Compositions and methods of use for the inhibition of TTK kinase

Abstract

Disclosed herein are novel compounds that are Mpsl / TTK inhibitors. Also disclosed are compositions comprising the compounds and methods of using the compounds in treating various diseases. 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

COMPOSITIONS AND METHODS OF USE FOR THE INHIBITION OF TTK KINASE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119 to U.S. Provisional Patent Application No.63 / 621,801, filed January 17, 2024, which is 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 Mps1 / 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 therapeutics to 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. Thesesevere 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 Mps1 / TTK kinase inhibitory compounds, compositions, and methods of use 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 instances, provided herein is a composition comprising a compound of Formula I: R4R3R5(Formula I),a solvate thereof, wherein R1is not H; R2is not H; R3is H, C1-C3alkyl, or a halide; R4is H or C1-C3 alkyl; when Z is N, R5is absent; when Z is C, R5is selected from the group consisting of morpholine, tetrahydrothiophene dioxide, -S(O)Me-NMe, an imidazole, a pyrazole, a triazole, a tetrazole, a thiacyclohexane dioxide, a thiomorpholine dioxide, and an E3-ligase binding moiety; R6is C1-C3alkyl, CN, SMe, XR8, or NHC(O)R9; R7is H or F; R8is C1-C3 alkyl or C1-C3 haloalkyl; R9is C1- C3 alkyl or C1-C3 alkenyl; W is NH or O;X is O, SO, or SO2; Y is CH, N, CF, or C-CH3; and Z is C or N.

[0008] Moreover, provided herein are compounds of other formulas. For example, provided herein are compounds of Formula II: 43R R R5(Formula II),a solvate thereof, wherein R2is not H; R3is H, C1-C3 alkyl, or a halide; R4is H or C1-C3alkyl; and R5is selected from the group consisting of morpholine, tetrahydrothiophene dioxide, -S(O)Me- NMe, an imidazole, a pyrazole, a triazole, a tetrazole, a thiacyclohexane dioxide, a thiomorpholine dioxide, and an E3-ligase binding moiety.

[0009] In some embodiments of compositions described herein, R1is not H. However, the identity of R1is not particularly limited. In some instances, for example, R1is C4-C8 cycloalkyl. Moreover, in some embodiments, R1is an unsubstituted or substituted phenyl group. For example, in some embodiments, a phenyl group may be substituted with an alkyl group, a hydroxyl group, a halide, or an amide group.

[0010] In some implementations, R2is not H. It is to be understood that in some instances, the identity of R2is not particularly limited. For example, in some embodiments, R2is a pyrrole. Moreover, in some instances, R2is a pyrazole. In some instances, a pyrazole is an unsubstituted pyrazole, a C1-C3 alkyl-substituted pyrazole, or a C1-C3 haloalkyl-substituted pyrazole. In someimplementations, R2is an oxazole. In some embodiments, R2is a thiazole. In some cases, R2is a triazole.

[0011] Turning to the R5position, in some implementations of compounds described herein, Z is N. In such embodiments, R5is absent. However, in some cases, when Z is C, R5is selected from the group consisting of morpholine, tetrahydrothiophene dioxide, -S(O)Me-NMe, an imidazole, a pyrazole, a triazole, a tetrazole, thiacyclohexane dioxide, a thiomorpholine dioxide, and an E3-ligase binding moiety. In some instances, R5is a 1,2,4-triazole selected from the group consisting of 4-methyl-1,2,4-triazole, 4-ethyl-1,2,4-triazole, 4-iso-propyl-1,2,4-triazole, and 4-n-propyl-1-2,4-triazole. In some embodiments, R5is a 1,2,3,4-tetrazole selected from the group consisting of 1-methyl-1,2,3,4-tetrazole, 1-ethyl-1,2,3,4-tetrazole, 1-iso-propyl-1,2,3,4- tetrazole, and 1-n-propyl-1,2,3,4-tetrazole.

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

[0013] Further, in yet another aspect, provided 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. In some instances, the disease is cancer. Such a composition may comprise any composition described herein.

[0014] Moreover, in another aspect, provided is a method of treating a patient in need of an inhibitor of protein kinase Mps1 / TTK, wherein the method comprises determining the level of Mps1 / TTK protein and / or Mps1 / TTK mRNA in a cell of the patient, and administering a therapeutically effective amount of a composition described herein to the patient if the presence of Mps1 / TTK protein and / or Mps1 / TTK mRNA is detected. In some implementations, the patient is a cancer patient. A composition may comprise any compound described herein. BRIEF DESCRIPTION OF THE FIGURES

[0015] Figure 1A illustrates a brightfield visible microscopy image of co-crystals formed between TTK1 and Compound 1 under crystallization condition 1 as described in Table 13.

[0016] Figure 1B illustrates a UV fluorescent microscopy image of co-crystals formed between TTK1 and Compound 1 under crystallization condition 1 as described in Table 13.

[0017] Figure 2A illustrates a brightfield visible microscopy image of TTK1 crystals formed under crystallization condition 2 as described in Table 13.

[0018] Figure 2B illustrates an UV fluorescent microscopy image of co-crystals formed under crystallization condition 2 as described in Table 13.

[0019] Figure 3A illustrates a brightfield visible microscopy image of co-crystals formed between TTK1 and Compound 1 under crystallization condition 3 as described in Table 13.

[0020] Figure 3B illustrates an UV fluorescent microscopy image of co-crystals formed between TTK1 and Compound 1 under crystallization condition 3 as described in Table 13.

[0021] Figure 4A illustrates a brightfield visible microscopy image of co-crystals formed between TTK1 and Compound 1 under crystallization condition 4 as described in Table 13.

[0022] Figure 4B illustrates a brightfield visible microscopy image of additional co-crystals formed between TTK1 and Compound 1 under crystallization condition 4 as described in Table 13.

[0023] Figure 5A illustrates a ribbon diagram of the TTK1– Compound 1 complex with Compound 1.

[0024] Figure 5B illustrates a PyMOL rendering of Compound 1 in its binding pocket in TTK1.

[0025] Figure 6A illustrates the electron density of a TTK1–Compound 1 complex.

[0026] Figure 6B illustrates the electron density of a TTK1–Compound 1 complex. DETAILED DESCRIPTION

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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. 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.

[0032] 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”).

[0033] 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

[0034] 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.

[0035] 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%.

[0036] 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 include those 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.

[0037] 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 includespreventing 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.

[0038] The terms “Mps1 / TTK kinase inhibitor compound” or “Mps1 / TTK kinase inhibitor” refer broadly to species and / or molecules that inhibit the activity of Mps1 / TTK kinase.

[0039] 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.

[0040] 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 enantiomers and 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 R1through 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, suchas 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.

[0041] The term “amino” and “amine” refer to nitrogen-containing groups such as NR3, 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).

[0042] 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.

[0043] 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 “C1 to C4 alkyl” or “C1-C4 alkyl” or “C1 to C4 alkyl” or “C1-C4 alkyl” group refers broadly to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.

[0044] 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. Examplesof 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-C5alkyl” 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.

[0045] 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: *

[0046] 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 also covers 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 unsubstituted. 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 C3-6monocyclic cycloalkyl groupC).

[0047] 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-1-propenyl, 1-butenyl, 2-butenyl, and the like. An alkenyl group may be unsubstituted or substituted.

[0048] 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.

[0049] 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 mono- cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl, and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0050] 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.

[0051] 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 C6-C14 aryl group, a C6-C10 aryl group, or a C6 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, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. A heteroaryl group may be substituted or unsubstituted.

[0052] 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-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, 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.

[0053] 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 naphthylalkyl.

[0054] 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.

[0055] 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.

[0056] 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 1,3-thiazinan-4-yl(methyl).

[0057] As used herein, the term “hydroxy” refers broadly to a –OH group.

[0058] 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-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy, and benzoxy. An alkoxy may be substituted or unsubstituted.

[0059] 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.

[0060] As used herein, a “cyano” group refers broadly to a “-CN” group.

[0061] The term “halogen atom” or “halogen” as used herein means any one of the radio- stable atoms of column 7 of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, and iodine.

[0062] 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 RAand RBcan 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.

[0063] An “N-carbamyl” group refers broadly to an “ROC(=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-carbamyl may be substituted or unsubstituted.

[0064] An “O-thiocarbamyl” group refers broadly to a “-OC(=S)-N(RARB)” group in which RAand RBcan 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.

[0065] An “N-thiocarbamyl” group refers broadly to an “ROC(=S)N(RA)-” group in which R and RAcan 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.

[0066] A “C-amido” group refers broadly to a “-C(=O)N(RARB)” group in which RAand RBcan 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.

[0067] An “N-amido” group refers broadly to a “RC(=O)N(RA)-” group in which R and RAcan 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.

[0068] 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.

[0069] An “N-sulfonamido” group refers broadly to a “RSO2N(RA)-” group in which R and RAcan 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.

[0070] 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.

[0071] 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.

[0072] A “nitro” group refers broadly to an “–NO2” group.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. A haloalkyl may be substituted or unsubstituted.

[0077] 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 tri- haloalkoxy). Such groups include but are not limited to chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0078] The terms “amino” and “unsubstituted amino” as used herein refer broadly to a –NH2 group.

[0079] A “mono-substituted amine” group refers broadly to a “-NHRA” group in which RAcan 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 RAmay be substituted or unsubstituted. A mono-substituted amine group can include, for example, a mono-alkylamine group, a mono-C1-C6 alkylamine group, a mono- arylamine group, a mono-C6-C10 arylamine group, and the like. Examples of mono-substituted amine groups include but are not limited to −NH(methyl), −NH(phenyl), and the like.

[0080] A “di-substituted amine” group refers broadly to a “-NRARB” group in which RAand RB 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. RAand RBcan independently be substituted or unsubstituted. A di-substituted amine group can include, for example, a di-alkylamine group, a di-C1-C6 alkylamine group, a di- arylamine group, a di-C6-C10 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.

[0081] 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-C1-C6 alkylamine(C1-C6 alkyl) group, a mono-arylamine(alkyl group), a mono-C6-C10arylamine(C1-C6alkyl) 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.

[0082] 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-C1-C6 alkylamine(C1-C6 alkyl) group, a di-arylamine(alkyl) group, a di-C6-C10arylamine(C1-C6alkyl) 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.

[0083] 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 RBconnects 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.

[0084] 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 RDcan 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.

[0085] 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 RBconnects the two “O” groups and can be a substituted or unsubstituted alkylene group. RA can independently further be substituted or unsubstituted.

[0086] As used herein, the term “polyether” denotes a repeating –(ORB-)nORAgroup. For illustration, the term polyether can comprise -Oalkyl-Oalkyl-Oalkyl-Oalkyl-ORA. In some embodiments, the alkyl of the polyether 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. RAcan 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 independentlyfurther 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.

[0087] 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-C3alkoxyphenyl” 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.

[0088] 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 and scientific 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.

[0089] Provided herein are Mps1 / 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 proteinkinase. 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 re- duplication, 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 Mps1 / TTK results in chromosome missegregation 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 Mps1 / TTK, preventing its ubiquitination and degradation, suggesting BRAF V600E mutation may be a biomarker for cancers that are sensitive to treatment with Mps1 / TTK inhibitors. I. Compounds

[0090] In one aspect, provided herein are compositions comprising Mps1 / TTK kinase inhibitory compounds. In some embodiments, some such compositions may useful for the treatment of cancer. In some instances, provided herein is a composition comprising a compound of Formula I: R4R3I),or a tautomer, a pharmaceutically acceptable salt, and / or a solvate thereof, wherein R1is not H; R2is not H; R3is H, C1-C3 alkyl, or a halide; R4is H or C1-C3 alkyl; when Z is N, R5is absent; when Z is C, R5is selected from the group consisting of morpholine, tetrahydrothiophene dioxide, -S(O)Me-NMe, an imidazole, a pyrazole, a triazole, a tetrazole, a thiacyclohexane dioxide, a thiomorpholine dioxide, and an E3-ligase binding moiety; R6is C1-C3alkyl, CN, SMe, XR8, or NHC(O)R9; R7is H or F; R8is C1-C3alkyl or C1-C3haloalkyl; R9is C1- C3alkyl or C1-C3alkenyl; W is NH or O; X is O, SO, or SO2; Y is CH, N, CF, or C-CH3; and Z is C or N.

[0091] Compositions comprising compounds of other formulas are also provided herein. For example, in some embodiments, provided herein are compounds of Formula II: R4R3R5(Formula II),a solvate thereof, wherein R2, R3, R4, and R5are defined as above.

[0092] In some embodiments of compositions described herein, R1is not H. However, the identity of the moiety of R1is not limited. In some instances, R1is C4-C8cycloalkyl. In some embodiments, R1is selected from the group consisting of the structures shown below.in some implementations, R1is an unsubstituted or substituted phenyl group. For example, in some embodiments, a phenyl group may be substituted with an alkyl group, a hydroxyl group, a halide, or an amide group. In some cases, R1is the moiety shown below.R2is not H. However, the identity of the moiety of R2is not limited. In some embodiments, R2is a pyrrole. In some instances, R2is a pyrazole. A pyrazole 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-C3alkyl-substituted pyrazole, such as a 1- methylpyrazole. In other embodiments, a pyrazole is a C1-C3 haloalkyl-substituted pyrazole. Non-limiting examples of pyrazoles are shown below.NN NHNinconsistent with the technical objectives of the current disclosure. In some instances, the oxazole may be unsubstituted or substituted. For example, in some implementations, the 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. N N Nmoiety not inconsistent with the technical objectives of the current disclosure. In some instances, a thiazole may be unsubstituted or substituted. For example, in some embodiments, a thiazole isalkyl-substituted. In some implementations, an alkyl-substituted thiazole is a C1-C3 alkyl- substituted thiazole. Non-limiting examples of thiazoles are shown below. N N N notcurrent of triazoles are shown below. N N N NH N NHembodiments, a substituted triazole of R2is a N-alkyl triazole. Non-limiting example of an N- alkyl triazoles are shown below. N N Nin some cases, R4is a halide or a hydroxyl group.

[0098] Moreover, turning to other positions of compounds described herein, in some implementations, Z is N. In such implementations, R5is absent.

[0099] However, in some embodiments of compositions described herein, Z is C. In some such instances, R5may be one of several moieties. For example, in some instances, when Z is C, R5is a morpholine. An example of a morpholine is shown below.N OIt is t tood that in some cases, R5may also be a substituted morpholine moiety. Forexample, in some embodiments, a morpholine moiety may be substituted with an alkyl group or a halide group.

[0100] In some other instances, when Z is C, R5is tetrahydrothiophene dioxide, which is shown below below. O Oembodiments, when Z is C, R5is -S(O)Me-NMe.

[0102] In some instances, when Z is C, 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 include the structures shown below. H H N N Nimidazole may be an N-alkyl imidazole or a dimethylimidazole. Non-limiting examples of N-alkyl imidazoles and dimethyl imidazole are shown below.N Nmay 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-C3haloalkyl-substituted pyrazole. Non-limiting examples of pyrazoles in the R5position include the structures shown below below. NR5position may be any triazole moiety not inconsistent with the technical objectives of the current disclosure. Non-limiting examples of triazoles are shown below. N N N NH NIn some instances, a triazole may be unsubstituted or substituted. For example, in some embodiments, a substituted triazole in the R5position is a N-alkyl triazole. Non-limiting example of an N-alkyl triazoles are shown below. N N N N 1,2,4-triazolegroup 4-n- propyl-1-2,4-triazole, and 4-iso-propyl-1,2,4-triazole. Example 1,2,4-triazoles are shown below. N N N N NA tetrazole in the R5position may be any tetrazole moiety not inconsistent with the technical objectives of the current disclosure. Non-limiting examples of tetrazoles are shown below. N N NH N Nor substituted. For example, in some implementations, a tetrazole is an N-alkyl tetrazole. In some implementations, a tetrazole is a 1,2,3,4-tetrazole. In some embodiments, a 1,2,3,4-tetrazole is an N-alkyl substituted 1,2,3,4-tetrazole. In some instances, a 1,2,3,4-tetrazole is selected from the group consisting of 1-methyl- 1,2,3,4-tetrazole, 1-ethyl-1,2,3,4-tetrazole, 1-iso-propyl-1,2,3,4-tetrazole, and 1-n-propyl-1,2,3,4- tetrazole. Examples of 1,2,3,4-tetrazoles are shown below. N N N N N N Ndioxide. 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. Omoiety. For example, in some embodiments, a thiomorpholine dioxide moiety may be substituted with an alkyl group or a halide group.

[0108] Turning to additional R5groups, in some instances, R5has the following structure:(Formula III).(Formula IV).V),VIII),O CF3(Formula XII). imple5mentations, when Z is C, 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.

[0110] 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.

[0111] 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: L T ,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.

[0112] Additionally, the identity of L is not 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 some implementations, 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-C14aryl group, a C6-C10aryl group, or a C6 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 diether 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.

[0113] Moreover, the identity of T is not to be 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 202362 (3), 601- 623; Toriki, et al., Rational Chemical Design of Molecular Glue Degraders, ACS Central Science 20239 (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 202291, 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 Ligandsin Successful PROTACs: An Overview of Syntheses and Linker Attachment Points, Front Chem. 2021 Jul 5;9:707317, which are incorporated by reference herein.

[0114] 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

[0115] In another aspect, provided are compositions comprising a compound described herein, such as a compound of Formula I or Formula II. 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).

[0116] 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.

[0117] 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.

[0118] 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, concomitant therapies, 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 10-5g / kg to 1 g / kg, preferably, l x 10-3g / 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.

[0119] 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.

[0120] 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, semisolids, 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.

[0121] 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 free flowing 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.

[0122] 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.

[0123] 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.

[0124] 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 moresuitable pharmaceutical excipients. Preferably, in some instances, a compound described herein is present at a level of about 1-80 wt%.

[0125] 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 or an additional therapeutic agent, as described in Section III) to form a pharmaceutical composition described herein. III. Combination Therapy

[0126] 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.

[0127] In some embodiments, the one or more additional therapeutic agents is an anti- angiogenesis agent (e.g., an agent that stops tumors from developing new blood vessels). Non- limiting 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).

[0128] 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).

[0129] Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex®) and UCN 01 (Kyowa Hakka).

[0130] 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®).

[0131] 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®).

[0132] Other anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat®), and PCK 3145 (Procyon).

[0133] Other anti-angiogenesis agents include acitretin (Neotigason®), plitidepsin (Aplidine®), cilengtide (EMD 45121974), 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®).

[0134] 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, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan-erb, IGF IRinhibitors, 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.

[0135] 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®).

[0136] 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).

[0137] 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®).

[0138] Other examples of signal transduction inhibitors include ARRY 142886 (Array Biopharm), everolimus (Certican®), zotarolimus (Endeavor®), temsirolimus (Torisel®), AP 23573 (ARIAD), and VX 680 (Vertex).

[0139] Additionally, other signal transduction inhibitors include XL 647 (Exelixis), sorafenib (Nexavar®), LE-AON (Georgetown University), and GI-4000 (GlobeImmune).

[0140] 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.

[0141] In some embodiments, a compound disclosed herein is used together with classical antineoplastic 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 (HDAC) inhibitors, genesilencing 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.

[0142] 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.

[0143] 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-hydroxycamptothecin, irinotecan HCl (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), topotecan, camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, 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 (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin, and combinations thereof.

[0144] In some embodiments, a compound disclosed herein is used together with dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetresate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6- thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), pyrimidine antagonists), Alimta (premetrexed disodium, LY231514, MTA), 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.

[0145] 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 enhancesthe efficacy of cytotoxics), Theratope® (Biomira), Tretinoin (Vesanoid®), tirapazamine (Trizaone®), motexafin gadolinium (Xcytrin®) Cotara® (mAb), and NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax®) and combinations thereof.

[0146] 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 TNFalpha 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.), Provastatin (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.

[0147] 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.

[0148] 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.

[0149] 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.), BI-1387446 (Boehringer Ingelheim International GmbH), BMS-986301 (Bristol-Myers Squibb), DN-015089 (Shanghai De Novo Pharmatech Co. Ltd.), E-7766 (Eisai Co. Ltd.), GSK3745417 (GSK plc), 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.), BI-09 (Wistar Institute), c-Di-GMP (Hokkaido University), CRD-5500 (Takeda Pharmaceutical Co. Ltd.), NZ-IO-STING (Lidds AB; Stipe Therapeutics ApS; CS-BayTherapeutics Inc.), GSK-532 (GSK plc), IMGS-203 (Immunogenesis Inc.), IMSA-201 (ImmuneSensor Therapeutics Inc.), JNJ-4412 (Johnson & Johnson), JNJ-6196 (Johnson & Johnson; F-star Therapeutics Inc.), ONM-501 (OncoNano Medicine, Inc.), QHL-816 (Shanghai Affinity Biomedical Technology Co. Ltd.), RVU-24024 (Ryvu Therapeutics SA; University of Pennsylvania; Tsinghua University; Inimmune Corp), and combinations thereof.

[0150] 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.), STI-002 (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.).

[0151] 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.

[0152] 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.

[0153] 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. In some 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.

[0154] 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-PD1 / PD-L1 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 HER2 positive, ado- trastuzumab emtansine, capecitabine in combination with lapatinib or neratinib, paclitaxel incombination with neratinib, tucatinib in combination with trastuzuma and capecitabine, fam- trastuzumab 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 non- specific, 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, or pembrolizumab 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.

[0155] 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.

[0156] 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 isnot 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.

[0157] 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-Guérin (BCG).

[0158] 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.

[0159] 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.

[0160] 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 notlimited 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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 in combination 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

[0167] In some embodiments, provided are methods of inhibiting Mps1 / TTK kinase comprising, consisting of or consisting essentially of, contacting Mps1 / TTK with a compound, pharmaceutical compositon, 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: R4R3R5(Formula I),thereof; wherein R1is not H; R2is not H; R3is H, C1-C3 alkyl, or a halide; R4is H or C1-C3 alkyl; when Z is N, R5is absent;when Z is C, R5is selected from the group consisting of morpholine, tetrahydrothiophene dioxide, -S(O)Me-NMe, an imidazole, a pyrazole, a triazole, a tetrazole, a thiacyclohexane dioxide, a thiomorpholine dioxide, and an E3-ligase binding moiety; R6is C1-C3 alkyl, CN, SMe, XR8, or NHC(O)R9; R7is H or F; R8is C1-C3alkyl or C1-C3haloalkyl; R9is C1- C3 alkyl or C1-C3 alkenyl; W is NH or O; X is O, SO, or SO2; Y is CH, N, CF, or C-CH3; and Z is C or N.

[0168] In some instances, provided are methods of inhibiting Mps1 / TTK kinase comprising, consisting of or consisting essentially of, contacting Mps1 / TTK with a compound of Formula II: R4R3R5(Formula II),solvate thereof; wherein R2is not H; R3is H, C1-C3alkyl, or a halide; R4is H or C1-C3 alkyl; and R5is selected from the group consisting of morpholine, tetrahydrothiophene dioxide, -S(O)Me- NMe, an imidazole, a pyrazole, a triazole, a tetrazole, a thiomorpholine dioxide, and a E3-ligase binding moiety.

[0169] In some other embodiments, provided are methods of treating a disease comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I or Formula II, 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 Mps1 / 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 Mps1 / 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.

[0170] Moreover, in another embodiment, provided are methods of treating a disease mediated at least in part by protein kinase Mps1 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, non- small cell lung cancer, small cell lung cancer, or endometrial cancer. Moreover, in someinstances, the cancer is not necessarily defined by its tissue of origin but rather by a biomarker of susceptibility to Mps1 / TTK inhibition, as described above. For example, in some cases, the cancer comprises, consists of, or consists essentially of cells that overexpress protein kinase Mps1 / TTK such that expressing Mps1 / TTK at a level that is at least 120%, 150%, or 200% of the normal Mps1 / TTK expression level. The normal Mps1 / TTK expression level can be determined by Mps1 / 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.

[0171] 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 or Formula II, 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 Mps1 / 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.

[0172] 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 beany compound described in Section I. In some embodiments, the compounds are compounds of Formula I or Formula II, or a pharmaceutically acceptable salt and / or solvate thereof. In other 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 implementations, the cancer is not defined by its tissue of origin but rather by a biomarker of susceptibility to Mps1 / 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.

[0173] 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 or Formula II, 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 Mps1 / 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.

[0174] 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 Restrains Centrosome 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(1):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).

[0175] 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.

[0176] 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.

[0177] 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 toMpsl / TTK protein inhibition is detected. The level of susceptibility may be determined according to evaluation of a biomarker, as described above.

[0178] In some embodiments, the patient is administered a compound described herein after detection of a biomarker of susceptibility to Mps1 / 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 Mps1 / TTK inhibition.

[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 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.

[0180] 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.

[0181] 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 μg to about 900 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.01 μg to about 800 mg of the compound per gram of the composition. In some instances, the effective amount is from about 0.01 μg to about 700 mg of the compound per gram of the composition. In some cases, the effective amount is from about 0.01 μg to about 600 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.01 μg to about 500 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.01 μg to about 400 mg of the compound per gram of the like. In some implementations, the effective amount is from about 0.01 μg to about 300 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.01 μg to about 200 mg of the compound per gram of the composition. In some cases, the effective amount is from about 0.01 μg to about 100 mg of the compound per gram of the composition. In some embodiments, the effective amount is from about 0.1 μg to about 500 μg of the compound per gram of the composition.

[0182] 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.

[0183] 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 or Formula II. In some aspects, the instructions comprise, consist essentially of, or consist of a description of a method of treatment as described herein.

[0184] Some embodiments are further illustrated in the following non-limiting Examples. EXAMPLE 1

[0185] The following Examples describe the synthesis and testing of various novel small molecule Mps1 / TTK inhibitors as targeted therapies for cancer. Mps1 / TTK inhibitors were synthesized as indicated. The compounds were evaluated for their activity against Mps1 / TTK and tested using antiproliferative assays, and the data indicate the synthesized compounds possess activity against Mps1 / TTK and have anti-proliferative potential in cancer cell lines. Compound Synthesis

[0186] Mps1 / TTK inhibitor compounds and comparative compounds were synthesized making modifications of Formula I at R1, R2, R3, R4, R5, R6, R7, Z, and W as indicated in Tables 1 and 2, respectively. Table 1. Structures of Mps1 / TTK inhibitor compounds. No. R1R2R3R4R5R6R7Z W NH NH NH NH NH NHN H H N N OMe H C NH N N NH NH NH NH NH NH NH NH NH NH NH NH NHN H H O N S OMe H C NH N NH NH NH NH NH NH NH NH NH NH NH NH NHN H HN OOMe H C NH N NH NH O NH NH NH NH NH NH NH NH NH NHTable 2. Structures of comparative compounds. Comparative R1R2R3R4R5R6R7Z W No. NH NH NH NH NH NH

[0187] The synthesis of compounds 1, 3, 6-9, 11, 16-18, 24, and 37-48 is described herein. Other compounds shown in Tables 1 and 2 were synthesized in a similar manner to the compounds described herein. Preparation of Compound 1O N N S NFe, NHCl, H O,N NOCl2, DCE,N4 2N

[0188] In a reaction vial to a suspension of 3-methoxy-N-methyl-4-nitrobenzamide (550 mg, 1.0 eq., 2.62 mmol) in 1,2-dichloroethane (10 mL) was added thionyl chloride (759 µL, 4 eq., 10.5 mmol). The vial was capped and heated to 88°C while stirring for 2 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was treated with dimethylformamide (5 mL) and formic hydrazide (189 mg, 1.2 eq., 3.14 mmol) and stirred at 88 ⁰C overnight. The reaction was cooled to room temperature and quenched with water. The aqueous layer was extracted with ethyl acetate (5 x 25 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 10% methanol in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried using a 12 g column eluting with a gradient of methanol in ethyl acetate (0-20%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 3-(3-methoxy-4-nitrophenyl)- 4-methyl-4H-1,2,4-triazole (409 mg, 67%) as an off-white powder.1H NMR (400 MHz, DMSO- d6): δ 8.66 (s, 1H), 8.04 (d, J = 8.38 Hz, 1H), 7.67 (d, J = 1.60 Hz, 1H), 7.49 (dd, J = 8.38, 1.60 Hz, 1H), 4.00 (s, 3H), 3.81 (s, 3H).Step 2. Synthesis of 2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline.

[0189] In a reaction vial to a suspension of 3-(3-methoxy-4-nitrophenyl)-4-methyl-4H-1,2,4- triazole (0.3 g, 1.0 eq., 1.28 mmol) in ethanol (6.4 mL) was added a saturated aqueous ammonium chloride solution (953 µL) and iron powder (258 mg, 3.6 eq., 4.61 mmol). The vial was capped, and the reaction mixture was heated to 85°C overnight. The reaction mixture was cooled to room temperature, quenched with water, and extracted 5 times with ethyl acetate (~25 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12 g column eluting with a gradient of methanol in ethyl acetate (0-20%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried to afford 2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (163 mg, Yield: 62%) as an off-white powder.1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 7.11 (d, J = 1.80 Hz, 1H), 7.04 (dd, J = 8.06, 1.80 Hz, 1H), 6.73 (d, J = 8.06 Hz, 1H), 5.15 (s, 2H), 3.82 (s, 3H), 3.70 (s, 3H). Step 3. Synthesis of Compound 1 (7-cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3- yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0190] In a reaction vial, a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (53 mg, 1.0 eq., 168 µmol), 2-methoxy-4-(4-methyl-4H-1,2,4- triazol-3-yl)aniline (36 mg, 1.05 eq., 176 µmol), cesium carbonate (109 mg, 2 eq., 336 µmol), and XPhos (16 mg, 0.2 eq., 33.6 µmol) in 1,4-dioxane (530 µL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3 (15.4 mg, 0.1 eq., 16.8 µmol) was added to the vial, and the vial was capped and heated to 107°C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with 5% aqueous sodium sulfate. The resulting precipitate was collected on filter paper and washed with water. The precipitate was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g gold column eluting with a gradient of methanol in ethyl acetate (0-30%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with methanol, and the precipitate was collected on filter paper and dried under vacuum to afford 7- cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Compound 1) (34.5 mg, Yield: 43%) as an off-white powder.1H NMR (400 MHz, CDCl3): δ 8.94 (d, J = 8.42 Hz, 1H), 8.63 (s, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.58 (d, J = 0.5 Hz, 1H), 7.50 (s, 1H), 7.33 (d, J = 1.85 Hz, 1H), 7.23-7.23 (m, 1H),6.30 (s, 1H), 4.16-4.28 (m, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.81 (s, 3H), 2.80 -2.95 (m, 2H), 1.90- 1.99 (m, 2H), 1.77-1.90 (m, 3H), 1.30-1.46 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C26H30N9O, 484.3; found, 484.2. Preparation of Compound 3

[0191] To a solution of 2,4-dichloro-5-iodopyrimidine (15 g, 1.0 eq., 54.6 mmol) in ethanol (124 mL) at room temperature was added triethylamine (16 mL, 2.1 eq., 115 mmol) and cyclobutylamine hydrochloride (5.87 g, 1.0 eq., 54.6 mmol). The reaction mixture was stirred at room temperature for 23 hours. The reaction mixture was concentrated in vacuo. The residue was suspended in DCM (100 mL), and dry loaded onto silica gel (30 g). CombiFlash column chromatography was carried out using an 80 g column, eluting with a gradient of ethyl acetate in hexanes (0-0.4%) followed by 10% ethyl acetate in hexanes to elute the remaining product.Fractions containing the desired product were pooled together and concentrated in vacuo to yield 2-chloro-N-cyclobutyl-5-iodopyrimidin-4-amine (13.7 g) as a white powder.1H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 5.52 (s, 1H), 4.65 – 4.51 (m, 1H), 2.54 – 2.39 (m, 2H), 2.02 – 1.88 (m, 2H), 1.86 – 1.72 (m, 2H). Step 2. Synthesis of 2-chloro-N-cyclobutyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyrimidin-4- amine.

[0192] A mixture of 2-chloro-N-cyclobutyl-5-iodopyrimidin-4-amine (1.24 g, 1.0 eq., 3.99 mmol), and 4-ethynyl-1-methyl-1H-pyrazole (445 mg, 1.05 eq., 4.19 mmol) in dimethylformamide (19.9 mL) and triethylamine (1.67 mL, 3 eq., 12 mmol) was degassed by bubbling argon vigorously for 10 minutes. Pd(PPh3)2Cl2(140 mg, 0.05 eq., 199 µmol) and copper (I) iodide (38 mg, 0.05 eq., 199 µmol) were subsequently added, and the reaction mixture was stirred for 40 minutes at room temperature. The reaction was diluted with MTBE (125 mL), and the organic layer was washed twice with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 24 g column eluting with a gradient of ethyl acetate in hexanes (0-38%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 2-chloro-N-cyclobutyl-5-((1-methyl-1H-pyrazol-4- yl)ethynyl)pyrimidin-4-amine (932 mg, Yield: 81%) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 5.70 (d, J = 7.7 Hz, 1H), 4.71 – 4.57 (m, 1H), 3.94 (s, 3H), 2.54 – 2.41 (m, 2H), 2.03 – 1.88 (m, 2H), 1.84 – 1.73 (m, 2H). Step 3. Synthesis of 2-chloro-7-cyclobutyl-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidine.

[0193] In a reaction vial to a solution of 2-chloro-N-cyclobutyl-5-((1-methyl-1H-pyrazol-4- yl)ethynyl)pyrimidin-4-amine (0.9 g, 1.0 eq., 3.13 mmol) in THF (20.9 mL) was added a solution of 1 M TBAF in THF (9.38 mL, 3 eq., 9.38 mmol). The reaction mixture was heated at 70°C for 2 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (~100 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12 g column eluting with a gradient of ethyl acetate in hexanes (20-60%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 2-chloro-7-cyclobutyl-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (750 mg, Yield: 83%) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 6.38 (s, 1H), 4.97 – 4.83 (m, 1H), 4.02 (s, 3H), 3.43 – 3.28 (m, 2H), 2.38 – 2.25 (m, 2H), 2.12 – 1.98 (m, 1H), 1.84 – 1.68 (m, 1H). Step 4. Synthesis of Compound 3 (7-cyclobutyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3- yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0194] In a reaction vial, a mixture of 2-chloro-7-cyclobutyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (60 mg, 1.0 eq., 209 µmol), 2-methoxy-4-(4-methyl-4H-1,2,4- triazol-3-yl)aniline (44.7 mg, 1.05 eq., 219 µmol), cesium carbonate (136 mg, 2 eq., 417 µmol), and XPhos (19.9 mg, 0.2 eq., 41.7 µmol) in 1,4-dioxane (0.6 mL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3 (19.1 mg, 0.1 eq., 20.9 µmol) was then added to the vial, and the vial was capped and heated to 107°C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and 5% aqueous sodium sulfate. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g gold column eluting with a gradient of methanol in ethyl acetate (0-30%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was dissolved in methanol (400 µL) and loaded onto a reverse phase C1815.5 g gold column eluting with a gradient of methanol in water (10-100%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried under vacuum at 85°C overnight to afford 7-cyclobutyl-N-(2-methoxy-4-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine (compound 3) (21 mg, Yield: 22%) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.96 (d, J = 8.4 Hz, 1H), 8.64 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.25 (dd, J = 8.4, 1.9 Hz, 1H), 6.29 (s, 1H), 4.98 – 4.85 (m, 1H), 4.01 (s, 6H), 3.82 (s, 3H), 3.65 – 3.50 (m, 2H), 2.40 – 2.28 (m, 2H), 2.14 – 2.02 (m, 1H), 1.94 – 1.79 (m, 1H). MS (APCI) m / z: [M+H]+calcd for C24H26N9O, 456.2; found, 456.2. Preparation of Compound 6ONNFe,NNTfNH4Cl, 2O, NaN3,NHO, EtON M 0-20 °C N2 H,NStep 1. Synthesis of 5-(3-methoxy-4-nitrophenyl)-1-methyl-1H-tetrazole.

[0195] Triflic anhydride (0.8 mL, 2 eq., 4.76 mmol) was added dropwise to a suspension of 3-methoxy-N-methyl-4-nitrobenzamide (0.5 g, 1.0 eq., 2.38 mmol) and sodium azide (619 mg, 4 eq., 9.52 mmol) in acetonitrile (11.9 mL) at 0 °C. The reaction mixture was warmed up to room temperature 1 hour later by removing from the ice bath, and the resulting mixture was stirred for 2 hours. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate three times, and the combined organic layers were washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g column eluting with a gradient of ethyl acetate in hexanes (20-50%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 5-(3-methoxy-4-nitrophenyl)- 1-methyl-1H-tetrazole (406 mg, Yield: 73%) as a light-yellow solid.1H NMR (400 MHz,DMSO-d6): δ 8.11 (d, J = 8.35 Hz, 1H), 7.77 (d, J = 1.61 Hz, 1H), 7.57 (dd, J = 8.35, 1.61 Hz, 1H), 4.21 (s, 3H), 4.02 (s, 3H). Step 2. Synthesis of 2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)aniline.

[0196] To a suspension of 5-(3-methoxy-4-nitrophenyl)-1-methyl-1H-tetrazole (380 mg, 1.0 eq., 1.62 mmol) in ethanol (8.08 mL) was added a saturated aqueous ammonium chloride solution (1.21 mL) and iron powder (325 mg, 3.6 eq., 5.82 mmol). The reaction mixture was heated to 85⁰C overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a small plug of celite. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g column eluting with a gradient of ethyl acetate in hexanes (30-80%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)aniline (295 mg, Yield: 89%) as an off-white powder.1H NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 7.24 (d, J = 1.80 Hz, 1H), 7.21 (dd, J = 8.06, 1.80 Hz, 1H), 6.78 (d, J = 8.06 Hz, 1H), 5.42 (s, 2H), 4.14 (s, 3H), 3.84 (s, 3H). Step 3. Synthesis of Compound 6 (7-cyclohexyl-N-(2-methoxy-4-(1-methyl-1H-tetrazol-5- yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0197] In a reaction vial, a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (120 mg, 1.0 eq., 380 µmol), 2-methoxy-4-(1-methyl-1H-1,2,3,4- tetrazol-5-yl)aniline (81.9 mg, 1.05 eq., 399 µmol), cesium carbonate (124 mg, 1.0 eq., 380 µmol), and XPhos (36.2 mg, 0.2 eq., 76 µmol) in 1,4-dioxane (1.2 mL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3(34.8 mg, 0.1 eq., 38 µmol) was added to the vial, and the vial was capped and heated to 107⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and co-evaporated with toluene. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g gold column eluting with a gradient of ethyl acetate in hexanes (20- 100%). Fractions containing the desired product were pooled together, and concentrated in vacuo to afford 7-cyclohexyl-N-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)-6-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Compound 6) (86 mg, Yield: 47%) as a light green powder.1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 8.3 Hz, 1H), 8.71 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 0.8 Hz, 1H), 7.67 (d, J = 0.8 Hz, 1H), 7.52 – 7.44 (m, 2H), 6.43 (s, 1H), 4.30 –4.17 (m, 4H), 4.02 (s, 3H), 3.94 (s, 3H), 2.82 – 2.68 (m, 2H), 1.94 – 1.72 (m, 5H), 1.45 – 1.29 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C25H29N10O, 485.3; found, 485.2. Preparation of Compound 7 O Pd / C, SOCl2, DCE,N H2N N NN N N N N ClStep 1. Synthesis of 4-ethyl-3-(3-methoxy-4-nitrophenyl)-4H-1,2,4-triazole.

[0198] In a reaction vial to a suspension of N-ethyl-3-methoxy-4-nitrobenzamide (0.5 g, 1.0 eq., 2.23 mmol) in 1,2-dichloroethane (10 mL) was added thionyl chloride (647 µL, 4 eq., 8.92 mmol). The vial was capped and heated to 88°C while stirring for 2 hours. The reaction mixture was concentrated in vacuo. The resulting pale-yellow residue was treated with dimethylformamide (4.26 mL) and formic hydrazide (161 mg, 1.2 eq., 2.68 mmol) and stirred at 88 ⁰C overnight. The reaction was cooled to room temperature and quenched with water. The aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organics were washed with saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 10% methanol in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried using a 12 g columneluting with a gradient of methanol in ethyl acetate (0-20%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 4-ethyl-3-(3-methoxy-4- nitrophenyl)-4H-1,2,4-triazole (360 mg, Yield: 65%) as a white powder.1H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 4.16 (q, J = 7.3 Hz, 2H), 4.03 (s, 3H), 1.49 (t, J = 7.3 Hz, 3H). Step 2. Synthesis of 4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyaniline.

[0199] A solution of 4-ethyl-3-(3-methoxy-4-nitrophenyl)-4H-1,2,4-triazole (150 mg, 1.0 eq., 604 µmol) in methanol (12.1 mL) was cycled twice through the H-Cube®Mini Plus at a flow rate of 1 mL / min methanol. Reaction conditions are as follows: Temperature: 30°C, Catalyst: Pd / C (10%), Flow rate: 1 ml / min (MeOH), and Hydrogen Pressure: 2 bar. The reaction mixture was concentrated in vacuo to afford 4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2-methoxyaniline (126 mg, Yield: 96%) as a pale-yellow powder.1H NMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 7.16 (d, J = 1.8 Hz, 1H), 6.95 (dd, J = 8.0, 1.8 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.13 – 3.99 (m, 4H), 3.90 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H). Step 3. Synthesis of Compound 7 (7-cyclohexyl-N-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2- methoxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0200] In a reaction vial, a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (125 mg, 1.0 eq., 396 µmol), 4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2- methoxyaniline (90.7 mg, 1.05 eq., 416 µmol), cesium carbonate (258 mg, 2 eq., 792 µmol), and XPhos (37.7 mg, 0.2 eq., 79.2 µmol) in 1,4-dioxane (1.25 mL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3 (36.2 mg, 0.1 eq., 39.6 µmol) was added to the vial, and the vial was capped and heated to 107°C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and brine. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g gold column eluting with a gradient of methanol in ethyl acetate (0-30%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was redissolved in DCM and concentrated. The residue was triturated with methanol and the resulting precipitate was collected and dried to afford 7-cyclohexyl-N-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)-2- methoxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Compound7) (17.5 mg, Yield: 9%) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.94 (d, J = 8.4 Hz, 1H), 8.63 (s, 1H), 8.25 (s, 1H), 7.92 (s, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.49 (s, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 8.4, 1.8 Hz, 1H), 6.30 (s, 1H), 4.28 – 4.09 (m, 3H), 4.01 (s, 3H), 3.99 (s, 3H), 2.95 – 2.82 (m, 2H), 1.98 – 1.90 (m, 2H), 1.90 – 1.76 (m, 3H), 1.48 (t, J = 7.3 Hz, 3H), 1.44 – 1.28 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C27H32N9O, 498.3; found, 498.2. Preparation of Compound 8 O B N N

[0201] In a microwave vial equipped with a stir bar, a mixture of 2-bromo-1,5-dimethyl-1H- imidazole (240 mg, 1.0 eq., 1.37 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (342 mg, 1.0 eq., 1.37 mmol), and cesium fluoride (625 mg, 3 eq., 4.11 mmol), in 1,2- dimethoxyethane (2.66 mL) and methanol (1.33 mL) was degassed by bubbling with argon vigorously for 5 minutes. Pd(PPh3)4 (79.2 mg, 0.05 eq., 68.6 µmol) was added to the reactionmixture, and the vial was capped and heated at 150⁰C in the microwave for 10 minutes. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The aqueous layer was basified by the addition of 2 M aqueous Na2CO3and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g column eluting with a gradient of methanol in DCM (0-5%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with hexanes:ethyl acetate (70:30) to afford 4-(1,5-dimethyl- 1H-imidazol-2-yl)-2-methoxyaniline (154 mg, Yield: 52%) as an off-white solid.1H NMR (400 MHz, Chloroform-d) δ 7.11 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 8.0, 1.8 Hz, 1H), 6.83 (q, J = 1.0 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 3.92 (s, 2H), 3.89 (s, 3H), 3.56 (s, 3H), 2.25 (d, J = 1.1 Hz, 3H). Step 2. Synthesis of Compound 8 (7-cyclohexyl-N-(4-(1,5-dimethyl-1H-imidazol-2-yl)-2- methoxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0202] In a reaction vial, a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (125 mg, 1.0 eq., 396 µmol), 4-(1,5-dimethyl-1H-imidazol-2-yl)-2- methoxyaniline (90.3 mg, 1.05 eq., 416 µmol), cesium carbonate (258 mg, 2 eq., 792 µmol), and XPhos (37.7 mg, 0.2 eq., 79.2 µmol) in 1,4-dioxane (1.25 mL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3(36.2 mg, 0.1 eq., 39.6 µmol) was then added to the vial, and the vial was capped and heated to 107⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and brine. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g gold column eluting with a gradient of methanol in ethyl acetate (0-18%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with methanol, and the resulting precipitate was collected and dried to afford an off-white powder. The powder was dissolved in DCM and subjected to CombiFlash column chromatography using a 4 g gold column eluting with a gradient of methanol in DCM (0-10%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was dissolved in warm DMSO:DMF:DCM (400 µL:200 µL:10 µL) and loaded onto a 15.5 g C18 column.Reverse-phase CombiFlash column chromatography was carried out using a gradient of methanol in water (10-92%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with methanol, and the precipitate was collected and dried under vacuum overnight at 80⁰C to afford 7-cyclohexyl-N-(4-(1,5-dimethyl- 1H-imidazol-2-yl)-2-methoxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine (Compound 8) (32 mg, Yield: 16%) as a white powder.1H NMR (400 MHz, Chloroform-d) δ 8.86 (d, J = 8.3 Hz, 1H), 8.61 (s, 1H), 7.88 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.24 – 7.15 (m, 2H), 6.87 (d, J = 1.1 Hz, 1H), 6.29 (s, 1H), 4.26 – 4.15 (m, 1H), 4.01 (s, 3H), 3.97 (s, 3H), 3.63 (s, 3H), 2.97 – 2.83 (m, 2H), 2.28 (d, J = 1.0 Hz, 3H), 1.97 – 1.89 (m, 2H), 1.89 – 1.74 (m, 3H), 1.47 – 1.29 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C28H33N8O, 497.3; found, 497.2. Preparation of Compound 9 O N N NStep 1. Synthesis of 2-methoxy-4-(1-methyl-1H-1,2,3-triazol-4-yl)aniline.

[0203] In a microwave vial equipped with a stir bar, a mixture of 4-bromo-1-methyl-1H- 1,2,3-triazole (240 mg, 1.0 eq., 1.48 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (369 mg, 1.0 eq., 1.48 mmol), and cesium fluoride (675 mg, 3 eq., 4.44 mmol), in 1,2-dimethoxyethane (2.66 mL) and methanol (1.33 mL) was degassed by bubbling argon vigorously for 5 minutes. Pd(PPh3)4 (85.6 mg, 0.05 eq., 74.1 µmol) was added to the reaction mixture, and the vial was capped and heated at 150°C in the microwave for 10 minutes. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g column eluting with a gradient of ethyl acetate in hexanes (20-70%). Fractions containing the desired product were pooled together, and concentrated in vacuo to afford 2-methoxy-4-(1-methyl-1H-1,2,3-triazol-4- yl)aniline (207 mg, Yield: 68%) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 7.61 (s, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 8.0, 1.8 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.11 (s, 3H), 3.93 (s, 3H), 3.89 (s, 2H). Step 2. Synthesis of Compound 9 (7-cyclohexyl-N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-4- yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0204] In a reaction vial, a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (125 mg, 1.0 eq., 396 µmol), 2-methoxy-4-(1-methyl-1H-1,2,3- triazol-4-yl)aniline (84.9 mg, 1.05 eq., 416 µmol), cesium carbonate (258 mg, 2 eq., 792 µmol), and XPhos (37.7 mg, 0.2 eq., 79.2 µmol) in 1,4-dioxane (1.25 mL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3(36.2 mg, 0.1 eq., 39.6 µmol) was added to the vial, and the vial was capped and heated to 107°C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and brine. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g gold column eluting with a gradient of ethyl acetate in hexanes (60-100%) followed by a gradient of methanol in ethyl acetate (0-5%). Fractions containing the desired product were pooled together and concentrated in vacuo. The resulting residue was triturated with methanol, and the precipitate was collected and dried under vacuum at 85°C overnight to afford 7-cyclohexyl-N-(2-methoxy-4-(1-methyl-1H-1,2,3-triazol-4-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine (Compound 9) (60 mg, Yield: 31%).1H NMR (400 MHz, Chloroform-d) δ 8.84 (d, J = 8.4 Hz, 1H), 8.60 (s, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.58 (s, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.49 (s, 1H), 7.37 (dd, J = 8.4, 1.8 Hz, 1H), 6.28 (s, 1H), 4.27 – 4.16 (m, 2H), 4.15 (s, 3H), 4.01 (s, 6H), 2.97 – 2.84 (m, 2H), 2.00 – 1.92 (m, 2H), 1.90 – 1.78 (m, 3H), 1.52 – 1.27 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C26H30N9O, 484.3; found, 484.2.Preparation of O B NStep 1. Synthesis of 4-(1,2-dimethyl-1H-imidazol-4-yl)-2-methoxyaniline.

[0205] In a microwave vial equipped with a stir bar, a mixture of 4-bromo-1,2-dimethyl-1H- imidazole (240 mg, 1.0 eq., 1.37 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (342 mg, 1.0 eq., 1.37 mmol), and cesium fluoride (625 mg, 3 eq., 4.11 mmol), in 1,2- dimethoxyethane (2.45 mL) and methanol (1.22 mL) was degassed by bubbling with argonvigorously for 5 minutes. Pd(PPh3)4 (79.2 mg, 0.05 eq., 68.6 µmol) was added to the reaction mixture and the vial was capped and heated at 150°C in the microwave for 10 minutes. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g column eluting with a gradient of methanol in DCM (0-4%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 4-(1,2-dimethyl-1H-imidazol-4-yl)-2- methoxyaniline (160 mg, Yield: 54%) as an off-white fluffy powder.1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J = 1.8 Hz, 1H), 7.09 (dd, J = 8.0, 1.8 Hz, 1H), 6.95 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 2H), 3.57 (s, 3H), 2.41 (s, 3H). Step 2. Synthesis of Compound 11 (7-cyclohexyl-N-(4-(1,2-dimethyl-1H-imidazol-4-yl)-2- methoxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0206] In a reaction vial, a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (110 mg, 1.0 eq., 348 µmol), 4-(1,2-dimethyl-1H-imidazol-4-yl)-2- methoxyaniline (79.5 mg, 1.05 eq., 366 µmol), cesium carbonate (227 mg, 2 eq., 697 µmol), and XPhos (33.2 mg, 0.2 eq., 69.7 µmol) in 1,4-dioxane (1.1 mL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3 (31.9 mg, 0.1 eq., 34.8 µmol) was added to the vial, and the vial was capped and heated to 107°C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and brine. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g gold column eluting with a gradient of ethyl acetate in DCM (50-100%) followed by a gradient of methanol in ethyl acetate (0-25%). Fractions containing the desired product were pooled together and concentrated in vacuo. The resulting residue was triturated with methanol, and the precipitate was collected and dried under vacuum at 85°C overnight to afford 7-cyclohexyl-N-(4- (1,2-dimethyl-1H-imidazol-4-yl)-2-methoxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine (Compound 11) (32 mg, Yield: 18.5%) as a pale-yellow powder.1H NMR (400 MHz, Chloroform-d) δ 8.76 (d, J = 8.3 Hz, 1H), 8.58 (s, 1H), 7.83 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.48 (s, 1H), 7.38 – 7.29 (m, 2H), 7.07 (s, 1H), 6.26 (s, 1H), 4.25 –4.13 (m, 1H), 4.01 (s, 3H), 3.99 (s, 3H), 3.61 (s, 3H), 2.98 – 2.84 (m, 2H), 2.44 (s, 3H), 1.99 – 1.91 (m, 2H), 1.87 – 1.76 (m, 3H), 1.55 – 1.42 (m, 1H), 1.42 – 1.26 (m, 2H). MS (APCI) m / z: [M+H]+calcd for C28H33N8O, 497.3; found, 497.2. Preparation of Compound 16 N N N N ClStep 1. Synthesis of 2-chloro-N-cyclohexyl-5-iodopyrimidin-4-amine.

[0207] To a solution of commercially available 2,4-dichloro-5-iodopyrimidine (12 g, 1.0 eq., 43.7 mmol) in ethanol (99.5 mL, 0.44 M) at room temperature was added diisopropylethylamine (8.36 mL, 1.1 eq., 48 mmol) and cyclohexylamine (4.55 g, 1.1 eq., 45.8 mmol) dropwise. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using an 80 g column, eluting with a gradient of ethyl acetate in hexanes (0-2% then 10%). Fractions containing product were pooled together and concentrated in vacuo to afford 2-chloro-N-cyclohexyl-5-iodopyrimidin-4-amine (12.4 g) as a clear colorless oil.1H NMR (400 MHz, CDCl3): δ 8.23 (s, 1H), 5.31 (br d, 1H, J ~ 8 Hz), 3.96 – 4.08 (m, 1H), 1.96–2.06 (m, 2H), 1.70–1.81 (m, 2H), 1.61–1.69 (m, 1H), 1.39–1.52 (m, 2H), 1.19– .34 (m, 3H).Step 2. Synthesis of 2-chloro-N-cyclohexyl-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyrimidin-4- amine.

[0208] A mixture of bis(triphenylphosphine)palladium(II) dichloride (104 mg, 0.05 eq., 148 µmol) and copper (I) iodide (28.2 mg, 0.05 eq., 148 µmol) in dimethylformamide (14.8 mL, 0.2 M) and triethylamine (1.24 mL, 3 eq., 8.89 mmol) was degassed by bubbling with argon for 10 minutes.2-chloro-N-cyclohexyl-5-iodopyrimidin-4-amine (1 g, 1.0 eq., 2.96 mmol) and 4- ethynyl-1-methyl-1H-pyrazole (330 mg, 1.05 eq., 3.11 mmol) were sequentially added, and the reaction mixture was stirred for 40 minutes at room temperature. The reaction was quenched with water, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine twice, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 24 g column eluting with a gradient of ethyl acetate in hexanes (10-33%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 2-chloro-N-cyclohexyl-5-((1-methyl-1H-pyrazol-4- yl)ethynyl)pyrimidin-4-amine (706 mg, Yield: 75%) as a light orange powder.1H NMR (400 MHz, DMSO-d6): δ 8.14 (s, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 7.09 (br d, 1H, J ~ 8 Hz), 3.89–4.00 (m, 1H), 3.87 (s, 3H), 1.78–1.88 (m, 2H), 1.68-1.78 (m, 2H), 1.57-1.67 (m, 1H), 1.25-1.52 (m, 4H), 1.05-1.19 (m, 1H). Step 3. Synthesis of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidine.

[0209] In a reaction vial to a solution of 2-chloro-N-cyclohexyl-5-((1-methyl-1H-pyrazol-4- yl)ethynyl)pyrimidin-4-amine (1.05 g, 1.0 eq., 3.32 mmol) in THF (22.1 mL) was added a solution of 1M tetrabutylammonium fluoride in THF (9.96 mL, 3 eq.). The reaction mixture was heated at 70°C for 2 hours. The reaction was cooled to room temperature and quenched with water. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12 g column eluting with a gradient of ethyl acetate in hexanes (20-50%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidine (914 mg, Yield: 87%) as an off-white powder.1H NMR (400 MHz,DMSO-d6): δ 8.84 (s, 1H), 8.10 (s, 1H), 7.74 (s, 1H), 6.62 (s, 1H), 4.21-4.32 (m, 1H), 3.94 (s, 3H), 2.51-2.61 (m, 2H), 1.76-1.91 (m, 4H), 1.63-1.73 (m, 1H), 1.18-1.44 (m, 3H). Step 4. Synthesis of Compound 16 (7-cyclohexyl-N-(2-methoxy-4-morpholinophenyl)-6-(1- methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0210] In a reaction vial a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (120 mg, 1.0 eq., 380 µmol), 2-methoxy-4-(morpholin-4-yl)aniline (83.1 mg, 1.05 eq., 399 µmol), cesium carbonate (124 mg, 1.0 eq., 380 µmol), and XPhos (36.2 mg, 0.2 eq., 76 µmol) in 1,4-dioxane (1.2 mL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3(34.8 mg, 0.1 eq., 38 µmol) was added to the vial and the vial was capped and heated to 107 ⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and co-evaporated with toluene. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g gold column eluting with a gradient of ethyl acetate in hexanes (20-100%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with methanol, and the solid was filtered on filter paper and dried under vacuum to afford 7-cyclohexyl-N-(2-methoxy-4-morpholinophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine (compound 16) (37.6 mg, Yield: 20%), as an off-white powder.1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.24 (d, J = 8.7 Hz, 1H), 7.97 (s, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.57 (s, 1H), 6.69 (d, J = 2.6 Hz, 1H), 6.50 (dd, J = 8.7, 2.6 Hz, 1H), 6.33 (s, 1H), 4.20 – 4.08 (m, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.79 – 3.72 (m, 4H), 3.12 – 3.05 (m, 4H), 2.77 – 2.63 (m, 2H), 1.91 – 1.81 (m, 2H), 1.80 – 1.68 (m, 3H), 1.41 – 1.22 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C27H34N7O2, 488.3; found, 488.2. Preparation of Compound 17N N N -6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (compound 17).

[0211] In a reaction vial, a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (0.1 g, 1.0 eq., 317 µmol), 2-methoxy-4-(4-methyl-1- piperazinyl)aniline (73.6 mg, 1.05 eq., 332 µmol), cesium carbonate (206 mg, 2 eq., 633 µmol), and XPhos (30.2 mg, 0.2 eq., 63.3 µmol) in 1,4-dioxane (1 mL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3 (29 mg, 0.1 eq., 31.7 µmol) was added to the vial, and the vial was capped and heated to 107°C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g column eluting with a gradient of methanol in ethyl acetate (0-50%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with methanol, and the precipitate was collected on filter paper and dried under vacuum to afford 7-cyclohexyl-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-6-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Compound 17) (38 mg, Yield: 24%) as a tan powder.1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.97 (s, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.56 (s, 1H), 6.68 (d, J = 2.6 Hz, 1H), 6.49 (dd, J = 8.8, 2.6 Hz, 1H), 6.32 (s, 1H), 4.20 – 4.10 (m, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.14 – 3.07 (m, 4H), 2.77 –2.63 (m, 2H), 2.49 – 2.46 (m, 4H), 2.24 (s, 3H), 1.89 – 1.80 (m, 2H), 1.79 – 1.68 (m, 3H), 1.40 – 1.21 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C28H37N8O, 501.3; found, 501.3. Preparation of Compound 18 O O S O

[0212] In a reaction vial, a mixture of 4-fluoro-2-methoxy-1-nitrobenzene (0.6 g, 1.0 eq., 3.51 mmol), thiomorpholine 1,1-dioxide (664 mg, 1.4 eq., 4.91 mmol) and diisopropylethylamine (1.22 mL, 2 eq., 7.01 mmol) in dimethylformamide (6 mL) was heated to 95°C overnight. An additional aliquot of thiomorpholine 1,1-dioxide (2.37 g, 5 eq., 17.5 mmol) was added, and the reaction was heated to 85°C overnight. The reaction mixture was heated to 130°C for 6 hours. The reaction mixture was cooled to room temperature and quenched with water. The resulting precipitate was filtered on filter paper under vacuum and collected. The solid was dissolved in a mixture of methanol in DCM (10%) and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12 g column, eluting with a gradient of ethyl acetate in hexanes (10-100%) followed by isocratic elution with 10% methanolin DCM. Fractions were pooled together and concentrated in vacuo to afford 4-(3-methoxy-4- nitrophenyl)thiomorpholine 1,1-dioxide (348 mg, Yield: 35%) as a light orange powder.1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 9.3 Hz, 1H), 6.70 (dd, J = 9.3, 2.6 Hz, 1H), 6.64 (d, J = 2.6 Hz, 1H), 4.04 – 3.97 (m, 4H), 3.93 (s, 3H), 3.21 – 3.14 (m, 4H). Step 2. Synthesis of 4-(4-amino-3-methoxyphenyl)thiomorpholine 1,1-dioxide.

[0213] In a reaction vial to a suspension of 4-(3-methoxy-4-nitrophenyl)thiomorpholine 1,1- dioxide (335 mg, 1.0 eq., 1.17 mmol) in ethanol (5.85 mL) was added a saturated aqueous ammonium chloride solution (873 µL) and iron powder (235 mg, 3.6 eq., 4.21 mmol). The vial was capped, and the reaction mixture was heated to 85°C overnight. The reaction mixture was resuspended in ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo, dissolved in DCM, and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g column eluting with a gradient of ethyl acetate in hexanes (20-70%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried to afford 4-(4-amino-3-methoxyphenyl)thiomorpholine 1,1-dioxide (229 mg, 76%) as a light brown powder.1H NMR (400 MHz, DMSO-d6) δ 6.57 (d, J = 2.6 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.38 (dd, J = 8.4, 2.6 Hz, 1H), 4.31 (s, 2H), 3.75 (s, 3H), 3.53 – 3.46 (m, 4H), 3.18 – 3.10 (m, 4H). Step 3. Synthesis of Compound 18 (4-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)thiomorpholine 1,1-dioxide).

[0214] In a reaction vial, a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (65 mg, 1.0 eq., 206 µmol), 4-(4-amino-3- methoxyphenyl)thiomorpholine 1,1-dioxide (55.4 mg, 1.05 eq., 216 µmol), cesium carbonate (134 mg, 2 eq., 412 µmol), and XPhos (19.6 mg, 0.2 eq., 41.2 µmol) in 1,4-dioxane (650 µL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3 (18.8 mg, 0.1 eq., 20.6 µmol) was added to the vial, and the vial was capped and heated to 107°C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g column eluting with a gradient of ethyl acetate in hexanes (50-100%). Fractions containing the desired product were pooledtogether and concentrated in vacuo. The residue was triturated with methanol, and the precipitate was collected on filter paper and dried under vacuum to afford 4-(4-((7-cyclohexyl-6-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)thiomorpholine 1,1-dioxide (compound 18) (36 mg, Yield: 33%) as a light tan powder.1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.97 (s, 1H), 7.63 (d, J = 0.8 Hz, 1H), 7.60 (s, 1H), 6.76 (d, J = 2.6 Hz, 1H), 6.59 (dd, J = 8.8, 2.6 Hz, 1H), 6.33 (s, 1H), 4.20 – 4.10 (m, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.75 – 3.68 (m, 4H), 3.21 – 3.14 (m, 4H), 2.75 – 2.61 (m, 2H), 1.88 – 1.81 (m, 2H), 1.80 – 1.67 (m, 3H), 1.42 – 1.21 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C27H34N7O3S, 536.2; found, 536.2. Preparation of Compound 24 NStep 1. Synthesis of 4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyaniline.

[0215] In a microwave vial equipped with a stir bar, a mixture of 5-bromo-1,2-dimethyl-1H- imidazole (240 mg, 1.0 eq., 1.37 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (342 mg, 1.0 eq., 1.37 mmol), and cesium fluoride (625 mg, 3 eq., 4.11 mmol), in 1,2- dimethoxyethane (2.67 mL) and methanol (1.33 mL) was degassed by bubbling argon vigorously for 5 minutes. Pd(PPh3)4(79.2 mg, 0.05 eq., 68.6 µmol) was added to the reaction mixture, and the vial was capped and heated at 150°C in the microwave for 10 minutes. In a separate microwave vial equipped with a stir bar, a mixture of 5-bromo-1,2-dimethyl-1H-imidazole (60 mg, 1.0 eq., 343 µmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (85.4 mg, 1.0 eq., 343 µmol), and cesium fluoride (156 mg, 3 eq., 1.03 mmol), in 1,2-dimethoxyethane (667 µL) and methanol (333 µL) was degassed by bubbling argon vigorously for 5 minutes. Pd(PPh3)4(19.8 mg, 0.05 eq., 17.1 µmol) was added to the reaction mixture, and the vial was capped and heated at 150°C in the microwave for 10 minutes. The reaction was cooled to room temperature. The reaction mixtures were combined and diluted with ethyl acetate and water. The aqueous layer was basified by addition of 2 M aqueous Na2CO3and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g column eluting with a gradient of methanol in DCM (0-5%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with hot hexanes to afford 4-(1,2-dimethyl-1H- imidazol-5-yl)-2-methoxyaniline (266 mg, Combined Yield: 71%) as a light brown powder.1H NMR (400 MHz, Chloroform-d) δ 6.86 (s, 1H), 6.80 – 6.69 (m, 3H), 3.89 (s, 2H), 3.87 (s, 3H), 3.48 (s, 3H), 2.42 (s, 3H). Step 2. Synthesis of Compound 24 (7-cyclohexyl-N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2- methoxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0216] In a reaction vial, a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (125 mg, 1.0 eq., 396 µmol), 4-(1,2-dimethyl-1H-imidazol-5-yl)-2- methoxyaniline (90.3 mg, 1.05 eq., 416 µmol), cesium carbonate (258 mg, 2 eq., 792 µmol), and XPhos (37.7 mg, 0.2 eq., 79.2 µmol) in 1,4-dioxane (1.25 mL) was degassed by bubbling with argon for 5 minutes. Pd2(dba)3 (36.2 mg, 0.1 eq., 39.6 µmol) was added to the vial, and the vial was capped and heated to 107°C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and brine. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carriedout using a 4 g gold column eluting with a gradient of methanol in ethyl acetate (0-15%). Fractions containing the desired product were pooled together and concentrated in vacuo. The resulting residue was triturated with methanol and dried under vacuum overnight at 80°C to afford 7-cyclohexyl-N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Compound 24) (20 mg, Yield: 10%) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.85 (d, J = 8.4 Hz, 1H), 8.61 (s, 1H), 7.84 (s, 1H), 7.58 (d, J = 0.6 Hz, 1H), 7.49 (s, 1H), 7.00 (dd, J = 8.4, 1.8 Hz, 1H), 6.95 (s, 1H), 6.88 (d, J = 1.8 Hz, 1H), 6.29 (s, 1H), 4.26 – 4.14 (m, 1H), 4.01 (s, 3H), 3.95 (s, 3H), 3.55 (s, 3H), 2.96 – 2.83 (m, 2H), 2.45 (s, 3H), 1.98 – 1.90 (m, 2H), 1.88 – 1.76 (m, 3H), 1.50 – 1.27 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C28H33N8O, 497.3; found, 497.2. Preparation of Compound 37 N N O37 Step 1. Synthesis of (7-cyclohexyl-N-(3-methoxypyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0217] In a 1 dram vial a mixture of 6-chloro-1-cyclohexyl-2-(1-methyl-4-pyrazolyl)-1H- 1,5,7-triazaindene (0.1 g, 317 µmol), 3-methoxy-4-pyridylamine (41.3 mg, 1.05 eq., 332 µmol), cesium carbonate (206 mg, 2 eq., 633 µmol), and XPhos (30.2 mg, 0.2 eq., 63.3 µmol) in 1,4- dioxane (1 mL, 11.7 mmol) was degassed by bubbling with argon for 5 mins. The palladium catalyst Pd2dba3 (29 mg, 0.1 eq., 31.7 µmol) was then added to the vial, and the vial was capped and heated to 107⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and brine. The layers were separated, and the aqueous layer was extracted once more with dichloromethane. The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of methanol in ethyl acetate (0-13%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with methanol, and the solid was collected and dried under vacuum overnight at 85 ⁰C to afford 7- cyclohexyl-N-(3-methoxypyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine (Compound 37) (11.2 mg, Yield: 8.8%) as a white powder.1H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J = 5.4 Hz, 1H), 8.64 (s, 1H), 8.22 (d, J = 5.4 Hz, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.50 (s, 1H), 6.32 (s, 1H), 4.29 – 4.17 (m, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 2.92 – 2.78 (m, 2H), 2.01 – 1.93 (m, 2H), 1.90 – 1.79 (m, 3H), 1.48 – 1.28 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C22H26N7O, 404.2; found, 404.2. Preparation of Compound 38O N , H2Step 1. Synthesis of 4-[4-(benzyloxy)-3-methoxyphenyl]morpholine.

[0218] In a 6 dram vial a mixture of 1-(benzyloxy)-4-bromo-2-methoxybenzene (0.6 g, 1.0 eq., 2.05 mmol), morpholine (267 mg, 1.5 eq., 3.07 mmol), XPhos (97.6 mg, 0.1 eq., 205 µmol) and potassium tert-butoxide (459 mg, 2 eq., 4.09 mmol) in toluene (6 mL) was degassed by bubbling with argon for 5 mins. Pd2(dba)3 (93.7 mg, 0.05 eq., 102 µmol) was added the vial was capped and heated to 105⁰C while stirring for 2.5 hours. Toluene was removed under vacuum, and the crude residue was suspended in DCM and dry loaded onto silica gel. CombiFlash chromatography was carried out with a gradient of ethyl Acetate in hexanes as the eluent. Fractions containing the desired product were pooled together, concentrated in vacuo, and dried to afford 4-[4-(benzyloxy)-3-methoxyphenyl]morpholine (458 mg) as a tan powder.1H NMR (400 MHz, Chloroform-d) δ 7.47 – 7.40 (m, 2H), 7.38 – 7.32 (m, 2H), 7.31 – 7.26 (m, 1H), 6.81(d, J = 8.7 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 6.37 (dd, J = 8.7, 2.8 Hz, 1H), 5.08 (s, 2H), 3.88 (s, 3H), 3.87 – 3.82 (m, 4H), 3.10 – 3.03 (m, 4H). Step 2. Synthesis of 2-methoxy-4-morpholinophenol.

[0219] A solution of 4-[4-(benzyloxy)-3-methoxyphenyl]morpholine (229 mg, 1.0 eq., 765 µmol) in methanol (15.3 mL) was cycled twice through the H-Cube ® Mini Plus at a flow rate of 1 mL / min methanol. Reaction conditions are as follows: Temperature: 60°C, Catalyst: Pd / C (10%), Flow rate: 1 mL / min (MeOH), and Hydrogen Pressure: 1 bar. The flowthrough was concentrated in vacuo to afford 2-methoxy-4-morpholinophenol (154 mg) as an off-white powder which was taken forward to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 6.64 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H), 6.31 (dd, J = 8.5, 2.7 Hz, 1H), 3.74 (s, 3H), 3.73 – 3.68 (m, 4H), 2.99 – 2.92 (m, 4H). Step 3. Synthesis of Compound 38 (4-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)oxy)-3-methoxyphenyl)morpholine).

[0220] In a 1 dram vial a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (110 mg, 1.0 eq., 348 µmol), 2-methoxy-4-morpholinophenol (76.5 mg, 1.05 eq., 366 µmol), cesium carbonate (227 mg, 2 eq., 697 µmol), and XPhos (33.2 mg, 0.2 eq., 69.7 µmol) in 1,4-dioxane (1.1 mL) was degassed by bubbling with argon for 5 minutes. The palladium catalyst Pd2dba3 (31.9 mg, 0.1 eq., 34.8 µmol) was added, and the vial was capped and heated to 107⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and brine. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of ethyl acetate in hexanes (60-100%). Fractions containing the desired product were pooled together and concentrated in vacuo. The resulting residue was triturated with methanol, and the precipitate was collected and dried under vacuum at 85⁰C overnight to afford 4-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)- 3-methoxyphenyl)morpholine (Compound 38) (64 mg, Yield: 38%) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 7.55 (d, J = 0.7 Hz, 1H), 7.47 (d, J = 0.7 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.31 (s, 1H), 4.17–4.04 (m, 1H), 4.00 (s, 3H), 3.91–3.84 (m, 4H), 3.73 (s, 3H), 3.19–3.12 (m, 4H), 2.58–2.43 (m, 2H), 1.82–1.65 (m, 4H), 1.63–1.56 (m, 1H), 1.31–1.00 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C27H33N6O3, 489.3; found, 489.2. Preparation of Compound 39 TMS , , N N-4-pyrimidinyl}amine.

[0221] A mixture of N-cyclohexyl(2-chloro-5-iodo-4-pyrimidinyl)amine (12 g, 35.5 mmol), and ethynyltris(methyl)silane (6.07 mL, 1.2 eq., 42.7 mmol) in dimethylformamide (178 mL, 0.2M) and triethylamine (14.9 mL, 3 eq., 107 mmol) was degassed by bubbling argon vigorouslyfor 10 minutes. Bis(triphenylphosphine)palladium chloride (1.02 g, 0.041 eq., 1.46 mmol) and copper (I) iodide (338 mg, 0.05 eq., 1.78 mmol) were subsequently added, and the reaction mixture was stirred for 40 minutes at room temperature. DMF was removed by concentrating in vacuo. The residue was diluted with ethyl acetate. The organic layer was washed with brine twice, collected, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using an 80g column, eluting with a gradient of ethyl acetate in hexanes (0-3%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford N-cyclohexyl{2-chloro-5-[2- (trimethylsilyl)ethynyl]-4-pyrimidinyl}amine (9.7 g) as a pale yellow oil.1H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H), 5.56 (d, J = 8.1 Hz, 1H), 4.11 – 3.98 (m, 1H), 2.06 – 1.97 (m, 2H), 1.78 – 1.69 (m, 2H), 1.69 – 1.60 (m, 1H), 1.53 – 1.40 (m, 2H), 1.35 – 1.20 (m, 3H), 0.28 (s, 9H). Step 2. Synthesis of N-cyclohexyl[5-(2-bromoethynyl)-2-chloro-4-pyrimidinyl]amine.

[0222] N-bromosuccinimide was recrystallized from hot water.10 g N-bromosuccinimide was dissolved in 100 mL of water. The resulting crystals were filtered on filter paper and dried under vacuum. Silver nitrate (772 mg, 0.2 eq., 4.55 mmol) and the recrystallized N- bromosuccinimide (6.07 g, 1.5 eq., 34.1 mmol) were successively added to a solution of N- cyclohexyl{2-chloro-5-[2-(trimethylsilyl)ethynyl]-4-pyrimidinyl}amine (7 g, 22.7 mmol) in acetone (114 mL, 0.2M) under argon. The reaction mixture was wrapped in foil and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with 10% aqueous sodium thiosulfate, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM, and dry loaded onto silica gel. CombiFlash chromatography was carried out using an 80 g column, eluting with a gradient of ethyl acetate in hexanes (0-2.8%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford N-cyclohexyl[5-(2-bromoethynyl)-2-chloro-4- pyrimidinyl]amine (2.97 g) as a light yellow oil / foam.1H NMR (400 MHz, CDCl3): δ 8.09 (s, 1H), 5.42 (d, J = 8.1 Hz, 1H), 4.11 – 3.97 (m, 1H), 2.07 – 1.98 (m, 2H), 1.82 – 1.72 (m, 2H), 1.72 – 1.62 (m, 1H), 1.53 – 1.37 (m, 2H), 1.33 – 1.15 (m, 3H). Step 3. Synthesis of 6-bromo-2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine.

[0223] To a solution of N-cyclohexyl[5-(2-bromoethynyl)-2-chloro-4-pyrimidinyl]amine (2.92 g, 9.28 mmol) in tetrahydrofuran (66.3 mL, 0.14M) was added a solution of 1Mtetrabutylammoniumfluoride in THF (23.2 mL, 2.5 eq., 23.2 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction was concentrated in vacuo to remove THF. The residue was treated with brine while stirring / sonicating for ~15 mins. The resulting brown precipitate was filtered on a Buchner funnel under vacuum washing with water. The brown solid was dissolved in DCM and dry loaded onto silica gel. CombiFlash chromatography was carried out using a 40 g column eluting with a gradient of ethyl acetate in hexanes (0-3.3%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 6- bromo-2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine (1.52 g) as a white crystalline powder.1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 6.62 (s, 1H), 4.66 – 4.46 (m, 1H), 2.69 – 2.52 (m, 2H), 2.00 – 1.91 (m, 2H), 1.89 – 1.72 (m, 3H), 1.53 – 1.29 (m, 3H). Step 4. Synthesis of 5-(2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2- methyloxazole.

[0224] A mixture of 6-bromo-2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine (360 mg, 1.14 mmol) and 4,4,5,5-tetramethyl-2-(2-methyl-1,3-oxazol-5-yl)-1,3,2-dioxaborolane (251 mg, 1.05 eq., 1.2 mmol) was suspended in dimethylformamide (11.4 mL) / 2 M sodium carbonate in water (1.2 mL, 2.1 eq., 2.4 mmol). The mixture was degassed by bubbling with argon for 5 mins. Pd(PPh3)4 (66.1 mg, 0.05 eq., 57.2 µmol) was added and the reaction mixture was capped and heated at 85 ⁰C overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3x50 mL). The organic layers were washed with brine (2x200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12 g column, eluting with a gradient of ethyl acetate in hexanes (5-40%). Fractions containing the desired product were pooled together, and concentrated in vacuo to afford 5-(2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2-methyloxazole (104 mg) as a yellow powder.1H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 7.19 (s, 1H), 6.70 (s, 1H), 4.43 – 4.31 (m, 1H), 2.66 – 2.53 (m, 5H), 1.99 – 1.86 (m, 4H), 1.80 – 1.70 (m, 1H), 1.46 – 1.30 (m, 3H). Step 5. Synthesis of Compound 39 (7-cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3- yl)phenyl)-6-(2-methyloxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0225] In a 1 dram vial a mixture of 5-(2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin- 6-yl)-2-methyloxazole (34.2 mg, 108 µmol), 2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (23.2 mg, 1.05 eq., 113 µmol), cesium carbonate (70.3 mg, 2 eq., 216 µmol), and XPhos (10.3 mg, 0.2 eq., 21.6 µmol) in 1,4-dioxane (342 µL) was degassed by bubbling with argon for 5 mins. The palladium catalyst Pd2dba3(9.89 mg, 0.1 eq., 10.8 µmol) was added to the vial and the vial was capped and heated to 107 ⁰C while stirring for 16 hours. The reaction mixture was cooled to rt, diluted with water, and stirred for ~10 mins. The resulting precipitate was filtered on filter paper. The precipitate was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4g gold column eluting with a gradient of methanol in ethyl acetate (0-25%). Fractions containing the desired product were pooled together and concentrated in vacuo. The mixture was dissolved in warm methanol / DMSO (1mL / 0.3 mL) and prep-HPLC purification was carried out using a 20x150mm C18 HPLC column eluting with a gradient of methanol in water (50-100%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried overnight under vacuum at 85 ⁰C to afford 7-cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(2- methyloxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Compound 39) (22 mg, Yield: 42%) as a light yellow powder.1H NMR (400 MHz, Chloroform-d) δ 8.90 (d, J = 8.4 Hz, 1H), 8.70 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.26 (dd, J = 8.4, 1.9 Hz, 1H), 7.11 (s, 1H), 6.60 (s, 1H), 4.36 – 4.19 (m, 1H), 4.00 (s, 3H), 3.82 (s, 3H), 2.87 – 2.71 (m, 2H), 2.58 (s, 3H), 2.05 – 1.88 (m, 4H), 1.87 – 1.78 (m, 1H), 1.46 – 1.33 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C26H29N8O2, 485.2; found, 485.2. Preparation of Compound 40NBoc N NBoc O4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0226] In a 1 dram vial a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (120 mg, 380 µmol), tert-butyl 4-(4-amino-3-methoxyphenyl)-1- piperazinecarboxylate (123 mg, 1.05 eq., 399 µmol), cesium carbonate (248 mg, 2 eq., 760µmol), and XPhos (36.2 mg, 0.2 eq., 76 µmol) in 1,4-dioxane (1.2 mL) was degassed by bubbling with argon for 5 minutes. The palladium catalyst Pd2dba3(34.8 mg, 0.1 eq., 38 µmol) was added to the vial, and the vial was capped and heated to 88⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The aqueous layer was extracted with ethyl acetate three times (10 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of ethyl acetate in hexanes (50-100%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford tert-butyl 4-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (115 mg) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.67–8.60 (m, 1H), 8.56 (s, 1H), 7.59 (s, 1H), 7.56 (d, J = 0.7 Hz, 1H), 7.47 (s, 1H), 6.62–6.55 (m, 2H), 6.25 (s, 1H), 4.23–4.12 (m, 1H), 4.00 (s, 3H), 3.91 (s, 3H), 3.61 (t, J = 5.1 Hz, 4H), 3.09 (t, J = 5.1 Hz, 4H), 2.95–2.81 (m, 2H), 1.98–1.90 (m, 2H), 1.86–1.75 (m, 3H), 1.49 (s, 9H), 1.43–1.26 (m, 3H). Step 2. Synthesis of crude 7-cyclohexyl-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-6-(1-methyl- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine HCl.

[0227] To a solution of tert-butyl 4-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (200 mg, 341 µmol) in DCM (3.33 mL) / methanol (13.3 mL) was added 4 N HCl in dioxane (3.41 mL, 40 eq., 13.6 mmol). The reaction mixture was stirred at rt for 21 hours. The reaction mixture was concentrated to afford 203 mg (crude) which was used directly in the next step. Step 3. Synthesis of Compound 40 ((E)-1-(4-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-(4- methoxyphenyl)but-2-ene-1,4-dione).

[0228] In Vial 1, to a solution of (E)-3-(p-anisoyl)acrylic acid (66 mg, 320 µmol) in dimethylformamide (3.2 mL) was added N-ethyldiisopropylamine (112 µL, 2 eq., 640 µmol) followed by dropwise addition of a solution of 50% propanephosphonic acid anhydride (T3P) in 2-methyl-THF (306 µL, 1.5 eq., 480 µmol). The reaction mixture was stirred for 15 minutes at room temperature. In Vial 2, a mixture of the crude HCl salt from Step 2, 7-cyclohexyl-N-(2- methoxy-4-(piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine HCl (202 mg, crude) in dimethylformamide (3.2 mL), was treated with N- ethyldiisopropylamine (167 µL, 3 eq., 960 µmol). The solution of vial 2 was added to vial 1 dropwise. The final reaction mixture was stirred at room temperature for 21 hours. The reaction mixture was diluted with water (45 mL) and stirred to ensure uniform precipitation. The precipitate was collected on filter paper and dried. The precipitate was dissolved in 6 mL of DMSO and prep-HPLC purification was carried out using a 20 x 150mm C18 HPLC column eluting with a gradient of methanol in water (82-92%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried under vacuum at 70⁰C for 30 minutes to afford (E)-1-(4-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-(4-methoxyphenyl)but-2-ene-1,4-dione (Compound 40) (171 mg, 79% yield) as a light-yellowish tan powder. It is to be understood that in some instances, compounds with the same R5group as Compound 40 or a similar R5group as Compound 40 may be made in a similar manner.1H NMR (400 MHz, Chloroform-d) δ 8.68– 8.61 (m, 1H), 8.56 (s, 1H), 8.10–8.02 (m, 2H), 7.99 (d, J = 14.9 Hz, 1H), 7.60 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.53 (d, J = 14.9 Hz, 1H), 7.47 (s, 1H), 7.03 – 6.94 (m, 2H), 6.64–6.56 (m, 2H), 6.25 (s, 1H), 4.24–4.12 (m, 1H), 4.00 (s, 3H), 3.97–3.91 (m, 5H), 3.90 (s, 3H), 3.86–3.81 (m, 2H), 3.22–3.14 (m, 4H), 2.94–2.80 (m, 2H), 1.98–1.90 (m, 2H), 1.86–1.78 (m, 3H), 1.46–1.29 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C38H43N8O4, 675.3; found, 675.3. Preparation of Compound 41NBoc N OStep 1. Synthesis of tert-butyl 4-(4-((7-cyclohexyl-6-(oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin- 2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate.

[0229] In a 1 dram vial a mixture of 5-(2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin- 6-yl)oxazole (120 mg, 396 µmol), tert-butyl 4-(4-amino-3-methoxyphenyl)-1- piperazinecarboxylate (128 mg, 1.1 eq., 416 µmol), cesium carbonate (258 mg, 2 eq., 793 µmol), and XPhos (37.8 mg, 0.2 eq., 79.3 µmol) in 1,4-dioxane (1.2 mL) was degassed by bubbling with argon for 5 minutes. The palladium catalyst Pd2dba3 (36.3 mg, 0.1 eq., 39.6 µmol) was added to the vial, and the vial was capped and heated to 88 ⁰C while stirring for 16h. The reaction mixture was cooled to room temperature and quenched with water (10 mL). The aqueous layer was extracted with ethyl acetate three times (10 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of ethyl acetate in hexanes (50-100%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was dissolved in DMF / MeOH (2.5 mL / 1 mL), and prep-HPLC purification was carried out using a 20 x 150mm C18 HPLC column eluting with a gradient of methanol in water (90-100%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried under vacuum at 85⁰C for 30 minutes to afford tert-butyl 4-(4-((7-cyclohexyl-6- (oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1- carboxylate (77 mg) as a pale-yellow powder.1H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 8.58 (d, J = 9.0 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.24 (s, 1H), 6.68–6.50 (m, 3H), 4.31– 4.16 (m, 1H), 3.92 (s, 3H), 3.68–3.54 (m, 4H), 3.16–3.02 (m, 4H), 2.86–2.67 (m, 2H), 2.03–1.87 (m, 4H), 1.82 (s, 1H), 1.49 (s, 9H), 1.44–1.31 (m, 3H). Step 2. Synthesis of [2-methoxy-4-(1-piperazinyl)phenyl][1-cyclohexyl-2-(1,3-oxazol-5-yl)- 1,5,7-triaza-1H-inden-6-yl]amine-HCl.

[0230] To a solution of tert-butyl 4-(4-((7-cyclohexyl-6-(oxazol-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate (69 mg, 120 µmol) in DCM (1.2 mL) was added 4N HCl in dioxane (1.2 mL, 40 eq., 4.81 mmol). The reaction mixture was stirred at rt for 2 hours. The volatiles were removed, and the residue was triturated with ethyl acetate. The precipitate was filtered on filter paper, collected and dried under vacuum to afford [2-methoxy-4-(1-piperazinyl)phenyl][1-cyclohexyl-2-(1,3-oxazol-5-yl)-1,5,7-triaza-1H-inden-6- yl]amine-HCl (60.4 mg, crude) as a pale-yellow powder, which was used in the next step without further characterization or purification. Step 3. Synthesis of Compound 41 ((E)-1-(4-(4-((7-cyclohexyl-6-(oxazol-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-(4-methoxyphenyl)but-2-ene-1,4- dione).

[0231] In Vial 1, to a solution of (E)-3-(p-anisoyl)acrylic acid (20 mg, 97 µmol) in dimethylformamide (970 µL) was added N-ethyldiisopropylamine (33.8 µL, 2 eq., 194 µmol) followed by the dropwise addition of a solution of 50% propanephosphonic acid anhydride (T3P) in 2-methyl-THF (92.6 µL, 1.5 eq., 145 µmol). The reaction mixture was stirred for 15 minutes at room temperature. In Vial 2, as a separate mixture, a mixture of the crude HCl salt from the previous step ([2-methoxy-4-(1-piperazinyl)phenyl][1-cyclohexyl-2-(1,3-oxazol-5-yl)-1,5,7- triaza-1H-inden-6-yl]amine-HCl (59.9 mg, 1.06 eq., 103 µmol)) in dimethylformamide (970 µL) was treated with N-ethyldiisopropylamine (50.7 µL, 3 eq., 291 µmol). The solution of Vial 2 wasadded to Vial 1 dropwise. The final reaction mixture was stirred at room temperature for 20 hours. The reaction was quenched with 5% LiCl (aq) (25 mL). The aqueous layer was extracted 3 times with DCM (20 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was dissolved in DCM, and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of ethyl acetate in hexanes (50-100%) followed by methanol in ethyl acetate (0-10%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was dissolved in DMF (1.25 mL), and prep-HPLC purification was carried out using a 20 x 150mm C18 HPLC column eluting with a gradient of methanol in water. Fractions containing the desired product were pooled together, concentrated in vacuo, and dried under vacuum to afford (E)-1-(4-(4-((7-cyclohexyl-6-(oxazol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-(4-methoxyphenyl)but- 2-ene-1,4-dione (Compound 41) (24 mg). It is to be understood that in some instances, compounds with the same R5group as Compound 41 or a similar R5group as Compound 41 may be made in a similar manner.1H NMR (400 MHz, Chloroform-d) δ 8.65 (s, 1H), 8.63 – 8.57 (m, 1H), 8.09–8.03 (m, 2H), 8.02 (s, 1H), 7.99 (d, J = 14.8 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 14.9 Hz, 1H), 7.25 (s, 1H), 7.03–6.95 (m, 2H), 6.63 – 6.57 (m, 3H), 4.30–4.18 (m, 1H), 3.97–3.92 (m, 5H), 3.90 (s, 3H), 3.87–3.80 (m, 2H), 3.23–3.15 (m, 4H), 2.86–2.69 (m, 2H), 2.04–1.78 (m, 6H), 1.45–1.32 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C37H40N7O5, 662.3; found, 662.3. Preparation of Compound 42 (1.0 eq) O OStep 1. Synthesis of 7-cyclohexyl-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-6-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine-HCl. To a solution of tert-butyl 4-{4-[1-cyclohexyl-2-(1-methyl-4-pyrazolyl)-1,5,7-triaza-1H-inden-6- ylamino]-3-methoxyphenyl}-1-piperazinecarboxylate (90 mg, 153 µmol) in DCM (1.5 mL) / methanol (6 mL) was added 4 N HCl in dioxane (1.53 mL, 40 eq., 6.14 mmol). The reaction mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated directly to afford 7-cyclohexyl-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-6-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine-HCl (95.6 mg, crude) which was used in the next step without further purification. Step 2. Synthesis of Compound 42 (1-(4-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-(4- methoxyphenyl)butane-1,4-dione). In Vial 1, to a solution of 3-(p-anisoyl)propionic acid (15 mg, 72 µmol) in dimethylformamide (720 µL) was added N-ethyldiisopropylamine (25.1 µL, 2 eq., 144 µmol) followed by dropwise addition of a solution of 50% propanephosphonic acid anhydride (T3P) in 2-methyl-THF (68.8 µL, 1.5 eq., 108 µmol). The reaction mixture was stirred for 15 minutes at room temperature. In Vial 2, in a separate mixture, a mixture of the crude HCl salt from the previous step (7- cyclohexyl-N-(2-methoxy-4-(piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine-HCl (45.5 mg, crude)) in dimethylformamide (720 µL) was treated with N-ethyldiisopropylamine (37.6 µL, 3 eq., 216 µmol). The solution of Vial 2 was added to Vial 1 dropwise. The final reaction mixture was stirred at room temperature overnight. The reaction was quenched with 5% LiCl (aq) (~10 mL). The aqueous layer was extracted with DCM three times (10 mL each). The combined organic layers were dried over sodium sulfate, filtered, and dry loaded directly onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of methanol in ethyl acetate (0-5%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was dissolved in 1 mL of DMF, and prep-HPLC purification was carried out using a 20 x 150mm C18 HPLC column eluting with a gradient of methanol in water (84-94%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried under vacuum at 75⁰C for 1 hour to afford 1-(4-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)-4-(4-methoxyphenyl)butane-1,4-dione (Compound 42) (13.3 mg, yield: 27%) as a pale-yellow powder. It is to be understood that in some instances, compounds with the same R5group as Compound 42 or a similar R5group as Compound 42 may be made in a similar manner.1H NMR (400 MHz, Chloroform-d) δ 8.67 – 8.61 (m, 1H), 8.56 (s, 1H), 8.05 – 7.97 (m, 2H), 7.59 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.47 (s, 1H), 6.98 – 6.90 (m, 2H), 6.64 – 6.56 (m, 2H), 6.25 (s, 1H), 4.24 – 4.12 (m, 1H), 4.00 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H), 3.85 – 3.73 (m, 4H), 3.35 (t, J = 6.6 Hz, 2H), 3.21 – 3.08 (m, 4H), 2.95 – 2.79 (m, 4H), 1.98 – 1.91 (m, 2H), 1.88 – 1.76 (m, 3H), 1.47 – 1.27 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C38H45N8O4, 677.3; found, 677.4. Preparation of Compound 43 in MeOH,Step 1. Synthesis of 2-chloro-7-cyclohexyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine.

[0232] A mixture of 6-bromo-2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine (0.5 g, 1.59 mmol) and 4,4,5,5-tetramethyl-2-[1-(tetrahydro-2H-pyran-2-yl)-4-pyrazolyl]-1,3,2- dioxaborolane (464 mg, 1.1 eq., 1.67 mmol) was suspended in dimethylformamide (15.9 mL) / 2 M sodium carbonate in water (1.67 mL, 2.1 eq., 3.34 mmol). The mixture was degassed by bubbling with argon for 5 minutes. Pd(PPh3)4(91.8 mg, 0.05 eq., 79.5 µmol) was added, and the reaction mixture was capped and heated at 85⁰C overnight. The reaction was cooled to roomtemperature, quenched with water (20 mL), and stirred for 20 minutes. The resulting precipitate was filtered on filter paper and dried under vacuum. The precipitate was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 24 g column, eluting with a gradient of ethyl acetate in hexanes (0-30%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 2-chloro-7-cyclohexyl- 6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (422 mg) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.70 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 6.42 (s, 1H), 5.51–5.43 (m, 1H), 4.32–4.19 (m, 1H), 4.17–4.08 (m, 1H), 3.82–3.71 (m, 1H), 2.77–2.63 (m, 2H), 2.22–2.14 (m, 2H), 2.13–2.03 (m, 1H), 1.95–1.87 (m, 2H), 1.86–1.61 (m, 6H), 1.48–1.22 (m, 3H). Step 2. Synthesis of 7-cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6- (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine.

[0233] In a 1 dram vial a mixture of 2-chloro-7-cyclohexyl-6-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 233 µmol), 2-methoxy-4-(4-methyl-4H- 1,2,4-triazol-3-yl)aniline (50 mg, 1.1 eq., 245 µmol), cesium carbonate (152 mg, 2 eq., 466 µmol), and Xphos (22.2 mg, 0.2 eq., 46.6 µmol) in 1,4-dioxane (0.9 mL) was degassed by bubbling with argon for 5 minutes. The palladium catalyst Pd2dba3 (21.4 mg, 0.1 eq., 23.3 µmol) was then added to the vial, and the vial was capped and heated to 107⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature and diluted with DCM and brine. The layers were separated, and the aqueous layer was extracted again with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 4 g column, eluting with a gradient of methanol in ethyl acetate (0-17.6%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with methanol, and the resulting solid was collected on filter paper and dried under vacuum to afford 7-cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3- yl)phenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- amine (49 mg) as a light yellow crystalline powder.1H NMR (400 MHz, Chloroform-d) δ 8.94 (d, J = 8.5 Hz, 1H), 8.63 (s, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.75 (d, J = 0.8 Hz, 1H), 7.64 (d, J = 0.8 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.25 (dd, J = 8.5, 1.9 Hz, 1H), 6.32 (s, 1H), 5.50 – 5.43 (m, 1H), 4.27 – 4.16 (m, 1H), 4.16 – 4.09 (m, 1H), 4.00 (s, 3H), 3.81 (s, 3H), 3.80 – 3.72 (m, 1H),2.95 – 2.81 (m, 2H), 2.23 – 2.15 (m, 2H), 2.14 – 2.03 (m, 1H), 2.00 – 1.62 (m, 9H), 1.48 – 1.23 (m, 3H). Step 3. Synthesis of Compound 43 (7-cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3- yl)phenyl)-6-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0234] In a 1 dram vial a mixture to a suspension of 7-cyclohexyl-N-(2-methoxy-4-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine (25 mg, 45.2 µmol) in methanol (0.25 mL) was added 4N HCl in dioxane (0.25 mL). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under a gentle stream of nitrogen, re-suspended in methanol, and once again concentrated under a gentle stream of nitrogen. The resulting solid was triturated with ethyl acetate and filtered on filter paper. The precipitate was dissolved in methanol (0.5 mL), and saturated aqueous sodium bicarbonate solution was added dropwise until the solution became slightly cloudy. The reaction mixture was stirred for ~15 minutes. The mixture was further diluted with water and 10% methanol in DCM. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with methanol, and the resulting precipitate was collected and dried under vacuum overnight at 85⁰C to afford 7-cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (Compound 43) (11 mg, 52% yield) as a white powder.1H NMR (400 MHz, Chloroform-d) δ 10.51 (s, 1H), 8.94 (d, J = 8.4 Hz, 1H), 8.64 (s, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.73 (s, 2H), 7.33 (d, J = 1.9 Hz, 1H), 7.25 (dd, J = 8.4, 1.9 Hz, 1H), 6.35 (s, 1H), 4.26 – 4.15 (m, 1H), 4.00 (s, 3H), 3.82 (s, 3H), 2.94 – 2.81 (m, 2H), 2.00 – 1.76 (m, 5H), 1.45 – 1.26 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C25H28N9O, 470.2; found, 470.2. Preparation of Compound 44TMS HCl ,,2DMMF, h

[0235] To a solution of 2,4-dichloro-5-iodopyrimidine (15 g, 54.6 mmol) in ethanol (124 mL) at room temperature was added triethylamine (16 mL, 2.1 eq., 115 mmol) and cyclobutylamine hydrochloride (5.87 g, 54.6 mmol). The reaction mixture was stirred at room temperature for 23h. The reaction mixture was concentrated in vacuo. The residue was suspended in DCM (100 mL) and dry loaded onto silica gel (30g). CombiFlash column chromatography was carried out using an 80 g column, eluting with a gradient of ethyl acetate in hexanes (0-0.4%) followed by 10% ethyl acetate in hexanes to elute the remaining product. Fractions containing the desired product were pooled together and concentrated in vacuo to afford the desired regio isomer N-cyclobutyl(2-chloro-5-iodo-4-pyrimidinyl)amine (13.7 g) as a white powder. Step 2. Synthesis of N-cyclobutyl{2-chloro-5-[2-(trimethylsilyl)ethynyl]-4-pyrimidinyl}amine.

[0236] A mixture of N-cyclobutyl(2-chloro-5-iodo-4-pyrimidinyl)amine (13 g, 42 mmol) and ethynyltris(methyl)silane (7.17 mL, 1.2 eq., 50.4 mmol) in dimethylformamide (136 mL) and triethylamine (17.6 mL, 3 eq., 126 mmol) was degassed by bubbling argon vigorously for 10 minutes. Pd(PPh3)2Cl2 (1.21 g, 0.041 eq., 1.73 mmol) and copper (I) iodide (0.4 g, 0.05 eq., 2.1 mmol) were subsequently added, and the reaction mixture was stirred for 40 minutes at rt. DMF was removed using a rotary evaporator. The residue was diluted with ethyl acetate (100 mL). The organic layer was washed with brine twice, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 40 g column, eluting with a gradient of ethyl acetate in hexanes (0-0.2% followed by 2%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford N-cyclobutyl{2-chloro-5-[2- (trimethylsilyl)ethynyl]-4-pyrimidinyl}amine (10.8 g) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.08 (s, 1H), 5.71 (d, J = 7.6 Hz, 1H), 4.68 – 4.53 (m, 1H), 2.53 – 2.41 (m, 2H), 2.00 – 1.86 (m, 2H), 1.86 – 1.71 (m, 2H), 0.29 (s, 9H). Step 3. Synthesis of N-cyclobutyl(2-chloro-5-ethynyl-4-pyrimidinyl)amine.

[0237] To a solution of N-cyclobutyl{2-chloro-5-[2-(trimethylsilyl)ethynyl]-4- pyrimidinyl}amine (10 g, 35.7 mmol) in THF (179 mL) at 0°C was added dropwise a solution of 1 M TBAF in THF (39.3 mL, 1.1 eq., 39.3 mmol) over ~2 minutes. The reaction mixture was stirred for 5 minutes at 0 °C. The reaction mixture was quenched with brine (250 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate twice (125 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using an 80 g column eluting with a gradient of ethyl acetate in hexanes (0-10%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford N-cyclobutyl(2-chloro-5-ethynyl-4- pyrimidinyl)amine (6.97 g) as a clear colorless oil that turned pale purple upon standing at room temperature.1H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 5.74 (s, 1H), 4.70–4.56 (m, 1H), 3.57 (s, 1H), 2.52–2.39 (m, 2H), 2.01–1.87 (m, 2H), 1.86–1.70 (m, 2H). Step 4. Synthesis of N-cyclobutyl[5-(2-bromoethynyl)-2-chloro-4-pyrimidinyl]amine.

[0238] To a solution of N-cyclobutyl(2-chloro-5-ethynyl-4-pyrimidinyl)amine (6.95 g, 33.5 mmol) in acetone (167 mL) at room temperature was added silver nitrate (569 mg, 0.1 eq., 3.35mmol) and N-bromosuccinimide (7.15 g, 1.2 eq., 40.2 mmol). The flask was wrapped in foil to exclude light. The reaction mixture was stirred for 90 minutes at room temperature. The crude reaction mixture was dry loaded directly onto silica gel. CombiFlash column chromatography was carried out using a 40 g column, eluting with a gradient of ethyl acetate in hexanes (0-8.5%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford N-cyclobutyl[5-(2-bromoethynyl)-2-chloro-4-pyrimidinyl]amine (8.75 g) as a pale-yellow powder.1H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 5.65 (d, J = 7.7 Hz, 1H), 4.70 – 4.55 (m, 1H), 2.53 – 2.39 (m, 2H), 2.07 – 1.90 (m, 2H), 1.86 – 1.72 (m, 2H). Step 5. Synthesis of 6-bromo-2-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine.

[0239] To a solution of N-cyclobutyl[5-(2-bromoethynyl)-2-chloro-4-pyrimidinyl]amine (8.65 g, 30.2 mmol) in THF (520 mL) at 0⁰C was added tetrabutylammonium fluoride trihydrate (20.9 g, 2.2 eq., 66.2 mmol) portion-wise. The resulting mixture was warmed to room temperature by removing from ice bath, and the reaction mixture was stirred for 2.5 hours. The reaction mixture was quenched with water (520 mL) and concentrated in vacuo to remove THF. The resulting brown precipitate that formed during concentration on the rotary evaporator was filtered on filter paper and dried. The resulting brown precipitate was dissolved in DCM and dry loaded onto silica gel (24 g). CombiFlash column chromatography was carried out using an 80 g column, eluting with a gradient of ethyl acetate in hexanes (0-7%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 6-bromo-2-chloro-7- cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine (5.01 g) as a white crystalline powder.1H NMR (400 MHz, Chloroform-d) δ 8.68 (s, 1H), 6.61 (s, 1H), 5.27–5.13 (m, 1H), 3.37–3.21 (m, 2H), 2.51– 2.38 (m, 2H), 2.13–1.99 (m, 1H), 1.95–1.78 (m, 1H). Step 6. Synthesis of 5-(2-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-2- methyloxazole.

[0240] A mixture of 6-bromo-2-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidine (95 mg, 332 µmol) and 4,4,5,5-tetramethyl-2-(2-methyl-1,3-oxazol-5-yl)-1,3,2-dioxaborolane (72.8 mg, 1.1 eq., 348 µmol) was suspended in dimethylformamide (3.32 mL) / 2 M sodium carbonate in water (348 µL, 2.1 eq., 696 µmol). The mixture was degassed by bubbling with argon for 5 minutes. Pd(PPh3)4(19.2 mg, 0.05 eq., 16.6 µmol) was added, and the reaction mixture was capped and heated at 85⁰C overnight. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with brine twice. The organic layer was dried over sodium sulfate,filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12g column, eluting with a gradient of ethyl acetate in hexanes (5-45%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 5-(2-chloro-7-cyclobutyl-7H- pyrrolo[2,3-d]pyrimidin-6-yl)-2-methyloxazole (36.1 mg, crude) as an off-white powder after hexane trituration, which was carried forward without further purification.1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 7.22 (s, 1H), 6.69 (s, 1H), 5.12–4.98 (m, 1H), 3.29–3.14 (m, 2H), 2.59 (s, 3H), 2.48–2.35 (m, 2H), 2.09–1.97 (m, 1H), 1.92–1.75 (m, 1H). Step 7. Synthesis of Compound 44 (7-cyclobutyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3- yl)phenyl)-6-(2-methyloxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0241] In a 1 dram vial a mixture of 5-(2-chloro-7-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-6- yl)-2-methyloxazole (33 mg, 114 µmol), 2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (24.5 mg, 1.1 eq., 120 µmol), cesium carbonate (74.5 mg, 2 eq., 229 µmol), and XPhos (10.9 mg, 0.2 eq., 22.9 µmol) in 1,4-dioxane (330 µL) was degassed by bubbling with argon for 5 minutes. The palladium catalyst Pd2dba3 (10.5 mg, 0.1 eq., 11.4 µmol) was then added to the vial, and the vial was capped and heated to 107⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature, diluted with water, and stirred for ~10 minutes. The resulting precipitate was collected on filter paper. The precipitate was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column eluting with a gradient of methanol in ethyl acetate (0-25%). Fractions containing the desired product were pooled together and concentrated in vacuo. The mixture was dissolved in methanol (1 mL), and prep-HPLC purification was carried out using a 20 x 150mm C18 HPLC column eluting with a gradient of methanol in water (72-82%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried overnight under vacuum at 85⁰C to afford 7-cyclobutyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(2-methyloxazol-5-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine (Compound 44) (8.9 mg) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 8.4 Hz, 1H), 8.70 (s, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.26 (dd, J = 8.4, 1.9 Hz, 1H), 7.13 (s, 1H), 6.58 (s, 1H), 5.07–4.93 (m, 1H), 4.01 (s, 3H), 3.82 (s, 3H), 3.53–3.38 (m, 2H), 2.58 (s, 3H), 2.49–2.37 (m, 2H), 2.13–2.01 (m, 1H), 1.99–1.83 (m, 1H). MS (APCI) m / z: [M+H]+calcd for C24H25N8O2, 457.2; found, 457.3.Preparation of Compound 45 N N N 3, oC

[0242] To a solution of 6-bromo-2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine (1 g, 3.18 mmol) in THF (31.8 mL) at 0⁰C was added dropwise a solution of isopropylmagnesium chloride lithium chloride complex (3.91 mL, 1.6 eq., 5.09 mmol) over 2 minutes. The reaction mixture was stirred for an additional 15 minutes at 0⁰C. N,N-dimethylformamide (2.46 mL, 10 eq., 31.8 mmol) was then added at 0⁰C, and the mixture was allowed to warm slowly to room temperature while stirring for 1 hour (the ice bath was not maintained with more ice). The reaction mixture was quenched with saturated aqueous ammonium chloride (~20 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate twice (50 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 24 g column eluting with a gradient of ethyl acetate in hexanes (5-20%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 2-chloro-7-cyclohexyl-7H-pyrrolo[2,3- d]pyrimidine-6-carbaldehyde (576 mg) as a yellow powder.1H NMR (400 MHz, Chloroform-d) δ 9.93 (s, 1H), 8.99 (s, 1H), 7.31 (s, 1H), 5.33–5.21 (m, 1H), 2.58–2.44 (m, 2H), 1.96–1.89 (m, 2H), 1.88–1.79 (m, 2H), 1.79–1.71 (m, 1H), 1.54–1.33 (m, 3H). Step 2. Synthesis of 5-(2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)oxazole.

[0243] In a 20 mL vial to a suspension of 2-chloro-7-cyclohexyl-7H-pyrrolo[2,3- d]pyrimidine-6-carbaldehyde (0.1 g, 379 µmol) and potassium carbonate (78.6 mg, 1.5 eq., 569 µmol) in methanol (4.74 mL) was added toluenesulfonylmethyl isocyanide (88.8 mg, 1.2 eq., 455 µmol). The vial was capped and heated to 65⁰C for 150 minutes. The reaction was cooled to room temperature, and the volatiles were removed. The residue was triturated with water, and the resulting precipitate was collected and dried on filter paper under vacuum to afford 5-(2-chloro- 7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)oxazole (90 mg) as a light tan powder which was used in the next reaction without further purification.1H NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 8.07 (s, 1H), 7.36 (s, 1H), 6.76 (s, 1H), 4.43–4.31 (m, 1H), 2.64–2.50 (m, 2H), 2.02–1.85 (m, 4H), 1.83–1.66 (m, 1H), 1.47–1.30 (m, 3H). Step 3. Synthesis of Compound 45 (7-cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3- yl)phenyl)-6-(oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0244] In a 1 dram vial a mixture of 5-(2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin- 6-yl)oxazole (50 mg, 165 µmol), 2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (35.4 mg, 1.1 eq., 173 µmol), cesium carbonate (108 mg, 2 eq., 330 µmol), and XPhos (15.7 mg, 0.2 eq., 33 µmol) in 1,4-dioxane (0.5 mL) was degassed by bubbling with argon for 5 minutes. The palladium catalyst Pd2dba3 (15.1 mg, 0.1 eq., 16.5 µmol) was added to the vial, and the vial was capped and heated to 107⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature and quenched with water. The resulting precipitate was filtered and collected on filter paper. The precipitate was dissolved in DCM / MeOH and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of methanol in ethyl acetate (0-25%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford a residue. The residue was dissolved in warm DMF (1 mL) and prep-HPLC purification was carried out using a 20 x 150mm C18 HPLC column eluting with a gradient of methanol in water (72-82%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried overnight under vacuum at 95⁰C to afford 7-cyclohexyl-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-(oxazol-5-yl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine (Compound 45) (20 mg, 26% yield) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.90 (d, J = 8.4 Hz, 1H), 8.72 (s, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.30–7.23 (m, 2H), 6.65 (s, 1H), 4.34–4.22 (m, 1H), 4.01 (s, 3H), 3.82 (s, 3H), 2.88–2.68 (m, 2H), 2.04–1.88 (m, 4H), 1.87–1.77 (m, 1H), 1.48–1.32 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C25H27N8O2, 471.2; found, 471.3. Preparation of Compound 46 O O rt,

[0245] In a 40 mL vial, a mixture of zinc (609 mg, 2.2 eq., 9.31 mmol) in dimethylacetamide (4.58 mL) was treated with chlorotris(methyl)silane (164 µL, 0.3 eq., 1.29 mmol) at 65⁰C under argon followed by the dropwise addition of 1,2-dibromoethane (112 µL, 0.3 eq., 1.29 mmol). The reaction mixture was stirred at 65 ⁰C for 40 minutes. A solution of tert-butyl 3-iodo-1- azetidinecarboxylate (1.65 g, 1.4 eq., 5.82 mmol) in dimethylacetamide (2.29 mL) was added dropwise over ~2 minutes to the reaction mixture at 65⁰C. The reaction mixture was stirred for an additional 30 minutes at 65⁰C. A solution of 4-bromo-2-methoxy-1-nitrobenzene (1 g, 4.31 mmol) in dimethylacetamide (4.58 mL, 49.3 mmol) was added to the reaction mixture at 65⁰C, and the reaction mixture was briefly cooled to room temperature while it was bubbled vigorouslywith argon for 5 minutes. Copper (I) iodide (49.2 mg, 0.06 eq., 259 µmol) and [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (106 mg, 0.03 eq., 129 µmol) were added to the reaction mixture, and the vial was capped and heated to 85 ⁰C for 20 hours. The reaction mixture was cooled to room temperature, quenched with 10% aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate three times (50 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatograph was carried out using a 24 g column, eluting with a gradient of ethyl acetate in hexanes (0-40%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford tert-butyl 3-(3-methoxy-4-nitrophenyl)-1- azetidinecarboxylate (729 mg, crude) as a dark orange oil.1H NMR (400 MHz, Chloroform-d) δ 7.87 (d, J = 8.7 Hz, 1H), 7.02–6.94 (m, 2H), 4.37 (t, J = 8.7 Hz, 2H), 4.00–3.86 (m, 5H), 3.82– 3.72 (m, 1H), 1.47 (s, 9H). Step 2. Synthesis of tert-butyl 3-(4-amino-3-methoxyphenyl)-1-azetidinecarboxylate.

[0246] In a 40 mL vial to a solution of tert-butyl 3-(3-methoxy-4-nitrophenyl)-1- azetidinecarboxylate (455 mg, 1.48 mmol) in THF (13.4 mL) and methanol (8.68 mL) was added zinc (482 mg, 5 eq., 7.38 mmol) and ammonium chloride (395 mg, 5 eq., 7.38 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, washing with methanol. The filtrate was concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12 g column, eluting with a gradient of methanol in DCM (0-4%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford tert- butyl 3-(4-amino-3-methoxyphenyl)-1-azetidinecarboxylate (327 mg) as a tan powder.1H NMR (400 MHz, Chloroform-d) δ 6.75–6.65 (m, 3H), 4.28 (t, J = 8.6 Hz, 2H), 3.97–3.89 (m, 2H), 3.87 (s, 3H), 3.76 (s, 2H), 3.70–3.58 (m, 1H), 1.47 (s, 9H). Step 3. Synthesis of tert-butyl 3-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)azetidine-1-carboxylate.

[0247] In a 1 dram vial a mixture of 2-chloro-7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)- 7H-pyrrolo[2,3-d]pyrimidine (250 mg, 792 µmol), tert-butyl 3-(4-amino-3-methoxyphenyl)-1- azetidinecarboxylate (231 mg, 1.1 eq., 831 µmol), cesium carbonate (516 mg, 2 eq., 1.58 mmol), and XPhos (75.5 mg, 0.2 eq., 158 µmol) in 1,4-dioxane (2.5 mL) was degassed by bubbling withargon for 5 minutes. The palladium catalyst Pd2dba3 (72.5 mg, 0.1 eq., 79.2 µmol) was added to the vial, and the vial was capped and heated to 88⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature and quenched with brine. The aqueous layer was extracted with ethyl acetate three times (10 mL each). The combined organic layers were dried over sodium sulfate, filtered, and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12 g gold column, eluting with a gradient of ethyl acetate in hexanes (50-100%). Fractions containing the desired product were pooled together and concentrated in vacuo, and dried to afford tert-butyl 3-(4-((7-cyclohexyl-6-(1-methyl-1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)azetidine-1- carboxylate (179 mg).1H NMR (400 MHz, Chloroform-d) δ 8.74 (d, J = 8.3 Hz, 1H), 8.58 (s, 1H), 7.77 (s, 1H), 7.57 (d, J = 0.7 Hz, 1H), 7.48 (s, 1H), 6.93 (dd, J = 8.3, 2.0 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.27 (s, 1H), 4.34 (t, J = 8.6 Hz, 2H), 4.25 – 4.14 (m, 1H), 4.05 – 3.97 (m, 5H), 3.95 (s, 3H), 3.80 – 3.69 (m, 1H), 2.95 – 2.80 (m, 2H), 1.99 – 1.90 (m, 2H), 1.88 – 1.76 (m, 3H), 1.48 (s, 9H), 1.42 – 1.26 (m, 3H). Step 4. Synthesis of[4-(3-azetidinyl)-2-methoxyphenyl][1-cyclohexyl-2-(1-methyl-4-pyrazolyl)- 1,5,7-triaza-1H-inden-6-yl]amine-HCl.

[0248] To a solution of tert-butyl 3-(4-((7-cyclohexyl-6-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)azetidine-1-carboxylate (80 mg, 143 µmol) in DCM (1.43 mL) / methanol (5.61 mL) was treated with 4 N HCl in dioxane (1.43 mL, 40 eq., 5.74 mmol). The reaction mixture was stirred at room temperature overnight. The volatiles were evaporated, and the residue was triturated with ethyl acetate. The precipitate was collected on filter paper and dried under vacuum to afford [4-(3-azetidinyl)-2-methoxyphenyl][1- cyclohexyl-2-(1-methyl-4-pyrazolyl)-1,5,7-triaza-1H-inden-6-yl]amine-HCl (76.4 mg, crude) as a light brown powder, which was used in the next step without further characterization or purification. Step 5. Synthesis of Compound 46 ((E)-1-(3-{4-[1-cyclohexyl-2-(1-methyl-4-pyrazolyl)-1,5,7- triaza-1H-inden-6-ylamino]-3-methoxyphenyl}-1-azetidinyl)-4-(p-methoxyphenyl)-2-butene- 1,4-dione).

[0249] In Vial 1, to a solution of (E)-3-(p-anisoyl)acrylic acid (25.5 mg, 124 µmol) in dimethylformamide (1.24 mL) was added N-ethyldiisopropylamine (43.1 µL, 2 eq., 247 µmol) followed by dropwise addition of a solution of 50% propanephosphonic acid anhydride (T3P) in2-methyl-THF (118 µL, 1.5 eq., 186 µmol). The reaction mixture was stirred for 15 minutes at room temperature. In Vial 2, in a separate vial, a mixture of the crude HCl salt from the previous step ([4-(3-azetidinyl)-2-methoxyphenyl][1-cyclohexyl-2-(1-methyl-4-pyrazolyl)-1,5,7-triaza- 1H-inden-6-yl]amine-HCl (74.3 mg, 1.06 eq., 131 µmol)) in dimethylformamide (1.24 mL) was treated with N-ethyldiisopropylamine (64.6 µL, 3 eq., 371 µmol). The solution of Vial 2 was added to Vial 1 dropwise. The final reaction mixture was stirred at room temperature for 20 hours. The reaction was quenched with 5% LiCl (aq) (25 mL). The aqueous layer was extracted 3 times with DCM (20 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of methanol in ethyl acetate (0-10%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was dissolved in DMF (1.5 mL), and prep-HPLC purification was carried out using a 20 x 150mm C18 HPLC column eluting with a gradient of methanol in water (%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried under vacuum to afford (E)-1-(3-{4-[1-cyclohexyl-2-(1-methyl-4-pyrazolyl)-1,5,7-triaza-1H-inden-6-ylamino]-3- methoxyphenyl}-1-azetidinyl)-4-(p-methoxyphenyl)-2-butene-1,4-dione (Compound 46) (21.4 mg). It is to be understood that in some instances, compounds with the same R5group as Compound 46 or a similar R5group as Compound 46 may be made in a similar manner.1H NMR (400 MHz, Chloroform-d) δ 8.77 (d, J = 8.3 Hz, 1H), 8.59 (s, 1H), 8.11–7.99 (m, 3H), 7.78 (s, 1H), 7.57 (s, 1H), 7.48 (s, 1H), 7.12 (d, J = 15.0 Hz, 1H), 7.03–6.92 (m, 3H), 6.85 (d, J = 1.9 Hz, 1H), 6.28 (s, 1H), 4.79–4.70 (m, 1H), 4.61–4.52 (m, 1H), 4.42–4.34 (m, 1H), 4.30–4.15 (m, 2H), 4.01 (s, 3H), 3.97–3.85 (m, 7H), 2.86 (t, J = 12.3 Hz, 2H), 2.00–1.92 (m, 2H), 1.89– 1.77 (m, 3H), 1.48–1.24 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C37H40N7O4, 646.3; found, 646.3. Preparation of Compound 47O N O Npyran- - -

[0250] In a 6 dram vial a mixture of 2-chloro-7-cyclohexyl-6-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 389 µmol), 2-methoxy-4- morpholinoaniline (85 mg, 1.05 eq., 408 µmol), cesium carbonate (253 mg, 2 eq., 777 µmol), and XPhos (37.1 mg, 0.2 eq., 77.7 µmol) in 1,4-dioxane (1.5 mL) was degassed by bubbling with argon for 5 minutes. The palladium catalyst Pd2dba3 (35.6 mg, 0.1 eq., 38.9 µmol) was then added to the vial, and the vial was capped and heated to 107⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and stirred for 15 minutes. The resulting brown precipitate was filtered on filter paper, collected, and dried. The precipitate was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12 g column, eluting with a gradient of ethyl acetate in hexanes (60-100%), followed by a gradient of methanol in ethyl acetate (0-10%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford a crude material. The crude material was dissolved in 3 mL of MeOH. Prep-HPLC purification was carried out using a 20 x 150 mm C18 HPLC column, eluting with a gradient of methanol in water (82-92%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried under vacuum at 85⁰C to afford 7-cyclohexyl-N-(2-methoxy-4- morpholinophenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine (60.4 mg, 28% yield) as a tan powder.1H NMR (400 MHz, Chloroform-d) δ 8.66 – 8.59 (m, 1H), 8.56 (s, 1H), 7.72 (s, 1H), 7.63 (d, J = 0.9 Hz, 1H), 7.57 (s, 1H), 6.62– 6.54 (m, 2H), 6.27 (s, 1H), 5.50–5.42 (m, 1H), 4.23–4.09 (m, 2H), 3.93–3.86 (m, 7H), 3.82–3.71(m, 1H), 3.17–3.10 (m, 4H), 2.95–2.81 (m, 2H), 2.24–2.04 (m, 3H), 1.97–1.89 (m, 2H), 1.86– 1.61 (m, 6H), 1.46–1.23 (m, 3H). Step 2. Synthesis of Compound 47 (7-cyclohexyl-N-(2-methoxy-4-morpholinophenyl)-6-(1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine).

[0251] In a 1 dram vial a mixture to a suspension of 7-cyclohexyl-N-(2-methoxy-4- morpholinophenyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine (30 mg, 53.8 µmol) in methanol (0.3 mL) was added 4 N HCl in dioxane (0.3 mL). The reaction mixture was stirred at room temperature for 75 minutes. The reaction mixture was concentrated. The resulting solid was concentrated once again from methanol. The residue was triturated with ethyl acetate, and the solid was collected on filter paper. The HCl salt form was suspended in methanol (0.5 mL), and saturated aqueous sodium bicarbonate solution was added. The reaction mixture was stirred for ~15 minutes. The mixture was further diluted with water and DCM. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of methanol in DCM (0-4.8%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried at 95⁰C overnight to afford 7-cyclohexyl-N-(2-methoxy-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-amine (18 mg, 71% yield) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 10.28 (s, 1H), 8.66–8.59 (m, 1H), 8.57 (s, 1H), 7.71 (s, 2H), 7.58 (s, 1H), 6.62– 6.55 (m, 2H), 6.30 (s, 1H), 4.22–4.10 (m, 1H), 3.92 (s, 3H), 3.91–3.86 (m, 4H), 3.18–3.11 (m, 4H), 2.95–2.81 (m, 2H), 1.98–1.90 (m, 2H), 1.88–1.75 (m, 3H), 1.46–1.24 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C26H32N7O2, 474.3; found, 474.2. Preparation of Compound 48O S O N O S O pyrazol-4-yl)-7H--

[0252] In a 6 dram vial a mixture of 2-chloro-7-cyclohexyl-6-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 389 µmol), 4-(4-amino-3- methoxyphenyl)thiomorpholine 1,1-dioxide (105 mg, 1.05 eq., 408 µmol), cesium carbonate (253 mg, 2 eq., 777 µmol) and XPhos (37.1 mg, 0.2 eq., 77.7 µmol) in 1,4-dioxane (1.5 mL) was degassed by bubbling with argon for 5 minutes. The palladium catalyst Pd2dba3 (35.6 mg, 0.1 eq., 38.9 µmol) was then added to the vial, and the vial was capped and heated to 107⁰C while stirring for 16 hours. The reaction mixture was cooled to room temperature and quenched with brine (10 mL), and the aqueous layer was extracted with ethyl acetate three times (10 mL each). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column, eluting with a gradient of ethyl acetate in hexanes (60-100%). Fractions containing the desired product were pooled together and concentrated in vacuo. The residue was triturated with methanol, and the resulting precipitate was filtered on filter paper under vacuum. The solid was collected and dried to afford 4-(4-((7- cyclohexyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)amino)-3-methoxyphenyl)thiomorpholine 1,1-dioxide (88 mg, 37% yield) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 8.6 Hz, 1H), 8.57 (s, 1H), 7.73 (s, 1H), 7.63 (d, J = 0.7 Hz, 1H), 7.61 (s, 1H), 6.61 (dd, J = 8.7, 2.6 Hz, 1H), 6.58 (d, J = 2.6 Hz, 1H), 6.28 (s, 1H), 5.50–5.42 (m, 1H), 4.25–4.08 (m, 2H), 3.92 (s, 3H), 3.82–3.68 (m, 5H), 3.24– 3.13 (m, 4H), 2.93–2.77 (m, 2H), 2.25–2.04 (m, 3H), 1.98–1.89 (m, 2H), 1.88–1.60 (m, 6H), 1.43–1.25 (m, 3H).Step 2. Synthesis of Compound 48 (4-(4-((7-cyclohexyl-6-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-3-methoxyphenyl)thiomorpholine 1,1-dioxide).

[0253] In a 1 dram vial a mixture to a suspension of 4-(4-((7-cyclohexyl-6-(1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3- methoxyphenyl)thiomorpholine 1,1-dioxide (44 mg, 72.6 µmol) in methanol (0.44 mL) was added 4 N HCl in dioxane (0.44 mL). The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated. The residue was triturated with ethyl acetate, and the solid was collected on filter paper. The HCl salt form was suspended in methanol (0.5 mL), and saturated aqueous sodium bicarbonate solution was added. The reaction mixture was stirred for ~15 minutes. The mixture was further diluted with water and DCM. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 4 g gold column eluting with a gradient of methanol in DCM (0-3.3%). Fractions containing the desired product were pooled together, concentrated in vacuo, and dried at 95⁰C overnight to afford 4-(4-((7-cyclohexyl-6-(1H- pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)thiomorpholine 1,1- dioxide (Compound 48) (28.6 mg, 75% yield) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 10.28 (s, 1H), 8.66 (d, J = 8.7 Hz, 1H), 8.59 (s, 1H), 7.72 (s, 2H), 7.62 (s, 1H), 6.61 (dd, J = 8.6, 2.6 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.32 (s, 1H), 4.23–4.12 (m, 1H), 3.92 (s, 3H), 3.77–3.70 (m, 4H), 3.22–3.15 (m, 4H), 2.92–2.77 (m, 2H), 1.98–1.91 (m, 2H), 1.88–1.78 (m, 3H), 1.43–1.28 (m, 3H). MS (APCI) m / z: [M+H]+calcd for C26H32N7O3S, 522.2; found, 522.2. Preparation of Intermediates

[0254] Provided below are various synthesis schemes for the preparation of various intermediates used in the above mentioned preparation schemes. Preparation of 4-(4-amino-3-methoxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxideS OB

[0255] A mixture of 4-bromo-2-methoxy-1-nitrobenzene (1 g, 4.31 mmol), 2-(3,6-dihydro- 2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.17 g, 1.2 eq., 5.17 mmol), and sodium carbonate (914 mg, 2 eq., 8.62 mmol) in 1,4-dioxane (20 mL) / water (4 mL) was degassed by bubbling with argon for 10 minutes. Pd(dppf)Cl2(158 mg, 0.05 eq., 215 µmol) was added, and the reaction mixture was heated overnight at 80⁰C. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was resuspended in DCM and dry loaded onto silica gel. CombiFlash chromatography was carried out using a 24 g column, eluting with a gradient of ethyl acetate in hexanes (0-15%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 4-(3-methoxy-4-nitrophenyl)-3,6- dihydro-2H-thiopyran (890 mg) as an orange powder.1H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.4, 1.8 Hz, 1H), 6.33 – 6.25 (m, 1H), 3.98 (s, 3H), 3.40 – 3.34 (m, 2H), 2.94 – 2.87 (m, 2H), 2.74 – 2.65 (m, 2H). Step 2. Synthesis of 4-(3-methoxy-4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide.

[0256] To a vigorously stirring solution of 4-(3-methoxy-4-nitrophenyl)-3,6-dihydro-2H- thiopyran (445 mg, 1.0 eq., 1.77 mmol) in dichloromethane (17.7 mL) was added portionwise m- chlorobenzeneperoxycarboxylic acid 77% w / w (833 mg, 2.1 eq., 3.72 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with 10% aqueous sodium thiosulfate solution and diluted with ethyl acetate. The layers wereseparated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution twice, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g column, eluting with a gradient of ethyl Acetate in hexanes (20-60%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 4-(3-methoxy-4- nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (470 mg) as a light orange powder.1H NMR (400 MHz, Chloroform-d) δ 7.90 – 7.83 (m, 1H), 7.03 – 6.95 (m, 2H), 6.01 – 5.93 (m, 1H), 3.99 (s, 3H), 3.88 – 3.80 (m, 2H), 3.31 – 3.22 (m, 2H), 3.22 – 3.13 (m, 2H). Step 3. Synthesis of 4-(4-amino-3-methoxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide.

[0257] A solution of 4-(3-methoxy-4-nitrophenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (150 mg, 529 µmol) in methanol (10.6 mL) / tetrahydrofuran (6.23 mL) was cycled through the H- Cube®Mini Plus at a flow rate of 1 mL / min methanol. Reaction conditions are as follows: Temperature: 30°C, Catalyst: Pd / C (10%), Flow rate: 1 ml / min (MeOH), and Hydrogen Pressure: 10 bar. The reaction mixture was concentrated in vacuo to afford 4-(4-amino-3- methoxyphenyl)tetrahydro-2H-thiopyran 1,1-dioxide (114 mg) as an off-white powder.1H NMR (400 MHz, Chloroform-d) δ 6.70 – 6.61 (m, 3H), 3.85 (s, 3H), 3.75 (s, 2H), 3.18 – 3.05 (m, 4H), 2.75 – 2.62 (m, 1H), 2.45 – 2.30 (m, 2H), 2.24 – 2.15 (m, 2H). Preparation of 2-(4-amino-3-methoxyphenyl)tetrahydrothiophene 1,1-dioxide O S

[0258] To a solution of tetrahydrothiophene 1,1-dioxide (0.2 g, 1.0 eq., 1.66 mmol) in tetrahydrofuran (10 mL) was added LiHMDS (1.0 M, 2.50 mL, 1.50 eq) at -20°C. Then the solution was stirred at 20°C for 0.5 hour under argon. Zinc (II) chloride (340 mg, 1.5 eq., 2.5 mmol) was added to the mixture at -20°C, and the solution was stirred at 20°C for 1 hour under argon. To the mixture was added 4-bromo-2-methoxy-1-nitrobenzene (270 mg, 0.7 eq., 1.16mmol), palladium (II) acetate (18.7 mg, 0.05 eq., 83.2 µmol) and XPhos (79.3 mg, 0.1 eq., 166 µmol). Then the mixture was stirred at 65°C for 19 hours under argon. The reaction mixture was quenched with water. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g column eluting with a gradient of ethyl acetate in hexanes (20-80%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 2-(3-methoxy-4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (146 mg) as an orange oil.1H NMR (400 MHz, Chloroform-d) δ 7.89 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 7.04 (dd, J = 8.5, 1.8 Hz, 1H), 4.19 (dd, J = 12.0, 6.8 Hz, 1H), 3.99 (s, 3H), 3.41 – 3.30 (m, 1H), 3.27 – 3.15 (m, 1H), 2.66 – 2.53 (m, 1H), 2.53 – 2.36 (m, 2H), 2.35 – 2.17 (m, 1H). Step 2. Synthesis of 2-(4-amino-3-methoxyphenyl)tetrahydrothiophene 1,1-dioxide.

[0259] In a 6 dram vial to a suspension of 2-(3-methoxy-4-nitrophenyl)tetrahydrothiophene 1,1-dioxide (145 mg, 1.0 eq., 534 µmol) in ethanol (5.34 mL) was added saturated aqueous ammonium chloride (395 uL) and iron (107 mg, 3.6 eq., 1.92 mmol). The vial was capped, and the reaction mixture was heated to 70⁰C for 20 hour. An additional aliquot of iron (191 mg, 6.4 eq., 3.42 mmol) and saturated aqueous ammonium chloride (395 µL) was added. The reaction mixture was heated at 70⁰C for an additional 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a small plug of celite. The filtrate was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2- (4-amino-3-methoxyphenyl)tetrahydrothiophene 1,1-dioxide (123 mg) as a light-orange powder. The material was carried forward without further purification.1H NMR (400 MHz, Chloroform- d) δ 6.83 – 6.78 (m, 2H), 6.74 – 6.68 (m, 1H), 4.11 – 4.03 (m, 1H), 3.87 (s, 5H), 3.32 – 3.21 (m, 1H), 3.20 – 3.07 (m, 1H), 2.55 – 2.27 (m, 3H), 2.27 – 2.10 (m, 1H). Preparation of 4-amino-3-methoxyphenyl(methyl)(methylimino)-λ⁶-sulfanoneHN HCHO (aq.), SPhI(OAc)NH2,4HCOS 3,HCOOH, 100 MeOH O °C-λ6-sulfanone.

[0260] To a solution of 2-methoxy-4-(methylthio)-1-nitrobenzene (550 mg, 1.0 eq., 2.76 mmol) in methanol (25 mL) was added (diacetoxyiodo)benzene (1.96 g, 2.2 eq., 6.07 mmol) and ammonium hydrogencarbonate (327 mg, 1.5 eq., 4.14 mmol) at 20°C. The solution was stirred at 20 °C for 1 hour. The reaction mixture was concentrated in vacuo. The residue was suspended in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 12g column, eluting with a gradient of ethyl acetate in hexanes (40-100%) followed by methanol in ethyl acetate (0-7.7%). Fractions containing the desired product were pooled together, and concentrated in vacuo to afford imino(3-methoxy-4-nitrophenyl)(methyl)-λ6- sulfanone (527 mg).1H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.64= 8.4, 1.7 Hz, 1H), 4.53 (s, 1H), 4.02 (s, 3H), 3.16 (s, 3H).

[0261] Step 2. Synthesis of (3-methoxy-4-nitrophenyl)(methyl)(methylimino)- λ⁶-sulfanone. In a 6 dram vial to a solution of imino-3-methoxy-4-nitrophenyl(methyl)-λ⁶-sulfanone (230 mg, 1.0 eq., 999 µmol) in formic acid (5 mL) was added a 37% aqueous solution of formaldehyde (1.25 mL, 15 eq., 15.4 mmol). The reaction mixture was heated to 100°C while stirring for 15 hours. Water was added to the mixture, and the aqueous layer was extracted with DCM three times (10 mL each). The combined organic layers were dried over sodium sulfate and then concentrated in vacuo to afford (3-methoxy-4-nitrophenyl)(methyl)(methylimino)- λ⁶-sulfanone (120 mg, crude) as a sticky white gum. This material was taken forward to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.55 (dd, J = 8.3, 1.7 Hz, 1H), 4.02 (s, 3H), 3.22 (s, 3H), 2.50 (s, 3H). Step 3. Synthesis of (4-amino-3-methoxyphenyl)(methyl)(methylimino)- λ⁶-sulfanone.

[0262] In a 6 dram vial to a suspension of (3-methoxy-4-nitrophenyl)(methyl)(methylimino)- λ⁶-sulfanone (115 mg, crude) in ethanol (2.89 mL) and water (575 µL) was added ammonium chloride (126 mg, 5 eq., 2.35 mmol) and iron (131 mg, 5 eq., 2.35 mmol). The vial was capped, and the reaction mixture was heated to 80 ⁰C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a small plug of celite. The filtrate was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-amino-3-methoxyphenyl(methyl)(methylimino)-λ⁶-sulfanone (84 mg, crude) as a sticky orange solid, which was taken forward to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 7.15 (dd, J = 8.2, 2.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 5.58 (s, 2H), 3.82 (s, 3H), 2.98 (s, 3H), 2.44 (s, 3H). Preparation of 2-fluoro-4-(1H-imidazol-1-yl)-6-methoxyaniline. N N N

[0263] In a 100 mL flask a mixture of 1,5-difluoro-3-methoxy-2-nitrobenzene (2 g, 1.0 eq., 10.6 mmol), imidazole (720 mg, 10.6 mmol), and potassium carbonate (2.92 g, 2 eq., 21.2 mmol) in dimethylformamide (40 mL) was heated to 90⁰C while stirring overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum at 60⁰C on a Rotovap to remove most of the DMF. The residue was partitioned between ethyl acetate (~70 mL) and brine (~100 mL). The phases were separated, and the organic layer was once again washed with brine. The organic layer was washed with brine, dried over sodium sulfate, filtered, and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 24 g column ,eluting with a gradient of ethyl acetate in hexanes (40-100%) followed by a gradient of methanol in ethyl acetate (0-7 then 30%). Fractions containing the desired product were pooled together, and concentrated in vacuo to afford 1-(3-fluoro-5-methoxy-4-nitrophenyl)imidazole (286 mg) as an orange solid.1H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 1.1 Hz, 1H), 7.97 (t, J = 1.5 Hz, 1H), 7.65= 11.5, 2.1 Hz, 1H), 7.49 (t, J = 1.9 Hz, 1H), 7.17 (dd, J = 1.5, 0.8 Hz, 1H), 4.04 (s, 3H).Step 2. Synthesis of 2-fluoro-4-(1H-imidazol-1-yl)-6-methoxyaniline.

[0264] In a 6 dram vial to a suspension of 1-(3-fluoro-5-methoxy-4-nitrophenyl)imidazole (150 mg, 1.0 eq., 632 µmol) in ethanol (6.32 mL) was added saturated aqueous ammonium chloride (467 µL) and iron (127 mg, 3.6 eq., 2.28 mmol). The vial was capped, and the reaction mixture was heated to 70 ⁰C for 2 hours. Acetic acid (1 mL) was added and the reaction mixture was stirred for an additional 1.5 hours at 70 ⁰C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a small plug of celite. The filtrate was washed with brine, washed with saturated aqueous sodium bicarbonate, washed with brine again, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-fluoro-4-(1H- imidazol-1-yl)-6-methoxyaniline (122 mg, crude) as a dark brown oil. Which was carried to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.12 (t, J = 1.2 Hz, 1H), 7.64 (t, J = 1.4 Hz, 1H), 7.07 (dd, J = 11.5, 2.3 Hz, 1H), 7.04 (t, J = 1.1 Hz, 1H), 7.01 – 6.95 (m, 1H), 4.77 (s, 2H), 3.88 (s, 3H). Preparation of 2-methoxy-4-(1-methyl-1H-imidazol-2-yl)aniline N N

[0265] A mixture of 2-bromo-1-methylimidazole (250 mg, 1.0 eq., 1.55 mmol), 2-(3- methoxy-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (520 mg, 1.2 eq., 1.86 mmol) and sodium carbonate (329 mg, 2 eq., 3.11 mmol) in 1,4-dioxane (7.76 mL) / water (1.55 mL) was degassed by bubbling with argon for 10 minutes. Pd(dppf)Cl2(56.8 mg, 0.05 eq., 77.6 µmol) was added, and the reaction mixture was heated overnight at 80⁰C. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was resuspended in DCM and dry loaded onto silica gel. CombiFlash chromatography was carried out using a 12 g column elutingwith a gradient of methanol in ethyl Acetate (0-10%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 2-(3-methoxy-4-nitrophenyl)-1- methylimidazole (134 mg, crude) as light brown powder which was taken to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 8.4, 1.7 Hz, 1H), 7.36 (d, J = 1.1 Hz, 1H), 7.06 (d, J = 1.1 Hz, 1H), 3.99 (s, 3H), 3.85 (s, 3H). Step 2. Synthesis of 2-methoxy-4-(1-methyl-1H-imidazol-2-yl)aniline.

[0266] A solution of 2-(3-methoxy-4-nitrophenyl)-1-methylimidazole (67 mg, crude) in methanol (7 mL) / tetrahydrofuran (14 mL) was cycled through the H-Cube ® Mini Plus at a flow rate of 1 mL / min methanol. Reaction conditions are as follows: Temperature: 30°C, Catalyst: Pd / C (10%), Flow rate: 1 mL / min (MeOH), and Hydrogen Pressure: 10 bar. The reaction mixture was concentrated in vacuo to afford 2-methoxy-4-(1-methyl-1H-imidazol-2-yl)aniline (61 mg, crude) as an orange oil which was taken to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 7.13 (d, J = 1.2 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.97 (dd, J = 8.0, 1.9 Hz, 1H), 6.87 (d, J = 1.2 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 3.80 (s, 3H), 3.69 (s, 3H). Preparation of 2-methoxy-4-(4-propyl-4H-1,2,4-triazol-3-yl)aniline N N N

[0267] In a 6 dram vial to a solution of 3-methoxy-4-nitro-N-propylbenzamide (0.5 g, 1.0 eq., 2.1 mmol) in 1,2-dichloroethane (10 mL) was added thionyl chloride (609 µL, 4 eq., 8.39 mmol). The vial was capped and heated to 88⁰C while stirring for 2 hours. The reaction mixture was concentrated in vacuo. The resulting pale-yellow residue was treated with dimethylformamide (4.01 mL) and formic hydrazide (151 mg, 1.2 eq., 2.52 mmol) and stirred at 88⁰C overnight. The reaction was cooled to room temperature and quenched with water. The aqueous layer was extracted ethyl acetate three times (25 mL). The combined organics were washed with saturated aqueous sodium bicarbonate twice, washed with brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried using a 12 g column, eluting with a gradient of methanol in ethyl acetate (0-20%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford 3-(3-methoxy-4-nitrophenyl)-4-propyl- 4H-1,2,4-triazole (320 mg) as pale-yellow crystalline solid.1H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.20 (dd, J = 8.3, 1.7 Hz, 1H), 4.08 – 4.03 (m, 2H), 4.03 (s, 3H), 1.88 – 1.75 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). Step 2. Synthesis of 2-methoxy-4-(4-propyl-4H-1,2,4-triazol-3-yl)aniline.

[0268] A solution of 3-(3-methoxy-4-nitrophenyl)-4-propyl-4H-1,2,4-triazole (150 mg, 1.0 eq., 572 µmol) in methanol (11.4 mL) was cycled twice through the H-Cube®Mini Plus at a flow rate of 1 mL / min methanol. Reaction conditions are as follows: Temperature: 30°C, Catalyst: Pd / C (10%), Flow rate: 1 ml / min (MeOH), and Hydrogen Pressure: 2-3 bar. The reaction mixture was concentrated in vacuo to afford 2-methoxy-4-(4-propyl-4H-1,2,4-triazol-3- yl)aniline (144 mg, crude) as a light orange oil which was taken to the next step without purification. Preparation of 4-(4-isopropyl-4H-1,2,4-triazol-3-yl)-2-methoxyaniline. 88°C

[0269] To a solution of 3-methoxy-4-nitrobenzoic acid (1 g, 1.0 eq., 5.07 mmol), N- ethylbis(isopropyl)amine (2.65 mL, 3 eq., 15.2 mmol) and isopropylamine (1.3 mL, 3 eq., 15.2 mmol) in dimethylformamide (10 mL) was added HATU (2.89 g, 1.5 eq., 7.61 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenchedwith water and diluted with ethyl acetate (~100 mL). The organic layer was washed twice with brine, dried over sodium sulfate, filtered, and dry loaded onto silica gel. CombiFlash column chromatography was carried out using a 24 g column, eluting with a gradient of ethyl acetate in hexanes (20-60%). Fractions containing the desired product were pooled together and concentrated in vacuo to afford N-isopropyl-3-methoxy-4-nitrobenzamide (1.09 g) as a white powder.1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 7.7 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.55 (dd, J = 8.3, 1.6 Hz, 1H), 4.17 – 4.04 (m, 1H), 3.99 (s, 3H), 1.19 (d, J = 6.5 Hz, 6H). Step 2. Synthesis of 4-isopropyl-3-(3-methoxy-4-nitrophenyl)-4H-1,2,4-triazole.

[0270] In a 6 dram vial to a suspension of N-isopropyl-3-methoxy-4-nitrobenzamide (550 mg, 1.0 eq., 2.31 mmol) in 1,2-dichloroethane (10 mL) was added thionyl chloride (670 µL, 4 eq., 9.23 mmol). The vial was capped and heated to 88 ⁰C while stirring for 2 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene. The resulting white residue was treated with dimethylformamide (4.41 mL) and formic hydrazide (166 mg, 1.2 eq., 2.77 mmol) and stirred at 88 ⁰C overnight. The reaction was cooled to room temperature and quenched with water. The aqueous layer was extracted ethyl acetate three times (25 mL each). The combined organics were washed with saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in 10% methanol in DCM and dry loaded onto silica gel. CombiFlash column chromatography was carried using a 12g column eluting with a gradient of methanol in ethyl acetate (0-20%). Fractions the containing desired product were pooled together and concentrated in vacuo to afford 4-isopropyl- 3-(3-methoxy-4-nitrophenyl)-4H-1,2,4-triazole (221 mg) as a white powder.1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.34 (dd, J = 8.3, 1.6 Hz, 1H), 4.54 – 4.41 (m, 1H), 4.00 (s, 3H), 1.43 (d, J = 6.6 Hz, 6H). Step 3. Synthesis of 4-(4-isopropyl-4H-1,2,4-triazol-3-yl)-2-methoxyaniline.

[0271] A solution of 4-isopropyl-3-(3-methoxy-4-nitrophenyl)-4H-1,2,4-triazole (108 mg, 1.0 eq., 412 µmol) in methanol (8.24 mL) was cycled through the H-Cube at a flow rate of 1 mL / min methanol. Reaction conditions are as follows: Temperature: 30°C, Catalyst: Pd / C (10%), Flow rate: 1 mL / min (MeOH), and Hydrogen Pressure: 2 bar. The reaction mixture was concentrated in vacuo to afford 4-(4-isopropyl-4H-1,2,4-triazol-3-yl)-2-methoxyaniline (95.7 mg) as an off-white gummy solid.1H NMR (400 MHz, Chloroform-d) δ 8.28 (s, 1H), 7.10 (d, J= 1.8 Hz, 1H), 6.91 (dd, J = 8.0, 1.8 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.61 – 4.46 (m, 1H), 4.05 (s, 2H), 3.90 (s, 3H), 1.48 (d, J = 6.8 Hz, 6H). Preparation of 2-(methylthio)-4-morpholinoaniline O O-

[0272] In a 6 dram vial a mixture of 4-fluoro-2-(methylthio)-1-nitrobenzene (0.2 g, 1.0 eq., 1.07 mmol), morpholine (186 mg, 2 eq., 2.14 mmol), and potassium carbonate (295 mg, 2 eq., 2.14 mmol) in dimethylformamide (4 mL) was heated to 90⁰C overnight. The reaction was cooled to room temperature and diluted with water. The resulting brown precipitate was filtered on filter paper washing with water. The resulting brown solid was collected and dried under vacuum to afford 4-(3-(methylthio)-4-nitrophenyl)morpholine (232 mg) as a light brown powder which was taken to the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 9.4 Hz, 1H), 6.88 (dd, J = 9.5, 2.6 Hz, 1H), 6.63 (d, J = 2.6 Hz, 1H), 3.77 – 3.70 (m, 4H), 3.49 – 3.42 (m, 4H), 2.49 (s, 3H). Step 2. Synthesis of 2-(methylthio)-4-morpholinoaniline.

[0273] In a 6 dram vial to a suspension of 4-(3-(methylthio)-4-nitrophenyl)morpholine (150 mg, 1.0 eq., 590 µmol) in ethanol (5.9 mL) was added saturated aqueous ammonium chloride (436 µL) and iron (119 mg, 3.6 eq., 2.12 mmol). The vial was capped, and the reaction mixture was heated to 70⁰C overnight. Acetic acid (1 mL) was added to the reaction mixture, and the reaction mixture was stirred at 70⁰C for an additional 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through a small plug of celite. The filtrate was washed with brine, washed with saturated aqueous sodium bicarbonate, washed with brine again, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2- (methylthio)-4-morpholinoaniline (116 mg, crude) as a dark brown oil, which was taken to the next step without further purification.1H NMR (400 MHz, Chloroform-d) δ 6.99 (d, J = 2.7 Hz,1H), 6.76 (dd, J = 8.6, 2.7 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 4.04 (s, 2H), 3.88 – 3.81 (m, 4H), 3.07 – 2.95 (m, 4H), 2.37 (s, 3H). Preparation of 2-fluoro-6-methoxy-4-morpholinoaniline O OO

[0274] In a 6 dram vial a mixture of 1,5-difluoro-3-methoxy-2-nitrobenzene (0.2 g, 1.0 eq., 1.06 mmol), morpholine (92.1 mg, 1.0 eq., 1.06 mmol), and potassium carbonate (292 mg, 2 eq., 2.12 mmol) in dimethylformamide (4 mL) was heated to 90 ⁰C overnight. The reaction mixture was cooled to room temperature and diluted with water. The aqueous layer was extracted with ethyl acetate three times (12 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in DCM and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g column, eluting with a gradient of ethyl acetate in hexanes (5-13% then 30%). Fractions containing desired product were pooled together, and concentrated in vacuo to afford 4-(3- fluoro-5-methoxy-4-nitrophenyl)morpholine (116 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 6.59 (dd, J = 14.7, 2.5 Hz, 1H), 6.47 – 6.41 (m, 1H), 3.89 (s, 3H), 3.75 – 3.68 (m, 4H), 3.39 – 3.32 (m, 4H). Step 2. Synthesis of 2-fluoro-6-methoxy-4-morpholinoaniline.

[0275] In a 6 dram vial to a suspension of 4-(3-fluoro-5-methoxy-4-nitrophenyl)morpholine (108 mg, 1.0 eq., 421 µmol) in ethanol (4.21 mL) was added saturated aqueous ammonium chloride (311 µL) and iron (84.7 mg, 3.6 eq., 1.52 mmol). The vial was capped, and the reaction mixture was heated to 70 ⁰C for 3h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a small plug of celite. The filtrate was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-fluoro-6- methoxy-4-morpholinoaniline (88 mg) as a dark brown oil was taken to the next step withoutfurther purification.1H NMR (400 MHz, DMSO-d6) δ 6.39 – 6.34 (m, 1H), 6.30 (dd, J = 13.4, 2.5 Hz, 1H), 4.06 (s, 2H), 3.78 (s, 3H), 3.73 – 3.67 (m, 4H), 2.99 – 2.92 (m, 4H). Preparation of 4-(1H-imidazol-1-yl)-2-methoxyaniline N N N-

[0276] In a 6 dram vial a mixture of 4-fluoro-2-methoxy-1-nitrobenzene (0.6 g, 1.0 eq., 3.51 mmol), 1H-imidazole (334 mg, 1.4 eq., 4.91 mmol), and potassium carbonate (969 mg, 2 eq., 7.01 mmol) in acetonitrile (6 mL) was heated to reflux overnight. The reaction mixture was concentrated in vacuo and stirred / sonicated vigorously in water until a free-flowing precipitate was formed. The resulting precipitate was filtered on filter paper under vacuum and dried overnight at room temperature to afford 1-(3-methoxy-4-nitrophenyl)-1H-imidazole (723 mg) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J = 1.2 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.96 (t, J = 1.4 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.43 (dd, J = 8.8, 2.3 Hz, 1H), 7.17 (dd, J = 1.5, 0.9 Hz, 1H), 4.04 (s, 3H). Step 2. Synthesis of 4-(1H-imidazol-1-yl)-2-methoxyaniline.

[0277] In a 6 dram vial to a suspension of 1-(3-methoxy-4-nitrophenyl)-1H-imidazole (0.3 g, 1.0 eq., 1.37 mmol) in ethanol (6.84 mL) was added saturated aqueous ammonium chloride (1.02 mL) and iron (275 mg, 3.6 eq., 4.93 mmol). The vial was capped, and the reaction mixture was heated to 85 ⁰C overnight. The reaction dried up overnight, and there was still starting material present. Additional ethanol (6.84 mL, 117 mmol) and saturated aqueous ammonium hloride (1.02 mL) was added and heating to 85⁰C was continued for 2 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and dry loaded on silica gel. CombiFlash column chromatography was carried out using a 12 g column, eluting with a gradient of methanol in ethyl acetate (0-8.6%). Fractions containing desired product were pooledtogether and concentrated in vacuo to afford 4-(1H-imidazol-1-yl)-2-methoxyaniline (180 mg, crude) which was ~80% pure (contained starting material nitro for the remaining ~20%).1H NMR (400 MHz, DMSO-d6) δ 8.02 (t, J = 1.1 Hz, 1H), 7.54 (t, J = 1.3 Hz, 1H), 7.04 – 7.00 (m, 2H), 6.88 (dd, J = 8.3, 2.4 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 4.87 (s, 2H), 3.84 (s, 3H). General Preparation Schemes

[0278] Additional preparation schemes providing alternative and / or additional synthesis information for the disclosed compounds described herein are provided below. General Buchwald Scheme and Procedure R7R5R5material chloride (1.0 eq.), starting material amine (1.05 eq.), cesium carbonate (1.0-2.0 eq.), and XPhos (0.2 eq.) in 1,4-dioxane (10 volumes) was degassed by bubbling with argon for 5 minutes.

[0280] Tris(dibenzylideneacetone)dipalladium(0) (0.1 eq.) was added to the vial, and the vial was capped and heated to 107°C while stirring for 16 hours. Multiple workup and purification methods were utilized as indicated in Table 3. Compounds that were prepared according to this general procedure can be found in subsequent Table 3. Table 3. Compounds prepared using a general Buchwald scheme and procedure. No. Compound structure Startin Starting Workup, and tionT3-1 N N 2- methyl 4- The reaction chloro amino-3- mixture was O 7 h ed. was ilica lash O phy hyl n to mg he s an 400 O- , J = ), ), ), 0.8 7 (d, 1H), 8.6, ), 1.9 4 (s, 4.19 9 (s, (s, (s, 2.67 4 – H), (m, m / z: lcd 6O3, nd,T3-2 2- 2-methoxy- The reaction N N chloro 4-(4- mixture was 7 hl4H il ih 5% ate ith e er nd on by l sh phy in te) by ase sh phy 2O) mg he s an 400 d) δ 8.4 3 (s, (s, (s, , J = ), 0.7 3 (d, 1H), 8.4, ), ), (m, (s, (s, (s,3H), 2.75 (s, 2H), 2.19 – 2.05 2H 203 – H), (m, m / z: lcd 9O, d, on as th and ith te. after nd on by sh phy in te) y l to mg he d. 00 d) δ 8.3 3 (s, (s, (s, , J = ), ), (m, (s, 4.16(m, 1H), 4.05 (s, 3H), 4.02 (s, H 4 1 (s, 2.81 0 – H), (m, 1.28 S z: lcd 9O, d, on as th and ith te. after nd on by sh phy thyl (0- l in te) y l to mg he 1H 0 d) δ 8.3 2 (s, (s, , J =0.7 Hz, 1H), 7.52 (d, J = 1.9 H 1H 749 (s, d, J z, J = ), 1.9 0 (s, 4.15 1 (s, (s, (s, 2.83 8 – H), (m, 1.27 S z: lcd 8O, d, on as th and ith te. after nd on by sh phy thyl (0- l in te) y l toafford 47 mg (41%) of the 1H 0 d) δ 8.4 9 (s, (s, , J = ), 0.8 8 (d, H), ), 8.4, ), 1.9 7 (s, 4.15 1 (s, (s, (s, 2.84 0 – H), (m, 1.27 m / z: lcd 8O, d, on as th and ith te. after nd on by shpyrrol chromatography o[2,3- (60-100% ethyl i in (0- l in te) y ase sh phy in ord %) 1H 0 d) δ 8.8 9 (s, (s, , J = ), ), (m, , J = ), 2.3 7 (s, 4.14 1 (s, (s, (s, 2.85 0 – H), (m, 1.42 1 – H). m / z: lcd 8O, d,T3-7 2- 2-methoxy- The reaction N N chloro 4-(2- mixture was N 7 hl2H il ith and ith te. after nd on by l sh phy thyl n by l to mg he 1H 0 d) δ 8.3 0 (s, (s, (s, , J = ), 0.8 39 1.8 5 (d, 1H), ), ), (m, (s, 2.83 1 – H), (m, 1.28 S(APCI) m / z: [M+H]+calcd f H N9O, d, on as th and ith te. after nd on by sh phy thyl y in (0- d by l to mg he 1H 0 d) δ 8.3 9 (s, (s, , J = ), ), ), 8.3, ), 1.9 7 (s, 4.14 1 (s,3H), 3.95 (s, 3H), 3.89 (s, H 2 2.84 2 (s, 1.91 8 – H), (m, PCI) ]+O, d, on as th and ith te. after nd on by sh phy thyl y l to mg he 1H 0 d) δ 8.5 5 (s, (s, J = ), ), 1.9Hz, 1H), 7.34 (dd, J = 8.5, 1.9 H 1H 0 (s, 4.87 3 (s, (s, (s, 3.50 1 – H), (m, 1.79 S z: lcd 10O, d, on as th and ith te. after nd on by sh phy thyl y l to mg he 1H 0 d) δ 8.5 5 (s, (s,1H), 7.61 (d, J = 0.7 Hz, 1H), 7 2 1H), 1.9 30 1.9 3 (s, 4.67 2 (s, 3.99 1 – H), (m, 1.93 9 – H). m / z: lcd 10O, d, on as th d ith te. after nd on by sh phy thyl (0- l in te) y l to mg the 1HNMR (400 MHz, DMSO- 1 (s, (s, (s, , J = ), 8.7 2 (d, H), 8.7, ), ), (m, (s, 3.71 8 – H), (m, (s, 1.54 2 – H), (m, PCI) ]+O, d, on as th ith te. tion on, was ilica lash phy mn / thyl(75 acetate in mg, hexanes (50- 1 1 f ll wed ol to mg the 1H 0 d) δ (m, (s, 7.56 8 (s, 6.55 3 (s, 4.81 0 (s, (s, 3.86 6 – H), (m, 2.24 4 – H), (m, PCI) ]+2, nd, on as th ith te y ith er nd on, waspyrrol purified by silica o[2,3- gel CombiFlash i l phy mn / thyl 0- wed nol to mg the 1H 0 d) δ ), 8.5 9 (d, H), ), 0.7 0 – H), ), (m, (s, 3.83 9 – H), (m, 2.04 9 – H), (m, PCI) ]+2, nd,T3-14 N 2- 4-(4- The reaction N O chloro amino-3- mixture was O 7 h h il ith d ith te. tion on, was ilica lash phy n / thyl n 0- wed ol to mg the 1H 0 d) δ 8.3 8 (s, (s, , J = ), ), 8.4, ), 1.9 7 (s, 4.15 1 (s, (s, 3.10 4 – H), (m, 2.20 9 –1.90 (m, 2H), 1.89 – 1.78 (m, H 14 1.27 S z: lcd 3S, nd, on as th ith te. tion on, was ilica lash phy mn / thyl 0- wed ol to mg the 1H 0 d) δ 8.4 9 (s, (s, , J = ), ), 8.5, ), 2.0Hz, 1H), 6.28 (s, 1H), 4.25 – 4.13 2H 4 1 (s, (s, 3.26 5 – H), (m, 2.43 3 – H), (m, 1.92 7 – H), (m, PCI) ]+3S, nd, on as th ith te. tion on, was ilica lash phy n / thyl 0- wed l in (0- wed ol toafford 60 mg (34.9%) of the 1H 0 d) δ 8.6 4 (s, (s, , J = ), 8.6, ), 0.7 7 (d, H), ), (m, (s, (s, (s, 2.77 1 (s, 1.92 0 – H), (m, PCI) ]+2S, nd, on as th ith er nd on, was ilica lash phyo[2,3- 4 g gold column / d]pyri gradient of i i h l in (0- wed ol to mg the 1H 0 d) δ ), 1.2 4 (s, (s, 7.26 4 – H), = z, J = ), ), ), (m, (s, (s, 2.53 3 – H), (m, 1.16 5 – H). m / z: lcd N8O, nd,T3-18 N 2- 2-methoxy- The reaction N chloro 4-(1- mixture was 7 hl1H il ith d ith te. tion on, was ilica lash phy mn / f in (0- by ase n 2O) mg the 1H 0 d) δ 8.4 1 (s, (s, , J = ), ), 1.9 22 1.9 2 (d, 1H), 1.3 9 (s, 4.15 1 (s, (s, (s,3H), 2.98 – 2.82 (m, 2H), 1.99 – 1 2H), (m, 1.26 S z: lcd 8O, nd, on as th ith er nd on, was ilica lash phy mn / f in (0- wed hase n 2O) 5.3 ) of nd. 00 d) δ 8.4 3 (s, (s, (s, , J = ), 0.8 7 (d,J = 1.9 Hz, 1H), 7.21 (dd, J = 8.4, 1 H 1H), ), (m, 4.02 1 (s, (s, 2.82 8 – H), (m, J = MS z: lcd 9O, nd, on as th ith te. tion on, was ilica lash phy mn / f in (0- wed hase n 2O) mg the 1H 0Chloroform-d) δ 8.94 (d, J = 8.3 H 1H 3 (s, (s, (s, , J = ), 0.8 2 – H), ), (m, 4.15 1 (s, (s, 2.82 7 – H), (m, , J = ), (m, PCI) ]+O, nd, on as th ith te. tion on, was ilica lash phy mn / thyl 0-1.0 80%), followed eq., by methanol 21 i i to mg the 1H 0 d) δ 9.0 8 (s, (s, , J = ), ), 2.9 94 2.9 6 (s, 4.11 1 (s, 3.84 7 – H), (m, (s, 1.91 6 – H), (m, PCI) ]+S, nd, on as th ith te. tion on, wasyl)- purified by silica 7H- gel CombiFlash l l phy mn / thyl 0- wed ol to mg the 1H 0 d) δ ), 0.7 3 (s, d, J Hz, 6.29 4 (s, (s, 3.99 8 (s, 3.84 2 (s, 3.12 9 – H), (m, 1.57 8 – H). m / z: lcd O2, nd,T3-23 2- 4-(1H- The reaction N N chloro imidazol-1- mixture was 7 l 2 il ith ith te. tion on, was ilica lash phy n / f in (0- wed hase n 2O) 4.2 ) of nd. 400 d) δ 8.6 2 (s, J = ), ), 0.7 9 (s, J = ), 1.2 02 2.4 0 (d, 1H), ), (m, (s, (s,3H), 2.93 – 2.79 (m, 2H), 2.03 – 1 2H), (m, 1.27 S z: lcd 8O, nd, on as th ith te. tion on, was ilica lash phy mn / thyl 0- wed nol to mg the 1H 0 d) δ (m, (s, 7.55 1 (s, 6.54 5 (s, J = ),4.23 – 4.14 (m, 1H), 3.98 – 3.82 7H 21 – H), (m, 1.89 8 – H), 7.3 0 – H). m / z: lcd 7O2, nd, on as th ith te. tion on, was ilica lash phy mn / thyl 0- wed nol to mg the 1H 0 d) δ (m, (s, , J =0.8 Hz, 1H), 7.60 (s, 1H), 727 60.5 2 – H), ), (m, 3.86 8 – H), (m, 1.92 8 – H), (m, PCI) ]+O2, nd, on as th ith te. tion on, was ilica lash phy mn / thyl 0- wed ol to mg the 1H 0MHz, Chloroform-d) δ 1H), (m, (s, J = ), (m, (s, , J = ), (m, (s, 3.11 8 – H), (m, 1.72 1 – H). m / z: lcd 7O2, nd, on as th ith te. tion on, was ilica lash phy mn / thyl 0- wed ol to0.237 afford 34.2 mg mmol) (29.53%) of the 1H 0 d) δ (m, (s, (s, J = ), (m, (s, , J = ), (m, (s, 3.86 7 – H), (m, 1.84 4 – H), (m, PCI) ]+2, nd, on as th ith te. tion on, was ilica lash phy mn / midine gradient of ethyl (75 acetate in h 50- wed ol to mg the 1H 0 d) δ (m, (s, 7.57 8 (d, H), (m, (s, 4.14 3 – H), (m, 2.79 3 – H), (m, 1.28 9 (t, H). m / z: lcd 7O2, nd, on as th ith te. tion on, was ilicapyrrol gel CombiFlash o[2,3- column i h phy mn / thyl 0- wed l in (0- ed ol to mg the 1H 0 d) δ (m, (s, (s, J = ), 2.5 2 – H), 2.7, ), ), (m, 3.86 4 (s, 3.10 9 – H), (m, 1.74 1 – H). m / z: lcd 6O2, nd,T3-30 O methyl 2-methoxy- The reaction N O 4-(2- 4-(4- mixture was hl hl4H il ith ith er O nd on, was ilica lash phy mn / f in (0- wed hase n 2O) 8.5 ) of 1H 0 d) δ 8.5 1 (s, (s, (s, , J = ), 8.4, ), 2.0 2 (d, 1H), ), (m, (s, (s, (s, (s,3H), 2.96 – 2.79 (m, 2H), 1.98 – 1 1 2H), (m, 1.29 S z: lcd 8O3, nd, on as th he was he was ilica lash phy mn / f in (0- wed ol to mg the 1H 0 d) δ 8.4 7 (s, (s, (s, (s, , J = ), 1.9 8 (t, z, d, J= 8.4, 2.0 Hz, 1H), 6.40 (s, 1H 421 4.07 0 (s, (s, 2.81 0 – H), (m, 1.29 S z: lcd 9O, nd, on as th he was he was ilica lash phy mn / f in (0- wed hase n 2O) mg the 1H 0 d) δ 8.4 8 (s, (s,1H), 7.97 (s, 1H), 7.93 (s, 1H 7 (s, , J = ), 8.4, ), ), (m, (s, (s, 2.81 0 – H), (m, 1.28 S z: lcd 9O, nd, on as th ith er nd on, was ilica lash phy mn / f in (0- wed hase n 2O) 5.8mg (21.2%) of the compound. 1H NMR 400 d) δ 8.4 2 (s, (s, (s, , J = ), 0.9 3 (d, H), 8.4, ), ), (m, (s, (s, 3.64 5 – H), (m, 1.76 0 – H), (m, 1.06 S z: lcd 9O, nd, on as th he was he was ilica lash phypyrrol 4 g gold column / o[2,3- gradient of i h l in (0- wed hase n 2O) mg the 1H 0 d) δ 8.4 4 (s, (s, (s, , J = ), 8.5, ), 1.4 3 (t, H), ), (m, (s, (s, 2.82 7 (d, H), (m, 1.76 6 – H). m / z: lcd OS, nd,T3-35 2- 2-methoxy- The reaction N N chloro 4-(4- mixture was 7 hl4H il ith he was he was ilica lash phy mn / f in (0- wed hase n 2O) mg the 1H 0 d) δ 8.4 8 (s, (s, (s, (s, , J = ), 8.4, ), ), (m, (s, (s, (s, 2.78 3 – H), (m, 1.32 S(APCI) m / z: [M+H]+calcd f H N10O, nd, on as th he was he was ilica lash phy mn / f in (0- wed hase n 2O) 9.1 ) of nd. 00 d) δ 8.4 9 (s, (s, (s, (s, , J = ), 8.4, ), ), (m, (s, (s, (s, 2.76(m, 2H), 2.03 – 1.88 (m, 4H), 1 17 (m, 1.33 S z: lcd 10O, nd, on as th he was he was ilica lash phy mn / f in (0- wed hase n 2O) 3.7 ) of nd. 00 d) δ 8.4 72 0.9 1 (s, d, J z, (s, (s, 7.71 8 –7.40 (m, 1H), 7.34 (d, J = 1.9 H 1H 726 1.9 3 (s, 4.02 1 (s, (s, 2.83 7 – H), (m, 1.22 S z: lcd 8O, nd, on as th ith er nd on, was ilica lash phy mn / f in (0- wed hase n 2O) 2.2 ) of nd. 00Chloroform-d) δ 8.93 (d, J = 8.4 H 1H 75 – H), ), ), ), (m, d, J z, (s, 4.08 1 (s, (s, 2.86 0 – H), (m, 1.22 S z: lcd 8O, nd, on as th ith er nd on, was ilica lash phy mn / f in (0- wed hase n(MeOH in H2O) to afford 32.3 2 22%) of nd. 00 d) δ 0.7 2 (d, H), ), ), ), 0.7 4 (d, H), 8.5, ), ), (m, (s, (s, 2.80 8 – H), (m, 1.27 S z: lcd OS, nd, on as th ith er nd on, was ilica lash phyd]pyri 4 g gold column / midine gradient of h l in (0- wed hase n 2O) 2.1 ) of 1H 0 d) δ 8.4 1 (s, , J = ), ), ), 1.9 27 1.9 5 – H), 4.9, ), ), = z, (s, (s, d, J 7, H), ), = Hz, , J = H), (m, PCI) ]+C28H31N8O, 495.3; found, 4 4 on as th he was he was ilica lash phy mn / f in (0- wed ol to mg the 1H 0 d) δ 8.4 9 (s, d, J z, (s, (s, d, J z, , J = ), 8.0 26 1.9 0 (s, (s, (s, 2.80 6 (s, J =16.8 Hz, 4H), 1.77 (d, J = 12.3 H 1H 147 – H). m / z: lcd 8O, nd, on as th ith er nd on, was ilica lash phy mn / f in (0- wed hase n 2O) 0.6 ) of nd. 00 d) δ 8.4 7 (s, (s, (s, (s, , J = ), 8.4, ),6.48 (s, 1H), 4.29 – 4.17 (m, 1H 4 (s, (s, 2.81 0 (s, 1.74 8 – H). m / z: lcd OS, nd, on as th he was he was ilica lash phy mn / f in (0- wed hase n 2O) 6.5 ) of nd. 00 d) δ 8.4 0 (s, (s, (s, , J = ),7.24 (dd, J = 8.4, 1.9 Hz, 1H), 17 1H), (m, 3.95 1 (s, t, J z, 2.76 57 2.6 6 (d, H), 12.3 1 (d, H). m / z: lcd OS, nd, on as th ith te. tion on, was ilica lash phy mn / thyl 0- wed ous l to mg the 1HNMR (400 MHz, hl f d) δ (m, (s, d, J z, (s, d, J z, d, J z, 6.55 2 (s, 4.03 2 (s, 3.87 8 – H), (m, (s, 1.79 9 – H), (m, 1.14 S z: lcd 6O3, nd, on as th ith er nd on, was ilica lash phy mn / e(10 gradient of mg, methanol in 1 h l e (0- wed hase n 2O) 29 ) of nd. 00 d) δ 8.4 8 (s, (s, (s, (s, , J = ), 8.4, ), ), (m, (s, (s, 3.46 9 (s, 2.30 3 – H), (m, PCI) ]+S, nd, on as th ith er ndyl)- concentration, 7H- the residue was l ifi ilica lash phy mn / f in (0- wed hase n 2O) 4.8 ) of 1H 0 d) δ 8.4 6 – H), ), ), 1.9 6 – H), 8.4, ), ), (m, (s, (s, 3.45 5 – H), (m, 1.80 S z: lcd 8O,453.2; found, 453.3. N on as th ith er nd on, was ilica lash phy mn / f in (0- wed hase n 2O) 1.9 ) of nd. 00 d) δ 8.4 4 – H), 4.9, ), ), ), J = Hz, dd, J 0.9 8 (d, H), 8.5, ), ),4.86 – 4.73 (m, 1H), 4.02 (s, H 2 (s, 3.44 2 – H), (m, 1.75 S z: lcd 8O, nd, on as th d ith te. tion on, was ilica lash phy n / thyl 0- wed l in (0- ed ol to mg the 1H 0 O- (s, , J = ),8.00 (d, J = 0.8 Hz, 1H), 7.65 (d, H 1H), ), 2.6 53 2.6 3 (s, 4.54 2 (s, (s, 3.71 2 – H), 6.8 S z: lcd 7O2, nd, on as th ith te y ith er nd on, was ilica lash phy mn / thyl 0- wed ol to mg thecompound.1H NMR (400 MH d) δ 8.7 3 (s, , J = ), ), ), (m, (s, (s, (s, 3.86 1 – H), (m, 1.09 S z: lcd 7O2, nd, on as th ith er nd on, was ilica lash phy mn / f in (0- wed hase n0.155 (MeOH in H2O) mmol) to afford 17.3 24 %) of nd. 00 d) δ 8.4 8 (s, (s, (s, (s, (s, , J = ), 8.5, ), ), (m, 5.60 9 – H), ), MS z: lcd 9O2, nd, on as th d ith te. tion on, was ilica lash phy n / thylmidine hexanes (70- (75 100%) followed h l in (0- wed ol to mg the 1H 0 O- (s, , J = ), 0.8 8 (d, H), ), 2.6 48 2.6 6 (s, 4.35 3 – H), ), ), (m, 3.35 1 – H), (m, 1.66 S z: lcd 7O3, nd,T3-52 O tert- 2-methoxy- The reaction N O butyl 4- mixture was NN4 2 h li ed. was ilica lash phy n / thyl n 0- wed l in (0- wed ol to mg the 1H 0 O- (s, , J = ), ), 0.8 0 (s, , J = ), 8.9, ), ), (m, 4.04 2 (s, (s, 3.68 2 – H), (m, 1.69 5 (s, PCI) ]+calcd for C31H41N8O4, f nd, on as th he was he was ilica lash phy mn / f in (0- wed hase n 2O) 4.5 ) of nd. 00 d) δ 8.4 2 (s, (s, (s, , J = ), ), 1.9 24 1.9 5 (s, (s, (s, (s, (s, PCI)m / z: [M+H]+calcd for H N O, nd, on as th d ith te. tion on, was ilica lash phy n / thyl 0- wed l in (0- ed e to mg of the 1H 0 O- (s, , J = ), ), 0.8 3 (s, , J = ), 8.9, ), ),4.21 (s, 2H), 3.90 (s, 3H), 7 H), (m, 3.05 4 (s, PCI) ]+2, nd, on as th d ith te. tion on, was ilica lash phy ient tate 20- wed ol to mg the 1H 0 O- (s, , J = ), ), (m, , J = ), 8.8,2.6 Hz, 1H), 6.41 (s, 1H), 4 (m, (s, 3.72 2 – H), (m, 1.73 2 – H), (m, PCI) ]+2, nd, on as th d ith te. tion on, was ilica lash phy ient tate 20- wed ol to mg the 1H 0 O- (s, , J =8.7 Hz, 1H), 7.67 (s, 1H), 7 3.5 4 – H), 2.5 50 2.6 5 (s, 4.22 7 (s, 3.72 2 – H), (m, (s, 1.81 0 – H), (m, PCI) ]+2S, nd,General Suzuki Procedure 1 R2R21N Cl

[0281] In aeq.), starting material boronic acid or ester (1.05 eq.), and 2 M aqueous sodium carbonate (2.1 eq.) in DMF (0.1 M) was degassed by bubbling with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.05 eq.-0.1 eq.) was added to the vial, and the vial was capped and heated to 85 °C while stirring for 4-18 hours. Multiple workup methods were utilized and are as follows.

[0282] Workup method A: The reaction was quenched with water and the aqueous layer was extracted 3x with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.

[0283] Workup method B: The reaction was diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo.

[0284] Workup method C: The reaction was diluted with water, and the precipitate was collected. After following the above workup methods, the residue or precipitate was subjected to silica gel CombiFlash chromatography or HPLC purification to afford the title compound. Intermediates prepared according to the general procedure can be found in Table 4. Table 4. Intermediates prepared using General Suzuki Procedure 1. Intermediate Intermediate Structure Starting Starting material Workup, Compound material boronic ester or purification, and ion hod ue by h phy yl o g s an der. 00 -d6) H), 1.9 3 (s, J = 4.12 H), 2.39 H), (m, .55 0 – ).T4-2 N 6-bromo-2- 1-methyl-3- Workup method N chloro-7- (4,4,5,5- B. The residue lh l hl1 2 ifi by h phy yl o mg s an der. 00 d) δ 7.46 z, 1H), 2.3 1 – ), 2.76 H), (m, .67 7 – ). hod ue by h phy yl o mg s an der. 00 d) δ 7.61 z,1H), 7.56 (d, J = 0.8 Hz, 1H), 6.40 1H 4 3 – ), (m, .88 6 – ), (m, J = 1.47 H). hod ue by h phy yl o mg s a w MR , d) δ 7.61 (s, 1H), (m, J = 2.77 H), (m, .78 6 – ), (m, J = ).T4-5 N 6-bromo-2- 1-methyl-3- Workup method chloro-7- (4,4,5,5- B. The residue lh l hl1 2 ifi by h phy yl o mg s an der. 00 d) δ 6.78 z, J = 6.33 (dd, Hz, .37 (s, .66 6 – ), (m, .66 0 – ). hod ue by h phy yl o mg s an der. 00Chloroform-d) δ 8.68 (s, 1H), 7.00 2 Hz, J = 6.36 8 – ), 3.87 9 – ), (m, .78 5 – ), (m, hod ue by h phy yl o mg s a .1H Hz, d) δ 7.97 (q, J H), 0.4 0 (s, .09 6 – ), (m, .79 6 – ), (m,T4-8 F F 6-bromo-2- 4-(4,4,5,5- Workup method N F N chloro-7- tetramethyl-1,3,2- B. The residue lh l i l 2 ifi by h phy yl o mg s a .1H Hz, d) δ 7.97 (s, 1H), (m, .61 9 – ), (m, .69 5 – ). hod ue by h phy yl o mg s an der. 00 d) δ 7.61 (d, J H), 4.30– 4.18 (m, 1H), 3.75 – 3.65 (m, 1H 277 2.63 8 – ), (m, .67 7 – ), (m, .07 hod ue by h phy yl o mg s a .1H Hz, d) δ 7.15 z, .80 (s, .19 7 – ), 1.1 5 – ), (m, .66 8 – ).00T4-11 N N N 6-bromo-2- 1-methyl-4- Workup method chloro-7- (4,4,5,5- B. The residue lh l hl1 2 ifi by h phy yl o g s a .1H Hz, d) δ 7.76 (s, .71 (s, .61 7 – ), (m, .30 hod ue by h phy yl o g s an der. 00 d) δ 7.79 (s, .66 (s, .60(m, 2H), 1.96 – 1.85 (m, 4H), 1 1 1 (m, .29 hod ue by h phy yl o mg s a .1H Hz, d) δ 8.75 1.7 72 0.9 75 2.3, 7.46 4.9, 6.53 4 – ), (m, .77 2 – ), (m, hod ue by h phy yl oafford 85 mg (57%) of s a .1H Hz, d) δ 8.80 H), (m, 1H), (m, .65 5 – ), (m, .19 hod ue by h phy yl o g s a w MR , d) δ 0.7 9 (s, J = 6.64 0 – ), (m, .88 8 – ), (m, .23T4-16 N 6-bromo-2- 2-methyl-4- Workup method chloro-7- (4,4,5,5- B. The residue lh l hl1 2 ifi by h phy yl o mg s a w MR , d) δ 8.65 0.8 2 (s, .20 14 1.7, 6.53 8 – ), 2.88 z, .67 (s, .87 7 – ), 3.0 7 – ). hod as lica ash phy yl o mgcompound as an off-white fluffy 1H NMR , d) δ 8.59 0.9 63 2.3 (d, H), 4.14 H), (m, .76 3 – ), (m, hod ue by h phy yl rep- n m 8 mn, OH ford ) of s a .1H Hz, d) δ 7.69 (s, .20 (s, .61(m, 2H), 1.96 – 1.88 (m, 2H), 1 7 17 (m, .67 6 – ). hod ue by h phy yl o mg s an der. 00 d) δ 6.26 3 – ), (m, .34 9 (t, H), (m, .50 7 – ), (m, .28 hod ue by h phy yl o mg(crude) of compound as an ff hi wder. 00 d) δ 7.73 0.7 62 0.6 38 1.7 0 (s, .10 7 – ), (m, .61 5 – ). hod ue by h phy yl rep- n m 8 mn, O) to g s a .1H Hz, d) δ 7.69 (s, .84 8 –3.23 (m, 2H), 2.80 (s, 3H), 2.40 22 2H), (m, .69 hod ue by h phy yl o mg s an der. 00 d) δ 8.80 H), (m, 1H), (m, .18 1 – ), (m, .68 hod ue by h phy yl o mg s a .1HNMR (400 MHz, Chloroform-d) δ , = J (s, – , – .150 °C,

[0285] In aaryl bromide or aryl iodide (1.0 eq.), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 eq.), and cesium fluoride (3 eq.) in 1,2-dimethoxyethane:methanol (2:1 ratio, 16.7 volumes) was degassed by bubbling argon vigorously for 5 minutes. Pd(PPh3)4 (0.05 eq.) was added to the reaction mixture, and the vial was capped and heated at 150°C in the microwave for 2-10 minutes. The reaction was cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was basified by the addition of 2 M aqueous Na2CO3 and / or extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate (Na2SO4), and concentrated in vacuo. The residue was subjected toCombiFlash column chromatography to afford the title product. Intermediates prepared according to this general procedure can be found in Table 5. Table 5. Intermediates prepared using General Suzuki Procedure 2. Intermediate Intermediate structure Starting material Characterization s aphy in mg a ane 00 .88 Hz, 1.8 Hz, (s, s aphy in mg a ane 00 .48 (dd, 1 (d, J = 1.9 .88 s aphy in mg a R d) δ ), ), z,1H), 6.72 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H H (s, s aphy in mg an MR d) δ ), ), 1 (d, s, (s, s aphy in mg s an MR d) δ (m, H), H), H). s aphy in mg an r MR d) δ 1.8 .0, 8.0 .93General Reaction Scheme 3R2R1

[0286] To a solution of 2,4-dichloro-5-iodopyrimidine (1.0 eq.) in ethanol (0.44 M) at room temperature was added N,N-diisopropylethylamine (DIPEA) (1.1 eq.-2.1 eq.) and the correspondinghydrochloride (1.05-2.2 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was subjected to silica gel CombiFlash chromatography to afford the title compound. Intermediates prepared according to this general procedure step 1 can be found in Table 6. Table 6. Intermediates prepared using step 1 of General Reaction Scheme 3. Intermediate Intermediate structure Starting material Purification and N i h i ion ue ilica h (0- in rd f hite R(400 MHz, Chloroform-d) δ 8.24 1H 2 1H), H), Hz, ue ilica h (0- hyl s) to ) of hite R 8.27 H), H), H), H). ue ilica h (0- e in 2 g und oil. Hz, 8.26 H), H), H), H), H). ue ilica h (0- e in rd f hite RChloroform-d) δ 8.33 (s, 1H), 5.84 (s, 1H), 27 14 1H), H), H). ue ilica h (0- e in rd of hite R 8.28 J = 1 – 5 – 2 – 9 – 5 – ue ilica h (0- e in rd of hite R 8.28 J = 4 – 6 – 8 – 2 – . ue ilica h (0- hyl s) toafford 1.91 g (81.5%) of compound as a , (s, (0- in , ., and triethylamine (3 eq.) in DMF (0.2M) was degassed by bubbling with argon for 5 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.05 eq.) and copper (I) iodide (0.05 eq.) were subsequently added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes to 1 hour. Multiple workup and purification methods were utilized. Intermediates prepared according to this step 2 can be found in Table 7. Table 7. Intermediates prepared using step 2 of General Reaction Scheme 3.Intermedi Intermediate structure Starting material Starting Workup, ate iodide material Purification, lk rizat tion ed ter red The g ate cted fied gel ash gra 5% tate es) 342 ) of d as hite 1H 00 , 6) δ H), H), H), J = H), .22 3.87 1.22 6.6 ). tion ed ter e slayer was extracted 3x i h hyl The ed c ere with ied ium , and ated The was by el ash gra 0% tate es) 441 e) of d as hite 1H 00 , rm- (s, 3 (s, 7 (s, 4 (s, 3 (s, 5 – 1H), .86 0.66 m,T7-3 N 2-chloro-N- 4-ethynyl-1- The reaction N cyclopentyl-5- methyl-1H- was HN i i ii 4 l hed ter e us as d 3x hyl The ed c ere with ied ium e, and ated The was by el lash ogra 3% tate es) 414 ) of d as hite 1H 400 , rm- (s, 4 (s, 8 (s, 5 (d, Hz, 2 – 1H), 3H), .08 1.81– 1.60 (m, 4H), 1.53 – 14 2H). tion ed ter e g ate d. ous was 2x yl The ed c ere with ied ium , and ated The and ate ed fied gel ash gra 80% tate es) 371 ) of d as llow 1H 00 ,Chloroform- d) δ 8.19 (s, 1H 7 8 (s, 2 (s, (d, Hz, 3 – 1H), J = H), .56 3.95 ). tion ed ter e s as 3x yl The ed c ere with ied ium , and ated The was by el ash gra 70% tate es) 358 ) of d as hite 1HNMR (400 MHz, DM d6) δ H), H), H), J = H), .09 3.93 m, 5 – 2H), .65 ). tion ed ter red The g ate cted fied gel ash gra 60% tate es) 388 ) of d as hite 1H 00 , 6) δ H), H), H), J = H), .08(m, 1H), 4.06 – 3.92 (m, 2H 6 (s, 5 – 2H), .72 1.64 m, 0 (s, tion ed ter red The g ate cted fied gel ash gra 0% tate es) 372 ) of d as e 1H 00 , rm- (s, 5 (s, 9 (s, 7 (s, 3 (s, 4 (s, 4 (s,T7-8 N 2-chloro-5-iodo- 4-ethynyl-1- The reaction N N- methyl-1H- was HN l i ii l hed ter red The g ate cted fied gel ash gra 5% tate es) 333 ) of d as e 1H 00 , 6) δ H), H), J = H), J = H), H), J = H), H). tion ed ter e s as 3x yl The edorganic layers were h with ied ium , and ated The was by el ash gra 8% tate es) 388 ) of d as oil. R Hz, 6) δ H), .60 7.51 m, (d, Hz, 2 – 1H), .80 1.80 m, 8 – 1H), .41 1.39 m, 0 – 1H).T7-10 2-chloro-N- 2-ethynyl-5- The reaction S cyclohexyl-5- methylthioph was HN i i ii 4 hed ter e us as d 3x hyl The ed c ere with ied ium e, and ated The was by el lash ogra 8% tate es) 421 ) of d as ge H 400 , 6) δ 1H), .23 6.87 m, 5 (s, 0 – 1H), J = H), .78(m, 2H), 1.78 – 1.69 (m, – , – .a solution of 1 M tetrabutylammonium fluoride (TBAF) in THF (3 eq.). The reaction mixture was heated to 70°C while stirring for 2 hours or until the starting material disappeared by while monitoring the reaction progress by TLC. The reaction was diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was subjected to silica gel CombiFlash chromatography to afford the title compound. Intermediates prepared according to this general procedure step 3 can be found in Table 8. Table 8. Intermediates prepared using step 3 of General Reaction Scheme 3. Intermediate Intermediate structure Starting material alkyne Workup, C d P ifi ti and ion as ica sh hy yl nes) mg s a der. 00MHz, DMSO-d6) δ 8.84 (s, 1H), 8.13 1H 77 d, J ), .80 H), .63 z, as ica sh hy yl nes) mg an der. 00 rm- H), .8 (s, H), .38 H), m, .05 as ica sh hy yl nes) mg an der. 00 rm- H), .55 (s, .6927(m, 1H), 4.02 (s, 3H), 2.50 (dq, J = 14 H 2H), m, .91 – ). as ica sh hy yl nes) mg an der. 00 rm- H), .58 (s, .63 – 4.93 H), ). as ica sh hy yl nes) mg an der. 00 d6) δ .15 d, J ), .60 H), m, H),3.48 – 3.37 (m, 2H), 2.90 – 2.75 2H 1 1 – ). as ica sh hy yl nes) mg an der. 00 d6) δ .14 d, J ), .55 H), m, H), m, .56 – 1.46 as ica sh hy yl nes) mg an der. 00 rm- H), .8 (s, H), .529(s, 1H), 2.36 (s, 6H). N was ica sh hy yl nes) mg an der. 00 d6) δ .24 d, J ), .29 (s, H). as ica sh hy l nes) mg an der. 00 d6) δ .63 H), .15 H), m, .75 – 1.31 H).T8-10 2-chloro-N-cyclohexyl-5- The residue was S ((5-methylthiophen-2- purified by silica l h l i i i 4 l iFlash hy yl nes) mg an der. 00 d6) δ .18 z, .95 (s, .33 1 – 1.93 H), m, .19Mps1 / TTK Assays NanoBRET TTK Assay

[0289] HEK293 cells were grown to 70-80% confluency, trypsinized, and collected. A 10 µg / mL solution of DNA was prepared using serum-free OPTI-MEM without phenol red.9.0 µg of Transfection Carrier DNA and 1.0 µg of TTK-NanoLuc fusion vector DNA were mixed in 1 mL of media. To form a lipid:DNA complex, 30 µL 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.

[0290] 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.

[0291] 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.

[0292] 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 µM. Additionally, a set of samples was also prepared without the K5 tracer for background correction steps.

[0293] 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 IC50 curves of the NanoBRET response for the compounds were plotted, and the IC50values were calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. Results are shown in Table 9 for synthesized compounds and Table 10 for comparative compounds. “ND” indicates results were not determined. TTK Inhibition Assay

[0294] Base Reaction buffer containing 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35, 0.02 mg / ml BSA, 0.1 mM Na3VO4, 2 mM DTT, and 1% DMSO 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 IC50 curves for the synthesized compounds were plotted, and the IC50 valueswere calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. The results are shown in Table 9 for synthesized compounds and Table 10 for comparative compounds. “ND” indicates results were not determined. Cancer Cell Line Assays RPMI-8226 MTS Assay

[0295] 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 RPMI-8226 cell line was purchased from American Type Culture Collection (Manassas, VA). Cells were cultured in RPMI-1640 with 10% FBS and supplemented with 100 µg / mL of penicillin and 100 µg / mL of streptomycin. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2and 95% air.

[0296] 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 µL 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 µL 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 IC50curves were plotted, and the IC50values were calculated using the GraphPad Prism 4 program based on a sigmoidal dose-response equation. The results are shown in Table 9 for synthesized compounds and Table 10 for comparative compounds. “ND” indicates results were not determined. A375 Cell Titer-Glo Assay

[0297] 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 cellswere cultured in DMEM containing 10% FBS, 100 µg / ml of penicillin, and 100 µg / mL of streptomycin. Cultures were maintained at 37°C in a humidified atmosphere of 5% CO2and 95% air.

[0298] 50 µL 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 µM (test compounds) or 1 µM (bortezomib). Cells treated with 10 µM staurosporine were utilized as the background. The cells were incubated with the compounds at 37°C and 5% CO2 for 72 hours.

[0299] 50 µL 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 9 for synthesized compounds and Table 10 for comparative compounds. “ND” indicates results were not determined. A375 Cell Titer-Glo Serum Shift Assay

[0300] The above A375 CTG assay was repeated. However, the protocol was revised to incorporate 4.5% human serum albumin (HSA) and 0.14% alpha-1-acid glycoprotein (AAG) in the culture media during the 72 hours of incubation. The IC50curves were plotted, and the IC50values 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 9 for synthesized compounds and Table 10 for comparative compounds. “ND” indicates results were not determined. Table 9. IC50results for synthesized compounds.No. NanoBRET TTK RPMI-8226 A375 CTG A375 CTG A375 CTG IC50 (nM) IC50 MTS IC50 IC50 (nM) IC50, Serum IC50, Serum d27 <10 ND ND 120.8 ND ND 28 ND ND ND 950.6 ND NDa e .50resu s or compara ve compoun s. Comparative NanoBRET IC50 TTK IC50 RPMI-8226 MTS IC50 A375 CTG IC50 No.Conclusion

[0301] In view of the foregoing, some non-limiting observations are as follows. In contrast to previously described Mps1 / TTK inhibitors, synthesized compounds described herein have a Formula I described above in which the R1and R2positions are not hydrogen. In contrast to the synthesized compounds described herein, comparative compounds have at least one –H in R1or R2. Comparative compound 1 has a hydrogen in both the R1and R2positions, respectively. Substitution of the R1position with a cycloalkyl compound, specifically a C4-C6 cycloalkyl,decreased IC50 values in the NanoBRET assay, the assay against TTK activity, and the cellular assays, indicating an increase in potency. Further, substitution at R2with pyrazole, thiazole, oxazole, or triazole moieties also similarly decreased IC50values.

[0302] Both synthesized and comparative compounds were evaluated for their activity against Mps1 / TTK and using antiproliferative assays. In contrast to the comparative compounds, the data indicate activity against Mps1 / TTK at or below 10 nM for the synthesized compounds. Cellular assay data also show the anti-proliferative potential of the compounds in cancer cell lines. References 1. Winey M, Goetsch L, Baum P, Byers B.1991. MPSl and MPS2: Novel yeast genes defining distinct steps of spindle pole body duplication. J. of Cell Biol.114:745-54 2. 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 8:351-9 3. 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.267:16000-6 4. 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 100:14875-80 5. 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 21:4361-72 6. Liu J, Cheng X, Zhang Y, Li S, Cui H, et al.2013. Phosphorylation of Mpsl by BRAF V600E prevents Mpsl degradation and contributes to chromosome instability in melanoma. Oncogene 32:713-23 7. Kasbek C, Yang, C.-H., and Fisk, H. A.2009. Mpsl as a link between centrosomes and genetic instability. Environmental and Molecular Mutagenesis 50:654-65 8. Kasbek C, Yang C H, Fisk H A.2010. Antizyme Restrains Centrosome Amplification by Regulating the Accumulation of Mpsl 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. Mal Biol Cell 18:4457-69 10. Wei J H, Chou Y F, Ou Y H, Yeh Y H, Tyan S W, et al.2005. TTK / hMpsl participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68. Journal of Biological Chemistry 280: 7748-57 11. Mills G B, Schmandt R, Mcgill M, Amendola A, Hill M, et al.1992. Expression of Ttk, a Novel Human Protein Kinase, Is Associated with Cell-Proliferation. Journal of Biological Chemistry 267: 16000-6 12. Schmandt R, Hill M, Amendola A, Mills G B, Hogg D.1994. Il-2-Induced Expression of Ttk, a Serine, Threonine, Tyrosine Kinase, Correlates with Cell-Cycle Progression. Journal of Immunology 152:96-105 13. Saal L H, Gruvberger-Saal 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: 102-7 14. Lingle W L, Barrett S L, Negron V C, D' Assoro A B, Boeneman K, et al.2002. Centrosome amplification drives chromosomal instability in breast tumor development. Proceedings of the National Academy of Sciences of the United States of America 99: 1978-83 15. Lingle W L, Salisbury J L.1999. Altered centrosome structure is associated with abnormal mitoses in human breast tumors. Am J Pathol 155:1941-51. 16. Lingle W L, Lutz W H, Ingle J N, Maihle 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 95:2950-5 17. 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 190:25-34 18. Kwiatkowski N, Jelluma N, Filippakopoulos P, Soundararajan 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 MPSl in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine. Journal of Cell Biology 190:73-87 20. 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 l 0:2267-75 21. Tannous BA, Kerami M, Van der Stoop PM, Kwiatkowski N, Wang J, et al.2013. Effects of the selective MPSl inhibitor MPSl-IN-3 on glioblastoma sensitivity to antimitotic drugs. Journal of the National Cancer Institute 105:1322-31 EXAMPLE 2

[0303] In this example, Compound 1 was co-crystallized with the TTK1 protein, and the crystal structure was determined.12 mg / mL TTK1 stock concentrations were used for crystallization trials. The protein concentrations were confirmed with a NanoDrop2000 using the classic absorbance at 280 nm method with the E and MW method (user-entered molar extinction and molecular weight method) for each protein component of the target complexes. The protein information is indicated in Table 11. The information for the compound used for cocrystallization is shown in Table 12. Table 11. Protein Information. Protein TTK1 .4 .6 0Table 12. Compound Information. Compound Compound 1

[0304] Compound 1 was dissolved in DMSO to a stock concentration of 79.6 mM. This was an opaque slurry and thus needed to be diluted by half to 40 mM in DMSO and heat treated at 37-42ºC to fully dissolve and clarify. Compound 1 was added in approximately 2-fold molar excess in solution to drive complexation with TTK1 for co-crystallization trials. The solution was gently mixed and incubated on ice for 3 hours to ensure complexation and full occupation of the binding site. The initial mixture was a precipitate slurry that dissipated once gently pipetted. This solution contained 2.2% DMSO. The complex solution was centrifuged at 14,000 rpm for 15 minutes at 4°C. The supernatant was used to set the co-crystallization trial in the Ligand Friendly Screen (Molecular Dimensions). The ARI 96-3 Intelliplate was used to set crystallization drops for the three complex targets at 12 mg / mL and two ratios of 1:1 (200:200 nL) and 2:1 (300:150 nL) complex to crystallization conditions. Co-crystallization trials for the complex was done using the Ligand Friendly Screen (L.F.S.) commercial screen using the ARI Crystal Gryphon drop-setting robot. The plate was incubated at 20°C and observed after the initial set-up, after the first 24 and 72 hours in the first week, then once a week thereafter. Conditions that formed the best crystal morphology were chosen to harvest crystal samples.

[0305] Sixteen samples of the TTK1-Compound 1 co-crystals that formed in the L.F.S. were harvested and sent for X-ray diffraction at the EMBL Synchrotron. Conditions that formed the best crystal morphology were chosen to harvest crystal samples. Additionally, apo-TTK1 crystals that formed in 0.2 M sodium nitrate, 20% w / v PEG 3350, and 10% v / v ethylene glycol were soaked with the compound to ensure co-crystals would have ligand occupancy. At least 2-3 crystals per unique crystallization condition (Figs.1A-B, 2A-B, 3A-B, and 4A-B, Table 13) were harvested. Crystals were washed in their freezing condition to remove surrounding satellite crystals and / or precipitation. Crystals were supplemented with 20% glycerol as a cryo-protectant and frozen with LN2. The addition of cryoprotectant did not change the morphology of crystal samples during manipulation and harvest. Table 13. Crystallization Conditions. Crystallization Protein Temperature Ratio of Well Condition10% v / v EG 2 TTK1 alone 20°C 1:1 0.2 M sodium M 0%to processing was successful with the average resolution within 2.3-2.7 Å. The cubic, diamond, and 3D plate co-crystals maintained integrity during manipulation and were easily identified on the cryo-loop during collection. Out of the 16 samples sent, 13 were collected during the session. This included apo-TTK1 samples that were soaked with 0.8 mM Compound 1 for 20 min before freezing.

[0307] Six datasets were processed using XIA2 / DIALS. Molecular replacement was performed with a previously solved structure of TTK1 (PDB: 4BHZ). Analysis of the initial structure models confirmed the presence of compound 1, including the apo-TTK1 crystal that incorporated Compound 1 only after a 20-minute soak.

[0308] The structure model of TTK1-Compound 1 was built using Coot. One molecule of TTK1 protein was initially placed into electron density in the asymmetric unit. This molecule of TTK1 was properly built by renumbering the residues, building omitted residues at the N- terminus and gaps throughout the sequence, ensuring that the two disordered regions were true and could not be built into, and finally, placing Compound 1 into its designated electron density at its binding site with its specific binding mode. Multiple iterations of the structure build were refined using PHENIX.refine which utilizes the refmac program until the models were completed and meets validation standards by Molprobity. TTK1-Compound 1 X-ray crystallographic data and refinement statistics are shown in Table 14. Values in parentheses are for the highest resolution shell. Figure 5A shows the ribbon diagram of the TTK1-Compound 1 complex with Compound 1 in stick representation. Figure 5B shows a zoomed-in perspective of Compound 1in its binding pocket. Figure 6A shows the TTK1–Compound 1 complex structure zoomed in to Compound 1 with electron density to show the detail of interacting residues. Figure 6B shows the TTK1–Compound 1 complex structure zoomed in to Compound 1 with electron density to show the detail of interacting residues with 90° rotation. Table 14. TTK1–Compound 1 X-ray crystallographic data and refinement statistics. Space group C 2221 Cell Dimensions 36 0 .99) / 28 2)Bond Angles 0.91 Molprobity Statistics:n are as follows:

[0310] Embodiment 1. A composition comprising a compound of Formula I: R4R3R5(Formula I),a solvate thereof, wherein R1is not H; R2is not H; R3is H, C1-C3alkyl, or a halide; R4is H or C1-C3 alkyl; when Z is N, R5is absent; when Z is C, R5is selected from the group consisting of morpholine, tetrahydrothiophene dioxide, -S(O)Me-NMe, an imidazole, a pyrazole, a triazole, a tetrazole, a thiacyclohexane dioxide, a thiomorpholine dioxide, and an E3-ligase binding moiety; R6is C1-C3alkyl, CN, SMe, XR8, or NHC(O)R9; R7is H or F; R8is C1-C3 alkyl or C1-C3 haloalkyl; R9is C1-C3alkyl or C1-C3alkenyl;W is NH or O; X is O, SO, or SO2; Y is CH, N, CF, or C-CH3; and Z is C or N.

[0311] Embodiment 2. The composition of Embodiment 1, wherein: Z is C; and R5is a triazole.

[0312] Embodiment 3. The composition of Embodiment 1 or Embodiment 2, wherein: the triazole is a 1,2,4-triazole selected from the group consisting of 4-methyl-1,2,4-triazole, 4- ethyl-1,2,4-triazole, 4-iso-propyl-1,2,4-triazole, and 4-n-propyl-1-2,4-triazole.

[0313] Embodiment 4. The composition of Embodiment 1, wherein: Z is C; and R5is a tetrazole.

[0314] Embodiment 5. The composition of Embodiment 1 or Embodiment 4, wherein: the tetrazole is a 1,2,3,4-tetrazole selected from the group consisting of 1-methyl-1,2,3,4-tetrazole, 1-ethyl-1,2,3,4-tetrazole, 1-iso-propyl-1,2,3,4-tetrazole, and 1-n-propyl-1,2,3,4-tetrazole.

[0315] Embodiment 6. The composition of any of Embodiments 1-5, wherein: R1is C4-C8 cycloalkyl.

[0316] Embodiment 7. The composition of any of Embodiments 1-6, wherein: R2is an unsubstituted pyrazole, a C1-C3 alkyl-substituted pyrazole, a C1-C3 haloalkyl-substituted pyrazole, an oxazole, a thiazole, or a triazole.

[0317] Embodiment 8. The composition of Embodiment 1, wherein: R1is C4-C8cycloalkyl; and R2is an unsubstituted pyrazole, a C1-C3 alkyl-substituted pyrazole, a C1-C3 haloalkyl-substituted pyrazole, an oxazole, a thiazole, or a triazole.

[0318] Embodiment 9. The composition of Embodiment 1, wherein: Z is C; R1is C4-C8 cycloalkyl; R2is an unsubstituted pyrazole, a C1-C3alkyl-substituted pyrazole, a C1-C3haloalkyl-substituted pyrazole, an oxazole, a thiazole, or a triazole; and R5is selected from the group consisting of an imidazole, a pyrazole, a triazole, and a tetrazole.

[0319] Embodiment 10. The composition of Embodiment 9, wherein: R5is a triazole.

[0320] Embodiment 11. The composition of Embodiment 10, wherein: the triazole is a 1,2,4-triazole selected from the group consisting of 4-methyl-1,2,4-triazole, 4- ethyl-1,2,4-triazole, 4-iso-propyl-1,2,4-triazole, and 4-n-propyl-1-2,4-triazole

[0321] Embodiment 12. The composition of Embodiment 9, wherein: R5is a tetrazole.

[0322] Embodiment 13. The composition of Embodiment 12, wherein: the tetrazole is a 1,2,3,4-tetrazole selected from the group consisting of 1-methyl-1,2,3,4-tetrazole, 1-ethyl-1,2,3,4-tetrazole, 1-iso-propyl-1,2,3,4-tetrazole, and 1-n-propyl-1,2,3,4-tetrazole.

[0323] Embodiment 14. The composition of Embodiment 12, wherein: R1is C4-C6cycloalkyl; and R2is a C1-C3alkyl-substituted pyrazole.

[0324] Embodiment 15. The composition of Embodiment 1, wherein the compound is of Formula II: R4R3R5(Formula II).15, wherein: R2is an unsubstituted pyrazole, a C1-C3alkyl-substituted pyrazole, a C1-C3haloalkyl-substituted pyrazole, an oxazole, a thiazole, or a triazole.

[0326] Embodiment 17. The composition of Embodiment 16, wherein: Z is C; and R5is morpholine.

[0327] Embodiment 18. The composition of Embodiment 1, wherein:Z is C; and R5is morpholine.

[0328] Embodiment 19. The composition of Embodiment 1, wherein: Z is C; and R5is tetrahydrothiophene dioxide.

[0329] Embodiment 20. The composition of Embodiment 1, wherein: Z is C; and R5is S(O)Me-NMe.

[0330] Embodiment 21. The composition of Embodiment 1, wherein: Z is C; and R5is an imidazole.

[0331] Embodiment 22. The composition of Embodiment 1, wherein: Z is C; and R5is a pyrazole.

[0332] Embodiment 23. The composition of Embodiment 1, wherein: Z is C; and R5is a thiacyclohexane dioxide.

[0333] Embodiment 24. The composition of Embodiment 1, wherein: Z is C; and R5is a thiomorpholine dioxide.

[0334] Embodiment 25. The composition of Embodiment 1, wherein: Z is C; and R5has the following structure: O (Formula III).Z is C; and R5has the following structure:O (Formula IV). 1, wherein:Z is C; and R5has the following structure: O (Formula V).Z is C; and R5has the following structure: O VI).Z is C; and R5has the following structure:(Formula VII). Embodiment 1, wherein: Z is C; and R5has the following structure: O CF3(Formula VIII).1, wherein: Z is C; and R5has the following structure: OCF3(Formula IX).1, wherein: Z is C; and R5has the following structure:O (Formula X), of Embodiment 1, wherein:Z is C; and R5has the following structure: O , or 1, wherein:Z is C; and R5has the following structure: O CF3(Formula XII).1, wherein: Z is C; and R5is an E3-ligase binding moiety.

[0345] Embodiment 36. The composition of Embodiment 34, wherein: the E3-ligase binding moiety comprises a linker moiety covalently bonded to a terminal moiety: L T,the linker moiety and T comprises the terminal moiety.

[0346] Embodiment 37. The composition of any of Embodiments 18-36, wherein: R1is C4-C8cycloalkyl.

[0347] Embodiment 38. The composition of any of Embodiments 18-37, wherein: R2is a pyrrole.

[0348] Embodiment 39. The composition of any of Embodiments 18-37, wherein: R2is a pyrazole.

[0349] Embodiment 40. The composition of Embodiment 39, wherein: R2is a C1-C3 alkyl-substituted pyrazole.

[0350] Embodiment 41. The composition of Embodiments 39, wherein: R2is a C1-C3haloalkyl-substituted pyrazole.

[0351] Embodiment 42. The composition of any of Embodiments 18-37, wherein: R2is an oxazole.

[0352] Embodiment 43. The composition of any of Embodiments 18-37, wherein: R2is a thiazole.

[0353] Embodiment 44. The composition of any of Embodiments 18-37, wherein: R2is a triazole.

[0354] Embodiment 45. A pharmaceutical composition comprising: the composition of any of Embodiments 1-44; and a pharmaceutically acceptable carrier.

[0355] Embodiment 46. 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 1-44; wherein the disease is cancer.

[0356] Embodiment 47. The method of Embodiment 46, wherein the disease is characterized by a biomarker of susceptibility to Mps1 / TTK inhibition.

[0357] Embodiment 48. A method of treating a patient in need of an inhibitor of protein kinase Mps1 / TTK, wherein the method comprises: determining the level of Mps1 / TTK protein and / or Mps1 / TTK mRNA in a cell of the patient, and administering a therapeutically effective amount of the composition of any of Embodiments 1-44 to the patient if the presence of Mps1 / TTK protein and / or Mps1 / TTK mRNA is detected;wherein the patient is a cancer patient.

[0358] Embodiment 49. The method of Embodiment 48, wherein the patient is a brain cancer, glioblastoma multiforme, head and neck cancers, colorec...

Claims

CLAIMS 1. A composition comprising a compound of Formula I: 43R R R5(Formula I),a solvate thereof, wherein R1is not H; R2is not H; R3is H, C1-C3alkyl, or a halide; R4is H or C1-C3alkyl; when Z is N, R5is absent; when Z is C, R5is selected from the group consisting of morpholine, tetrahydrothiophene dioxide, -S(O)Me-NMe, an imidazole, a pyrazole, a triazole, a tetrazole, a thiacyclohexane dioxide, a thiomorpholine dioxide, and an E3-ligase binding moiety; R6is C1-C3 alkyl, CN, SMe, XR8, or NHC(O)R9; R7is H or F; R8is C1-C3 alkyl or C1-C3 haloalkyl; R9is C1- C3 alkyl or C1-C3 alkenyl; W is NH or O; X is O, SO, or SO2; Y is CH, N, CF, or C-CH3; and Z is C or N.

2. The composition of claim 1, wherein: Z is C; and R5is a triazole.

3. The composition of claim 2, wherein: the triazole is a 1,2,4-triazole selected from the group consisting of 4-methyl-1,2,4-triazole, 4- ethyl-1,2,4-triazole, 4-iso-propyl-1,2,4-triazole, and 4-n-propyl-1-2,4-triazole.

4. The composition of claim 1, wherein: Z is C; and R5is a tetrazole.

5. The composition of claim 4, wherein: the tetrazole is a 1,2,3,4-tetrazole selected from the group consisting of 1-methyl-1,2,3,4- tetrazole, 1-ethyl-1,2,3,4-tetrazole, 1-iso-propyl-1,2,3,4-tetrazole, and 1-n-propyl-1,2,3,4- tetrazole.

6. The composition of claim 1, wherein: R1is C4-C8cycloalkyl.

7. The composition of claim 1, wherein: R2is an unsubstituted pyrazole, a C1-C3alkyl-substituted pyrazole, a C1-C3haloalkyl-substituted pyrazole, an oxazole, a thiazole, or a triazole.

8. The composition of claim 1, wherein: R1is C4-C8cycloalkyl; and R2is an unsubstituted pyrazole, a C1-C3 alkyl-substituted pyrazole, a C1-C3 haloalkyl-substituted pyrazole, an oxazole, a thiazole, or a triazole.

9. The composition of claim 1, wherein: Z is C; R1is C4-C8cycloalkyl; R2is an unsubstituted pyrazole, a C1-C3 alkyl-substituted pyrazole, a C1-C3 haloalkyl-substituted pyrazole, an oxazole, a thiazole, or a triazole; andR5is selected from the group consisting of an imidazole, a pyrazole, a triazole, and a tetrazole.

10. The composition of claim 9, wherein: R5is a triazole.

11. The composition of claim 10, wherein: the triazole is a 1,2,4-triazole selected from the group consisting of 4-methyl-1,2,4-triazole, 4- ethyl-1,2,4-triazole, 4-iso-propyl-1,2,4-triazole, and 4-n-propyl-1-2,4-triazole.

12. The composition of claim 9, wherein: R5is a tetrazole.

13. The composition of claim 12, wherein: the tetrazole is a 1,2,3,4-tetrazole selected from the group consisting of 1-methyl-1,2,3,4- tetrazole, 1-ethyl-1,2,3,4-tetrazole, 1-iso-propyl-1,2,3,4-tetrazole, and 1-n-propyl-1,2,3,4- tetrazole.

14. The composition of claim 12, wherein: R1is C4-C6cycloalkyl; and R2is a C1-C3 alkyl-substituted pyrazole.

15. The composition of claim 1, wherein the compound is of Formula II:R4R3R5(Formula II).

16. The composition of claim 15, wherein: R2is an unsubstituted pyrazole, a C1-C3 alkyl-substituted pyrazole, a C1-C3 haloalkyl-substituted pyrazole, an oxazole, a thiazole, or a triazole.

17. The composition of claim 16, wherein: Z is C; and R5is morpholine.

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

19. 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.

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

21. A method of treating a patient in need of an inhibitor of protein kinase Mps1 / TTK, wherein the method comprises: determining the level of Mps1 / TTK protein and / or Mps1 / 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 Mps1 / TTK protein and / or Mps1 / TTK mRNA is detected; wherein the patient is a cancer patient.

22. The method of claim 21, 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.

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