc.

[0127] The amount of a compound 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 will contain from 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 instances, a compound described herein is present at a level of about 1-80 wt%.

[0128] A pharmaceutical composition described herein may be made in any manner not inconsistent with the technical objectives of the current disclosure. For example, in some embodiments, a compound may be mixed (such as with a high shear mixer) with one or more additional components (such as a pharmaceutically acceptable excipient) to form a pharmaceutical composition described herein.III. Combination Therapy

[0129] In some embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents for treating a subject in need thereof. A compound used in combination therapy may comprise any compound described herein in Section I. In some embodiments, the one or more additional therapeutic agents are selected from anti-cancer compounds. When a combination therapy is used, the one or more additional therapeutic agents may be administered sequentially or simultaneously with a compound described herein. In some embodiments, the one or more additional therapeutic agents is administered prior to the administration of a compound described herein. In some embodiments, the one or more additional therapeutic agents is administered after the administration of a compound described herein. In some embodiments, the one or more additional therapeutic agents is administered concurrently with the administration of a compound described herein.

[0130] In some embodiments, the one or more additional therapeutic agents is an antiangiogenesis agent (e.g., an agent that stops tumors from developing new blood vessels). Nonlimiting examples of anti-angiogenesis agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE -2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKC-beta inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v / beta-3), MMP-2 (matrix metalloproteinase-2) inhibitors, and MMP-9 (matrix metalloproteinase-9) inhibitors. Some preferred anti-angiogenesis agents include sunitinib (Sutent®), bevacizumab (Avastin®), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer).

[0131] Additional anti-angiogenesis agents include vatalanib (CGP 79787), Sorafenib (Nexavar®), pegaptanib octasodium (Macugen®), vandetanib (Zactima®), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis®), Neovastat® (AE 941), tetrathio-molybdata (Coprexa®), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer).

[0132] Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex®) and UCN 01 (Kyowa Hakka).

[0133] Other examples of anti-angiogenesis agents which can be used in conjunction with a compound disclosed herein include celecoxib (Celebrex®), parecoxib (Dynastat®), deracoxib (SC 59046), lumiracoxib (Preige®), valdecoxib (Bextra®), rofecoxib (Vioxx®), iguratimod (Careram®), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia®).

[0134] Other anti-angiogenesis agents include exisulind (Aptosyn®), salsalate (Amigesic®), diflunisal (Dolobid®), ibuprofen (Motrin®), ketoprofen (Orudis®), nabumetone, (Relafen®), piroxicam (Feldene®), naproxen (Aleve®, Naprosyn®) diclofenac (Voltaren®), indomethacin (Indo-cin®), sulindac (Clinoril®), tolmetin (Tolectin®), etodolac (Lodine®), ketorolac (Toradol®), and oxaprozin (Daypro®).

[0135] Other anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat®), and PCK 3145 (Procyon).

[0136] Other anti-angiogenesis agents include acitretin (Neotigason®), plitidepsin (Aplidine®), cilengtide (EMD 45 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), alofuginone (Tempostatin®), Panzem® (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab®), lenalidomide (Revlimid®) squalamine (EVIZON®), thalidomide (Thalomid®), Ukrain® (NSC 631570), Vitaxin® (MEDI 522), and zoledronic acid (Zometa®).

[0137] In some embodiments, the anti-cancer agent is a so called “signal transduction inhibitor” (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of 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, famesyl protein transferase inhibitors, EGF inhibitor, 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 inhibitor, P70S6 kinase inhibitors, inhibitors of the WNT pathway and so called multi-targeted kinase inhibitors.

[0138] 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®), binimetinib (Mektovi®), selumetinib (Koselugo®), and cobimetinib (Cotellic®).

[0139] Additional examples of signal transduction inhibitors include BMS 214662 (Bristol- Myers Squibb), lonafamib (Sarasar®), pelitrexol (AG 2037), matuzumab (EMD 7200),nimotuzumab (TheraCIM h-R3®), panitumumab (Vectibix®), Vandetanib (Zactima®), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and Cervene® (TP 38).

[0140] Other examples of signal transduction inhibitor include PF-2341066 (Pfizer), PF- 299804 (Pfizer), canertinib (CI 1033), pertuzumab (Omnitarg®), Lapatinib (Tycerb®), pelitinib (EKB 569), miltefosine (Miltefosin®), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge®), NeuVax® (E75 cancer vaccine), Osidem® (IDM 1), mubritinib (TAK-165), CP- 724,714 (Pfizer), panitumumab (Vectibix®), lapatinib (Tycerb®), PF-299804 (Pfizer), and pertuzumab (Onmitarg®).

[0141] Other examples of signal transduction inhibitors include ARRY 142886 (Array Biopharm), everolimus (Certican®), zotarolimus (Endeavor®), temsirolimus (Torisel®), AP 23573 (ARIAD), and VX 680 (Vertex).

[0142] Additionally, other signal transduction inhibitors include XL 647 (Exelixis), sorafenib (Nexavar®), LE-AON (Georgetown University), and GL4000 (Globelmmune).

[0143] Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032 (Bristol-Myers Squibb), PD 0332991 (Pfizer), AG 024322 (Pfizer), 35 LOXO-101 (Loxo Oncology), crizotinib, and ceritinib.

[0144] In some embodiments, a compound disclosed herein is used together with classical anti neoplastic agents. Classical antineoplastic agents include but are not limited to hormonal modulators such as hormonal agents, anti-hormonal agents, androgen agonist agents, androgen antagonist and anti-estrogen therapeutic agents, histone deacetylase (HD AC) inhibitors, gene silencing agents or gene activating agents, ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecin derivatives, Topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-I (PARP-1) inhibitor, microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum-coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins.

[0145] Examples of classical antineoplastic agents used in combination therapy with a compound 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, megestrol acetate (Megace),mifepristone (RU-486), Selective Estrogen Receptor Modulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi)), Selective Estrogen- Receptor Downregulators (SERDs; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), gonadotropin-releasing hormone (GnRH; also commonly referred to as luteinizing hormone-releasing hormone (LHRH)) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), bicalutamide (Casodex), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide, tamoxifen, exemestane, anastrozole, fadrozole, formestane, letrozole, and combinations thereof.

[0146] Other examples of classical antineoplastic agents used in combination with a compound disclosed herein include, but are not limited to, suberolanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS- 275, pivaloyloxymethyl butyrate and PXD-101, Onconase (ranpimase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxy camptothecin, irinotecan HC1 (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), topotecan, camptothecin, 10- hydroxy camptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxy carbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosf amide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds, such as cisplatin, Paraplatin (carbopl atin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin, and combinations thereof.

[0147] In some embodiments, a compound disclosed herein is used together with dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetresateglucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6- thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), pyrimidine antagonists), Alimta (premetrexed disodium, LY231514, MT A), capecitabine (Xeloda®), cytosine arabinoside, Gemzar® (gemcitabine, Eli Lilly), Tegafur (UFT Orzel or Uforal and including TS-1, a combination of tegafur, gimestat and otostat), doxifluridine, carmofur, cytarabine (including ocfosfate, phosphate stearate, sustained release, and liposomal forms), enocitabine, 5-azacitidine (Vidaza), decitabine, ethynylcytidine, and other antimetabolites, such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine, trimetrexate, N-(5-[N- (3,4-di-hydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals) and GPI 18180 (Guilford Pharm Inc.) and combinations thereof.

[0148] Other examples of classical antineoplastic cytotoxic agents used in combination therapy with a compound disclosed herein, optionally with one or more other agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere ), Ortataxel, paclitaxel (including Taxoprexin, a DHA / paciltaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (Telcyta®), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar®), Efaproxiral (Efaproxyn®-radiation therapy), bexarotene (Targretin®), Tesmilifene (DPPE, which enhances the efficacy of cytotoxics), Theratope® (Biomira), Tretinoin (Vesanoid®), tirapazamine (Trizaone®), motexafm gadolinium (Xcytrin®) Cotara® (mAb), and NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax®) and combinations thereof.

[0149] Further examples of classical antineoplastic agents used in combination therapy with a compound disclosed herein, optionally with one or more other agents, include, but are not limited to, as Advexin (ING 201), TNFerade (GeneVec, one or more compounds which express TNF alpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin 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), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and a combination thereof.

[0150] In some embodiments, a compound disclosed herein is used together with immune checkpoint inhibitors. Immune checkpoint inhibitors include, but are not limited to, PD-1 inhibitors, such as pembrolizumab, nivolumab, and cemiplimab; PD-L1 inhibitors, such as atezolizumab, avelumab, and durvalumab; CTLA-4 inhibitors, such as ipilimumab and tremelimumab; and LAG-3 inhibitors, such as relatlimab; and a combination thereof.

[0151] In some cases, a compound disclosed herein is used together with CDK4 / 6 inhibitors. In some embodiments, CDK4 / 6 inhibitors include but are not limited to palbociclib (Ibrance®), ribociclib (Kisqali®), abemaciclib (Verzenio®), and combinations thereof.

[0152] In some instances, the one or more additional therapeutic agents are stimulator of interferon genes (STING) agonists. STING agonists include but are not limited to CDK-002 (Codiak Biosciences, Inc.), SB-11285 (F-star Therapeutics, Inc.), ulevostinag (Merck & Co. Inc.), BL1387446 (Boehringer Ingelheim International GmbH), BMS-986301 (Bristol-Myers Squibb), DN-015089 (Shanghai De Novo Pharmatech Co. Ltd.), E-7766 (Eisai Co. Ltd.), GSK3745417 (GSK pic), HG-381 (HitGen Inc.), MK-2118 (Merck & Co., Inc.), ONO-7914 (Ono Pharmaceutical Co. Ltd.), SNX-281 (Stingthera Inc.), SYNB-1891 (Synlogic Inc.), 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 (Aligos Therapeutics Inc.), BL09 (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 pic), 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 (Ryvu Therapeutics SA; University of Pennsylvania; Tsinghua University; Inimmune Corp), and combinations thereof.

[0153] Further examples of STING agonists used in combination therapy with a compound 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.), STL002 (Stimunity 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; Arcus Biosciences Inc.; HitGen Inc.; Nimbus Therapeutics LLC; Bicycle Therapeutics), TTI-10001 (Trillium Therapeutics Inc.), XMT-2056 (Mersana Therapeutics Inc.), and ADUS-100 (Chinook Therapeutics Inc.).

[0154] In some embodiments, a compound herein is used with therapies for colorectal cancer. In some cases, a compound herein is used with fluoropyrimidine-based therapeutics. In some instances, for example, fluoropyrimidine-based therapeutics include but are not limited to capecitabine, fluorouracil (5-FU), FOLFOX (a combination of folinic acid, 5-FU, and oxaliplatin), FOLFIRI (a combination of folinic acid, 5-FU, and irinotecan), CAPOX (a combination of capecitabine and oxaliplatin), floxuridine, irinotecan, and combinations thereof. In other implementations, a compound described herein is used with other known treatments for colorectal cancer, including but not limited to bevacizumab, cetuximab, panitumumab, pembrolizumab, nivolumab, a combination of trastuzumab with pertuzumab and lapatinib, regorafenib, trifluridine, tipiracil, ipilimumab, trastuzumab, ziv-aflibercept, ramucirumab, encorafenib, or a combination thereof.

[0155] In some instances, a compound disclosed herein is used together with a compound used for treatment of glioblastoma multiforme. In some instances, a compound used for treatment of glioblastoma multiforme used with a compound disclosed herein includes, but is not limited to, procarbazine, lomustine, vincristine, temozolomide, bevacizumab, selumetinib, compounds for treating NTRK gene fusion tumors, such as larotrectinib and entrectinib, or combinations thereof.

[0156] In some embodiments, a compound disclosed herein is used together with one or more BRAF inhibitors. In some instances, the BRAF inhibitor is an inhibitor of a mutant BRAF, such as a mutation at BRAF V600. However, the mutation of BRAF is not necessarily limited. Insome embodiments, the BRAF mutation may be BRAF V600E, BRAF V600K, BRAF V600R, BRAF V600L, or BRAF V600D. Moreover, the identity of the BRAF inhibitor is not necessarily limited. In some cases, BRAF inhibitors include, but are not limited to, dabrafenib, encorafenib, and vemurafenib. In some embodiments, one or more BRAF inhibitors can 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 disease for which the combination of a compound disclosed herein and a BRAF inhibitor or the combination of a compound disclosed herein, a BRAF inhibitor, and a MEK inhibitor may be used to treat is not limited. For example, in some embodiments, such combination treatments may be used to treat glioblastoma multiforme, melanoma, or colorectal cancer.

[0157] In some instances, a compound disclosed herein is used in combination with a compound used for the treatment of various metastatic cancers, wherein the cancer has metastasized to the brain, central nervous system, or bone, and may be characterized by molecular markers. In some cases, for example, if the metastatic cancer is NTRK gene positive, NTRK gene fusion tumor treatments, such as larotrectinib and entrectinib, may be used with a compound described herein. In other cases, if the metastasic cancer is PD-1 / PD-L1 postive, pembrolizumab or nivolumab or other anti-PDl / PD-Ll antibody is used in combination with a compound described herein. In other cases, if the metastatic cancer is ALK rearrangement positive or ROS1 positive, crizotinib is used in combination with a compound described herein. In some other cases, if metastasis of a breast cancer has occurred and it is HERZ positive, ado- trastuzumab emtansine, capecitabine in combination with lapatinib or neratinib, paclitaxel in combination with neratinib, tucatinib in combination with trastuzuma and capecitabine, famtrastuzumab deruxtecan-nxki, pertuzumab, or high-dose trastuzumab may be used with a compound described herein. In some embodiments, if the breast cancer metastasis is HER2 nonspecific, capecitabine, cisplatin, etoposide, cisplatin in combination with etoposide, or high-dose methotrexate may be used with a compound described herein. In some embodiments, if metastasis of melanoma has occurred, and the metastatic melanoma is BRAF V600E positive, a combination of dabrafenib-trametinib or the combination of vemurafenib and cobimetinib may be used with a compound described herein. In other embodiments, if the melanoma is BRAF non-specific, a combination of ipilimumab and nivolumab, ipilimumab, nivolumab, orpembrolizumab may be used with a compound described herein. In some instances, if small cell lung cancer metastasis has occurred, topotecan is used in combination with a compound described herein. In some other instances, if lung cancer metastasis has occurred, for example, metastatic non-small cell lung cancer (NSCLC), and the metastatic NSCLC is EGFR-sensitizing mutation positive, osimertinib, erlotinib, afatinib, or gefitinib is used with a compound described herein. In other embodiments, if the metastatic NSCLC is MET exon 14 mutated, capmatinib is used with a compound described herein. In some other embodiments, if the metastatic NSCLC is RET fusion positive, selpercatinib is used with a compound described herein. In other embodiments, if the metastatic NSCLC is ALK rearrangement positive, brigatinib, lorlatinib, alectinib, ceritinib, or crizotinib is used with a compound described herein. In some other embodiments, if the metastatic NSCLC is ROS1 positive, crizotinib is used with a compound described herein. In other embodiments, if lymphoma metastasis has occurred, high-dose methotrexate is used with a compound described herein.

[0158] Moreover, in some embodiments, a compound disclosed herein is used together with a compound used for treatment of melanoma. In some embodiments, a compound used for treatment of melanoma used with a compound disclosed herein includes, but is not limited to, trametinib, dabrafenib, ipilimumab, vemurafenib, pembrolizumab, nivolumab, nivolumab in combination with relatlimab, binimetinib, encorafenib, talimogene laherparepvec, or a combination thereof.

[0159] Additionally, in some embodiments, a compound disclosed herein is used together with a compound used for treatment of pancreatic cancer. In some embodiments, a compound used for treatment of pancreatic cancer used with a compound disclosed herein includes but is not limited to FOLFIRINOX (a combination of folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), a combination of gemcitabine and albumin-bound paclitaxel with or without subsequent chemoradiation, gemcitabine in combination with cisplatin followed by chemoradiation, liposomal irinotecan in combination with fluorouracil and leucovorin, carboplatin, mitomycin C, olaparib, rucaparib, or a combination thereof.

[0160] Also, in some embodiments, a compound disclosed herein is used together with a compound used for treatment of bladder cancer. In some embodiments, a compound used for treatment of bladder cancer used with a compound disclosed herein includes, but is not limited to, mitomycin, epirubicin, pirarubicin, gemcitabine, avelumab, carboplatin, atezolizumab,pembrolizumab, paclitaxel, gemcitabine, vinflunine, granulocyte colony-stimulating factor (G- CSF), enfortumab vedotin-ejfv, DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin), or a combination thereof. In some other embodiments, a compound disclosed herein is used together with intravesical immunotherapy with Bacillus Calmette-Guerin (BCG).

[0161] In some instances, a compound disclosed herein is used together with a compound used for treatment of stomach or gastric cancer. In some cases, a compound used for treatment of stomach or gastric cancer used with a compound disclosed herein includes, but is not limited to, FLOT (a combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel), capecitabine, cisplatin, irinotecan, trastuzumab, nivolumab, pembrolizumab, ramucirumab, paclitaxel, a combination of trifluridine and tipiracil, or a combination thereof.

[0162] Moreover, in some instances, a compound disclosed herein is used together with a compound used for treatment of kidney cancer or renal cell carcinoma. In some embodiments, a compound used for treatment of kidney cancer or renal cell carcinoma used with a compound disclosed herein includes, but is not limited to, IL-2, interferon alfa, sunitinib, bevacizumab in combination with interferon, pazopanib, temsirolimus, everolimus, lenvatinib in combination with everolimus, nivolumab, nivolumab in combination with ipilimumab or cabozantinib, avelumab in combination with axitinib, cabozantinib, sorafenib, axitinib, avelumab, pembrolizumab, floxuridine (FUDR), 5-FU, vinblastine, paclitaxel, carboplatin, ifosfamide, gemcitabine, doxorubicin, or a combination thereof.

[0163] Further, in some cases, a compound disclosed herein is used in combination with a compound used for therapies for ovarian cancer. In some cases, for example, a compound used for treatment of ovarian cancer used with a compound disclosed herein includes, but is not limited to, a combination of cyclophosphamide and bevacizumab, docetaxel, etoposide, gemcitabine, liposomal doxorubicin 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 leuprolide, megestrol, or tamoxifen, or a combination thereof.

[0164] In some embodiments, a compound disclosed herein is used with therapies for the treatment of endometrial carcinoma. In some instances, for example, a compound used for the treatment of endometrial carcinoma includes, but is not limited to, cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel (Abraxane), doxorubicin, liposomal doxorubicin, docetaxel,ifosfamide, topotecan, trastuzumab, bevacizumab, pembrolizumab, lenvatinib, tamoxifen, letrozole, medroxyprogesterone, levonorgestrel, or a combination thereof.

[0165] Additionally, in some instances, a compound disclosed herein is used in combination with a compound used for the treatment of head and neck cancers. In some cases, for example, a compound used for the treatment of head and neck cancers includes, but is not limited to, cisplatin, cetuximab, paclitaxel, 5-FU, carboplatin, pembrolizumab, methotrexate, docetaxel, capecitabine, afatinib, nivolumab, pembrolizumab, gemcitabine, or a combination thereof.

[0166] In some cases, a compound disclosed herein is used in combination with a compound used for the treatment of breast cancer. In some instances, for example, a compound used for the treatment of breast cancer includes, but is not limited to, carboplatin, cyclophosphamide, doxorubicin, epirubicin, capecitabine, gemcitabine, methotrexate, vinorelbine, ado-trastuzumab emtansine, denosumab, trastuzumab, pertuzumab, a combination of trastuzumab and hyaluronidase, trastuzumab deruxtecan, sacituzumab govitecan, a combination of pertuzumab with trastuzumab and hyaluronidase, lapatinib, neratinib, tucatinib, eribulin, docetaxel, paclitaxel, ixabepilone, anastrozole, letrozole, exemestane, palbociclib, ribociclib, abemaciclib, olaparib, talazoparib, tamoxifen, raloxifene, toremifene, elacestrant, atezolizumab, alpelisib, or a combination thereof.

[0167] Some embodiments relate to a method for the treatment of cancer in a subject in need of such treatment, comprising administering to said subject an amount of a compound disclosed herein, in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of trastuzumab, tamoxifen, docetaxel, paclitaxel, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole and anastrozole.

[0168] A combination therapy comprising a compound described herein and one or more additional therapeutic agents may be made in any manner not inconsistent with the technical objectives of the current disclosure. For example, in some embodiments, a compound described herein and one or more additional therapeutic agent may be mixed (such as with a high shear mixer) to form a pharmaceutical composition.

[0169] Moreover, in some embodiments, compounds described herein may be used with different types of therapies. For example, in some cases, a compound disclosed herein is used in combination with radiotherapy. In other cases, a compound disclosed herein is used incombination with alternating electric field therapy. In some instances, specifically, a compound disclosed herein is used in combination with tumor treating fields therapy.IV. Treatment of Diseases

[0170] In some embodiments, provided are methods of inhibiting Mpsl / TTK kinase comprising, consisting of or consisting essentially of, contacting Mpsl / TTK with a compound, pharmaceutical composition, or combination therapy described herein. A compound may be any compound described in Section I. In some embodiments, a compound comprises a compound of Formula I:or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, whereinR1is H;R2is H;R3is not H;R4is selected from the group consisting of -ZR15or -ZR19, whereinZ is NH, N-methyl, or O;R15is a six-membered ring having the following structureR16is selected from the group consisting of hydrogen, halo, -O-R20, -C(O)-R20, -C(O)O- R20, -NR20R21, -C(S)NR20R21, -NR23C(O)NR20R21, -NR23C(S)NR20R21, -O-C(O)NR20R21, -S(O)2NR20R21, -O-S(O)2NR20R21, -NR23-S(O)2NR20R21, -CN, -NO2, C1-C6 alkyl, and - S(O)2-R22;R18is selected from the group consisting of hydrogen, halo, -O-R20, -C(O)-R20, -C(O)O- R20, -NR20R21, -C(O)NR20R21, -C(S)NR20R21, -NR23C(O)NR20R21, -NR23C(S)NR20R21, - O-C(O)NR20R21, -S(O)2NR20R21, -O-S(O)2NR20R21, -NR23-S(O)2NR20R21, -CN, -NO2, C1-C6 alkyl, and -S(O)2-R22;R19is selected from the group consisting of linear C1-C16 alkyl, branched C1-C16 alkyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, iso-hexyl, sec-hexyl, tert-hexyl, neo-hexyl, cyclo-butyl, and cyclo-pentyl;R20, R21, and R23are each independently hydrogen or Ci-Ce alkyl; andR22is Ci-Ce alkyl;R5is selected from the group consisting of C1-C4 alkyl, a substituted or unsubstituted 4- to 7- membered heterocycle, a sulfoximine, a sulfonamide, and a spirocyclic heterocycle that is fused or bridged, an E3-ligase binding moiety, -NHR24, and -NR24R31,R24is selected from the group consisting of C1-C4 alkyl halide, -R25-O-R26, -R27- C(O)NH-R28, -R29NHC(O)-R30, a substituted or unsubstituted 4-membered heterocycle, and a substituted or unsubstituted cyclobutane,R25is C1-C4 alkyl,R26is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide,R27and R28are each independently C1-C4 alkyl,R29and R30are each independently C1-C4 alkyl, andR31is C1-C4 alkyl or C1-C4 alkyl halide;R6is hydrogen, methyl, -CN, -S-methyl, or -XR8, wherein X is O, S, or SO2and R8is C1-C3 alkyl or CI-C3 haloalkyl;R7is H, CN, OCH3, or F;Y is CH, N, CF, or C-CH3; and- represents a single or double bond.

[0171] In some embodiments, provided are methods of inhibiting Mpsl / TTK kinase comprising, consisting of or consisting essentially of, contacting Mpsl / TTK with a compound of Formula II:(Formula II), or a tautomer, a pharmaceutically acceptable salt and / or solvate thereof; wherein R3, R5, R6, and R7are defined as above.

[0172] In some embodiments, provided are methods of inhibiting Mpsl / TTK kinase comprising, consisting of or consisting essentially of, contacting Mpsl / TTK with a compound of Formula III:(Formula III), or a tautomer, a pharmaceutically acceptable salt and / or solvate thereof; wherein R3, R5, and R7are defined as above.

[0173] In some other embodiments, provided are methods of treating a disease comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of acompound described herein, such as a compound of Formula I, Formula II, or Formula III, or a tautomer, a pharmaceutically acceptable salt and / or solvate thereof, to a patient in need thereof (including, if desired, as part of a pharmaceutical compositon or combination therapy described herein). The compound may be any compound described in Section I. In some instances, the disease is cancer. In some embodiments, the disease is correlated with a biomarker of susceptibility to Mpsl / TTK inhibition. In some implementations, the biomarker can be a negative or positive selection biomarker wherein the presence / increase or absence / decrease, respectively, of the biomarker relative to a normal sample, suggesting the disease is susceptible to Mpsl / TTK inhibition. For example, in some instances, the biomarker may be characterized as the presence of cells that overexpress protein kinase Mpsl / TTK, such as expressing Mpsl / TTK at a level that is at least 120%, 150%, or 200% of the normal Mpsl / TTK expression level. The normal Mpsl / TTK expression level can be determined by Mpsl / TTK expression levels of healthy individuals or cells using methods known in the art. In some embodiments, the biomarker is related to the status of the STING and / or MAVS signalling pathways. For example, in some instances, the STING and / or MAVS signalling pathway is reduced or repressed, for example, by epigenetic methylation, in the disease. However, in some cases, with this reduction and / or repression, the STING and / or MAVS signalling pathway is still competent. In some instances, the STING and / or MAVS pathway is not reduced or repressed. In some cases, the biomarker is a KRAS, LKB1, and / or BRAF mutation.

[0174] Moreover, in another embodiment, provided are methods of treating a disease mediated at least in part by protein kinase Mpsl in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt and / or solvate thereof (or a pharmaceutical composition or combination therapy including the compound). The compound may be any compound described in Section I. In some cases, the disease is cancer. In some implementatons, the disease is brain cancer, glioblastoma multiforme, head and neck cancers, 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, nonsmall cell lung cancer, small cell lung cancer, or endometrial cancer. Moreover, in some instances, the cancer is not necessarily defined by its tissue of origin but rather by a biomarker of susceptibility to Mpsl / TTK inhibition, as described above. For example, in some cases, thecancer comprises, consists of, or consists essentially of cells that overexpress protein kinase Mpsl / TTK such that expressing Mpsl / TTK at a level that is at least 120%, 150%, or 200% of the normal Mpsl / TTK expression level. The normal Mpsl / TTK expression level can be determined by Mpsl / TTK expression levels of healthy individuals or healthy cells using methods known in the art. In some cases, the cancer comprises cells with a competent STING and / or MAVS signalling pathway. In some embodiments, the cancer comprises cells with mutated KRAS, LKB1, and / or BRAF.

[0175] Further, in some instances, provided are compounds for use in the treatment of cancer. A compound may be any compound described in Section I. In some embodiments, the compounds are compounds of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the cancer is brain cancer, glioblastoma multiforme, head and neck cancers, 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 rather by a biomarker of susceptibility to Mpsl / TTK inhibition. For example, in some instaces, the cancer comprises, consists of or consists essentially of, cells that over express protein kinase Mpsl / TTK, such as expressing Mpsl / TTK at a level that is at least 120%, 150%, or 200% of the normal Mpsl / TTK expression level. The normal Mpsl / TTK expression level can be determined by Mpsl / TTK expression levels of healthy individuals using methods known in the art. In some cases, the cancer comprises cells with a competent STING and / or MAVS signalling pathway. In some instances, the cancer comprises cells with mutated KRAS, LKB1, and / or BRAF.

[0176] In another instance, provided are uses of compounds described herein for the manufacture of a medicament for use in treatment of cancer. In some embodiments, the cancer is brain cancer, glioblastoma multiforme, head and neck cancers, 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. A compound may be any compound described in Section I. In some embodiments, the compounds are compounds of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt and / or solvatethereof. In other embodiments, the cancer isbrain cancer, glioblastoma multiforme, head and neck cancers, 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, the cancer is not defined by its tissue of origin but rather by a biomarker of susceptibility to Mpsl / TTK inhibition, as described above. In some embodiments, the cancer comprises, consisting of or consisting essentially of, cells that over express protein kinase Mpsl / TTK, such as expressing Mpsl / TTK at a level that is at least 120%, 150%, or 200% of the normal Mpsl / TTK expression level. The normal Mpsl / TTK expression level can be determined by Mpsl / TTK expression levels of healthy individuals using methods known in the art. In some cases, the cancer comprises cells with a competent STING and / or MAVS signalling pathway. In some embodiments, the cancer comprises cells with mutated KRAS, LKB1, and / or BRAF.

[0177] In some implementations, provided are uses of a compound described herein for the treatment of cancer. A compound may be any compound described in Section I. In some embodiments, the compound is a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the cancer is brain cancer, glioblastoma multiforme, head and neck cancers, 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 instances, the cancer is not defined by its tissue of origin but rather by a biomarker of susceptibility to Mpsl / TTK inhibition. For example, in some cases, the cancer comprises, consisting of or consisting essentially of, cells that over express protein kinase Mpsl / TTK, such as expressing Mpsl / TTK at a level that is at least 120%, 150%, or 200% of the normal Mpsl / TTK expression level. The normal Mpsl / TTK expression level can be determined by Mpsl / TTK expression levels of healthy individuals using methods known in the art. In some cases, the cancer comprises cells with a competent STING and / or MAVS signalling pathway. In some instances, the cancer comprises cells with mutated KRAS, LKB1, and / or BRAF.

[0178] Methods for determining the presence and level of Mpsl / TTK protein and / or mRNA are known in the art, such as those described in Kasbek C, et al. 2010. Antizyme RestrainsCentrosome Amplification by Regulating the Accumulation of Mpsl at Centrosomes. Molecular Biology of the Cell 21 :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 STING and MAVS pathway status and / or competency are known in the art, such as those described in Kitajima S, et al. 2019. Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer. Cancer Discov. Jan;9(l):34-45; Kitajima S, et al. 2022. MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer. Cancer Cell. 2022 Oct 10;40(10): 1128-1144. e8; and Sasaki et al., RNA sensing induced by chromosome missegregation augments anti-tumor immunity, Molecular Cell (2024).

[0179] In a still further instance, provided is a method of treating a patient in need of an inhibitor of protein kinase Mpsl / TTK, which method comprises, consists of, or consists essentially of determining the level of Mpsl / TTK protein and / or mRNA in a cell, such as a cancer cell, of the patient, and administering a therapeutically effective amount of a compound of a compound described herein, or a tautomer, and / or a pharmaceutically acceptable salt and / or solvate thereof, to the patient if the presence of Mpsl / TTK protein and / or mRNA is detected.

[0180] In some embodiments, the patient is administered a compound described herein after detection of an over-expression of Mpsl / TTK in a cell of the patient, such as an expression of Mpsl / TTK that is at least 120%, 150%, or 200% of the normal Mpsl / TTK expression level. In some aspects, the patient is a cancer patient. In some cases, the patient is a brain cancer, glioblastoma multiforme, head and neck cancers, 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 patient.

[0181] Moreover, in some implementations, provided is a method of treating a patient in need of an inhibitor of protein kinase Mpsl / TTK. In some embodiments, such a method comprises, consists of, or consists essentially of determining the level of susceptibility to Mpsl / TTK protein inhibition in a cell, such as a cancer cell, of the patient, and administering a therapeutically effective amount of a compound described herein, or a tautomer, and / or a pharmaceutically acceptable salt and / or solvate thereof, to the patient if the suseptibility to Mpsl / TTK protein inhibition is detected. The level of susceptibility may be determined according to evaluation of a biomarker, as described above.

[0182] In some embodiments, the patient is administered a compound described herein after detection of a biomarker of susceptibility to Mpsl / TTK inhibition. In some cases, a biomarker is an over-expression of Mpsl / TTK in a cell of the patient, such as an expression of Mpsl / TTK that is at least 120%, 150%, or 200% of the normal Mpsl / TTK expression level. In some instances, the biomarker may be an indicator of a competent STING and / or MAVS signalling 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 is a 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, or endometrial cancer patient. In other cases, the patient is a one whose disease is characterized by a biomarker of susceptibility to Mpsl / TTK inhibition.

[0183] In a still further instance, provided is a method of treating a patient in need of an inhibitor of protein kinase Mpsl / TTK, which method comprises, consists of, or consists essentially of, determining the triple negative status of a breast cancer patient in a cancer cell of the patient; and administering a therapeutically effective amount of a compound of a compound described herein, or a tautomer, and / or a pharmaceutically acceptable salt and / or solvate thereof, to the patient if the cancer cell is triple negative status. A compound may be any compound described in Section I. In some embodiments, the compound is a compound of Formula I, or a tautomer, and / or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the compound is a compound of Formula II, or a tautomer, and / or a pharmaceutically acceptable salt and / or solvate thereof. In some other embodiments, the compound is a compound of Formula III, or a tautomer, and / or a pharmaceutically acceptable salt and / or solvate thereof.

[0184] In any of the embodiments of the methods described herein, the method may involve the administration of a pharmaceutical composition, where the pharmaceutical composition includes any one of the embodiments of the compounds of the present technology or a pharmaceutically acceptable salt thereof as well as a pharmaceutically acceptable carrier or excipient.

[0185] In any of the embodiments of the methods described herein, the method may involve the administration of a pharmaceutical composition, where the pharmaceutical composition includes an effective amount of any one of the embodiments of the compounds of the presenttechnology or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In some embodiments, the effective amount is from about 0.01 pg to about 900 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.01 pg to about 800 mg of the compound per gram of the composition. In some instances, the effective amount is from about 0.01 pg to about 700 mg of the compound per gram of the composition. In some cases, the effective amount is from about 0.01 pg to about 600 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.01 pg to about 500 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.01 pg to about 400 mg of the compound per gram of the like. In some implementations, the effective amount is from about 0.01 pg to about 300 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.01 pg to about 200 mg of the compound per gram of the composition. In some cases, the effective amount is from about 0.01 pg to about 100 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.1 pg to about 500 pg of the compound per gram of the 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 therein. In some embodiments, the effective amount of the compound is from about 10 mg to about 500 mg. In some embodiments, the compositions per unit dosage contain from about 0.1 % to about 99% of the compound. In some embodiments, the compositions per unit dosage contain from about 10% to about 60% of the compound.

[0187] In some aspects, provided is a kit comprising, consisting essentially of, or consisting of an effective amount of a compound described herein, and optionally instructions for use. A compound may be any compound described in Section I, such a compound of Formula I, Formula II, or Formula III. In some aspects, the instructions comprise, consist essentially of, or consist of a description of a method of treatment as described herein.

[0188] Some embodiments are further illustrated in the following non-limiting Examples.EXAMPLES

[0189] The following Examples describe the synthesis and testing of various novel small molecule Mpsl / TTK inhibitors as targeted therapies for cancer. Mpsl / TTK inhibitors were synthesized as indicated. The compounds were evaluated for their activity against Mpsl / TTK and tested using antiproliferative assays. The data from the assays indicate the synthesized compounds possess activity against Mpsl / TTK and have anti-proliferative potential in cancer cell lines.Compound Synthesis

[0190] Mpsl / TTK inhibitor compounds and comparative compounds were synthesized making modifications of Formula I at R1, R2, R3, R4, R?, R6, R7, and Y as indicated in Tables 1 and 2, respectively.Table 1. Structures of Mpsl / TTK inhibitor compounds.Table 2. Structures of comparative compounds.

[0191] The synthesis of compounds 1, 2, 4, 6, 9, 33, 40, 43, 45, 49, 53, 54, 56, 67, and 68 is described herein. Other compounds shown in Tables 1 and 2 were synthesized in a similar manner to the compounds described herein.Step 1. Synthesis of Compound B.

[0192] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (Compound A) (100 g, 532 mmol, 1.00 eq) in DCM (700 mL) NBS (94.7 g, 532 mmol, 1.00 eq) was added. The mixture was stirred at 25°C for 4 hours. LC-MS showed the desired MS was detected. Two batches were completed and combined. The reaction was diluted with H2O (350 mL) and extracted with ethyl acetate three times (300 mL each). The organic layers were separated, washed with aqueous NaHCCh twice (400 mL each), washed with brine twice (400 mL each), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The crude product was triturated withMeCN at 25°C for 12 hours. 5-Bromo-2,4-dichloro-lH-pyrrolo[2,3-d]pyrimidine (Compound B) (250 g, 937 mmol, 88.1% yield) was obtained as a brown solid.Step 2. Synthesis of Compound C.

[0193] To a solution of 5-bromo-2,4-dichloro-lH-pyrrolo[2,3-d]pyrimidine (Compound B) (50.0 g, 187 mmol, 1.00 eq) in THF (600 mL), n-BuLi (2.50 M, 299 mL, 4.00 eq) was slowly added dropwise at -70°C. After the reaction mixture was stirred at -70°C for 1.5 hours, CH3I (79.8 g, 562 mmol, 35.0 mL, 3.00 eq) was added. The reaction mixture was stirred at -70 °C for 1.5 hours. LC-MS showed the desired MS was detected. The reaction was quenched with aqueous NH4CI solution (800 mL) at 10°C. The mixture was extracted with ethyl acetate three times (500 mL each). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was triturated with ethyl acetate at 25°C for 12 hours. 2,4- Dichloro-5-methyl-lH-pyrrolo[2,3-d]pyrimidine (Compound C) (32.0 g, 158 mmol, 84.6% yield) was obtained as a brown solid.Step 3. Synthesis of Compound D.

[0194] To a solution of 2,4-dichloro-5-methyl-lH-pyrrolo[2,3-d]pyrimidine (Compound C) (30.0 g, 148 mmol, 1.00 eq) in DCM (180 mL), TsCl (29.7 g, 156 mmol, 1.05 eq), DMAP (1.81 g, 14.8 mmol, 14.0 mL, 0.10 eq), and DIPEA (21.1 g, 163 mmol, 1.10 eq) were added under N2. The mixture was stirred at 20°C for 1 hour. LC-MS indicated the desired MS was detected. The reaction was quenched by H2O and diluted with ethyl acetate. The organic layers were washed with 1 M HC1. The pH was adjusted to 7 with NaHCCh. The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was triturated 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) (40.0 g, 112 mmol, 75.6% yield) was obtained as a white solid.Step 4. Synthesis of Compound E.

[0195] 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 eq) in DMF (175 mL), dioxane (175 mL), DIPEA (50.8 g, 393 mmol, 68.4 mL, 4.00 eq), and cyclohexylamine (19.5 g, 196 mmol, 2.00 eq) were added. The mixture was stirred at 25°C for 12 hours. LC-MS showed the desired compound was detected. The reaction mixture was quenched by the addition of H2O (200 mL) at 25°C and then extracted with DCM (400 mL). The combined organic layers were washed with brine, driedover Na2SO4, filtered, and concentrated under reduced pressure to yield a residue. The crude product was triturated with ethyl acetate at 25°C for 12 hours. Compound E (30.0 g, 71.6 mmol, 72.9% yield) was obtained as a white solid.Step 5. Synthesis of Compound F.

[0196] To a solution of Compound E (8.00 g, 19.1 mmol, 1.00 eq) in DMF (80.0 mL) 2- methoxy-4-(4-morpholinyl)aniline (4.77 g, 22.9 mmol, 1.20 eq), CS2CO3 (12.4 g, 38.2 mmol, 2.00 eq) and XPhos (1.82 g, 3.82 mmol, 0.20 eq) were added. The mixture was degassed and purged with N2 3 times. Then, Pd2(dba)3 (1.75 g, 1.91 mmol, 0.10 eq) was added. The mixture was stirred at 120°C for 12 hours. LC-MS showed the desired compound was detected. The reaction mixture was filtered, and the filter liquid was diluted with H2O (240 mL) and extracted with a total of 320 mL of DCM over three extractions (160 mL, 100 mL, and 60.0 mL in the extractions, respectively). The combined organic layers were washed with brine twice (20 mL each), dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate at 25°C for 2 hours. Compound F (5.00 g, 8.46 mmol, 44.3% yield) was obtained as a yellow solid.Step 6. Synthesis of Compound 1.[00197J To a solution of Compound F (5.00 g, 8.46 mmol, 1.00 eq) in Methanol (50.0 mL) and THF (50.0 mL) was added NaOH (744 mg, 18.6 mmol, 2.20 eq). The mixture was stirred at 70°C for 12 hour. LC-MS showed the desired compound was detected. The reaction mixture was filtered. The filter cake was eluted with Methanol (30.0 mL) and dried under vacuum to afford the product. Compound 1 (1.10 g, 2.52 mmol, 29.8% yield) was obtained as an off-white solid. 'H NMR (400 MHz, DMSO) 5 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: [M+H]1calcd for C24H32N6O2: 437.26; found: 437.3.Preparation of Compound 2Step 1. Synthesis of Compound H.

[0198] To a mixture of Compound G (1.30 g, 2.96 mmol, 1.00 eq) and 2-methoxy-4-(4- morpholinyl)aniline (925.01 mg, 4.44 mmol, 1.50 eq) in Z-BuOH (10 mL), Pd2(dba)3 (271.16 mg, 296.11 pmol, 0.10 eq), XPhos (141.16 mg, 296.11 pmol, 0.10 eq), and LBuONa (569.13 mg, 5.92 mmol, 2.00 eq) were added at 20°C. Then, the mixture was stirred at 100°C for 12 hours under N2. LC-MS showed the reaction was complete. Compound G was consumed, and the desired target MS was detected. H2O (10 mL) was added to the mixture, and the aqueous portion was extracted with DCM three times (5 mL each). 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 obtained as a black solid.Step 2. Synthesis of Compound I.

[0199] To a solution of Compound H (300.00 mg, 502.69 pmol, 1.00 eq) and MeNFk (50.91 mg, 754.03 pmol, 1.50 eq) in DMF (1 mL), HATU (286.71 mg, 754.03 pmol, 1.50 eq) and TEA (152.60 mg, 1.51 mmol, 209.90 pL, 3.00 eq) were added at 20°C. Then, the solution was stirred at 20°C for 2 hours. LC-MS showed Compound H was consumed and the desired target mass was detected. The mixture was concentrated. H2O (10 mL) was added to the solution. Then, the solution was extracted with ethyl acetate three times (10 mL each). The organic layers were dried with Na2SO4 and then concentrated. The residue was purified with preparative TLC (SiCh, Petroleum ether: Ethyl acetate = 0: 1). Compound I (274.00 mg, crude) was obtained as a brown solid.Step 3. Synthesis of Compound J.

[0200] A solution of Compound I (150.00 mg, 245.97 pmol, 1.00 eq) in TFA (1 mL) and DCM (1 mL) was stirred at 20°C for 1 hour. LC-MS showed Compound I was consumed and the desired target mass was detected. The mixture was concentrated. Compound J (120.00 mg, crude, TFA) was obtained as a brown solid.Step 4. Synthesis of Compound 2.

[0201] To a solution of Compound J (120.00 mg, 192.42 pmol, 1.00 eq, TFA) in THF (1 mL) and Methanol (1 mL) and NH4OH (4 mL) were added at 20°C. Then, the solution was stirred at 20°C for 12 hours. LC-MS showed Compound J was consumed 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 pmol, 28.44% yield, 99.03 % purity) was obtained as a white solid. 'H NMR (DMSO- e 400 MHz) 5 = ppm 9.58 (br d, J= 7.60 Hz, 1H) 8.28 (d, .7= 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: [M+H]‘ calcd for C25H33N7O3:480.26; found: 480.2.Compound 4Step 1 . Synthesis of Compound L.

[0202] To a solution of Compound K (500.00 mg, 2.38 mmol, 1.00 eq) in DCE (8 mL) SOCh (1.42 g, 11.89 mmol, 862.84 pL, 5.00 eq) was added at 20°C. Then, the solution was stirred at 90°C for 2 hours. Then, the solution was concentrated, and the residue was dissolved in DMF (4 mL). Formic hydrazide (285.72 mg, 4.76 mmol, 2.00 eq) was added to the solution, and the mixture was stirred at 100°C for 12 hours. LC-MS showed Compound K was consumed and the desired target mass was detected. Saturated aqueous NFLCl (5 mL) was added to the solution, and then, the mixture was extracted with ethyl acetate three times (10 mL each). The combined organic layers were dried over Na2SCU and then concentrated. The residue was purified via preparative TLC (SiCh, Ethyl acetate: Methanol = 5: 1). Compound L (180.00 mg, crude) was obtained as a white solid.Step 2. Synthesis of Compound M.

[0203] To a solution of Compound L (150.00 mg, 640.45 pmol, 1.00 eq) in EtOH (2 mL) and FEO (0.40 mL) was added Fe (178.83 mg, 3.20 mmol, 5.00 eq) and NFLCl (171.29 mg, 3.20 mmol, 5.00 eq) at 20°C. Then, the solution was stirred at 80°C for 12 hours. LC-MS showed Compound L was synthesized and consumed and that 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 then the solution was extracted with ethyl acetate three times (15 mL each). The organic layers were dried with Na2SO4 and then concentrated. Compound M (130.00 mg, 636.54 pmol, 99.39% yield) was obtained as a brown solid.Step 3. Synthesis of Compound 4.

[0204] To a solution of Compound M (110.00 mg, 538.61 pmol, 1 .00 eq) and Compound N (171.12 mg, 646.34 pmol, 1.20 eq) in LBuOH (5 mL), Pd2(dba)3(49.32 mg, 53.86 pmol, 0.10 eq), XPhos (25.68 mg, 53.86 pmol, 0.10 eq) and Z-BuONa (103.53 mg, 1.08 mmol, 2.00 eq) were added at 20 °C. Then, the solution was stirred at 100°C for 2 hours under N2. LC-MS showed Compound M was consumed and the desired target mass was detected. The mixture was concentrated. The residue was purified by preparative HPLC. Compound 4 (34.50 mg, 69.49 pmol, 12.90% yield, 96.39% purity) was obtained as a white solid.1H NMR (DMSO-t / c, 400 MHz) 8 = ppm 10.63-10.93 (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: [M+H]+calcd for C23H28N O: 433.24; found:433.2.Preparation of Compound 6Step 1. Synthesis of Compound P.

[0205] To a solution of Compound O (25.00 g, 177.13 mmol, 1.00 eq) in acetic acid (AcOH) (200 mL) Bn (33.97 g, 212.55 mmol, 10.96 mL, 1.20 eq) was added at 20°C. Then, the solution was stirred at 20°C for 12 hours. LC-MS showed Compound O was consumed and that the desired target MS was detected. H2O (200 mL) was added to the mixture, and then, the mixture was extracted with ethyl acetate three times (200 mL). The combined organic layers were washed with brine (100 mL), then dried over Na2SO4, and then concentrated to yield 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 obtained as a yellow solid.Step 2. Synthesis of Compound Q.

[0206] To a solution of Compound P (5.00 g, 22.72 mmol, 1.00 eq) in Methanol (20 mL), TEA (4.60 g, 45.45 mmol, 6.33 mL, 2.00 eq) and Pd(dppf)C12 were added. DCM was added (1.86 g, 2.27 mmol, 0.10 eq) at 20°C, and then, the solution was stirred at 110°C for 12 hours under CO. LC-MS showed the reaction was completed. Compound P was consumed, and the desired target MS 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 obtained as a white solid.Step 3. Synthesis of Compound R.

[0207] To a solution of Compound Q (1.00 g, 5.02 mmol, 1.00 eq) in EtOH (10 mL), NH2NH2was added. H2O (1.28 g, 25.10 mmol, 1.24 mL, 98% purity, 5.00 eq) was then added at 20 °C, and the solution was stirred at 80 °C for 12 hours. LC-MS showed the reaction was completed. Compound Q was consumed, and the desired target MS was detected. The mixture was concentrated. H2O (20 mL) was added to the mixture, and the aqueous portion was extracted with DCM three times (20 mL each). The combined organic layers were dried over Na2SCU and then concentrated under reduced pressure. The residue was purified by MPLC (SiC>2, Ethyl acetate:Methanol = 1 :0 to 0: 1 ). Compound R (500.00 mg, 2.51 mmol, 50.00% yield) was obtained as a yellow solid.Step 4. Synthesis of Compound S.

[0208] To a solution of Compound R (500.00 mg, 2.51 mmol, 1.00 eq) in MeCN (10 mL), DMF-DMA (1.50 g, 12.55 mmol, 1.67 mL, 5.00 eq) was added at 20°C. Then, the solution was stirred at 60 °C for 1 hour. LC-MS showed that the reaction was completed. Compound R was consumed, and the desired target MS was detected. The mixture was concentrated. Compound S (600.00 mg, crude) was obtained as a yellow oil.Step 5. Synthesis of Compound T.

[0209] Compound S (600.00 mg, 2.36 mmol, 1.00 eq) and MeNEE (318.66 mg, 4.72 mmol, 2.00 eq, HC1) in MeCN (10 mL) were added to AcOH (212.56 mg, 3.54 mmol, 202.64 pL, 1.50 eq) at 20 °C, and then, the solution was stirred at 80°C for 12 hours. LC-MS showed the reaction was completed. Compound T was consumed, and the desired target MS was detected. H2O (20 mL) was added to the solution. Then, the mixture was concentrated to remove MeCN. The solution was extracted with ethyl acetate three times (15 mL). The organic layers were dried with Na2SO4 and then concentrated. The residue was purified by MPLC (SiCh, Petroleum ether:Ethyl acetate = 1 :0 to 0: 1). Compound T (200.00 mg, 900.02 pmol, 38.14% yield) was obtained as a white solid.Step 6. Synthesis of Compound 6.

[0210] To a solution of Compound T (107.96 mg, 485.81 pmol, 1.50 eq) and Compound U (100.00 mg, 323.87 pmol, 1.00 eq) in Z-BuOH (10 mL), Pd2(dba)s (29.66 mg, 32.39 pmol, 0.10 eq), XPhos (15.44 mg, 32.39 pmol, 0.10 eq) and K2CO3 (89.52 mg, 647.75 pmol, 2.00 eq) were added at 20°C. Then, the solution was stirred at 100°C for 12 hours under N2. LC-MS showedthe reaction was completed. Compound T was consumed, and the desired target MS 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 pm; mobile phase: A: formic acid in H2O, B: MeCN; gradient: 5% - 45% B over 8 min). Compound 6 (13.00 mg, 25.73 pmol, 7.94% yield, 97.88% purity) was obtained as a white solid.1H NMR (DMSO- e 400 MHz) 8 = 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: [M+H]+calcd for C24H27FN8O3: 495.22; found: 495.2.Step 1. Synthesis of Compound W.

[0211] To a mixture of Compound V (5.00 g, 25.11 mmol, 1.00 eq) and pyridine (3.97 g, 50.22 mmol, 4.05 mL, 2.00 eq) in Methanol (100 mL), NaSMe (4.64 g, 66.20 mmol, 4.22 mL, 2.64 eq) was added at 0°C, and then, the mixture was stirred at 20°C for 12 hours. TLC (SiCh, Petroleum etherEthyl acetate = 5: 1) indicated Compound V was consumed, and one spot was detected. The reaction mixture was quenched with the addition of 200 mL of saturated aqueous NH4CI at 0°C. Then, the reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate three times (100 mL each). The combined organic layers were washed with brine 3 times (100 mL each), dried over Na2SCU, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, Petroleum etherEthyl acetate = 1 :0 to 0: 1). Compound W (1.00 g, crude) was obtained as a yellow solid.Step 2. Synthesis of Compound X.

[0212] To a mixture of Compound W (1.00 g, 4.40 mmol, 1.00 eq) in Methanol (20 mL) and H2O (4 mL), LiOH was added. H2O (369.34 mg, 8.80 mmol, 2.00 eq) was added at 20°C, and then, the mixture was stirred at 20°C for 2 hours. LC-MS showed the reaction was complete. Compound W was consumed, and the desired target mass was detected. The mixture was concentrated to remove Methanol (20 mL). Then, H2O (20 mL) was added to the mixture, and then, HC1 (12 M) was added to the mixture to adjust the pH to 3. Then, the mixture was filtered, and the filtrate was concentrated. Compound X (1.00 g, crude) was obtained as a yellow solid. Step 3. Synthesis of Compound Y.

[0213] To a mixture of Compound X (1.00 g, 4.69 mmol, 1.00 eq) and MeNH2 (633.35 mg, 9.38 mmol, 2.00 eq, HC1) in DCM (50 mL), HATU (2.68 g, 7.04 mmol, 1.50 eq) and DIPEA (1.21 g, 9.38 mmol, 1.63 mL, 2.00 eq) were added at 20°C. Then, the mixture was stirred at 20°C for 2 hours. LC-MS showed the reaction was complete. Compound X was consumed, and the desired target mass was detected. H2O (500 mL) was added to the mixture, and the aqueous portion was extracted with DCM three times (300 mL each). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by preparative TLC (SiCh, Petroleum ether: Ethyl acetate = 3: 1). Compound Y (1.00 g, 4.42 mmol, 94.24% yield) was obtained as a yellow solid.Step 4. Synthesis of Compound Z.

[0214] To a mixture of Compound Y (1.00 g, 4.42 mmol, 1.00 eq) in MeCN (50 mL), NaNi (0.58 g, 8.92 mmol, 2.02 eq) and POCI3 (3.39 g, 22.10 mmol, 2.05 mL, 5.00 eq) were added at 0°C. Then, the mixture was stirred at 80°C for 12 hours under N2. LC-MS showed the reaction was complete. Compound Y was consumed, and the desired target mass was detected. Saturated aqueous Nal lCCh (100 mL) was added to the mixture to adjust pH to 7. Then, the mixture was extracted with ethyl acetate three times (3 each). The combined organic layers were dried over Na2SO4 and then concentrated. The aqueous phase was quenched by NaClO (200 mL). The residue was purified by preparative TLC (SiCh, Petroleum ether:Ethyl acetate = 3: 1). Compound Z (490.00 mg, 1.95 mmol, 44.12% yield) was obtained as a yellow solid.Step 5. Synthesis of Compound AA.

[0215] To a mixture of Compound Z (480.00 mg, 1.91 mmol, 1.00 eq) in EtOH (20 mL) and H2O (4 mL), Fe (533.41 mg, 9.55 mmol, 5.00 eq) and NH4CI (510.93 mg, 9.55 mmol, 5.00 eq)were added at 20°C. Then, the mixture was stirred at 80°C for 2 hours. LC-MS showed the reaction was complete. Compound Z was consumed, 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 was extracted with DCM three times (30 mL each). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. Compound AA (400.00 mg, crude) was obtained as a yellow solid.Step 6. Synthesis of Compound 9.

[0216] To a mixture of Compound AA (86.28 mg, 389.89 pmol, 1.20 eq) and Compound AS (100.00 mg, 324.91 pmol, 1.00 eq) in / -BuOH (5 mL), Pd2(dba)3(29.75 mg, 32.49 pmol, 0.10 eq), XPhos (15.49 mg, 32.49 pmol, 0.10 eq), and Z-BuONa (62.45 mg, 649.82 qmol, 2.00 eq) were added at 20°C. Then, the mixture was stirred at 100°C for 12 hours. LC-MS showed the reaction was complete. Compound AA was consumed, 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 (21.10 mg, 41.85 pmol, 12.88% yield, 97.7% purity) was obtained as a white solid. ’H NMR (DMSO- r, 400 MHz) 5 = 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: [M+H]+calcd for C23H28N10OS: 493.22; found: 493.2.Preparation of Compound 33Compound AECompound 33Step 1. Synthesis of Compound AC.

[0217] To a solution of Compound AB (5.00 g, 25.36 mmol, 1.00 eq) and M0NH2 (1.58 g, 23.33 mmol, 0.92 eq, HC1) in THF (250 mL) DIPEA (4.92 g, 38.04 mmol, 6.63 mL, 1.50 eq) and HATU (12.54 g, 32.97 mmol, 1.30 eq) were added at 20°C. Then, the solution was stirred at 20°C for 12 hours. LC-MS showed the reaction was completed. Compound AB was consumed, and the desired target MS was detected. The mixture was concentrated to remove THF. Then, H2O (150 mL) was added to the solution. Then, the solution was extracted with ethyl acetate three times (200 mL each), and the organic layers were dried with Na2SO4 and then concentrated. The residue was purified by MPLC (SiCh, Petroleum ether:Ethyl acetate = 1 :0 to 0: 1).Compound AC (4.10 g, crude) was obtained as a yellow solid.Step 2. Synthesis of Compound AD.

[0218] To a mixture of Compound AC (1.00 g, 4.76 mmol, 1.00 eq) and NaNs (1.180 g, 18.15 mmol, 3.82 eq) in MeCN (20 mL), TfzO (2.68 g, 9.52 mmol, 1.57 mL, 2.00 eq) was added at -10°C. Then, the mixture was stirred at 20°C for 3 hours. TLC (SiCh, Petroleum ether:Ethyl acetate = 1:1) indicated Compound AC was consumed, and one spot was detected. Saturated aqueous NaHCOi was added to the mixture to adjust the pH to 7, and then, the mixture was extracted with ethyl acetate three times (100 mL each). The combined organic layers were dried over Na2SO4 and then concentrated. The residue was purified by column chromatography (SiCh,Petroleum etherEthyl acetate = 1 :0 to 0: 1). Compound AD (540.00 mg, 1.95 mmol, 41.02% yield, 85% purity) was obtained as a yellow solid.Step 3. Synthesis of Compound AE.

[0219] To a mixture of Compound AD (200.00 mg, 850.34 pmol, 1.00 eq) in Methanol (3 mL) 10% Pd / C (100.00 mg, 50% purity) was added at 20°C. Then, the mixture was stirred at 20°C for 2 hours under H2 (15 psi). LC-MS showed the reaction was complete. Compound AD was consumed, and the desired target MS was detected. The mixture was filtered, and the filtrate was concentrated. Compound AE (136.00 mg, crude) was obtained as a white solid. Step 4. Synthesis of Compound 33.

[0220] To a mixture of Compound AE (136.00 mg, 662.72 pmol, 1.00 eq) and Compound N (210.55 mg, 795.26 pmol, 1.20 eq) in Z-BuOH (5 mL), Pd2(dba)3(60.69 mg, 66.27 pmol, 0.10 eq), XPhos (31.59 mg, 66.27 pmol, 0.10 eq), and Z-BuONa (127.38 mg, 1.33 mmol, 2.00 eq) were added at 20 °C. Then, the mixture was stirred at 100°C for 12 hours. LC-MS showed the reaction was complete. Compound AE was consumed, and the desired target MS was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC. Compound 33 (48.6 mg, 99.57 pmol, 15.03% yield, 98.25% purity) was obtained as a white solid. ’H NMR (DMSO-t / e 400 MHz) 5 = ppm 10.97 - 10.81 (m, 1H), 8.89 (d, .7= 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: [M+H]+calcd for C22H27N9O: 434.23; found: 434.1.Preparation of Compound 40Step 1. Synthesis of Compound B.

[0221] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (Compound A) (100 g, 532 mmol, 1.00 eq) in DCM (700 mL), NBS (94.7 g, 532 mmol, 1.00 eq) was added. The mixture was stirred at 25°C for 4 hours. LC-MS showed the desired MS was detected. Two batches were completed and combined. The reaction was diluted with H2O (350 mL) and extracted with ethyl acetate three times (300 mL each). The organic layers were separated, washed with aqueous NaHCCh twice (400 mL each), washed with brine twice (400 mL each), dried over Na2SO4, and concentrated under reduced pressure to give a residue. The crude product was triturated with MeCN at 25°C for 12 hours. 5-Bromo-2,4-dichloro-lH-pyrrolo[2,3- d]pyrimidine (Compound B) (250 g, 937 mmol, 88.1% yield) was obtained as a brown solid. Step 2. Synthesis of Compound C.

[0222] To a solution of 5-bromo-2,4-dichloro-lH-pyrrolo[2,3-d]pyrimidine (Compound B) (50.0 g, 187 mmol, 1.00 eq) in THF (600 mL), / z-BuLi (2.50 M, 299 mL, 4.00 eq) was slowly added dropwise at -70°C. After the reaction mixture was stirred at -70°C for 1.5 hours, CH3I (79.8 g, 562 mmol, 35.0 mL, 3.00 eq) was added. The reaction mixture was stirred at -70 °C for 1.5 hours. LC-MS showed the desired MS was detected. The reaction was quenched with aqueous NH4CI solution (800 mL) at 10°C. The mixture was extracted with ethyl acetate three times (500 mL each). The organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated. The crude product was triturated with ethyl acetate at 25°C for 12 hours. 2,4- Dichloro-5-methyl-lH-pyrrolo[2,3-d]pyrimidine (Compound C) (32.0 g, 158 mmol, 84.6% yield) was obtained as a brown solid.Step 3. Synthesis of Compound D.

[0223] To a solution of 2,4-dichloro-5-methyl-lH-pyrrolo[2,3-d]pyrimidine (Compound C) (30.0 g, 148 mmol, 1.00 eq) in DCM (180 mL), TsCl (29.7 g, 156 mmol, 1.05 eq), DMAP (1.81 g, 14.8 mmol, 14.0 mL, 0.10 eq), and DIPEA (21.1 g, 163 mmol, 1.10 eq) were added under N2. The mixture was stirred at 20°C for 1 hour. LC-MS indicated the desired MS was detected. The reaction was quenched by H2O and diluted with ethyl acetate. The organic layers were washed with 1 M HC1. The pH was adjusted to 7 with NaHCC . The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was triturated 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) (40.0 g, 112 mmol, 75.6% yield) was obtained as a white solid.Step 4. Synthesis of Compound E.

[0224] 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 eq) in DMF (175 mL), dioxane (175 mL), DIPEA (50.8 g, 393 mmol, 68.4 mL, 4.00 eq), and cyclohexylamine (19.5 g, 196 mmol, 2.00 eq) were added. The mixture was stirred at 25°C for 12 hours. LC-MS showed the desired compound was detected. The reaction mixture was quenched by the addition of 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 yield a residue. The crude product was triturated with ethyl acetate at 25°C for 12 hours. Compound E (30.0 g, 71.6 mmol, 72.9% yield) was obtained as a white solid.Step 5. Synthesis of Compound AG.

[0225] To a solution of Compound E (10.0 g, 23.8 mmol, 1.00 eq) in DMF (100 mL), Compound AF (5.99 g, 28.6 mmol, 1.20 eq, preparation described below), CS2CO3 (11.7 g, 35.8 mmol, 1.50 eq) and XPhos (2.28 g, 4.77 mmol, 0.20 eq) were added. The mixture was degassed and purged with N2 3 times. Pd2(dba)3 (2.19 g, 2.39 mmol, 0.10 eq) was added. The mixture was degassed and purged with N2 3 times. Then, the mixture was stirred at 130°C for 12 hours. TLC (Petroleum etherEthyl acetate = 1 : 1, Rf = 0.41) indicated Compound E was consumed completely. The reaction mixture was fdtered, and the fdter liquid was diluted with H2O (200 mL) and extracted with DCM three times (80.0 mL, 60.0 mL, and 30.0 mL for each extraction, respectively). The combined organic layers were washed with brine twice (50.0 mL each), driedover Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether:Ethyl acetate = 30: 1 to 10: 1). Compound AG (8.50 g, 14.4 mmol, 60.2% yield) was obtained as a yellow solid.Step 6. Synthesis of Compound 40.

[0226] To a solution of Compound AG (3.00 g, 5.07 mmol, 1.00 eq) in Methanol (30.0 mL) and THF (30.0 mL), NaOH (446 mg, 11.1 mmol, 2.20 eq) was added. The mixture was stirred at 70°C for 12 hours. LC-MS show the desired MS was detected. The reaction mixture was filtered, and the filter cake was eluted with Methanol (20.0 mL) and dried under vacuum to afford Compound 40. Compound 40 (1.00 g, 2.11 mmol, 41.6% yield, HC1) was obtained as an off-Compound AH Compound Al Compound AJCompound 43Step 1. Synthesis of Compound Al.

[0227] To a mixture of Compound AH (500.00 mg, 2.92 mmol, 1.00 eq) and 2- methylimidazole (359.84 mg, 4.38 mmol, 1.50 eq) in DMF (10 mL), CS2CO3 (1.90 g, 5.84 mmol, 2.00 eq) was added at 20°C. Then, the mixture was stirred at 80°C for 2 hours. LC-MS showed the reaction was complete. Compound AH was consumed, and the desired target MS was detected. H2O (100 mL) was added to the mixture, and the aqueous portion was extracted with DCM three times (30 mL each). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. Compound Al (600.00 mg, crude) was obtained as a yellow solid.Step 2. Synthesis of Compound AJ.

[0228] To a mixture of Compound Al (600.00 mg, 2.57 mmol, 1.00 eq) in Methanol (20 mL), 10%Pd / C (400.00 mg, 50% purity) was added at 20 °C. Then, the mixture was stirred at 20°C for 2 hours under H2 (15 psi). LC-MS showed the reaction was complete. Compound Al was consumed, and the desired target MS was detected. The mixture was filtered, and the filtrate was concentrated. Compound AJ (660.00 mg, crude) was obtained as a black oil.Step 3. Synthesis of Compound 43.

[0229] To a mixture of Compound AJ (78.99 mg, 388.65 pmol, 1.20 eq) and Compound U (100.00 mg, 323.87 pmol, 1.00 eq) in / -BuOH (5 mL), Pd2(dba)s (29.66 mg, 32.39 pmol, 0.10 eq), XPhos (15.44 mg, 32.39 pmol, 0.10 eq), and Z-BuONa (62.25 mg, 647.75 pmol, 2.00 eq) were added at 20°C. Then, the mixture was stirred at 100°C for 2 hours under N2. LC-MS showed the reaction was complete. Compound AJ was consumed, and the desired target MS 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 pmol, 29.91% yield, 98.69% purity) was obtained as a white solid.1H NMR (DMSO- is, 400 MHz) 8 = 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: [M+H]+calcd for C25H29N7O3: 476.23; found: 476.2.Preparation of Compound 45Compound AECompound 45Step 1. Synthesis of Compound AC.

[0230] To a solution of Compound AB (5.00 g, 25.36 mmol, 1.00 eq) and MeNIE (1.58 g, 23.33 mmol, 0.92 eq, HC1) in THF (250 mL), DIPEA (4.92 g, 38.04 mmol, 6.63 mL, 1.50 eq) and HATU (12.54 g, 32.97 mmol, 1.30 eq) were added at 20°C. Then, the solution was stirred at 20°C for 12 hours. LC-MS showed the reaction was completed. Compound AB was consumed, and the desired target MS was detected. The mixture was concentrated to remove THF. H2O (150 mL) was added to the solution, and then the solution was extracted with ethyl acetate three times (200 mL each). The organic layers were dried with Na2SO4 and then concentrated. The residue was purified by MPLC (SiCh, Petroleum ethenEthyl acetate = 1 :0 to 0: 1). Compound AC (4.10 g, crude) was obtained as a yellow solid.Step 2. Synthesis of Compound AD.

[0231] To a mixture of Compound AC (1.00 g, 4.76 mmol, 1.00 eq) and NaNs (1.180 g, 18.15 mmol, 3.82 eq) in MeCN (20 mL), Tf2O (2.68 g, 9.52 mmol, 1.57 mL, 2.00 eq) was added at -10°C. Then, the mixture was stirred at 20 °C for 3 hours. TLC (SiCh, Petroleum etherEthyl acetate = 1 :1) indicated Compound AC was consumed, and one spot was detected. Aqueous saturated NaHCCh was added to the mixture to adjust the pH to 7, and then, the mixture was extracted with ethyl acetate three times (100 mL each). The combined organic layers were dried over Na2SO4 and then concentrated. The residue was purified by column chromatography (SiCh,Petroleum etherEthyl acetate = 1 :0 to 0: 1). Compound AD (540.00 mg, 1.95 mmol, 41.02% yield, 85% purity) was obtained as a yellow solid.Step 3. Synthesis of Compound AE.

[0232] To a mixture of Compound AD (200.00 mg, 850.34 pmol, 1.00 eq) in Methanol (3 mL), 10% Pd / C (100.00 mg, 50% purity) was added at 20 °C. Then, the mixture was stirred at 20°C for 2 hours under H2 (15 psi). LC-MS showed the reaction was complete, Compound AD was consumed, and the desired target MS was detected. The mixture was filtered, and the filtrate was concentrated. Compound AE (136.00 mg, crude) was obtained as a white solid.Step 4. Synthesis of Compound 45.

[0233] To a mixture of Compound AE (100.00 mg, 487.29 pmol, 1.00 eq) and Compound U (180.55 mg, 584.75 pmol, 1.20 eq) in Z-BuOH (5 mL), Pd2(dba)3(44.62 mg, 48.73 pmol, 0.10 eq), XPhos (23.23 mg, 48.73 pmol, 0.10 eq), and K2CO3 (134.69 mg, 974.58 pmol, 2.00 eq) were added at 20°C. Then, the mixture was stirred at 100°C for 12 hours under N2. LC-MS showed the reaction was complete, Compound AE was consumed, and the desired target MS 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 pmol, 3.05% yield, 99.31 % purity) was obtained as a white solid.1H NMR (DMSO-t / e, 400 MHz) 8 = 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: [M+H]+calcd for C23H27N9O3: 478.22; found: 478.2.Step 1. Synthesis of Compound AM.

[0234] To a solution of Compound AK (1.62 g, 7.00 mmol, 1.00 eq) and Compound AL (1.90 g, 8.40 mmol, 1.20 eq) in dioxane (48 mL), H2O (12 mL), Na2COs (1.48 g, 14.00 mmol, 2.00 eq), and Pd(dppf)C12 (512.30 mg, 700.15 pmol, 0.10 eq) were added at 20 °C. Then, the solution was stirred at 80°C for 12 hours. LC-MS showed that the reaction was completed. Compound AK was consumed, and the desired target mass was detected. H2O (80 mL) was added to the solution. Then, the solution was extracted with ethyl acetate three times (80 mL each). The organic layers were dried with Na2SO4 and then concentrated. The residue was purified by MPLC (SiCh, Petroleum ether:Ethyl acetate = 0: 1 to 1 :0). Compound AM (2.65 g, crude) was obtained as a yellow solid.Step 2. Synthesis of Compound AN.

[0235] To a solution of Compound AM (1.95 g, 7.76 mmol, 1.00 eq) in DCM (30 mL), m- CPBA (4.73 g, 23.28 mmol, 85% purity, 3.00 eq) was added at 0°C. The mixture was stirred at 25°C for 12 hours. LC-MS showed the reaction was complete. Compound AM was consumed, and the desired target mass was detected. The mixture was quenched with aqueous saturated Na2SC>3 (20 mL), and then, aqueous saturated Na2CO3 was added to the solution to adjust the pH to7. H2O (50 mL) was added to the solution. Then the solution was extracted with DCM three times (100 mL each). The organic layers were dried with Na2SC>4 and then concentrated. The residue was purified by column chromatography (Plate 1 : Ethyl acetate:Petroleum ether 3 : 1 (UV 254 nm), SiCh, Petroleum etherEthyl acetate = 99: 1 to 10: 1; Ri=0.49). Compound AN (590.00 mg, 2.08 mmol, 26.84% yield) was obtained as a white solid.Step 3. Synthesis of Compound AO.

[0236] To a solution of Compound AN (500.00 mg, 1.76 mmol, 1.00 eq) in Methanol (10 mL) 10% Pd / C (100.00 mg, 50% purity) was added at 25 °C. The mixture was stirred at 25°C for 12 hours under H2 (15 psi). LC-MS showed the reaction was complete. Compound AN was consumed, and the desired target mass was detected. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (SiCh, Petroleum etherEthyl acetate = 3: 1). Compound AO (420.00 mg, 1.64 mmol, 93.20% yield) was obtained as a black solid.Step 4. Synthesis of Compound 49.

[0237] To a solution of Compound AO (100.00 mg, 391.65 pmol, 1.00 eq) in / -BuOH (5 mL), XPhos (18.67 mg, 39.17 pmol, 0.10 eq), Pd2(dba).3 (35.86 mg, 39.17 pmol, 0.10 eq), K2CO3 (162.38 mg, 1.17 mmol, 3.00 eq), and Compound U (120.93 mg, 391.65 pmol, 1.00 eq) were added at 25 °C. The mixture was stirred at 100°C for 12 hours. LC-MS showed the reaction was complete. Compound AO was consumed, and the desired target mass was detected. H2O (5 mL) was added to the mixture, and the aqueous was extracted with ethyl acetate three times (5 mL each). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by preparative HPLC. Compound 49 (29.60 mg, 53.84 pmol, 13.75% yield, 95.98 % purity) was obtained as a white solid. ’H NMR (DMSO-r / e, 400 MHz) 5 = ppm 11.97 (br s, 1H), 8.43 (br d, J=8.4 Hz, 2H), 8.32 (s, 0.5 H), 7.66 (d, .7=1.2 Hz, 1H), 7.27 (s, 1H), 6.88 (s, 1H), 6.79 (d, .7=8.4 Hz, 1H), 3.99-4.11 (m, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.29 (br s, 2H), 3.11 (br d, .7=11.8 Hz, 2H), 2.89 (td, .7=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: [M+H]1calcd for C26H33N5O5S: 528.22; found: 528.2.Step 1. Synthesis of Compound AP.

[0238] To a solution of Compound A (10.00 g, 53.19 mmol, 1.00 eq) in DMF (80 mL), NIS (13.16 g, 58.51 mmol, 1.10 eq) was added at 0°C. The mixture was stirred at 20°C for 12 hours.LC-MS showed Compound A was consumed completely 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 yield a residue. Compound AP (14.00 g, crude) was obtained as a yellow solidStep 2. Synthesis of Compound AQ.

[0239] To a mixture of Compound AP (10.00 g, 31.86 mmol, 1.00 eq) in THF (150 mL), NaH (1.91 g, 47.78 mmol, 60% purity, 1.50 eq) was added at 0°C. Then, the mixture was stirred at 0°C for 0.5 hour. Then, SEM-C1 (6.37 g, 38.23 mmol, 6.77 mL, 1.20 eq) was added to the mixture at 20°C. Then, the mixture was stirred at 20°C for 12 hours. LC-MS showed the reaction was complete. H2O (200 mL) at 0°C was added to the mixture, and the aqueous portion was extracted with DCM three times (100 mL each). The combined organic layers were dried over Na SO4 and then concentrated under reduced pressure. Multiple batches were made and combined. The residue was purified by column chromatography (SiCh, Petroleum ether:Ethyl acetate = 1 :0 to 0: 1). Compound AQ (24.00 g, crude) was obtained as a yellow solid Step 3. Synthesis of Compound AR.

[0240] To a mixture of Compound AQ (5.00 g, 11.26 mmol, 1.00 eq) and cyclohexanamine (1.12 g, 11.26 mmol, 1.29 mL, 1.00 eq) in MeCN (100 mL), TEA (2.28 g, 22.51 mmol, 3.13 mL, 2.00 eq) was added at 20°C. Then, the mixture was stirred at 60°C for 12 hours. LC-MS showed the reaction was complete, Compound AQ was consumed, and the desired target MS was detected. The mixture was concentrated, H2O (50 mL) was added to the mixture, and the aqueous portion was extracted with DCM three times (20 mL). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, Petroleum ether:Ethyl acetate = 1 :0 to 0:1). Compound AR (5.00 g, crude) was obtained as a blue oil.Step 4. Synthesis of Compound G.

[0241] To a mixture of Compound AR (1.00 g, 1.97 mmol, 1.00 eq) in Methanol (10 mL), Pd(dppf)Ch (144.35 mg, 197.28 pmol, 0.10 eq) and TEA (399.26 mg, 3.95 mmol, 549.19 uL, 2.00 eq) were added at 20°C. Then, the mixture was stirred at 70°C for 2 hours under CO (15 psi). LC-MS showed the reaction was complete, Compound AR was consumed, and the desired target MS was detected. The mixture was concentrated. The residue was purified by columnchromatography (SiCh, Petroleum ether:Ethyl acetate = 1 :0 to 0:1). Compound G (500.00 mg, crude) was obtained as a yellow oil.Step 5. Synthesis of Compound AT.

[0242] To a mixture of Compound G (130.00 mg, 296.11 pmol, 1.00 eq) and 2-methoxy-4- (4-morpholinyl)aniline (92.50 mg, 444.17 pmol, 1.50 eq) in / -BuOI I (5 mL), Pd2(dba).3 (27.12 mg, 29.61 pmol, 0.10 eq), XPhos (14.12 mg, 29.61 pmol, 0.10 eq), and K2CO3 (81.85 mg, 592.22 pmol, 2.00 eq) were added at 20°C. Then, the mixture was stirred at 100°C for 12 hours under N2. LC-MS showed the reaction was complete, Compound G was consumed, and the desired target MS was detected. The mixture was concentrated. H2O (10 mL) was added to the mixture, and the aqueous was extracted with DCM three times (5 mL each). The combined organic layers were dried over Na2SC>4 and then concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, Petroleum ether:Ethyl acetate = 1 :0 to 0: 1). Compound AT (50.00 mg, crude) was obtained as a yellow solid.Step 6. Synthesis of Compound 53.

[0243] To a mixture of Compound AT (140.00 mg, 229.20 pmol, 1.00 eq) in DCM (2 mL), TFA (2 mL) was added at 20°C. Then, the mixture was stirred at 20°C for 2 hours. LC-MS showed Compound AT was not consumed, the intermediate was detected, and desired target MS was not detected. Then, the mixture was concentrated to dryness under a stream of N2. K2CO3 (158.38 mg, 1.15 mmol, 5.00 eq) and Methanol (4 mL) were added to the mixture. Then, the mixture was stirred at 60°C for 12 hours. LC-MS showed the reaction was complete, Compound AT was consumed, and the desired target MS 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 pmol, 3.81% yield, 100.00% purity) was obtained as a white solid.1H NMR (DMSO- de, 400 MHz) 5 = 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: [M+H]+calcd for C25H32N6O4: 481.25; found: 481.1.Preparation of Compound 54Step 1. Synthesis of Compound AU.

[0244] To a solution of Compound AH (1.00 g, 5.84 mmol, 1.00 eq) and imidazole (795.64 mg, 11.69 mmol, 2.00 eq) in MeCN (10 mL), K2CO3 (1.62 g, 11.69 mmol, 2.00 eq) was added at 20°C. Then, the solution was stirred at 80°C for 12 hours. LC-MS showed the reaction was completed. Compound AH was consumed, and the desired target mass was detected. The mixture was concentrated to remove MeCN added to the solution, and then, the solution was extracted with ethyl acetate three times (10 mL each). The organic layers were dried with Na2SC>4 and then concentrated. The residue was purified by preparative TLC (SiCh, Petroleum etherEthyl acetate = 0: 1). Compound AU (1.24 g, 5.66 mmol, 96.81% yield) was obtained as a white solid.Step 2. Synthesis of Compound AV.

[0245] To a solution of 10% Pd / C (250.00 mg, 50% purity, 1.00 eq) in Methanol (10 mL), Compound AU (500.00 mg, 2.28 mmol, 1.00 eq) was under N2 atmosphere. The suspension was degassed and purged with H2 5 times. The mixture was stirred under H2 (15 psi) at 25°C for 12 hours. LC-MS showed the reaction was completed. Compound AU was consumed, and the desired target mass was detected. Then, the mixture was filtered, and the filtrate was concentrated. Compound AV (120 mg, 634.20 pmol, 27.80% yield) was obtained as a yellowish solid.Step 3. Synthesis of Compound AX.

[0246] To a solution of Compound AV (129.30 mg, 683.34 pmol, 1.20 eq) and Compound G (250 mg, 569.45 pmol, 1.00 eq) in / -BuOH (4 mL), K2CO3 (157.40 mg, 1.14 mmol, 2.00 eq), Pd2 (dba)3 (52.15 mg, 56.94 pmol, 0.10 eq) and XPhos (27.15 mg, 56.94 pmol, 0.10 eq) were added at 20 °C. Then, the solution was stirred at 100 °C for 12 hours under N2. LC-MS showed the reaction was completed. Compound AV was consumed, and the desired target mass was detected. H2O (10 mL) was added to the solution, and then the solution was extracted with ethyl acetate three times (10 mL). The organic layers were dried with Na2SO4 and then concentrated. The residue was purified by preparative TLC (SiCh, Ethyl acetate :Methanol = 3: 1). Compound AX (300.00 mg, 506.95 pmol, 89.02% yield) was obtained as a brown solid.Step 4. Synthesis of Compound AY.

[0247] A solution of Compound AX (300.00 mg, 506.95 pmol, 1.00 eq) in TFA (5 mL) and DCM (2 mL) was stirred at 20°C for 1 hour. LC-MS showed the reaction was completed. Compound AX was consumed, and the desired target mass was detected. The mixture was concentrated. Compound AY (300.00 mg, 495.41 pmol, 97.72% yield) was obtained as a yellow oil.Step 5. Synthesis of Compound 53.

[0248] To a solution of Compound AY (300.00 mg, 495.41 pmol, 1.00 eq) in Methanol (1 mL) and THF (1 mL), NH3 was added. H2O (3.82 mL, 25% purity) was added at 20°C. Then, the solution was stirred at 20°C for 12 hours. LC-MS showed the reaction was completed.Compound AY was consumed, 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 pmol, 2.93% yield, 100.00 % purity) was obtained as a white solid. *11 NMR (DMSO- e, 400 MHz) 8 = 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: [M+H]+calcd for C24H27N7O3: 462.22; found: 462.2.Preparation of Compound 56Compound 56Step 1. Synthesis of Compound BC.

[0249] To a solution of Compound AR (1 g, 1.97 mmol, 1 eq) and Compound BB (496.85 mg, 3.95 mmol, 2 eq) in dioxane (10 mL) and H2O (2.5 mL) XPhosPdGs (166.99 mg, 197.28 pmol, 0.1 eq) and KOAc (387.24 mg, 3.95 mmol, 2 eq) were added. The mixture was stirred at 100°C for 12 hours under N2. LC-MS showed Compound AR was consumed completely, and the desired mass was detected. The mixture was diluted with 30 mL of H2O and extracted with 30 mL of ethyl acetate three times (90 mL). Then, the product was dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Petroleum etherEthyl acetate=l :0 to 0: 1 ). Compound BC (240 mg, 520.52 pmol, 26.38% yield) was obtained as a brown oil. MS (ESI+): m / z 461.3 [M+H], Step 2. Synthesis of Compound BE.

[0250] To a solution of Compound BC (110 mg, 238.57 pmol, 1 eq) and Compound BD (49.68 mg, 238.57 pmol, 1 eq) in t-BuOH (2 mL) XPhos (11.37 mg, 23.86 pmol, 0.1 eq), t- BuONa (45.86 mg, 477.15 pmol, 2 eq) and Pd2(dba)s (21.85 mg, 23.86 pmol, 0.1 eq) were added. The mixture was stirred at 80°C for 2 hr under N2. LC-MS showed Compound BC was consumed completely, and the desired mass was detected. The mixture was diluted with 5 mL of H2O and extracted with 5 mL of ethyl acetate three times (15 mL). Then, the product was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residuewas purified by column chromatography (SiCh, Petroleum etherEthyl acetate=l :0 to 0: 1). Compound BE (85 mg, 134.31 pmol, 56.30% yield) was obtained as a brown oil.LCMS (ESI+): m / z 633.6 (M + H)Step 2. Synthesis of Compound BF.

[0251] To a solution of Compound BE (85 mg, 134.31 pmol, 1 eq) in DCM (1 mL) TFA (767.50 mg, 6.73 mmol, 0.5 mL, 50.12 eq) was added. The mixture was stirred at 20°C for 2 hours. LC-MS showed Compound BE was consumed completely, and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was used directly for the next step without purification. Compound BF was obtained as a black solid.Step 2. Synthesis of Compound 56.

[0252] To a solution of Compound BF (85 mg, 159.58 pmol, 1 eq) in THF (1.5 mL) and Methanol (0.5 mL) NH3 in H2O (455.00 mg, 3.25 mmol, 0.5 mL, 25% purity, 20.34 eq) was added. The mixture was stirred at 20°C for 12 hours. LC-MS showed Compound BF was consumed completely, and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC.Compound 56 (14.9 mg, 29.65 pmol, 18.58% yield) was obtained as a white solid. ’H NMR (400 MHz, DMSO-d6) 5 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, .7= 8 Hz, 1H) 6.46 (dd, .7= 8.88, 2 Hz, 1H) 6.64 (d, ,7= 2.4 Hz, 1H) 6.74 (d, .7 - 2 Hz, 1H) 7.02 (s, 1H) 7.51 (s, 1H) 7.8O (s, 1H) 8.29 (d, J - 8.8 Hz, 1H) 11.10 (s, 1H) MS (ESI+): m / z 503.3 [M + H],Preparation of Compound 67Step 1. Synthesis of Compound BG.

[0253] To a solution of tert-butyl piperazine- 1 -carboxylate (21.60 g, 115.97 mmol, 1.10 eq) and Compound AH (18 g, 105.19 mmol, 1 eq) in DMF (80 mL) was added K2CO3 (14.54 g, 105.19 mmol, 1 eq). The mixture was stirred at 90°C for 12 hours. LC-MS showed Compound AH was consumed completely, and the desired mass was detected. The mixture was added to H2O (150 mL) at 20°C. Then the solid was filtered, washed with H2O 3 times (50 mL each), and dried under high vacuum. The crude product was triturated in ethyl acetate (40 mL) at 20°C for 20 min two times. The solid was filtered, and the filter cake was dried to give pure product.Compound BG (25 g, 74.10 mmol, 70.45% yield) was obtained as a yellow solid.Step 2. Synthesis of Compound BH.

[0254] To a solution of Compound BG (6 g, 17.78 mmol, 1 eq) in Methanol (200 mL) was added Pd / C (946.32 mg, 4.45 mmol, 50% purity, 0.25 eq) under N2. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (35.85 mg, 17.78 mmol, 1 eq) (50 psi.) at 20 °C for 12 hours. LC-MS showed Compound BG was consumed completely, and the desired mass was detected. The reaction mixture was fdtered, and the fdtrate was concentrated under high vacuum. Compound BH (5 g, 16.27 mmol, 91.46% yield) was obtained as a pink solid.Step 3. Synthesis of Compound BI.

[0255] A mixture of Compound BH, 2-chloro-N-cyclohexyl-5-(l-methylpyrazol-4-yl)-7-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-amine (1.80 g, 3.90 mmol, 1 eq, Compound BC), CS2CO3 (2.54 g, 7.81 mmol, 2 eq), XPhos (372.21 mg, 780.77 pmol, 0.2 eq) and Pd2(dba).3 (357.48 mg, 390.39 pmol, 0.1 eq in dioxane (50 mL) was degassed and purged with N2 3 times, and then, the mixture was stirred at 90°C for 4 hours under a N2 atmosphere. TLC indicated Compound BH was consumed completely, and one new main spot formed. The reaction mixture was partitioned between H2O (150 mL) and ethyl acetate three times (120 mL each), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound BI (2 g, 2.73 mmol, 69.99% yield) was obtained as a yellow solid.Step 4. Synthesis of Compound BJ.

[0256] To a solution of Compound BI (1 g, 1.37 mmol, 1 eq) in THF (15 mL) TBAF (1 M,6.83 mL, 5 eq) was added. The mixture was stirred at 70 °C for 12 hours. LC-MS showed Compound BI was consumed completely and desired mass was detected. The reaction mixture was partitioned between H2O (60 mL) and ethyl acetate (50 mL) 3 times, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography. Compound BJ (500 mg, 830.92 pmol, 60.82% yield) was obtained as a yellow solid.Step 5. Synthesis of Compound BK.

[0257] A mixture of Compound BJ (500 mg, 830.92 pmol, 1 eq) in HCl / ethyl acetate (4 M, 15 mL, 72.21 eq) was stirred at 20°C for 1 hour. LC-MS showed Compound BJ was consumed completely, and the desired mass was detected. The reaction mixture was concentrated underreduced pressure to give a residue. Compound BK (400 mg, crude, HC1) was obtained as a pink solid.Step 6. Synthesis of Compound 67.

[0258] To a solution of (E)-4-(4-methoxyphenyl)-4-oxo-but-2-enoic acid (122.62 mg, 594.70 pmol, 0.8 eq) in DMF (2 mL) DIEA (192.15 mg, 1.49 mmol, 258.96 pL, 2 eq) and a solution of T4P (1.07 g, 1.49 mmol, 50% purity, 2 eq) in 2-methyltetrahydrofuran (0.5 mL) were added dropwise to create Solution A. To a solution of Compound BK (400 mg, 743.38 pmol, 1 eq, HC1) in DMF (3 mL) DIEA (288.23 mg, 2.23 mmol, 388.45 pL, 3 eq) was added to yield Solution B. Then, Solution B was added into Solution A. The mixture was stirred at 20°C for 2 hours. LC-MS showed Compound BK was consumed completely, and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. Compound 67 (126 mg, 167.87 pmol, 22.58% yield, 91.90% purity) was obtained as a yellow solid. It is to be understood that in some instances, compounds with the same R5group as Compound 67 or a similar R?group as Compound 67 may be made in a similar manner.1H NMR (400 MHz, DMSO-de) 8 = 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, .7= 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, , / = 10.4 Hz, 3H), 0.89-0.83 (m, 1H). MS (ESI+): m / z found: 690.4 (M + H).Preparation of Compound 68Step 1. Synthesis of Compound 68.

[0259] To a solution of 4-(4-methoxyphenyl)-4-oxo-butanoic acid (92.87 mg, 446.03 pmol, 0.8 eq in DMF (1 mL) DIEA (144.11 mg, 1.12 mmol, 194.22 pL, 2 eq and a solution of T4P (803.42 mg, 1.12 mmol, 50% purity, 2 eq in 2-methyltetrahydrofuran (0.5 mL) were added dropwise tp create Solution A. Compound BK was synthesized as described for Compound 67. To a solution of Compound BK (300 mg, 557.53 pmol, 1 eq, HC1) in DMF (2 mL) was added DIEA (216. 17 mg, 1.67 mmol, 291.33 pL, 3 eq) to create Solution B. Then Solution B was added into Solution A. The mixture was stirred at 20°C for 2 hours. LC-MS showed Compound BK was consumed completely, and the desired mass was detected. The reaction mixture was filtered, and the filtrate concentrated under high vacuum. The residue was purified by prep- HPLC. Compound 68 (111 mg, 153.88 pmol, 27.60% yield, 95.91% purity) was obtained as a white solid. It is to be understood that in some instances, compounds with the same R5group as Compound 68 or a similar R5group as Compound 68 may be made in a similar manner.1H NMR (400 MHz, DMSO-de) 5 = 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+): m / z found: 692.5 (M + H).Step 1. Synthesis of Compound BA.

[0260] To a solution of 6-chloro-2-methoxy-3-nitropyridine (Compound AZ) (9.50 g, 50.4 mmol, 1.00 eq) in MeCN (66.5 mL), morpholine (5.27 g, 60.4 mmol, 5.32 mL, 1.20 eq) and K2CO3 (13.9 g, 100 mmol, 2.00 eq) were added. The mixture was stirred at 70°C for 12 hours. TLC (Petroleum etherEthyl acetate = 1:1, Rf = 0.38) indicated Compound AZ was consumed completely and one new spot formed. The reaction mixture was diluted with 120 mL of H2O andextracted with DCM (100 mL, 50 mL, and 20 mL for three extractions). The combined organic layers were washed with brine twice (100 mL each), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was used to the next step without purification. Compound BA (9.50 g, crude) was obtained as a yellow solid. Step 2. Synthesis of Compound AF.

[0261] To a solution of Compound BA (9.50 g, 39.7 mmol, 1.00 eq) in EtOH (76.0 mL) and H2O (9.50 mL), Fe (6.65 g, 119 mmol, 3.00 eq) and NH4CI (8.50 g, 159 mmol, 4.00 eq) were added. The mixture was stirred at 80°C for 12 hours. TLC (Petroleum etherEthyl acetate = 0: 1, Rf = 0.31) indicated Compound BA was consumed completely and many new spots formed. The mixture was filtered, and the filter cake was washed with EtOH (200 mL). The combine filtrates were concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (SiO2, Petroleum etherEthyl acetate = 20: 1 to 0: 1). Compound AF (6.50 g, 78.0% yield) was obtained as a black brown solid. ’H NMR (400 MHz, CDCI3) 8 6.90 (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).Mpsl TTK AssaysNanoBRET TTK Assay

[0262] HEK293 cells were grown to 70-80% confluency, trypsinized, and collected. A 10 pg / mL solution of DNA was prepared using serum-free OPTLMEM without phenol red. 9.0 pg of Transfection Carrier DNA and 1.0 pg of TTK-NanoLuc fusion vector DNA were mixed in 1 mL of media. To form a lipid:DNA complex, 30 pL was added into 1 mL of the DNA mixture, and the mixture was inverted. To allow the complexes to form, the mixture was allowed to incubate at ambient temperature for 20 minutes.

[0263] For transfection, in a sterile conical tube, the lipid:DNA complex mixture was diluted 20-fold with HEK293 cells in suspension and mixed by inversion gently. The cell-complex mixture was dispensed in a sterile tissue culture dish and incubated for 22-24 hours.

[0264] Each synthesized compound was applied to the wells of a 384-well white non-binding surface plate using an Echo 550. The medium was removed from the dish containing the transfected HEK293 cells via aspiration. The cells were trypsinized and allowed to dissociate from the dish. The trypsin was neutralized using medium containing serum, and the cells werecentrifuged at 200 x g for 5 minutes to pellet the cells. The cells were adjusted to a density of 2 x 105cells / mL in OPTI-MEM without phenol red. One part Complete 20X NanoBRET Tracer K5 Reagent was added to 20 parts cells in a tube, and the cells were mixed with the reagent by inversion.

[0265] This cell suspension was dispensed into the white 384 non-binding surface plate containing the test compounds, and the plate was incubated at 37°C and 5% CO2for 1 hour. In this mixture, the final tracer K5 concentration is 1 pM. Additionally, a set of samples was also prepared without the K5 tracer for background correction steps.

[0266] After incubation, the cell plate was removed from the incubator and allowed to equilibrate at room temperature for 15 minutes. Then, 3X Complete Substrate Plus Inhibitor Solution in Assay Medium (OPTI-MEM I Reduced Serum Medium, no phenol red), which was prepared promptly before application, was added to each well, and the plate was allowed to incubate for 2-3 minutes at room temperature. Then, the donor emission was measured at 460 nm, and the acceptor emission was measured at 600 nm using an Envison 2104 plate reader. To generate the raw BRET ratio values, the acceptor emission value (600 nm) was divided by the donor emission value (460 nm) for each sample, and to correct for background, the BRET ratio in the absence of the tracer (average of no-tracer control samples) was subtracted from the BRET ratio of each sample. The ICso curves of the NanoBRET response for the compounds were plotted, and the ICso values were calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. Results are shown in Table 3 for synthesized compounds and Table 4 for comparative compounds. “ND” indicates results were not determined.TTK Inhibition Assay

[0267] Base Reaction buffer containing 20 mM HEPES (pH 7.5), 10 mM MgCh, 1 mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM NaaVCU, 2 mM DTT, and 1% DMSO was prepared. TTK was added to the reaction for final concentrations in the range of 40-75 nM. The synthesized compounds were delivered in the nL range to the reaction mixture in 100% DMSO using an Echo 550. The mixtures were incubated for 20 minutes at room temperature.33P-ATP was added into the reaction mixture to initiate the reaction. The reaction mixture was incubated for two hours. Kinase activity was detected using the P81 filter-binding method. The kinetic constants and the ICso curves for the synthesized compounds were plotted, and the ICso valueswere calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. The results are shown in Table 3 for synthesized compounds and Table 4 for comparative compounds. “ND” indicates results were not determined.Cancer Cell Line AssaysCOLO205 Cell Titer-Gio Assay

[0268] The reference compound staurosporine was purchased from Sigma-Aldrich (Saint Louis, MI). Cell Titer-Gio® 2.0 Luminescent cell viability assay reagent was purchased from Promega (Madison, WI). The COLO205 cell line was purchased from American Type Culture Collection (Manassas, VA). COLO205 cells were cultured in RPMI medium supplemented with 10% FBS, 100 pg / mL of penicillin, and 100 pg / mL of streptomycin. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0269] 25 pL of culture media containing 2,000 COLO205 cells were added to each well of the cell culture plate. The cells were left to adhere for 24 hours. The compounds and reference compound staurosporine were diluted in RPMI with 0.3% DMSO with 10-dose and 3-fold dilution in a source plate starting at 30 pM (compounds) and 60 pM (staurosporine). 5 pL of compounds or staurosporine was delivered from the source plate to each well of the 384-well cell culture plate in duplicate. The cells were incubated with the compounds at 37°C and 5% CO2 for 120 hours. 30 pL of Cell Titer Gio 2.0 reagent was added to each well. The contents were mixed on an orbital shaker for 2 min and incubated at room temperature for 15 min to stabilize luminescent signal. Luminescence was recorded using an Envision 2104 Multilabel Reader (PerkinElmer, Santa Clara, CA). The number of viable cells in culture was determined based on quantitation of the ATP present in each culture well. The IC50 curves for the compounds were plotted, and the IC50 values were calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. Results are shown in Table 3 for synthesized compounds and Table 4 for comparative compounds. “ND” indicates results were not determined.RPM1-8226 MTS Assay

[0270] Reference compound staurosporine was purchased from Sigma-Aldrich (Saint Louis, MI). CellTiter 96 AQueous One Solution Reagent (MTS assay reagent) was purchased from Promega (Madison, WI). The RPML8226 cell line was purchased from American Type CultureCollection (Manassas, VA). Cells were cultured in RPMI-1640 with 10% FBS and supplemented with 100 pg / mL of penicillin and 100 pg / mL of streptomycin. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0271] Each compound and staurosporine were diluted in DMSO with a 10-dose, 3 -fold dilution in a source plate starting at 3.33 mM (test compounds) and 1 mM (staurosporine). 25 nL of the compounds or staurosporine were delivered from the source plate to each well of a 384- well cell culture plate by an Echo 550. 25 pL of culture medium containing 5,000 RPMI-8226 cells were delivered to each well of the cell culture plate in duplicate. The cells in cell culture plates were incubated with the compounds at 37°C and 5% CO2 for 96 hours. 5 pL of CellTiter 96® AQueous One Solution Reagent (MTS assay reagent) were 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 colored formazan product was used to determine the viable cells present in each well. The IC50 curves were plotted, and the IC50 values were calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. The results are shown in Table 3 for synthesized compounds and Table 4 for comparative compounds. “ND” indicates results were not determined.A 375 Cell Titer-Gio Assay

[0272] The reference compound bortezomib was purchased from Selleckchem (Houston, TX). Staurosporine was purchased from Sigma-Aldrich (Saint Louis, MI). CellTiter-Glo® 2.0 Luminescent cell viability assay reagent was purchased from Promega (Madison, WI). The A375 cell line was purchased from American Type Culture Collection (Manassas, VA). A375 cells were cultured in DMEM containing 10% FBS, 100 pg / ml of penicillin, and 100 pg / mL of streptomycin. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2 and 95% air.

[0273] 50 pL of culture media containing 250 A375 cells were added to each of the wells of several 384-well tissue culture plates using a Multidrop Dispenser. The cells were incubated overnight at 37°C and 5% CO2. The following day, the compounds, the reference compound bortezomib, and staurosporine were added to the tissue culture plates using a Tecan D300e Digital Dispenser. The test compounds and bortezomib were added to the plates with 8-dose, 3- fold dilution, in duplicate starting at 3 pM (test compounds) or 1 pM (bortezomib). Cells treatedwith 10 pM staurosporine were utilized as the background. The cells were incubated with the compounds at 37°C and 5% CChfor 72 hours.

[0274] 50 pL of CellTiter-Glo 2.0 reagent were added to each well. The contents were mixed on an orbital shaker for 2 min and incubated at room temperature for 15 minutes to stabilize the luminescent signal. Luminescence was recorded using an Envision 2104 Multilabel Reader (PerkinElmer, Santa Clara, CA). The number of viable cells in culture was determined based on quantitation of the ATP present in each culture well. The IC50 curves were plotted, and the IC50 values were calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. The results are shown in Table 3 for synthesized compounds and Table 4 for comparative compounds. “ND” indicates results were not determined.A375 Cell Titer -Gio Serum Shift Assay

[0275] The above A375 CTG assay was repeated. However, the protocol was revised to incorporate 4.5% human serum albumin (HSA) and 0.14% alpha-l-acid glycoprotein (AAG) in the culture media during the 72 hours of incubation. The ICso curves were plotted, and the IC50 values were calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. Serum shift-fold values were determined by dividing the IC50 value determined in the presence of serum proteins by the IC50 value determined in the assay without supplemental human serum proteins. The results are shown in Table 3 for synthesized compounds and Table 4 for comparative compounds. “ND” indicates results were not determined.Table 3. IC50 results for synthesized compounds.Table 4. IC50 results for comparative compounds.CYP Inhibition Assay

[0276] Select compounds, including comparative compounds, were tested for their ability to inhibit isoforms of cytochrome P450 (CYP) in vitro. Experiments were conducted in a plate format. Stocks for the selected compounds were created between 0.005-5.0 mM. Stocks of the positive controls (a-naphthoflavone at 100 pM, ticlopidine at 300 pM, montelukast at 300 pM, sulfaphenazole at 300 pM, (+)-N-3-benzylnirvanol at 100 pM, quinidine at 300 pM, and ketoconazole at 300 pM) were prepared. Human liver microsomes (HLMs) were prepared by diluting in 100 mM potassium phosphate buffer to 0.127 mg / mL.

[0277] A substrate stock solution was prepared for the various CYP isoforms. Phenacetin was prepared at 75 pM for CYP1A2. Bupropion was prepared at 80 pM for CYP2B6. Amodiaquine was prepared at 2 pM for CYP2C8. Diclofenac was prepared at 10 pM for CYP2C9. S-mephenytoin was prepared at 20 pM for CYP2C19. Dextromethorphan was prepared at 10 pM for CYP2D6. Midazolam was prepared at 2 pM for CYP3A4-M. Testosterone was prepared at 40 pM for CYP3A4-T.

[0278] 20 pL of the substrate stock solution was added to the corresponding well. 20 pL of100 mM potassium phosphate buffer was used as a blank control. 2 pL of the selected compounds (final concentration between 0.05-50 pM) and positive control solution (final concentration between 1-3 pM) was added to the corresponding well. 2 pL of solvent (DMSO or Methanol) was used as a no inhibitor well and added to blank wells. 158 pL HLMs (final concentration of 0.1 mg / mL in the reaction) were added to each well. The plate was warmed for 10 minutes at 37°C. 20 pL of NADPH cofactor solution at 10 mM in 33 mM MgCE (NADPH final concentration of 1 mM in the reaction) was added to each well. The wells were mixed. The reactions were incubated at 37°C for 20 minutes for CYP2C19 and CYP2D6, for 3 minutes for CYP3A4-M and CYP3A4-T, and for 10 minutes for the remaining CYP isoforms. The reaction was terminated using 400 pL of cold stop solution. The samples were centrifuged at 4000 rpm for 20 minutes to precipitate the proteins. 200 pL of supernatant was diluted with 100 pL of HPLC water. The sample was shaken for 10 minutes. The samples were then analyzed using LC / MS / MS analysis.I l l

[0279] Microsoft Excel or SigmaPlot was used to plot the percent of control versus the test compound concentrations and for non-linear regression analysis of the data. IC50 values were determined using 3- or 4- parameter logistic equation. IC50 values were reported as “>50 pM” when % inhibition at the highest concentration (50 pM) is less than 50%. The IC50 results in pM for the isoforms CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4-M, and CYP3A4-T are shown in Table 5. In Table 5, “Comp.” is the abbreviation for comparative.Table 5. IC50 results for select compounds for a CYP inhibition assay.Conclusion

[0280] In view of the foregoing, some non-limiting observations are as follows. In contrast to previously described Mpsl / TTK inhibitors, such as comparative compound 4, synthesized compounds described herein have a Formula I described above in which the R3position is not a hydrogen atom. Substitution of the R3position for a variety of moieties imparted an increase in potency for the synthesized compounds compared to the comparative compounds. For the synthesized compounds, positions R1and R2are hydrogen atoms. In the comparative compounds (specifically comparative compounds 1, 2, 3, 6, and 7), position R1or R2contain a methyl or Cl and are not as potent as the synthesized compounds, which have a hydrogen atom at these positions.

[0281] Both synthesized and comparative compounds were evaluated for their activity against Mpsl / TTK and using antiproliferative assays. In contrast to the comparative compounds, data indicate activity against Mpsl / TTK at or below 15 nM for the synthesized compounds. Assay data also show the anti-proliferative potential of the compounds in cancer cell lines.References1. Winey M, Goetsch L, Baum P, Byers B. 1991. MPS1 and MPS2: Novel yeast genes defining distinct steps of spindle pole body duplication. J. of Cell Biol. 114:745-542. Lindberg RA, Fischer W H, Hunter T. 1993. Characterization of a human protein threonine kinase isolated by screening an expression library with antibodies to phosphotyrosine. Oncogene 8:351-93. 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. J. Biol. Chem. 267: 16000-64. Fisk HA, Mattison C P, Winey M. 2003. Human Mpsl protein kinase is required for centrosome duplication and normal mitotic progression. Proceedings of the National Academy of Sciences of the United States of America 100:14875-805. Yang C H, Kasbek C, Majumder S, Mohd Yusof A, Fisk H A. 2010. Mpsl phosphorylation sites regulate the function of Centrin 2 in centriole assembly. Molecular Biology of the Cell 21 :4361-726. Liu J, Cheng X, Zhang Y, Li S, Cui H, et al. 2013. Phosphorylation ofMpsl by BRAF V600E prevents Mpsl degradation and contributes to chromosome instability in melanoma. Oncogene 32:713-237. Kasbek C, Yang, C.-H., and Fisk, H. A. 2009. Mpsl as a link between centrosomes and genetic instability. Environmental and Molecular Mutagenesis 50:654-658. Kasbek C, Yang C H, Fisk H A. 2010. Antizyme Restrains Centrosome Amplification by Regulating the Accumulation ofMpsl at Centrosomes. Molecular Biology of the Cell 21 :3879- 899. KasbekC, YangC H, YusofAM, ChapmanH M, Winey M, Fisk HA. 2007. Preventing the degradation of mpsl at centrosomes is sufficient to cause centrosome reduplication in human cells. Mai Biol Cell 18:4457-6910. Wei J H, Chou Y F, Ou Y H, Yeh Y H, Tyan S W, et al. 2005. TTK / hMpsl participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68. Journal of Biological Chemistry 280: 7748-5711. 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: 16000-612. 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 152:96-10513. Saal L H, Gruvberger-Saal SK, Persson C, Loevgren 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: 102-714. 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: 1978-8315. 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 NJ, 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 95:2950-517. Hewitt L, Tighe A, Santaguida S, White AM, Jones C D, et al. 2010. Sustained Mpsl activity is required in mitosis to recruit O-Mad2 to the Madl-C-Mad2 core complex. Journal of Cell Biology 190:25-3418. Kwiatkowski N, Jelluma N, Filippakopoulos P, Soundararaj an M, Manak M S, et al. 2010. Small-molecule kinase inhibitors provide insight into Mpsl cell cycle function. Nature Chemical Biology 6:359-6819. 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 190:73-8720. TardifK 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 1 0:2267-7521. Tannous BA, Kerami M, Van der Stoop PM, Kwiatkowski N, Wang J, et al. 2013. Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs. Journal of the National Cancer Institute 105: 1322-31

[0282] Additional exemplary embodiments contemplated herein are as follows:

[0283] Embodiment 1. A composition comprising a compound of Formula I:(Formula I), or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, whereinR1is H;R2is H;R3is not H;R4is selected from the group consisting of -ZR15or -ZR19, whereinZ is NH, N-methyl, or O;R13is a six-membered ring having the following structureR18is selected from the group consisting of hydrogen, halo, -O-R20, -C(O)-R20, -C(O)O-R20, - NR20R21, -C(O)NR20R21, -C(S)NR20R21, -NR23C(O)NR20R21, -NR23C(S)NR2OR21, -O- C(O)NR20R21, -S(O)2NR20R21, -O-S(O)2NR20R21, -NR23-S(O)2NR20R21, -CN, -NO2, C1-C6 alkyl, and -S(O)2-R22;R19is selected from the group consisting of linear C1-C16 alkyl, branched C1-C16 alkyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, iso-hexyl, sec-hexyl, tert-hexyl, neo-hexyl, cyclo-butyl, and cyclo-pentyl;R20, R21, and R23are each independently hydrogen or Ci-Ce alkyl; andR22is Ci-Ce alkyl;R5is selected from the group consisting of C1-C4 alkyl, a substituted or unsubstituted 4- to 7- membered heterocycle, a sulfoximine, a sulfonamide, and a spirocyclic heterocycle that is fused or bridged, an E3-ligase binding moiety, -NHR24, and -NR24R31,R24is selected from the group consisting of C1-C4 alkyl halide, -R25-O-R26, -R27-C(O)NH-R28, - R29NHC(O)-R30, a substituted or unsubstituted 4-membered heterocycle, and a substituted or unsubstituted cyclobutane,R25is C1-C4 alkyl,R26is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide,R27and R28are each independently C1-C4 alkyl,R29and R30are each independently C1-C4 alkyl, andR31is C1-C4 alkyl or C1-C4 alkyl halide;R6is hydrogen, methyl, -CN, -S-methyl, or -XR8, wherein X is O, S, or SO2and R8is C1-C3 alkyl or CI-C3 haloalkyl;R7is H, CN, OCH3, or F;Y is CH, N, CF, or C-CH3; and- represents a single or double bond.

[0284] Embodiment 2. The composition of Embodiment 1, wherein R5is a 5- to 7-membered heterocycle substituted with one or two oxo and / or R17, wherein R17is independently selected from the group consisting of -O-R10, -NR10C(O)R12, -wherein R10, R11, and R13are each independently hydrogen or Ci-Ce alkyl; and wherein R12is independently Ci-Ce alkyl.[002851 Embodiment 3. The composition of Embodiment 1, wherein R5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, a tetrahydrothiophene dioxide, a thiacyclohexane dioxide, a thiazolidine, thiadiazolidine, a sulfoximine, or a sulfonamide.

[0286] Embodiment 4. The composition of any of Embodiments 1-3, wherein:R3is 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-iso-propyl, -C(O)O-butyl, -CH2OH, -C(O)NH-methyl, -C(O)O-cycloalkyl, -C(O)OH, - CN, an alkyl nitrile, an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, a thiazole, -C(O)R9, or -C(O)NHR9; andR9is H or C1-C4 alkyl.

[0287] Embodiment 5. The composition of Embodiment 4, whereinR3is C1-C4 alkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-butyl, -C(O)O-iso- propyl, -C(O)O-butyl, an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, a thiazole, or C(O)NHR9; andR9is H or C1-C4 alkyl.

[0288] Embodiment 6. The composition of Embodiment 1, whereinR3is C1-C4 alkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-butyl, -C(O)O- isopropyl, an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, a thiazole, or C(O)NHR9;R5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, a tetrahydrothiophene dioxide, a thiacyclohexane dioxide, a thiazolidine, thiadiazolidine, a sulfoximine, or a sulfonamide; andR9is H or C1-C4 alkyl.

[0289] Embodiment 7. The composition of Embodiment 6, whereinR3is a pyrazole or a triazole; andR is a morpholine or a thiomorpholine dioxide.

[0290] Embodiment 8. The composition of any of Embodiments 1-7, wherein the compound is of Formula II:(Formula II).

[0291] Embodiment 9. The composition of Embodiment 8, whereinR3is an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, or a thiazole.

[0292] Embodiment 10. The composition of Embodiment 8, whereinR3is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, or a thiacyclohexane dioxide.

[0293] Embodiment 11. The composition of Embodiment 8, whereinR3is an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, or a thiazole; andR5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, or a thiacyclohexane dioxide.

[0294] Embodiment 12. The composition of Embodiment 11, whereinR3is a pyrazole or a triazole; andR5is a morpholine or a thiomorpholine dioxide.

[0295] Embodiment 13. The composition of any of Embodiments 1-12, wherein the compound is of Formula III:(Formula III).

[0296] Embodiment 14. The composition of Embodiment 13, whereinR3is an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, or a thiazole.

[0297] Embodiment 15. The composition of Embodiment 13, whereinR5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, or a thiacyclohexane dioxide.

[0298] Embodiment 16. The composition of Embodiment 13, whereinR3is an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, or a thiazole; andR5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, or a thiacyclohexane dioxide.

[0299] Embodiment 17. The composition of Embodiment 1, whereinR5is Ci-C4alkyl.

[0300] Embodiment 18. The composition of Embodiment 1, whereinR3is an imidazole.

[0301] Embodiment 19. The composition of Embodiment 1, wherein R5is a pyrazole.

[0302] Embodiment 20. The composition of Embodiment 1, wherein R5is a triazole.

[0303] Embodiment 21. The composition of Embodiment 1, wherein R5is a tetrazole.

[0304] Embodiment 22. The composition of Embodiment 1, wherein R3is a pyrazolidinone.

[0305] Embodiment 23. The composition of Embodiment 1, wherein R5is an oxazolidinone.

[0306] Embodiment 24. The composition of Embodiment 1, wherein R5is a morpholine.

[0307] Embodiment 25. The composition of Embodiment 1, wherein R3is a thiomorpholine dioxide.

[0308] Embodiment 26. The composition of Embodiment 1, wherein R5is a tetrahydrothiophene dioxide.

[0309] Embodiment 27. The composition of Embodiment 1, wherein R5is a thiacyclohexane dioxide.

[0310] Embodiment 28. The composition of Embodiment 1, wherein R5is a thiazolidine.

[0311] Embodiment 29. The composition of Embodiment 1, wherein R5is a thiadiazolidine.

[0312] Embodiment 30. The composition of Embodiment 1, wherein R5is a substituted or unsubstituted 4- to 7-membered heterocycle.

[0313] Embodiment 31. The composition of Embodiment 30, wherein R5has the following structure:(Formula IV).

[0314] Embodiment 32. The composition of Embodiment 29, wherein R5has the following structure:(Formula V).

[0315] Embodiment 33. The composition of Embodiment 30, whereinR5has the following structure:(Formula VI).

[0316] Embodiment 34. The composition of Embodiment 30, whereinR5has the following structure:

[0317] Embodiment 35. The composition of Embodiment 30, whereinR5has the following structure:

[0318] Embodiment 36. The composition of Embodiment 30, wherein R5has the following structure:

[0319] Embodiment 37. The composition of Embodiment 30, wherein R5has the following structure:(Formula X).

[0320] Embodiment 38. The composition of Embodiment 30, wherein R5has the following structure:(Formula XI).

[0321] Embodiment 39. The composition of Embodiment 30, wherein R5has the following structure:

[0322] Embodiment 40. The composition of Embodiment 30, wherein R5has the following structure:(Formula XIII).

[0323] Embodiment 41. The composition of Embodiment 1, whereinR5is a sulfoximine.

[0324] Embodiment 42. The composition of Embodiment 1, wherein R5is a sulfonamide.

[0325] Embodiment 43. The composition of Embodiment 1, whereinR5is a spirocyclic heterocycle that is fused or bridged.

[0326] Embodiment 44. The composition of Embodiment 1, whereinR5is -NHR24or -NR24R31,R24is selected from the group consisting of C1-C4 alkyl halide, -R25-O-R26, -R27-C(O)NH-R28, - R29NHC(O)-R30, a substituted or unsubstituted 4-membered heterocycle, and a substituted or unsubstituted cyclobutane,R25is C1-C4 alkyl,R26is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide,R27and R28are each independently C1-C4 alkyl,R29and R30are each independently C1-C4 alkyl, andR31is C1-C4 alkyl or C1-C4 alkyl halide.

[0327] Embodiment 45. The composition of Embodiment 43, whereinR24is a substituted or unsubstituted 4-membered heterocycle.

[0328] Embodiment 46. The composition of Embodiment 1, whereinR5is an E3-ligase binding moiety.

[0329] Embodiment 47. The composition of Embodiment 45, wherein an E3-ligase binding moiety comprises a linker moiety covalently bonded to a terminal moiety:wherein L comprises the linker moiety and T comprises the terminal moiety.

[0330] Embodiment 48. The composition of any of Embodiments 17-47, wherein R3is Ci-C4alkyl.

[0331] Embodiment 49. The composition of any of Embodiments 17-47, wherein R3is C3-C4 cycloalkyl.

[0332] Embodiment 50. The composition of any of Embodiments 17-47, wherein R3is -C(O)O-methyl.

[0333] Embodiment 51. The composition of any of Embodiments 17-47, wherein R3is -C(O)O-ethyl.

[0334] Embodiment 52. The composition of any of Embodiments 17-47, wherein R3is -C(O)O-propyl.

[0335] Embodiment 53. The composition of any of Embodiments 17-47, wherein R3is -C(O)O-isopropyl.

[0336] Embodiment 54. The composition of any of Embodiments 17-47, whereinR3is -C(O)O-butyl.

[0337] Embodiment 55. The composition of any of Embodiments 17-47, wherein R3is -CH2OH.

[0338] Embodiment 56. The composition of any of Embodiments 17-47, wherein R3is -C(O)N-methyl.

[0339] Embodiment 57. The composition of any of Embodiments 17-47, wherein R3is -C(O)O-cycloalkyl.

[0340] Embodiment 58. The composition of Embodiment 57, whereinR3is -C(O)O-cyclopropyl, -C(O)O-cyclobutyl, -C(O)O-cyclopentyl, or -C(O)O-cyclohexyl.

[0341] Embodiment 59. The composition of any of Embodiments 17-47, whereinR3is -C(O)OH.

[0342] Embodiment 60. The composition of any of Embodiments 17-47, whereinR3is -CN.

[0343] Embodiment 61. The composition of any of Embodiments 17-47, whereinR3is an alkyl nitrile.

[0344] Embodiment 62. The composition of any of Embodiments 17-47, whereinR3is an imidazole.

[0345] Embodiment 63. The composition of any of Embodiments 17-47, whereinR3is a pyrazole.

[0346] Embodiment 64. The composition of any of Embodiments 17-47, whereinR3is a triazole.

[0347] Embodiment 65. The composition of any of Embodiments 17-47, whereinR3is a tetrazole.

[0348] Embodiment 66. The composition of any of Embodiments 17-47, whereinR3is an oxazole.

[0349] Embodiment 67. The composition of any of Embodiments 17-47, whereinR3is an isoxazole.

[0350] Embodiment 68. The composition of any of Embodiments 17-47, whereinR3is a thiazole.

[0351] Embodiment 69. The composition of any of Embodiments 17-47, whereinR3is -C(O)R9, andR9is H or C1-C4 alkyl.

[0352] Embodiment 70. The composition of any of Embodiments 17-47, whereinR3is C(O)NHR9, andR9is H or C1-C4 alkyl.

[0353] Embodiment 71. A pharmaceutical composition comprising the composition of any of Embodiments 1-70; and a pharmaceutically acceptable carrier.

[0354] Embodiment 72. A method of treating a disease in a patient in need thereof, wherein the method comprises:administering to the patient a therapeutically effective amount of the composition of any of Embodiments 1-70; wherein the disease is cancer.

[0355] Embodiment 73. The method of Embodiment 72, wherein the disease is characterized by a biomarker of susceptibility to Mpsl / TTK inhibition.

[0356] Embodiment 74. A method of treating a patient in need of an inhibitor of protein kinaseMpsl / TTK, wherein the method comprises: determining the level of Mpsl / TTK protein and / or Mpsl / TTK mRNA in a cell of the patient, and administering a therapeutically effective amount of the composition of any of Embodiments 1-70 to the patient if the presence of Mpsl / TTK protein and / or Mpsl / TTK mRNA is detected; wherein the patient is a cancer patient.

[0357] Embodiment 75. The method of Embodiment 74, wherein the patient is a brain cancer, glioblastoma multiforme, head and neck cancers, 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 patient.

[0358] All patent documents referred to herein are incorporated by reference in their entireties. Various embodiments of the invention have been described in fulfillment of the various objectives of the invention. It should be recognized that these embodiments are merely illustrative of the principles of the present invention. Numerous modifications and adaptations thereof will be readily apparent to those skilled in the art without departing from the spirit and scope of the invention.

Claims

CLAIMS1. A composition comprising a compound of Formula I:(Formula I), or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, whereinR1is H;R2is H;R3is not H;R4is selected from the group consisting of -ZR15or -ZR19, whereinZ is NH, N-methyl, or O;R15is a six-membered ring having the following structure, whereinR16is selected from the group consisting of hydrogen, halo, -O-R20, -C(O)-R20, -C(O)O- R20, .NR20R21 -C(S)NR20R21, -NR23C(O)NR20R21, -NR23C(S)NR20R21, -O-C(O)NR20R21, -S(O)2NR20R21, -O-S(O)2NR20R21, -NR23-S(O)2NR20R21, -CN, -NO2, C1-C6 alkyl, and - S(O)2-R22;R18is selected from the group consisting of hydrogen, halo, -O-R20, -C(O)-R20, -C(O)O- R20, -NR20R21, -C(O)NR20R21, -C(S)NR20R21, -NR23C(O)NR20R21, -NR23C(S)NR20R21, -O-C(O)NR20R21, -S(O)2NR20R21, -O-S(O)2NR20R21, -NR23-S(O)2NR20R21, -CN, -NO2, C1-C6 alkyl, and -S(O)2-R22;R19is selected from the group consisting of linear C1-C16 alkyl, branched C1-C16 alkyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, sec-pentyl, tert-pentyl, neo-pentyl, iso-hexyl, sec-hexyl, tert-hexyl, neo-hexyl, cyclo-butyl, and cyclo-pentyl;R20, R21, and R23are each independently hydrogen or Ci-Ce alkyl; andR22is Ci-Ce alkyl;R5is selected from the group consisting of C1-C4 alkyl, a substituted or unsubstituted 4- to 7- membered heterocycle, a sulfoximine, a sulfonamide, and a spirocyclic heterocycle that is fused or bridged, an E3-ligase binding moiety, -NHR24, and -NR24R31,R24is selected from the group consisting of C1-C4 alkyl halide, -R25-O-R26, -R27-C(O)NH-R28, -R29NHC(O)-R30, a substituted or unsubstituted 4-membered heterocycle, and a substituted or unsubstituted cyclobutane,R25is C1-C4 alkyl,R26is hydrogen, C1-C4 alkyl, or C1-C4 alkyl halide,R27and R28are each independently C1-C4 alkyl,R29and R30are each independently C1-C4 alkyl, andR31is C1-C4 alkyl or C1-C4 alkyl halide;R6is hydrogen, methyl, -CN, -S-methyl, or -XR8, wherein X is O, S, or SO2 and R8is C1-C3 alkyl or CI-C3 haloalkyl;R7is H, CN, OCH3, or F;Y is CH, N, CF, or C-CH3; and- represents a single or double bond.

2. The composition of claim 1, wherein R5is a 5- to 7-membered heterocycle substituted with one or two oxo and / or R17, wherein R17is independently selected from the group consisting of-O-R10, -wherein R10, R11, and R13are each independently hydrogen or Ci-Ce alkyl; andwherein R12is independently Ci-Ce alkyl.

3. The composition of claim 1, wherein R5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, a tetrahydrothiophene dioxide, a thiacyclohexane dioxide, a thiazolidine, a thiadiazolidine, a sulfoximine, or a sulfonamide.

4. The composition of claim 1, wherein:R3is C1-C4 alkyl, C3-C4 cycloalkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-iso- propyl, -C(O)O-butyl,-CH2OH, -C(O)NH-methyl, -C(O)O-cycloalkyl, -C(O)OH, -CN, an alkyl nitrile, an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, a thiazole, - C(O)R9, or -C(O)NHR9; andR9is H or C1-C4 alkyl.

5. The composition of claim 4, whereinR3is C1-C4 alkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-iso-propyl, -C(O)O- butyl, an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, a thiazole, or C(O)NHR9; andR9is H or C1-C4 alkyl.

6. The composition of claim 1, whereinR3is C1-C4 alkyl, -C(O)O-methyl, -C(O)O-ethyl, -C(O)O-propyl, -C(O)O-isopropyl, an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, a thiazole, or C(O)NHR9; R5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, a tetrahydrothiophene dioxide, a thiacyclohexane dioxide, a thiazolidine, a thiadiazolidine, a sulfoximine, or a sulfonamide; andR9is H or C1-C4 alkyl.

7. The composition of claim 6, whereinR3is a pyrazole or a triazole; andR5is a morpholine or a thiomorpholine dioxide.

8. The composition of claim 1, wherein the compound is of Formula II:(Formula II).

9. The composition of claim 8, whereinR3is an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, or a thiazole.

10. The composition of claim 8, whereinR5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, or a thiacyclohexane dioxide.

11. The composition of claim 8, whereinR3is an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, or a thiazole; and R5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, or a thiacyclohexane dioxide.

12. The composition of claim 11, whereinR3is a pyrazole or a tri azole; andR is a morpholine or a thiomorpholine dioxide.

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

14. The composition of claim 13, whereinR3is an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, or a thiazole.

15. The composition of claim 13, whereinR5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, or a thiacyclohexane dioxide.

16. The composition of claim 13, whereinR3is an imidazole, a pyrazole, a triazole, a tetrazole, an oxazole, an isoxazole, or a thiazole; and R5is an imidazole, a pyrazole, a triazole, a tetrazole, a pyrazolidinone, an oxazolidinone, a morpholine, a thiomorpholine dioxide, or a thiacyclohexane dioxide.

17. A pharmaceutical composition comprising the composition of claim 1; and a pharmaceutically acceptable carrier.

18. A method of treating a disease in a patient in need thereof, wherein the method comprises: administering to the patient a therapeutically effective amount of the composition of claim 1; wherein the disease is cancer.

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

20. A method of treating a patient in need of an inhibitor of protein kinase Mpsl / TTK, wherein the method comprises: determining the level of Mpsl / TTK protein and / or Mpsl / TTK mRNA in a cell of the patient, and administering a therapeutically effective amount of the composition of claim 1 to the patient if the presence of Mpsl / TTK protein and / or Mpsl / TTK mRNA is detected; wherein the patient is a cancer patient.

21. The method of claim 20, wherein the patient is a brain cancer, glioblastoma multiforme, head and neck cancers, 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 patient.