Amino pyrimidine and amino triazine analogs for treating cancer

Abstract

The disclosure provides for compounds, compositions, and methods for modulating c-MYC.

Description

AMINO PYRIMIDINE AND AMINO TRIAZINE ANALOGS FOR TREATING CANCERCROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 717,416 filed November 7, 2024; which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Originally identified as the cellular counterpart of the avian myelocytomatosis virus oncogene (v-myc), the proto-oncogene MY C, encodes a transcription factor that plays a crucial role in normal cellular functions, including regulating cell growth, proliferation, differentiation, and apoptosis. In normal cells, MY C activity is tightly controlled to ensure proper cellular responses to growth signals and environmental cues. However, in tumor cells, MYC is often dysregulated due to gene amplification, overexpression, or translocation, leading to uncontrolled cell proliferation, metabolic reprogramming, inhibition of differentiation, and evasion of apoptosis. MYC dysregulation contributes to pathology of breast, ovarian, colorectal, lung cancers, and many others. Consequently, MYC is a key focus for cancer research and drug development.

[0003] MYC regulation is a complex process involving multiple layers of control to ensure precise cellular functions. At the transcriptional level, MYC expression is tightly regulated by various signaling pathways and transcription factors. Post-transcriptionally, MYC mRNA stability and translation are modulated by RNA-binding proteins and microRNAs. Post-translationally, MYC protein stability and activity are regulated through phosphorylation, ubiquitination, and interactions with other proteins. Key phosphorylation sites, such as Ser62 and Thr58, play crucial roles in MYC's stability and degradation, with kinases like ERK and GSK-3β mediating these modifications. This multi-faceted regulation ensures that MY C activity is finely tuned to respond to cellular signals, and dysregulation at any level can contribute to oncogenesis. Given the complex regulation, targeting MYC directly or modulating its regulatory pathways are crucial to tackle MYC-driven pathologies.

[0004] Given the significant role of Myc in the development and progression of a wide variety of cancers, there is an urgent need for more potent Myc modulators, particularly c-Myc modulators.SUMMARY

[0005] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0006] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0007] In one aspect, disclosed herein is a method of modulating MY C (e.g., c-MY C) activity in a subject in need thereof, the method comprising administering to the subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein is a method of modulating c-MYC activity in a subject in need thereof, the method comprising administering to the subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0008] Also disclosed herein is a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is triple -negative breast cancer, ovarian cancer, or lung cancer.INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTIONDefinitions

[0010] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0011] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0012] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0013] ‘ ‘Oxo” refers to =0.

[0014] ‘ ‘Amino” refers to -NH2.

[0015] “Hydroxy” refers to -OH.

[0016] “Carboxyl” refers to -COOH.

[0017] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2 -methyl -2 -propyl, 2-methyl-l-butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2 -methyl- 1 -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3 -methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-1 -butyl, 2 -ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range, such as “Ci-Ce alkyl,” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a Ci-Ce alkyl, a Ci-C5 alkyl, a C1-C4 alkyl, or a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is independently optionally substituted with halogen.

[0018] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6 alkenyl,” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments,the alkenyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is independently optionally substituted with halogen.

[0019] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6 alkynyl,” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is independently optionally substituted with halogen.

[0020] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is independently optionally substituted with halogen.

[0021] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is independently optionally substituted with halogen.

[0022] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl,pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is independently optionally substituted with halogen.

[0023] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 - to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered fully saturated cycloalkyl or a 5 - to 6-membered cycloalkenyl.Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclofl. l.l]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, spiro[4.2]heptyl, spiro [4.3] octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is independently optionally substituted with halogen.

[0024] ‘ ‘Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. In some embodiments, halogen is chloro.

[0025] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3 -bromo-2 -fluoropropyl, 1,2-dibromoethyl, and the like.

[0026] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0027] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0028] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0029] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is independently optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, OH, -OMe, NH2, or -NO2. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, OH, or -OMe. In some embodiments, the heteroalkyl is independently optionally substituted with halogen.

[0030] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 8-membered partially or fully saturated ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered partially or fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered fully saturated ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydroforyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzoforan-l-yl, 3-oxo-l,3-dihydroisobenzoforan-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkylis a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF₃, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is independently optionally substituted with halogen.

[0031] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl is a 5 - to 10-membered ring comprising one, two, or three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5 -membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is independently optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF₃, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is independently optionally substituted with halogen. In some embodiments, the heteroaryl is independently optionally substituted with on oxo to form an N-oxide.

[0032] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc ).

[0033] The term “one or more” when referring to an optional substituent means that the subject group is independently optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is independently optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is independently optionally substituted with one, two, or three substituents. In some embodiments, the subject group is independently optionally substituted with one or two substituents. In some embodiments, the subject group is independently optionally substituted with one substituent. In some embodiments, the subject group is independently optionally substituted with two substituents. In some embodiments, the subject group is independently optionally substituted with three substituents.

[0034] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0035] ‘ ‘Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition subsequent to the initiation of apathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.

[0036] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

[0037] As used herein, a “disease or disorder associated with c-MY C” or, alternatively, “a c-MY C-mediated disease or disorder” means any disease or other deleterious condition in which c-MY C, or a mutant thereof, is known or suspected to play a role. Similarly, a “disease or disorder associated with MY C” or, alternatively, “a MY C-mediated disease or disorder” means any disease or other deleterious condition in which MYC (e.g., c-MYC), or a mutant thereof, is known or suspected to play a role.Compounds

[0038] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of a disease or disorder associated with c-MYC.

[0039] Disclosed herein is a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:R1is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;X2is N or CR2;R2is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;X3is N or CR3;R3is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;X4is N or CR8;R8is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;Ring A is aryl or heteroaryl;each R4is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R4on the same atom form an oxo;n is 0, 1, 2, 3, or 4;Y is N or CR5;R5is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;or R1and R5are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;or R1and one R4are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R;R6is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;Ring B is heteroaryl;each R7is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R7on the same atom form an oxo;m is 0, 1, 2, 3, or 4;each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl,Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl,Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; andL is absent or Ci-Csalkylene independently optionally substituted with one or more R;each Ris independently halogen, -CN, -OH, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, -S(=O)2NH2, - S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci- C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci-Cealkyl. Ci-Csalkoxy, Ci-Cshaloalkyl, Ci-Cshaloalkoxy, Ci-Cshydroxyalkyl, Ci-CCaminoalkyl. Ci-Cehctcroalkyl. Cs-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen;and / or two R on the same atom form an oxo.

[0040] In some embodiments of a compound of Formula (A), Ring C is. In someembodiments of a compound of Formula (A), Ring C is

[0041] In some embodiments of a compound of Formula (A), R4is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl. In some embodiments of a compound of Formula (A), R4is hydrogen, halogen, -CN, -OH, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl. In some embodiments of a compound of Formula (A), R4is hydrogen, halogen, -ORa, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (A), R4is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (A), R4is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (A), R4is hydrogen or halogen. In some embodiments of a compound of Formula (A), R4is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (A), R4is hydrogen.

[0042] In some embodiments of a compound of Formula (A), R1and R5are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R.

[0043] In some embodiments of a compound of Formula (A), R1and R5are taken together to form an heterocycloalkyl independently optionally substituted with one or more R.

[0044] In some embodiments of a compound of Formula (A), R1and R5are taken together to form a 6-to 8-membered ring heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, N, and S; and independently optionally substituted with one or more R.

[0045] In some embodiments of a compound of Formula (A), R1and R5are taken together to form a 7-to 8-membered ring heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, N, and S; and independently optionally substituted with one or more R.

[0046] In some embodiments of a compound of Formula (A), R1and R5are taken together to form a 7-to 8-membered ring heterocycloalkyl comprising one or two heteroatoms that are O; and independently optionally substituted with one or more R.

[0047] In some embodiments of a compound of Formula (A), R1and R5are taken together to form a 7-to 8-membered ring heterocycloalkyl comprising one or two heteroatoms that are O.

[0048] In some embodiments of a compound of Formula (A), R1and one R4are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R.

[0049] In some embodiments of a compound of Formula (A), R1and one R4are taken together to form an heterocycloalkyl independently optionally substituted with one or more R.

[0050] In some embodiments of a compound of Formula (A), R1and one R4are taken together to form a 6- to 8-membered ring heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, N, and S; and independently optionally substituted with one or more R.

[0051] In some embodiments of a compound of Formula (A), R1and one R4are taken together to form a 7- to 8-membered ring heterocycloalkyl comprising one or two heteroatoms selected from the group consisting of O, N, and S; and independently optionally substituted with one or more R.

[0052] In some embodiments of a compound of Formula (A), R1and one R4are taken together to form a 7- to 8-membered ring heterocycloalkyl comprising one or two heteroatoms that are O; and independently optionally substituted with one or more R.

[0053] In some embodiments of a compound of Formula (A), R1and one R4are taken together to form a 7- to 8-membered ring heterocycloalkyl comprising one or two heteroatoms that are O.

[0054] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:X1is N or CR1;R1is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;X2is N or CR2;R2is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;X3is N or CR3;R3is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;Ring A is aryl or heteroaryl;each R4is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R4on the same atom form an oxo;n is 0, 1, 2, 3, or 4;Y is N or CR5;R5is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;R6is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;Ring B is heteroaryl;each R7is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R7on the same atom form an oxo;m is 0, 1, 2, 3, or 4;each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl,Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl,Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; andL is absent or Ci-Csalkylene independently optionally substituted with one or more R;each Ris independently halogen, -CN, -OH, -S(=0)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, -S(=O)2NH2, - S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci- C3alkyl, -C(=0)0H, -C(=O)OCi-C3alkyl, -C(=0)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2Ci-Cealkyl. Ci-Csalkoxy, Ci-Cshaloalkyl, Ci-Cshaloalkoxy, Ci-Cshydroxyalkyl, Ci-CCaminoalkyl. Ci-Cehctcroalkyl. Cs-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen;and / or two R on the same atom form an oxo.

[0055] In some embodiments, the compound is not

[0056] In some embodiments of a compound of Formula (A) or (I), X1is N. In some embodiments of a compound of Formula (I), X1is CR1.

[0057] In some embodiments of a compound of Formula (A) or (I), X2is N. In some embodiments of a compound of Formula (I), X2is CR2.

[0058] In some embodiments of a compound of Formula (A) or (I), X3is N. In some embodiments of a compound of Formula (I), X3is CR3.

[0059] In some embodiments of a compound of Formula (A) or (I), Y is N. In some embodiments of a compound of Formula (I), Y is CR5.

[0060] In some embodiments of a compound of Formula (I), the compound is of Formula (la):Formula (la).

[0061] In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R1is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl.

[0062] In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R1is hydrogen, halogen, -CN, -OH, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl.

[0063] In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R1is hydrogen, halogen, -ORa, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0064] In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R1is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R1is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R1is hydrogen or halogen. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R1is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R1is hydrogen.

[0065] In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R1is hydrogen, -OH, -ORa, or Ci-Cealkyl.

[0066] In some embodiments of a compound of Formula (A), (I), or (la), R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl.

[0067] In some embodiments of a compound of Formula (A), (I), or (la), R2is hydrogen, halogen, -CN, -OH, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl.

[0068] In some embodiments of a compound of Formula (A), (I), or (la), R2is hydrogen, halogen, -ORa, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0069] In some embodiments of a compound of Formula (A), (I), or (la), R2is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (A), (I), or (la), R2is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), or (la), R2is hydrogen or halogen. In some embodiments of a compound of Formula (A), (I), or (la), R2is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), or (la), R2is hydrogen.

[0070] In some embodiments of a compound of Formula (A), (I), or (la), R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl.

[0071] In some embodiments of a compound of Formula (A), (I), or (la), R3is hydrogen, halogen, -CN, -OH, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl.

[0072] In some embodiments of a compound of Formula (A), (I), or (la), R3is hydrogen, halogen, -ORa, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0073] In some embodiments of a compound of Formula (A), (I), or (la), R3is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (A), (I), or (la), R3is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), or (la), R3is hydrogen or halogen. In some embodiments of a compound of Formula (A), (I), or (la), R3is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), or (la), R3is hydrogen.

[0074] In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R5is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl.

[0075] In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R5is hydrogen, halogen, -CN, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Cehydroxyalkyl.

[0076] In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R5is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R5is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R5is hydrogen or halogen. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R5is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R5is hydrogen. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R5is Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), (la), or (Ic), R5is halogen or Ci-Cealkyl.

[0077] In some embodiments of a compound of Formula (A), (I), or (la), R6is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (A), (I), or (la),, R6is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), or (Ia)„ R6is hydrogen or halogen. In some embodiments of a compound of Formula (A), (I), or (Ia)„ R6is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (A), (I), or (Ia)„ R6is hydrogen.

[0078] In some embodiments of a compound of Formula (I) or (la), the compound is of Formula (lb):Formula (lb).

[0079] In some embodiments of a compound of Formula (I) or (la), the compound is of Formula (Ic):Formula (Ic).

[0082] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is phenyl, a 5- to 6-membered monocyclic heteroaryl, or a 8- to 12-membered bicyclic heteroaryl.

[0083] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is phenyl.

[0084] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is 5- to 6-membered monocyclic heteroaryl.

[0085] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is 5- to 6-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

[0086] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is 6-membered monocyclic heteroaryl comprising one or two heteroatoms that are N.

[0087] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is pyridinyl, pyrimidinyl, or pyrazinyl.

[0088] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is pyridinyl or pyrimidinyl.

[0089] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is 5-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

[0090] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is 5-membered monocyclic heteroaryl comprising one or two heteroatoms selected from the group consisting ofN, O, and S.

[0091] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is 5-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting ofN and O.

[0092] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is 5-membered monocyclic heteroaryl comprising one or two heteroatoms selected from the group consisting ofN and O.

[0093] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, ortriazolyl.

[0094] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is pyrazolyl.

[0095] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is an 8- to 12-membered bicyclic heteroaryl.

[0096] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is an 8- to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting ofN, O, and S.

[0097] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is an 8- to 10-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting ofN, O, and S.

[0098] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is an 8- to 10-membered bicyclic heteroaryl comprising one, two, or three heteroatoms selected from the group consisting ofN, O, and S.

[0099] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is an 8- to 10-membered bicyclic heteroaryl comprising one or two heteroatoms selected from the group consisting of N, O, and S

[0100] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is an 8- to 10-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting ofN and O.

[0101] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is an 8- to 10-membered bicyclic heteroaryl comprising one, two or three heteroatoms selected from the group consisting ofN and O.

[0102] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is an 8- to 10-membered bicyclic heteroaryl comprising one or two heteroatoms selected from the group consisting of N and O.

[0103] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is a 9-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms that are N.

[0104] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is a 9-membered bicyclic heteroaryl comprising one, two, or three heteroatoms that are N.

[0105] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is a 9-membered bicyclic heteroaryl comprising one or two heteroatoms that are N.

[0106] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is indazolyl, pyrrolopyridinyl, 3,4-dihydropyridooxazinyl, or dioxolopyridinyl.

[0107] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring A is dihydropyrazolooxazinyl, tetrahydropyrazolopyrazinyl, dihydropyrrolopyrazolyl, or dihydropyrazolooxazolyl.In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring

[0109] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently halogen, -CN, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0110] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently halogen, -CN, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0111] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently halogen, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)ORb, Ci-C6alkyl, Ci-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0112] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently -ORa, -S(=O)Ra, -S(=O)2Ra, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)ORb, Ci-C6alkyl, Ci-C6haloalkyl, or -L-heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R.

[0113] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently -ORa, -S(=O)Ra, -NRbC(=O)NRcRd, Ci-C6alkyl, or heterocycloalkyl.

[0114] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently -ORaor Ci-C6alkyl.

[0115] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently Ci-C6alkyl.

[0116] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently -ORa. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently -S(=O)Ra. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently -NRbC(=O)NRcRd. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently Ci-C6alkyl. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R4is independently heterocycloalkyl.

[0117] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), n is 0, 1, or 2. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), n is 1 or 2. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), n is 0 or 1. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), n is 0. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), n is 1.(R4)n - ( A

[0119] In some embodiments of a compound of Formula ( ' is

[0120] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5- or 6-membered monocyclic heteroaryl or a 8 - to 12-membered bicyclic heteroaryl.

[0121] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5- or 6-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S or a 8- to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of O, S, and N.

[0122] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5- or 6-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S or a 8- to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of O and N.

[0123] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5- or 6-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

[0124] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5- or 6-membered monocyclic heteroaryl comprising one, two, or three heteroatoms selected from the group consisting ofN, O, and S.

[0125] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5- or 6-membered monocyclic heteroaryl comprising one or two heteroatoms selected from the group consisting of N, O, and S.

[0126] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 6-membered monocyclic heteroaryl comprising one or two heteroatoms that are N.

[0127] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is pyridinyl, pyrimidinyl, or pyrazinyl.

[0128] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is pyridinyl.

[0129] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is pyridinyl or pyrimidinyl.

[0130] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

[0131] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5-membered monocyclic heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0132] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5-membered monocyclic heteroaryl comprising one or two heteroatoms selected from the group consisting ofN, O, and S.

[0133] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting ofN and O.

[0134] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5-membered monocyclic heteroaryl comprising one, two, or three heteroatoms selected from the group consisting ofN and O.

[0135] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is 5-membered monocyclic heteroaryl comprising one or two heteroatoms selected from the group consisting ofN and O.

[0136] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, ortriazolyl.

[0137] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is pyrazolyl.

[0138] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is a 8- to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting ofN, O, and S. In some embodiments, the bicyclic heteroaryl comprises an aromatic ring (e.g., phenyl or 5-6 membered heteroaryl) fused with a heterocycloalkyl ring (e.g., the bicyclic heteroaryl iscomprising two fused aromatic rings (e.g., the bicyclic heteroaryl is

[0139] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is an 8- to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of O and N.

[0140] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is an 8- to 10-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting ofN, O, and S.

[0141] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), Ring B is an 8- to 10-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N and O.

[0144] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently halogen, -CN, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R.

[0145] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently halogen, -CN, -OH, -ORa, -SRa, -S(=O)Ra, -S(=O)2Ra, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6heteroalkyl, C2-C6alkenyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, alkenyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R.

[0146] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently halogen, -CN, -OH, -ORa, -NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments, the cycloalkyl is a C3-C6membered cycloalkyl, which is optionally substituted with one or more R. In some embodiments, the cycloalkyl is cyclopropyl, which is optionally substituted with one or more R. In some embodiments, the cycloalkyl is cyclopropyl, which is optionally substituted with one or more halogen. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl, which is optionally substituted with one or more R. In some embodiments, the heterocycloalkyl is oxetane, which is optionally substituted with one or more R.

[0147] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently halogen, -ORa, Ci-Cealkyl, Ci-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0148] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently -ORa, Ci-C6alkyl, Ci-C6haloalkyl, or cycloalkyl.

[0149] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently -ORa, Ci-C6alkyl, Ci-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R.

[0150] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently -ORa, Ci-C6alkyl, Ci-C6haloalkyl, cycloalkyl, or heterocycloalkyl.

[0151] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently -ORa. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently Ci-C6alkyl. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently Ci-C6haloalkyl. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently cycloalkyl. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), each R7is independently heterocycloalkyl.

[0152] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 1 and R7is -ORa. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 1 and R7is Ci-C6alkyl. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 1 and R7is Ci-C6haloalkyl. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 1 and R7is cycloalkyl. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 1 and R7is cyclopropyl.

[0153] In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 0, 1, or 2. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 1 or 2. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 0 or 1. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 0. In some embodiments of a compound of Formula (A), (I), or (la)-(Ic), m is 1.

[0156] In some embodiments of a compound disclosed herein, each Rais independently Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, eachRais independently Ci-C6alkyl, Ci-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-C6alkyl,Ci-C6haloalkyl, or -L-cycloalkyl; wherein each alkyl, or cycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-C6alkyl or -L-cycloalkyl; wherein each alkyl, or cycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-C6alkyl or -L-cycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-C6alkyl or cycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-C6alkyl.

[0157] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-C6alkyl or Ci-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-C6alkyl, or Ci-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or Ci-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently Ci-C6alkyl.

[0158] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-C6heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-C6alkyl or Ci-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-C6alkyl, or Ci-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or Ci-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-C6alkyl.

[0159] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.

[0160] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is absent or -CH2-. In some embodiments of a compound disclosed herein, L is Ci-Csalkylene independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2- or -CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2-.

[0161] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHC1-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, or Ci-C3heteroalkyl; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C3-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each Ris independently halogen, -CN, -OH, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, Ci-C3haloalkyl, Ci-C3haloalkoxy, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, or Ci-C3heteroalkyl; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, Ci-C3alkoxy, or Ci-C3haloalkyl; and / or two Ron the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, or Ci-C3alkyl; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, or Ci-C3alkyl; and / or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen or Ci-C3alkyl; and / or two R on the same atom form an oxo.

[0162] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0163] In some embodiments the compound disclosed herein is selected from a compound found in table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.Table 1Ex. StructureEx. Structure* stereochemistry assigned arbitrarily.Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0164] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers havedistinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled compounds

[0165] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes, such as3H and14C, are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred fortheir ease of preparation and detectability. Further, substitution with heavy isotopes, such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents. In some embodiments, one or more -CH3 in a compound disclosed herein has been replaced by a -CDs.

[0166] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, biolumine scent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0167] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0168] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, toform a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0169] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0170] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene sulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4 ’-methylenebis-(3 -hydroxy-2 -ene-1 -carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0171] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrativeexamples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1. C4 alkyl)4 hydroxide, and the like.

[0172] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0173] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0174] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Tautomers

[0175] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.Method of Treatment

[0176] Disclosed herein is a method of modulating c-MYC activity in a subject in need thereof, comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0177] Also disclosed herein is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is triple -negative breast cancer, ovarian cancer, or lung cancer.Breast Cancer

[0178] Two large genomic studies of breast cancers identified MYC amplifications in 26.6% and 21.9% of samples analyzed, respectively. Breast cancer can be divided into distinct subtypes based on histological and molecular classifications that have prognostic and therapeutic values. MYC amplification and MYC pathway activation are hallmark features of the basal subtype (55.6% with MYC amplification), a subtype associated with aggressive disease and poor prognosis, and lacking targeted therapeutic options. MYC amplification is also present in a substantial portion of other subtypes representing receptor-positive disease: HER2 -positive (34.1%), luminal B (31.5%), and luminal A (12.8%). MYC amplification is also associated with poor overall survival and poor recurrence-free rates, with MYC copy number gains increasing post-treatment in some instances.Ovarian and Endometrial Cancers

[0179] Ovarian and endometrial cancers are two common cancers in women, and across both cancers, patients with advanced stage, high-grade subtypes have a high incidence of mortality. TCGA analyses of ovarian carcinomas (557 samples) and endometrial carcinomas (373 samples) showed that MYC is amplified in 30.7% and 10.8% of tumors, respectively. In ovarian cancer, MYC amplification is correlated with inactivation in the breast and ovarian cancer susceptibility protein (BRCA) and retinoblastoma-associated protein (RBI) pathways; in endometrial cancer, MYC amplification is associated with low estrogen receptor (ER) / FOXA1 activity and TP53 mutations. The high-grade subtype of both ovarian and endometrial cancers harbors a high frequency oiMYC amplification, along with TP53, BRCA1 / 2 mutations, and RBI loss.Colorectal Cancer

[0180] Colorectal cancer is a leading cause of cancer mortality in the world, and can be subdivided into four consensus molecular subtypes (CMS 1-4), as defined by transcriptomics with different genetic and biological features. TCGA analysis (220 samples) and a larger meta-analysis (503 samples) identified the frequency of MY C amplification at 6% overall, while frequencies in the different subtypes ranged from 5% to 11%. The MYC transcriptional program is specifically enriched in the epithelial CMS2 subtype, with activated WNT pathway signaling, which has been shown to transcriptionally activate MYC expression. Furthermore, frequent inactivating mutations of the E3 ubiquitin ligase FBXW7 and transcriptional regulators SMAD andARIDlA may result in increased protein stability and mRNA transcription, respectively.Prostate Cancer

[0181] Prostate cancer is one of the most common adult malignancies, with a subset of men progressing to the development of aggressive metastatic disease. In a TCGA study of 333 primary prostate carcinomas, MYC focal amplifications were reported in 8% of the tumors. A second study of 277 nonindolent localized prostate cancers identified recurrent CNAs, including amplification of MYC, and deletion of PTEN, TP53, and NKX3-1. Overall, these studies indicated evidence of MYC family involvement in prostate cancer. Patients with metastatic castration-resistant prostate cancer (CRPC) treated androgen-directed therapies, including enzalutamide and abiraterone acetate, eventually developresistance characterized by low or absent androgen receptor (AR) expression and a neuroendocrine (CRPC-NE) phenotype. In addition to the loss of RBI (70% of CRPC-NE) and mutations or deletions of TP53 (67% of CRPC-NE), somatic allele-specific CNAs of MYC andMYCN were evident in 45% and 15% of CRPC-NE, respectively. This suggests a strong evolutionary divergence in the development of neuroendocrine prostate cancer from the prostate adenocarcinoma, and hints at differential importance of MYC amplification in these subtypes.Lung Cancer

[0182] Lung cancer can be characterized by two histopathological classes: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC); the latter being the predominant class. The SCLC cell of origin has been proposed to be of neuroendocrine character, while NSCLC comprises squamous cell carcinoma (SCC), which originates from the proximal airway and adenocarcinoma that arises from distal regions and classifies into multiple subtypes. A TCGA study of 178 SCC lung patient samples provided insights into the genomic and epigenomic status of these tumors, with an average of 323 CNAs, 360 exonic mutations, and 165 genomic rearrangements per tumor reported, including MYC w MYCL amplifications observed at a frequency of 5% and 4%, respectively.

[0183] In a recent study, 183 NSCLC adenocarcinomas were profiled with whole -exome / genome sequencing. Among the 25 genetic alterations identified, MYC amplification was observed in 31% of cases. In another comprehensive analysis of lung adenocarcinoma, somatic CNAs exhibited a very similar profile with significant MYC amplification. Recurrent loss-of-fiinction mutations in the MGA gene, which encodes a MAX interactor, are observed in 8% of lung adenocarcinoma specimens and appear to be mutually exclusive with MYC amplification. In another study that comparatively analyzed 660 lung adenocarcinomas and 484 SCC cases MYC amplification was observed in both adenocarcinoma and SCC tumors, with MYCL significantly more amplified in lung adenocarcinoma.Pancreatic Cancer

[0184] In a study of over 500 pancreatic ductal adenocarcinoma (PDAC) samples, MYC amplification was observed in 14% of PDAC and was enriched in the aggressive adenosquamous histological subtype. MYC copy number was also an independent marker of poor outcome, with an overall survival of less than 10 months in the high copy number cohort.Renal Clear Cell Carcinoma and Adrenal Cell Carcinoma

[0185] Renal cell carcinoma (RCC) is the most common type of kidney cancer, with clear cell RCC (ccRCC) representing approximately 75% of all RCCs. In a study by Sato et al., more than 100 ccRCC cases were analyzed by whole-genome, whole-exome, and RNA sequencing, as well as array-based gene expression, copy number and methylation analyses, finding significant focal alterations at 20 loci, including copy number gains in MYC in 23% of the cases. TCGA analysis investigated more than 400 tumors and observed amplifications in MYC in 15% of cases.Medulloblastoma

[0186] Medulloblastoma is a pediatric malignant brain tumor that can be classified into four distinct subtypes as the result of transcriptional profiling: two that are associated with deregulation in theWNT / p-catenin and sonic hedgehog (SHH) signaling pathways, and two less well-characterized subtypes, termed Groups 3 and 4. MYC and its family members have been implicated in all four subtypes, with MYC amplification and elevated MYC mRNA expression predominantly observed in Group 3. In a genomic study of 827 tumors, 16.7% of Group 3 tumors were AfTC-amplified. Three other studies showed 3-17.6% of cases with A TC amplifications in Group 3. In this subtype, MYC expression may also be elevated through additional non-coding mechanisms: (1) PVT1 -MYC fusions exist in 60% of A TC-amplified cases, and the long non-coding RNA PVT1 creates a positive feedback loop to maintain high MY C expression; (2) the MYC amplicon contains a medulloblastoma-specific enhancer (high histone H3K27 acetylation clusters) to enforce high MYC expression.

[0187] MYC and MYCN are target genes of the WNT / p-catenin and SHH pathways, respectively, with elevated mRNA expression seen in these two subtypes. The SHH subtype also harbors AfTGV-amplified (7.7-16.7%) and MYCL -amplified tumors (2.3%), although the biological role of L-MYC in medulloblastoma is unknown. Group 4 also has 5-10.5% of cases with MYCN amplification. This, along with N-MYC-driven mouse models that give rise to Group 4-like medulloblastoma, implicates N-MYC in the oncogenesis of this subtype.

[0188] In a genomic study comparing primary and metastatic tumor samples, MYC amplification was present in matched primary tumors and metastases, whereas MYCN amplification was only present in primary tumors but not their matched metastases. This suggests that MYC and N-MYC may be involved in different stages of the oncogenic process. Increased frequencies oiMYC anAMYCN amplifications also emerged in tumors of relapsed patients compared to a diagnosis. The aggressive nature of these relapsed tumors may be driven by the combined acquisition of MYC / MYCN amplifications and TP 53 mutations. The diversity of MYC family deregulation in medulloblastoma illustrates that, while MYC family members can all drive oncogenesis, they may have distinct roles in giving rise to cancers of different molecular and clinical phenotypes.Neuroblastoma

[0189] Neuroblastoma is a childhood malignancy that afflicts the developing sympathetic nervous system and accounts for up to 10% of all childhood cancers, with 80% of neuroblastomas occurring before the age of five. Early work identified MYCN amplification in approximately 40% of patient cases, correlating with advanced disease (stage III or IV) and poor prognosis. The majority of neuroblastoma patients can be classified into three distinct genomic types: type A tumors with only numerical changes of whole chromosomes, but without any detectable structural rearrangement; type B tumors characterized by the presence of only partial chromosome imbalances (excluding MYCN amplification) in the absence of any numerical chromosomal aberrations; and type C tumors that harbor MYCN amplification without numerical chromosomal aberrations. Two additional genomic types, D and E, account for mixed profiles with respect to their segmental or numerical aberrations and MYCN amplification. Recently, Westermann et al. examined the relationship between MYC wAMYCN amplification in neuroblastoma, which are known to transcriptionally repress of one another. They found that MYC expression in MYCN amplifiedneuroblastoma is not generally observed, and when MY C is over-expressed, it is dominant over N-MY C expression.

[0190] Recently, a number of whole-genome and whole-exome sequencing studies have broadened our understanding of the role MYCN amplification plays in this cancer. The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative analyzed specimens from 240 cases by a combination of whole-exome and whole-genome sequencing, where amplification of the MYCN oncogene was observed in 32% of the cases (confirmed by fluorescence in situ hybridization) and a recurrent MYCN mutation was observed in 1.7% of the cases. Another study, consisting of a wholegenome sequencing data of 87 neuroblastoma specimens identified chromothripsis, a local shredding of chromosomes, in 18% of late stage neuroblastomas associated with poor outcomes. These chromothripsis-related structural aberrations were associated with amplification oYMYCN. and in one tumor, resulted in MYC amplification and overexpression.

[0191] A study examining 217 neuroblastoma tumors by whole-genome sequencing, including 75 high-risk tumors, found that most high-risk tumors harbored either MYCN amplification, TERT rearrangements or ATRX mutations, all of which can contribute to telomere lengthening and could be useful in the molecular classification of high-risk neuroblastoma. MYCN is a known transcriptional activator of TERT, yet MYCN amplifications were mutually exclusive with TERT rearrangements, as well as ATRX alterations, a gene associated with alternate lengthening of telomeres, suggesting that these alterations may share a similar role in neuroblastoma.Dosing

[0192] In certain embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by any suitable methods.Routes of Administration

[0193] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.Pharmaceutical Compositions / Formulations

[0194] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0195] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.Combination

[0196] Disclosed herein are methods of treating a disease or disorder associated with c-MY C using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0197] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.EXAMPLES

[0198] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0199] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or bycombining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.Example 1:

[0200] Step 1: To a solution of 2-Chloro-4-(2-chloropyridin-4-yl)pyrimidine (600 mg, 2.65 mmol, 1.00 eq) and 2-(4-methylpiperazin-l-yl)pyridin-4-amine (765 mg, 3.98 mmol, 1.50 eq) in dioxane (15 mL) was added t-BuOK (596 mg, 5.31 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 60 °C for 3 h. LC-MS showed that 2-Chloro-4-(2-chloropyridin-4-yl)pyrimidine was consumed and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was diluted with H2O (5 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, DCM / MeOH = 1 / 0 to 1 / 1) to afford the product.

[0201] Step 2: To a solution of the N-substituted aminopyrimidine intermediate (110 mg, 288 pmol, 1.00 eq) and l-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (108 mg, 432 pmol, 1.50 eq) in dioxane (1 mL) and H2O (0.25 mL) were added Pd(dppf)C12 (21.1 mg, 28.8 pmol, 0.100 eq) and K2CO3 (79.6 mg, 576 pmol, 2.00 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 12 h under N2. LC-MS showed that the N-substituted aminopyrimidine intermediate was consumed and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was diluted with H2O (3 mL) and extracted with EtOAc (3 mL * 3). The combined organic layers were washed with brine (3 mL * 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 25% B over 5.0 min) to afford the final product (43.7 mg, 80.6 pmol, 28.0% yield, 95.1% purity, 1 FA). 'HNMR DMSO-d6400 MHz 5 = ppm 10.02 (s, 1H), 8.76 (d, J= 5.2 Hz, 1H), 8.72 (d, J= 5.2 Hz, 1H), 8.62 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 7.97 (d, J = 5.6 Hz, 1H), 7.88 (dd, J= 5.2, 1.6 Hz, 1H), 7.70 (d, J= 5.2 Hz, 1H), 7.58 (d, J= 1.2 Hz,1H), 7.05 (d, J= 5.6 Hz, 1H), 5.66 (quin, J= 12 Hz, 1H), 4.99 - 4.94 (m, 4H), 3.49 (br s, 4H), 2.37 (br s, 4H), 2.20 (s, 3H). LCMS (ESI+): m / z 470.2 (M+H)+.Example 2:

[0202] To a solution of the chloropyridine starting material (110 mg, 288 pmol, 1.00 eq) and 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-[l,3]dioxolo[4,5-b]pyridine (108 mg, 432 pmol, 1.50 eq) in dioxane (1 mL) and H2O (0.25 mL) were added Pd(dppf)C12 (21.1 mg, 28.8 pmol, 0.100 eq) and K2CO3 (79.6 mg, 576 pmol, 2.00 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 12 h under N2. LC-MS showed that chloropyridine starting material was consumed and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (3 mL) and extracted with EtOAc (3 mL * 3). The combined organic layers were washed with brine (3 mL * 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge 150 * 25 mm 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 30% - 60% B over 9.0 min) to afford the final product (18.7 mg, 39.9 pmol, 13.9% yield, 100% purity). 'H NMR DMSO-de 400 MHz 5 = ppm 10.04 (s, 1H), 8.85 (d, J= 5.2 Hz, 1H), 8.78 (d, J= 5.2 Hz, 1H), 8.56 (s, 1H), 8.47 (d, J= 1.8 Hz, 1H), 8.05 (dd, J = 5.2, 1.2 Hz, 1H), 7.98 (d, J= 2.0 Hz, 1H), 7.96 (d, J= 5.6 Hz, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.58 (s, 1H), 7.03 (dd, J= 5.6, 1.6 Hz, 1H), 6.25 (s, 2H), 3.41 (t, J= 4.8 Hz, 4H), 2.32 (t, J= 4.8 Hz, 4H), 2.19 (s, 3H). LCMS (ESI+): m / z 469.1 (M+H)Example 3:pos2, 34,dioxane, H2O, 25-80 °C, 1 h

[0203] Step 1: To a solution of 2-(trifluoromethyl)pyridin-4-amine (861 mg, 5.31 mmol, 1.00 eq) in 2-Me THF (20 mL) was added NaH (425 mg, 10.6 mmol, 60.0% purity, 2.00 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 0.5 h, followed by the addition of 2-Chloro-4-(2-chloropyridin-4-yl)pyrimidine (1.20 g, 5.31 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 90 °C for 12 h, quenched with saturated aqueous NH4Cl (20 mL) at 0 °C, and extracted with EtOAc (20 mL * 3). The combinedorganic layers were washed with brine (20 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (SiO₂, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to afford the product (300 mg, 853 pmol, 16.1% yield). ’HNMR DMSO-de 400 MHz 5 = ppm 10.79 (s, 1H), 8.90 (d, J= 5.2 Hz, 1H), 8.69 (d, J= 5.2 Hz, 1H), 8.61 (br d, J= 5.6 Hz, 1H), 8.53 (d, J= 1.2 Hz, 1H), 8.26 (s, 1H), 8.17 (brd, J= 5.2 Hz, 1H), 7.98 (br d, J= 4.0 Hz, 1H), 7.86 (d, J= 5.2 Hz, 1H)

[0204] Step 2: To a solution of the chloropyridine starting material (150 mg, 426 pmol,1.00 eq) in dioxane (2 mL) and H2O (1 mL) were added l-methyl-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea (141 mg, 512 pmol, 1.20 eq), K3PO4 (181 mg, 853 pmol, 2.00 eq) and XPHOS-PD-G2 (33.6 mg, 42.7 pmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 1 h. LCMS showed that chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% PA) - MeCN]; gradient:20% - 50% B over 8.0 min) to afford the final product (31.8 mg, 67.6 pmol, 15.8% yield, 98.9% purity). 'HNMR DMSO-d6400 MHz 5 = ppm 10.75 (s, 1H), 8.88 (d, J= 4.8 Hz, 1H), 8.84 (d, J= 4.8 Hz, 1H), 8.78 (s, 1H), 8.59 (d, J= 5.6 Hz, 1H), 8.56 - 8.51 (m, 2H), 8.10 (d, J= 8.8 Hz, 2H), 8.04 - 7.97 (m, 2H), 7.93 (d, J= 5.2 Hz, 1H), 7.58 (d, J= 8.8 Hz, 2H), 6.18 - 6.07 (m, 1H), 2.68 (d, J= 4.4 Hz, 3H). LCMS (ESI+): m / z 466.1 (M+H)+.Example 4:

[0205] Step l: To amixture of the bromide starting material (10.0 g, 36.6 mmol, 1.00 eq) in DME (250 mL) were added 3-iodooxetane (20.2 g, 110 mmol, 3.00 eq), TTMSS (13.7 g, 54.9 mmol, 16.9 mL, 1.50 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;dichloronickel (729 mg, 1.83 mmol, 0.0500 eq), Na₂CO₃ (7.76 g, 73.2 mmol, 2.00 eq) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(l+);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (411 mg, 366 pmol, 0.0100 eq) under N2. The mixture was pumped by Pump 1 (SI, Pl, 40.4 mL / min) to flow reactor 1 (FLR1, FEP, Coils reactor, 3.175(1 / 8”) mm, 54.95 mL, 395 nm, 200 W * 2, 55 °C). The residence time of flow reactor 1 was (FLR1, 1.36 min). After 8 h, LCMS showed that bromide starting material was not consumed completely and a peak with the desired mass was detected. The mixture wasdiluted with H2O (500 mL) and extracted with EtOAc (200 mL * 3). The combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to afford the product (5.50 g, 22.0 mmol, 55.0% yield).

[0206] Step 2: A solution of the Boc protected amine starting material (5.50 g, 22.0 mmol, 1.00 eq) and TFA (15.4 g, 135 mmol, 10.0 mL, 6.13 eq) in DCM (30 mL) was stirred at 25 °C for 2 h. LC-MS showed that Boc protected amine starting material was consumed completely and one major peak with the desired mass was detected. The mixture was adjusted pH to 7 with Na₂CO₃, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18250 * 70 * 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 0% - 10% B over 20.0 min) to afford the product (2.40 g, 16.0 mmol, 72.7% yield).

[0207] Step 3: To a solution of the amine starting material (300 mg, 2.00 mmol, 1.00 eq) and 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (497 mg, 2.20 mmol, 1.10 eq) in dioxane (8 mL) were added Cs₂CO₃ (1.30 g, 4.00 mmol, 2.00 eq), Xantphos (231 mg, 399 pmol, 0.200 eq) and Pd(OAc)2 (45.0 mg, 200 pmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 12 h under N2, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 * 40 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 20% - 55% B over 8.0 min) to afford the product (140 mg, 412 pmol, 20.6% yield). 'HNMR DMSO-d6400 MHz 5 = ppm 10.35 (s, 1H), 8.79 (d, J= 5.2 Hz, 1H), 8.64 (d, J= 5.0 Hz, 1H), 8.41 (d, J= 5.6 Hz, 1H), 8.22 (s, 1H), 8.14 (dd, J= 5.2, 1.4 Hz, 1H), 7.87 (d, J= 1.8 Hz, 1H), 7.74 (d, J = 5.2 Hz, 1H), 7.63 (dd, J = 5.6, 2.0 Hz, 1H), 4.92 (dd, J = 8.6, 5.6 Hz, 2H), 4.80 (dd, J= 6.6, 5.8 Hz, 2H), 4.35 - 4.31 (m, 1H).

[0208] Step 4: To a solution of the chloropyridine starting material (140 mg, 412 pmol, 1.00 eq) and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (309 mg, 1.24 mmol, 3.00 eq) in dioxane (5 mL) and H2O (1 mL) were added K2CO3 (114 mg, 825 pmol, 2.00 eq) and Pd(dppf)C12 (30.2 mg, 41.3 pmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 2 h under N2, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 30% B over 8.0 min) to afford the final product (11.7 mg, 26.5 pmol, 6.42% yield, 96.7% purity). ’H NMR DMSO-de 400 MHz 5 = ppm 10.31 (s, 1H), 8.80 (d, J= 5.2 Hz, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.63 (s, 1H), 8.43 (d, J= 5.6 Hz, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 7.92 (dd, J= 5.2, 1.6 Hz, 1H), 7.90 (d, J= 1.8 Hz, 1H), 7.78 (d, J= 5.2 Hz, 1H), 7.71 (dd, J= 5.8, 2.0 Hz, 1H), 5.67 (quin, J= 6.8 Hz, 1H), 4.97 - 4.94 (m, 4H), 4.90 (dd, J= 8.6, 5.4 Hz, 2H), 4.81 (dd, J= 6.8, 5.4 Hz, 2H), 4.35 - 4.33 (m, 1H). LCMS (ESI+): m / z 428.1 (M+H)+.Example 5

[0209] Step 1: To a solution of 2-cyclopropylpyridin-4-amine (475 mg, 3.54 mmol, 1.00 eq) in 2-MeTHF (10 mL) was added NaH (283 mg, 7.08 mmol, 60.0% purity, 2.00 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 0.5 h, followed by the additional of chloropyrimidine starting material (800 mg, 3.54 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 90 °C for 12 h, quenched with saturated aqueous ammonium chloride solution (10 mL) at 0 °C, then diluted with H2O (20 mL), and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over ISfeSCh, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (SiC>2, Petroleum ether: Ethyl acetate = 1 / 0 to 1 / 1) to afford the product (150 mg, 463 pmol, 13.1% yield).

[0210] Step 2: To a solution of chloropyridine starting material (120 mg, 371 pmol, 1.00 eq) in THF (2 mL) and H2O (0.5 mL) were added l-methyl-3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea (123 mg, 445 pmol, 1.20 eq), K3PO4 (157 mg, 741 pmol, 2.00 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (29.2 mg, 37.2 pmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 12 h, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2 % FA) - MeCN]; gradient: 5% - 35% B over 8.0 min) to afford the final product (13.5 mg, 30.9 pmol, 8.33% yield, 100.0% purity). ’HNMR DMSO-de 400 MHz 5 = ppm 10.22 (s, 1H), 8.83 (d, J= 4.8 Hz, 1H), 8.80 (d, J= 5.2 Hz, 1H), 8.75 (s, 1H), 8.57 (s, 1H), 8.24 (d, J = 5.6 Hz, 1H), 8.10 (br d, J= 8.8 Hz, 2H), 8.01 - 7.96 (m, 1H), 7.89 (s, 1H), 7.83 (d, J= 5.2 Hz, 1H), 7.60 - 7.53 (m, 3H), 6.10 (br d, J= 4.4 Hz, 1H), 2.68 (d, J= 4.4 Hz, 3H), 2.08 - 1.96 (m, 1H), 0.93 (br d, J= 5.8 Hz, 4H). LCMS (ESI+): m / z 438.2 (M+H)+.Example 6:

[0211] To a solution of chloropyridine starting material (120 mg, 341 pmol, 1.00 eq) in dioxane (4 mL) and H2O (1 mL) were added l-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (102 mg, 409 pmol, 1.20 eq), K3PO4 (145 mg, 682 pmol, 2.00 eq), Pd(dppf)C12 (25.0 mg, 34.1 pmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 1 h. LCMS showed that chloropyridinestarting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 3 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 15% - 45% B over 8.0 min) to give the final product (41.2 mg, 91.9 pmol, 26.9% yield, 98.0% purity). ’H NMR DMSO-de 400 MHz 5 = ppm 10.75 (s, 1H), 8.88 (d, J= 5.2 Hz, 1H), 8.75 (d, J= 5.2 Hz, 1H), 8.64 (s, 1H), 8.60 (d, J = 5.6 Hz, 1H), 8.51 (d, J= 1.6 Hz, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.06 - 8.00 (m, 1H), 7.95 - 7.90 (m, 1H), 7.88 (d, J = 5.2 Hz, 1H), 5.67 (quin, J = 6.8 Hz, 1H), 5.04 - 4.91 (m, 4H). LCMS (ESI+): m / z 440.1 (M+H)+.Example 7 and Example 8:

[0212] To a solution of chloropyridine starting material (200 mg, 618 pmol, 1.00 eq) in dioxane (3.5 mb) and H2O (0.5 mb) were added Pd(dppf)C12 (45.2 mg, 61.8 pmol, 0.100 eq), K2CO3 (213 mg, 1.54 mmol, 2.50 eq) and 4,4,5,5-tetramethyl-2-(4-methylsulfinylphenyl)-l,3-dioxolane (182 mg, 679 pmol, 1.10 eq) at 25 °C. The mixture was stirred at 90 °C for 1 h under N2 atmosphere. LC-MS showed that chloropyridine starting material was consumed and one main peak with the desired mass was detected. The mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC: (CD24-WePure Biotech XPT Cl 8 (150 * 25 mm, 7 um); flow rate: 25 mL / min; gradient: 23% -53%, B over 10 min; mobile phase A: H2O (10 mM NH4HCO3), mobile phase B: acetonitrile) to afford the product (160 mg, 373 pmol, 60.3% yield, 99.6% purity). The racemate (160 mg, 373 pmol, 99.6% purity) was separated by SFC (column: SFC-OJ-30-DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 um); mobile phase: [CCE-MeOH (0.1% NH3H2O)]; B%: 47%, isocratic elution mode) to afford the final product (S configuration) (63.4 mg, 144 pmol, 38.7% yield, 97.1% purity) and the final product (R configuration) (61.4 mg, 142 pmol, 38.2% yield, 99.2% purity). Two isomers were assigned arbitrarily.

[0213] ’HNMR DMSO-d6400 MHz 5 = ppm 10.21 (s, 1H), 8.93 (d, J= 5.2 Hz, 1H), 8.81 (d, J= 5.2 Hz, 1H), 8.70 (s, 1H), 8.40 (d, J= 8.4 Hz, 2H), 8.23 (d, J= 5.6 Hz, 1H), 8.13 (dd, J = 5.2, 1.6 Hz, 1H), 7.86 - 7.83 (m, 4H), 7.58 (dd, J = 5.6, 2.0 Hz, 1H), 2.82 (s, 3H), 2.03 - 1.96 (m, 1H), 0.91 (s, 3H), 0.90 -0.89 (m, 1H). LCMS (ESI+): m / z 428.2 (M+H)+.

[0214] ' H NMR DMSO-d6400 MHz 5 = ppm 10.21 (s, 1H), 8.93 (d, J= 5.2 Hz, 1H), 8.83 (d, J = 5.2 Hz, 1H), 8.70 (s, 1H), 8.39 (d, J= 8.4 Hz, 2H), 8.23 (d, J= 5.6 Hz, 1H), 8.13 (dd, J = 5.2, 1.6 Hz, 1H),7.86 - 7.82 (m, 4H), 7.58 (dd, J= 5.6, 2.0 Hz, 1H), 2.82 (s, 3H), 2.02 - 1.96 (m, 1H), 0.91 (s, 3H), 0.90 -0.89 (m, 1H). LCMS (ESI+): m / z 428.2 (M+H)+.Example 9 and Example 10:

[0215] Step 1: To a solution of 2-methyl-2,3-dihydrobenzofuran-5-amine (660 mg, 4.42 mmol, 1.00 eq) in 2-Me THF (20 mL) was added NaH (212 mg, 5.31 mmol, 60.0% purity, 1.20 eq) at 0 °C. The mixture was stirred at 25 °C for 30 min under N2 atmosphere, followed by the addition of chloropyrimidine starting material (1.00 g, 4.42 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 90 °C for 16 h under N2 atmosphere. LCMS showed that chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 2 / 3 to 3 / 7) to afford the product (430 mg, 1.25 mmol, 28.3% yield, 98.6% purity).1H NMR 400 MHz DMSO-d6400 MHz 5 = ppm 9.59 (s, 1H), 8.60 (dd, J = 52, 1.8 Hz, 2H), 8.17 (s, 1H), 8.09 (dd, J = 52, 1.4 Hz, 1H), 7.60 (d, J= 1.8 Hz, 1H), 7.49 (d, J = 5.0 Hz, 1H), 7.36 (dd, J= 8.6, 2.2 Hz, 1H), 6.68 (d, J= 8.6 Hz, 1H), 4.92 - 4.86 (m, 1H), 3.34 - 3.29 (m, 1H), 2.79 (dd, J= 15.8, 7.6 Hz, 1H), 1.38 (d, J= 6.4 Hz, 3H).

[0216] Step 2: A mixture of the chloropyridine starting material (430 mg, 1.25 mmol, 1.00 eq), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (313 mg, 1.25 mmol, 1.00 eq), Pd(dppf)C12 (91.5 mg, 125 pmol, 0.100 eq) and K2CO3 (346 mg, 2.50 mmol, 2.00 eq) in dioxane (8 mL) and H2O (2 mL) was degassed and purged with N23 times at 25 °C. The mixture was stirred at 80 °C for 2 h under N2. LC-MS showed that chloropyridine starting material was consumed completely and one main peak with the desired mass was detected. The mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA condition; column: CD05-Phenomenex Luna C18 100 * 40 mm * 10 um; mobile phase: [H2O(0.225% FA) - MeCN]; gradient: 28% - 58% B over 13.0 min) to afford the product (200 mg, 412 pmol, 33.0% yield, 87.9% purity).Step 3: The racemate was separated by SFC: (column: SFC-IK-30-DAICEL CHIRAL IK (250 mm * 30 mm, 10 um); mobile phase: [CO2 - MeOH (0.1% NH3H2O)]; B%: 45%, isocratic elution mode) to afford the final product (R configuration) (59.4 mg, 139 pmol, 44.9% yield, 99.7% purity) and the final product (S configuration) (44.5 mg, 104 pmol, 33.6% yield, 99.5% purity). Two isomers were assigned arbitrarily.

[0217] 'HNMR DMSO-d6400 MHz 5 = ppm 9.54 (s, 1H), 8.69 (d, J= 5.2 Hz, 1H), 8.66 - 8.60 (m, 2H), 8.32 (s, 1H), 8.24 (s, 1H), 7.86 (dd, J= 5.2, 1.2 Hz, 1H), 7.66 (s, 1H), 7.52 (d, J= 5.2 Hz, 1H), 7.44 (dd, J= 8.4, 1.6 Hz, 1H), 6.70 (d, J= 8.4 Hz, 1H), 5.66 (quin, J= 6.8 Hz, 1H), 4.99 - 4.90 (m, 5H), 3.34 -3.30 (m, 1H), 2.81 (dd, J= 15.6, 7.6 Hz, 1H), 1.39 (d, J= 6.4 Hz, 3H). LCMS (ESI+): m / z 427.2 (M+H)+.

[0218] 'HNMR DMSO-d6400 MHz 5 = ppm 9.54 (s, 1H), 8.69 (d, J= 5.2 Hz, 1H), 8.66 - 8.56 (m, 2H), 8.32 (s, 1H), 8.24 (s, 1H), 7.86 (dd, J= 5.2, 1.6 Hz, 1H), 7.66 (s, 1H), 7.52 (d, J= 5.2 Hz, 1H), 7.44 (dd, J= 8.4, 1.6 Hz, 1H), 6.70 (d, J= 8.4 Hz, 1H), 5.66 (quin, J= 6.8 Hz, 1H), 4.99 - 4.90 (m, 5H), 3.34 -3.30 (m, 1H), 2.81 (dd, J= 15.6, 7.6 Hz, 1H), 1.39 (d, J= 6.4 Hz, 3H). LCMS (ESI+): m / z 427.2 (M+H)+.,

[0219] Step 1: To a solution of the chloropyridine starting material (20.0 mg, 61.8 pmol, 1.00 eq) and tributyl-(l-tritylimidazol-4-yl)stannane (74.1 mg, 124 pmol, 2.00 eq) in toluene (1 mL) was added Pd(PPh3)4 (7.14 mg, 6.18 pmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 120 °C for 12 h under N2, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 * 40 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 75% - 98% B over 8.0 min) to afford the final product (8.70 mg, 14.0 pmol, 22.7% yield, 96.3% purity). 'HNMR DMSO-d6400 MHz 5 = ppm 10.23 (s, 1H), 8.76 (d, J= 5.2 Hz, 1H), 8.73 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.20 (d, J= 5.6Hz, 1H), 7.96 (s, 1H), 7.91 (dd, J= 5.2, 1.4 Hz, 1H), 7.68 (d, J= 5.2 Hz, 1H), 7.56 (s, 1H), 7.48 - 7.42 (m, 11H), 7.18 (br d, J= 7.2 Hz, 6H), 2.18 - 2.14 (m, 1H), 0.89 - 0.83 (m, 4H). LCMS (ESI+): m / z 356.1 (M-Trt+H).Example 12:

[0220] To a solution of the chloropyridine starting material (100 mg, 309 pmol, 1.00 eq) and l-(oxetan-3-yl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (100 mg, 402 pmol, 1.30 eq) in dioxane (2 mL) and H2O (0.5 mL) were added Pd(dppf)C12 (22.6 mg, 30.9 pmol, 0.100 eq) and K2CO3 (85.4 mg,618 pmol, 2.00 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 12 h under N2, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 5% - 35% B over 8.0 min) to afford the final product (90.3 mg, 203 pmol, 65.6% yield, 97.5% purity, 0.5 FA salt). ’H NMR DMSO-d6400 MHz 5 = ppm 10.21 (s, 1H), 8.78 (dd, J= 9.0, 5.2 Hz, 2H), 8.71 (s, 1H), 8.24 (d, J = 5.6 Hz, 1H), 8.14 (s, 0.5H), 8.03 (d, J= 2.4 Hz, 1H), 8.01 - 8.00 (m, 1H), 7.73 (s, 1H), 7.70 (d, J = 5.2 Hz, 2H), 6.96 (d, J= 2.4 Hz, 1H), 5.68 (quin, J= 7.0 Hz, 1H), 5.03 - 4.97 (m, 4H), 2.00 (quin, J= 6.4 Hz, 1H), 0.90 (d, J= 6.4 Hz, 4H). LCMS (ESI+): m / z 412.1 (M+H)+.Example 13:

[0221] Step 1: To a solution of l-ethyl-3-methyl-pyrazol-4-amine (277 mg, 2.21 mmol, 1.00 eq) in 2-methyltetrahydrofuran (10 mL) was added NaH (106 mg, 2.65 mmol, 60.0% purity, 1.20 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h under N2, followed by the additional of chloropyrimidine starting material (500 mg, 2.21 mmol, 1.00 eq). The mixture was stirred at 90 °C for 16 h under N2, quenched with water (40 mL) at 0 °C, and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate, from 100 / 0 to 65 / 35) to afford the product (250 mg, 662 pmol, 29.9% yield, 83.3% purity). 'H NMR DMSO-d6400 MHz 5 = ppm 8.58 (t, J= 6.0 Hz, 2H), 8.14 (br s, 1H), 8.06 (br d, J= 3.8 Hz, 1H), 7.90 (br s, 1H), 7.62 - 7.55 (m, 1H), 7.44 (d, J= 5.0 Hz, 1H), 4.04 (q, J= 7.2 Hz, 2H), 2.13 (s, 3H), 1.36 (t, J= 7.2 Hz, 3H).

[0222] Step 2: To a solution of the chloropyridine starting material (80.0 mg, 212 pmol, 1.00 eq) in dioxane (1.5 mL) and H2O (0.3 mL) were added Pd(dppf)C12 (15.5 mg, 21.2 pmol, 0.100 eq), K2CO3 (73.2 mg, 529 pmol, 2.50 eq) and l-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (53.0 mg, 212 pmol, 1.00 eq) at 25 °C. The mixture was stirred at 90 °C for 1 h under N2, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC: (CD24-WePure Biotech XPT C18 (150 * 25 mm, 7 um); flow rate: 25 mL / min; gradient: 13% - 43%, B over 10 min; mobile phase A: H2O (10 mM NH4HCO3), mobile phase B: MeCN) to afford the final product (17.4 mg, 42.5 pmol, 20.1% yield, 98.4% purity). 'H NMR DMSO-d6400 MHz 5 = ppm 8.94 (br s, 1H), 8.68 (d, J= 5.0 Hz, 1H), 8.60 (s, 1H), 8.57 (d, J= 5.0 Hz, 1H), 8.30 (s, 1H), 8.24 (s, 1H), 7.95 (br s, 1H), 7.84 (br d, J= 4.8 Hz, 1H), 7.47 (d, J= 5.0 Hz, 1H), 5.65 (quin, J= 6.8 Hz, 1H), 4.99 - 4.93 (m, 4H), 4.06 (q, J= 7.2 Hz, 2H), 2.15 (s, 3H), 1.36 (t, J= 7.2 Hz, 3H). LCMS (ESI+): m / z 403.2 (M+H)+.Example 14:

[0223] Step 1: To a mixture of 2-(dimethylamino)ethanol (4.51 g, 50.6 mmol, 5.08 mL, 1.30 eq) in toluene (50 mL) was added NaH (3.89 g, 97.2 mmol, 60.0% purity, 2.50 eq) at 25 °C. The mixture was stirred at 25 °C for 40 min, followed by the addition of the chloropyridine starting material (5.00 g, 38.9 mmol, 1.00 eq) at 25 °C. The mixture was stirred at 110 °C for 12 h under N2, quenched with water (20 mL) at 0 °C, and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Si O2- PE / EtOAc = 1 / 0 to 0 / 1, then PE / MeOH = 0 / 1) to afford the crude product (1.20 g) as a brown solid. 'HNMR CDCh 400 MHz 5 = ppm 7.81 (d, J= 5.6 Hz, 1H), 6.20 (dd, J= 5.6, 2.0 Hz, 1H), 5.99 (d, J= 2.0 Hz, 1H), 4.36 (t, J= 5.6 Hz, 2H), 4.06 (br s, 2H), 2.70 (t, J= 5.6 Hz, 2H), 2.33 (s, 6H).

[0224] Step 2: To a solution of the amine starting material (1.10 g, 6.07 mmol, 1.00 eq) in THF (20 mL) was added NaHMDS (1.00 M, 7.28 mL, 1.20 eq) at -10 °C under N2. The mixture was stirred at 25 °C for 0.1 h, followed by the addition of 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (1.37 g, 6.07 mmol, 1.00 eq). The mixture was stirred at 25 °C for 0.9 h, quenched with saturated NH4CI solution (10 mL) at 0 °C, and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM / MeOH = 5 / 1) to afford the product (500 mg, 1.13 mmol, 18.6% yield, 83.6% purity).

[0225] Step 3: To a solution of the chloropyridine starting material (80.0 mg, 216 pmol, 1.00 eq) and lH-pyrazol-3-ylboronic acid (145 mg, 1.29 mmol, 6.00 eq) in H2O (16 mL) and EtOH (80 mL) were added K3PO4 (91.6 mg, 431 pmol, 2.00 eq) and BrettPhos Pd G3 (19.6 mg, 21.6 pmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 12 h under N2, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 urn; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 30% B over 8.0 min) to afford the final product (51.6 mg, 117 pmol, 54.1% yield, 99.4% purity, 0.8 FA salt). 'HNMR DMSO-d6400 MHz 5 = ppm 10.34 (s, 1H), 8.81 (dd, J= 5.2, 4.0 Hz, 2H), 8.69 (s, 1H), 8.21 (s, 0.8H), 8.00 - 7.99 (m, 2H), 7.83 (d, J= 1.6 Hz, 1H), 7.73 (d, J = 5.2 Hz, 1H), 7.46 (d, J= 1.6 Hz, 1H), 7.39 (dd, J= 5.8, 1.8 Hz, 1H), 6.95 (s, 1H), 4.36 (t, J= 5.6 Hz, 2H), 2.71 (t, J= 5.6 Hz, 2H), 2.28 (s, 6H). LCMS (ESI+): m / z 403.2 (M+H)+.Example 15:

[0226] To a solution of the chloropyridine starting material (80.0 mg, 235 pmol, 1.00 eq) and 1H-pyrazol-3-ylboronic acid (263 mg, 2.35 mmol, 10.0 eq) in dioxane (80 mL) and H2O (16 mL) were added K3PO4 (100 mg, 471 pmol, 2.00 eq) and XPhos-Pd-G2 (18.5 mg, 23.5 pmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 100 °C for 12 h under N2, then concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase:[H2O (0.2% FA) - MeCN]; gradient: 1% - 35% B over 8.0 min) to afford the final product (12.9 mg, 32.7 pmol, 13.9% yield, 100% purity, 0.5 FA salt). 'HNMR DMSO-d6400 MHz 5 = ppm 10.36 (s, 1H), 8.79 (d, J= 5.0 Hz, 2H), 8.70 (br s, 1H), 8.42 (d, J= 5.6 Hz, 1H), 8.14 (s, 0.5H), 8.02 (dd, J= 5.2, 1.2 Hz, 1H), 7.92 (d, J= 1.6 Hz, 1H), 7.85 (br s, 1H), 7.74 (d, J= 5.2 Hz, 1H), 7.69 (dd, J= 5.8, 2.0 Hz, 1H), 6.94 (d, J= 1.4 Hz, 1H), 4.90 (dd, J= 8.8, 5.6 Hz, 2H), 4.82 - 4.79 (m, 2H), 4.40 - 4.34 (m, 1H). LCMS (ESI+): m / z 372.1 (M+H)+.Example 16:

[0227] A mixture of the Trt protected starting material (280 mg, 468 pmol, 1.00 eq) in HCI / EtOAc (4.00 M, 5.00 mL, 42.7 eq) was stirred at 25 °C for 2 h. LC-MS showed that Trt protected starting material was consumed and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 10% - 25% B over 8.0 min) to afford the final product (10.5 mg, 25.6 pmol, 96.6% purity, 0.9 FA salt). 'HNMR DMSO-d6400 MHz 5 = ppm 10.23 (s, 1H), 8.77 (br d, J= 4.8 Hz, 1H), 8.71 - 8.70 (m, 2H), 8.21 (br d, J= 5.6 Hz, 1H), 8.16 (br s, 1H), 7.98 (br s, 0.9H), 7.90 (br d, J= 4.4 Hz, 1H), 7.78 (br s, 2H), 7.69 (br d, J= 4.8 Hz, 1H), 7.51 (br d, J= 5.2 Hz, 1H), 2.19 - 2.16 (m, 1H), 0.92 (d, J= 6.4 Hz, 4H). LCMS (ESI+): m / z 356.1 (M+H)+.Example 17:

[0228] Step 1: To a solution of the alcohol starting material (1.00 g, 6.57 mmol, 1.00 eq) in DMF (20 mL) were added imidazole (537 mg, 7.89 mmol, 1.20 eq) and TBSC1 (1.09 g, 7.23 mmol, 890 pL, 1.10 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h, diluted with saturated aqueous Na₂CO₃ solution to pH = 13, and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO₂, DCM / MeOH = 10 / 1) to afford the product (400 mg, 1.50 mmol, 22.9% yield). 'H NMR CDCh 400 MHz 5 = ppm 8.12 (d, J= 5.8 Hz, 1H), 6.44 - 6.41 (m, 2H), 3.67 (t, J= 6.3 Hz, 2H), 2.73 (dd, J= 8.8, 7.0 Hz, 2H), 1.96 - 1.91 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H).

[0229] Step 2: To a solution of the amine starting material (380 mg, 1.43 mmol, 1.00 eq) and 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (387 mg, 1.71 mmol, 1.20 eq) in THF (6 mL) was added NaHMDS (1.00 M, 2.14 mL, 1.50 eq) dropwise at -10 °C under N2. The mixture was stirred at 25 °C for 1 h under N2, diluted with saturated aqueous NH4CI solution (10 mL) at 0 °C, and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM / MeOH = 5 / 1) to afford the product (370 mg, 811 pmol, 56.9% yield).

[0230] Step 3: To a solution of the chloropyridine starting material (360 mg, 789 pmol, 1.00 eq) and 1H-pyrazol-3-ylboronic acid (707 mg, 6.32 mmol, 8.00 eq) in EtOH (5 mL) and H2O (1 mL) were added K3PO4 (335 mg, 1.58 mmol, 2.00 eq) and BrettPhos Pd G3 (71.6 mg, 79.0 pmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 2 h under N2, then concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM / MeOH = 5 / 1) to afford the product (80.0 mg, 164 pmol, 20.8% yield).

[0231] Step 4: A solution of the TBS protected starting material (75.0 mg, 154 pmol, 1.00 eq) in THF (2 mL) and HC1 (1.00 M, 0.400 mL, 2.60 eq) was stirred at 25 °C for 0.5 h. LC-MS showed that TBS protected starting material was consumed completely and one main peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was triturated with THF (3 mL * 2), filtered, and the filter cake was dried in vacuo to afford the final product (29.4 mg, 71.2 pmol, 46.3% yield, 99.2% purity, HC1 salt). 'H NMR DMSO-d6400 MHz 5 = ppm 14.70 (br s, 1H), 11.55 (s, 1H), 8.98 (d, J= 5.0 Hz, 1H), 8.84 (d, J= 5.4 Hz, 1H), 8.80 (s, 1H), 8.52 (br d, J= 6.4 Hz, 1H), 8.35 (br s, 1H), 8.12 (dd, J= 5.4, 1.6 Hz, 1H), 8.04 (br d, J= 5.2 Hz, 2H), 7.88 (d, J= 2.0 Hz, 1H), 7.02 (d, J= 2.4 Hz, 1H), 3.47 (br t, J= 6.0 Hz, 2H), 3.02 (br t, J= 7.6 Hz, 2H), 1.94 - 1.87 (m, 2H). LCMS (ESI+): m / z 374.1 (M+H)+.Example 18:

[0232] Step 1: To a solution of 2-cyclopropylpyridin-4-amine (712 mg, 5.31 mmol, 1.00 eq) in 2-methyltetrahydrofuran (12 mL) was added NaH (255 mg, 6.37 mmol, 60.0% purity, 1.20 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min, followed by the addition 2-Chloro-4-(2-chloropyridin-4-yl)pyrimidine (1.20 g, 5.31 mmol, 1.00 eq) at 25 °C under N2. The resulting mixture was stirred at 90 °C for 12 h under N2, quenched by addition of H2O (10 mL) at 0 °C and extracted with EtOAc (20 mL * 5). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to afford the product (300 mg, crude).

[0233] Step 2: To a solution of chloropyridine starting material (200 mg, 618 pmol, 1.00 eq) and 1-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (206 mg, 741 pmol, 1.20 eq) in THF (3 mL) and H2O (0.6 mL) were added Xphos-Pd-G2 (48.6 mg, 61.8 pmol, 0.100 eq) and K3PO4 (262 mg, 1.24 mmol, 2.00 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 12 h under N2, then concentrated under reduced pressure. The residue was diluted with H2O (2 mL) and extracted with EtOAc (3 mL * 3). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 1 / 1) to give the product (80.0 mg, 159 pmol, 25.7% yield, 87.1% purity).

[0234] Step 3: A solution of the THP protected product (70.0 mg, 159 pmol, 1.00 eq) in TFA (0.25 mL) and DCM (0.5 mL) was stirred at 25 °C for 8 h. The mixture was adjusted pH to 7 with DIPEA and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 30% B over 8.0 min) to afford the product (18.5 mg, 50.6 pmol, 31.8% yield, 97.2% purity). ’HNMR DMSO-de 400MHz 5 = ppm 13.08 (s, 1H), 10.28 (br s, 1H), 8.79 (d, J= 5.2 Hz, 1H), 8.73 (br s, 1H), 8.23 (d, J= 5.6 Hz, 1H), 8.13 (s, 1H), 8.01 (br d, J= 5.2 Hz, 1H), 7.91 (s, 1H), 7.82 (br s, 1H), 7.73 (d, J= 5.2 Hz, 1H), 7.56 (br d, J= 5.6 Hz, 1H), 6.93 (s, 1H), 2.09 - 2.05 (m, 1H), 0.95 - 0.90 (m, 4H). LCMS (ESI+): m / z 356.1 (M+H)+.Example 19:

[0235] Step 1: To a solution of 2-cyclopropylpyridin-4-amine (15.7 g, 117 mmol, 1.00 eq) and tert-butyl (NZ)-N-[(tert-butoxycarbonylamino)-methylsulfanyl-methylene]carbamate (37.4 g, 129 mmol, 1.10 eq) in DMF (500 mL) were added HgCl₂ (33.8 g, 124 mmol, 6.21 m, 1.06 eq) and TEA (37.9 g, 374 mmol, 52.1 mb, 3.20 eq) at 25 °C. The mixture was stirred at 60 °C for 12 h, diluted with H2O (800 mb) and extracted with EtOAc (100 mL * 4). The combined organic layers were washed with brine (300 mL* 4), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to afford the product (25.4 g, 23.0 mmol, 19.7% yield, 34.1% purity). ’HNMR CDCh 400 MHz 5 = ppm 11.58 (br s, 1H), 10.46 (br s, 1H), 8.33 (d, J= 6.0 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.38 (s, 1H), 2.05 - 1.99 (m, 1H), 1.54 (brd, J= 6.0 Hz, 18H), 0.97 (br dd, J= 6.8, 2.0 Hz, 4H).Step 2: A solution of the pyridine starting material (25.4 g, 67.5 mmol, 1.00 eq) in TFA (192 g, 1.69 mol, 125 mL, 25.0 eq) and DCM (60 mL) was stirred at 25 °C for 2 h, then concentrated under reduced pressure. The residue was diluted with MeCN (50 mL) and then adjusted pH to 7 with K2CO3. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the crude product (44.5 g).

[0236] Step 3: To a solution of (E)-l-(2-chloro-4-pyridyl)-3-(dimethylamino)prop-2-en-l-one (14.0 g, 66.5 mmol, 1.00 eq) and the pyridine starting material (43.0 g, 244 mmol, 3.67 eq) in DMA (400 mL) was added EtONa (9.04 g, 132 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 12 h, poured into ice water (1500 mL) and filtered. The filter cake was triturated with EtOAc (20 mL) at 25 °C for 10 min three times to afford the product (6.20 g, 19.2 mmol, 28.8% yield). 'H NMR DMSO-de 400 MHz 5 = ppm 10.21 (s, 1H), 8.79 (d, J= 4.8 Hz, 1H), 8.65 (d, J= 5.2 Hz, 1H), 8.23 - 8.14 (m, 2H), 8.13 (d, J = 5.0 Hz, 1H), 7.76 (d, J= 1.2 Hz, 1H), 7.73 (d, J= 5.2 Hz, 1H), 7.53 (dd, J= 5.6, 1.6 Hz, 1H), 2.02 - 1.99 (m, 1H), 0.92 - 0.91 (m, 4H).

[0237] Step 4: To a solution of the chloro-pyridine starting material (6.80 g, 21.0 mmol, 1.00 eq) and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (6.83 g, 27.3 mmol, 1.30 eq) in dioxane (1000 mL) and H2O (250 mL) were added Pd(dppf)C12 (1.54 g, 2.10 mmol, 0.100 eq) and K2CO3 (5.81 g, 42.0 mmol, 2.00 eq) at 25 °C under N2. The mixture was stirred at 80 °C for 12 h under N2, then concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with EtOAc (200 mL * 5). The combined organic layers were washed with brine (100 mL * 2), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si O2- Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1), then the crude product was triturated with THF (20 mL) at 25 °C for 30 min three times. The obtained product was dissolved in H2O (50 mL) and THF (100 mL) and concentrated under reduced pressure to remove THF. The aqueous phase was lyophilized to afford the product (4.06 g, 9.66 mmol, 46.0% yield, 97.9% purity). ’H NMR DMSO-d6400 MHz 5 = ppm 10.20 (s, 1H), 8.79 (d, J = 5.2 Hz, 1H), 8.73 (d, J= 5.2 Hz, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.23 (d, J= 5.6 Hz, 1H), 7.91 (dd, J= 5.2, 0.8 Hz, 1H), 7.79 (d, J= 1.4 Hz, 1H), 7.75 (d, J= 5.2 Hz, 1H), 7.59 (dd, J= 5.6, 1.8 Hz, 1H), 5.66 (quin, J = 6.8 Hz, 1H), 4.99 - 4.93 (m, 4H), 2.01 - 1.98 (m, 1H), 0.91 (d, J= 6.4 Hz, 4H). LCMS (ESI+): m / z 412.1 (M+H)+.

[0238] To a solution of 4-(2-chloropyridin-4-yl)-N-(2-cyclopropylpyridin-4-yl)pyrimidin-2 -amine starting material (20.0 mg, 61.8 pmol, 1.00 eq) and tributyl-(l-tritylimidazol-4-yl)stannane (74.1 mg, 124 pmol, 2.00 eq) in toluene (1 mL) was added Pd(PPh3)4 (7.14 mg, 6.18 pmol, 0.100 eq) at 25 °C under N2. The reaction mixture was stirred at 120 °C for 12 h under N2. LC-MS showed that chloropyridine starting material was not consumed completely and a peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: WePure Biotech XP tC18 150 * 40 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 75% - 98% B over 8.0 min) to afford the final product (8.70 mg, 14.0 pmol, 22.7% yield, 96.3% purity) as a white solid.

[0239] A mixture of Trt protected starting material (280 mg, 468 pmol, 1.00 eq) in HCl / EtOAc (4.00 M, 5.00 mL, 42.7 eq) was stirred at 25 °C for 2 h. LC-MS showed that Trt protected starting material was consumed and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give 180 mg of crude product. 80 mg crude product was submitted for purification by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 10% - 25% B over 8.0 min) to afford the final product (10.5 mg, 25.6 pmol, 96.6% purity, 0.9 FA salt) as a pale purple oil.

[0240] To a solution of the imidazole starting material (100 mg, 281pmol, 1.00 eq) and 3-iodooxetane (207 mg, 1.13 mmol, 4.00 eq) in DMA (3 mL) was added Cs₂CO₃ (183 mg, 563 pmol, 2.00 eq) at 25 °C.The mixture was stirred at 120 °C for 12 h. LC-MS showed that the reaction was incomplete. 3-iodooxetane (207 mg, 1.13 mmol, 4.00 eq) was added into reaction mixture and then the mixture was stirred at 120 °C for 12 h. LC-MS showed that the imidazole starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex lima C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 10% - 25% B over 8.0 min) to afford the final product (8.20 mg, 19.8 pmol, 7% yield, 98.1% purity).1H NMR ( DMSO-d6400 MHz): 5 = ppm 10.24 (s, 1H), 8.78 - 8.74 (m, 2H), 8.72 (d, J = 5.2 Hz, 1H), 8.21 (d, J= 5.6 Hz, 1H), 8.16 (br d, J= 3.2, 1H), 8.01 (dd, J= 13.2, 1.2 Hz, 2H), 7.93 (dd, J= 5.2, 1.6 Hz, 1H), 7.70 (d, J= 5.2 Hz, 1H), 7.49 (dd, J= 5.6, 2.0 Hz, 1H), 5.55 (br t, J= 6.4 Hz, 1H), 4.97 (t, J= 9.2 Hz, 2H), 4.88 - 4.84 (m, 2H), 2.23 - 2.20 (m, 1H), 0.94 - 0.82 (m, 4H). LCMS (ESI+): m / z 412.1 (M+H)+.Example 334:

[0241] To a solution of the alcohol starting material (990 mg, 7.17 mmol, 1.00 eq) in DMF (10 mL) were added imidazole (1.22 g, 17.9 mmol, 2.50 eq) and TBSC1 (2.16 g, 14.3 mmol, 1.76 mL, 2.00 eq) at 25 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed that the alcohol starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with saturated aqueous NaHCOs solution (30 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiC Petroleum ether / THF = 0 / 1) to afford the product (1.54 g, 6.10 mmol, 85% yield).

[0242] To a solution of the resulting amine (640 mg, 2.54 mmol, 1.00 eq) and 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (688 mg, 3.04 mmol, 1.20 eq) in THF (20 mL) was added NaHMDS (1.00 M, 3.80 mL, 1.50 eq) at -10 °C under N2. The mixture was stirred at 25 °C for 2 h under N2. The mixture was diluted with saturated aqueous NH4CI solution (20 mL) at 0 °C and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / THF = 1 / 0 to 7 / 3) to afford the product (377 mg, 853 pmol, 34% yield).

[0243] To a solution of the resulting chloropyridine (200 mg, 452 pmol, 1.00 eq) and lH-pyrazol-3-ylboronic acid (506 mg, 4.52 mmol, 10.0 eq) in dioxane (4 mL) and H2O (0.8 mL) were added Brettphos Pd G3 (41.0 mg, 45.2 pmol, 0.100 eq) and K3PO4 (192 mg, 905 pmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 12 h under N2. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered and the filtrateconcentrated under reduced pressure. The residue was purified by prep-TLC (SiC>2, Petroleum ether / THF = 1 / 3) to afford the product (120 mg, 253 pmol, 56% yield).

[0244] To a solution of the TBS-protected intermediate (110 mg, 232 pmol, 1.00 eq) in THF (2 mL) was added HC1 (1.00 M, 1.00 mL, 4.31 eq at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 3 um; mobile phase: [FLO (0.04% HC1) - MeCN]; gradient: 5% - 35% B over 18.0 min) to afford the final product (15.1 mg, 37.6 pmol, 16% yield, 98.5% purity, 1.0 HC1 salt). 'H NMR ( DMSO-d6400 MHz): 5 = ppm 14.86 (br s, 1H), 11.58 (s, 1H), 9.00 (d, J = 5.2 Hz, 1H), 8.87 (dd, J = 3.6, 1.2 Hz, 2H), 8.54 (br d, J= 6.6 Hz, 1H), 8.41 (br s, 1H), 8.25 - 8.17 (m, 1H), 8.08 (d, J= 5.2 Hz, 2H), 7.92 (d, J= 2.4 Hz, 1H), 7.12 (d, J= 2.4 Hz, 1H), 3.85 (t, J= 5.8 Hz, 2H), 3.14 (t, J= 5.8 Hz, 2H). LCMS (ESI+): m / z 360.1 (M+H)+.Example 336:

[0245] To a solution of the bromide starting material (2.50 g, 12.1 mmol, 1.00 eq) in dioxane (40 mL) and H2O (10 mL) were added l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (3.37 g, 12.1 mmol, 1.00 eq), Pd(dppf)C12. CH2C12 (989 mg, 1.21 mmol, 0.100 eq) and K3PO4 (7.71 g, 36.3 mmol, 3.00 eq) at 25 °C. The reaction mixture was stirred at 100 °C for 12 h under N2. LCMS showed that the bromide starting material consumed completely and a peak with the desired mass was detected. To the reaction mixture was added H2O (30 mL) at 15 °C, and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over anhydrous NaiSCL, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 5 / 1 to 1 / 1) to afford the crude product (3.00 g).

[0246] To a solution of the chloropyridine intermediate (1.50 g, 5.40 mmol, 1.00 eq) in dioxane (15 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.78 g, 7.02 mmol, 1.30 eq), XPhos (515 mg, 1.08 mmol, 0.200 eq), KOAc (1.59 g, 16.2 mmol, 3.00 eq) and Pd(dppf)C12 (395 mg, 540 pmol, 0.100 eq) at 25 °C. The reaction mixture was stirred at 100 °C for 12 h under N2. LCMS showed that the chloropyridine starting material consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to afford the crude product (1.50 g).

[0247] To a solution of the boronic acid ester intermediate (500 mg, 1.35 mmol, 1.00 eq) in dioxane (12 mL) and H2O (3 mL) were added 4-chloro-N-(2-cyclopropyl-4-pyridyl)pyrimidin-2 -amine (401 mg, 1.62 mmol, 1.20 eq), Na₂CO₃ (287 mg, 2.71 mmol, 2.00 eq) and Pd(dppf)C12 (99.1 mg, 135 pmol, 0.100 eq) at 25 °C. The reaction mixture was stirred at 80 °C for 12 h under N2. LC-MS showed that the boronic acid ester starting material was consumed completely and a peak with the desired mass was detected. To the reaction mixture was added H2O (20 mL) at 0 °C, and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to afford the product (200 mg, 441 pmol, 32.6% yield) as a white solid.

[0248] To a solution of the starting material (200 mg, 441 pmol, 1.00 eq) in DCM (2 mL) was added TFA (3.07 g, 26.9 mmol, 2.00 mL, 61.1 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. Then saturated NaOH solution (10 mL) was added to the reaction mixture to adjust to pH = 8 at 0 °C, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 5% -30% B over 8.0 min) to afford the final product (38.5 mg, 98.3 pmol, 23% yield, 95.5% purity, 0.1 FA salt). ’H NMR ( DMSO-d6400 MHz): 5 = ppm 13.08 (br s, 1H), 10.26 (br s, 1H), 8.74 (d, J= 5.2 Hz, 1H), 8.62 (br d, J= 4.8 Hz, 1H), 8.20 (d, J= 5.6 Hz, 1H), 8.14 (s, 0.1H), 7.86 - 7.74 (m, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.59 (dd, J= 5.6, 1.8 Hz, 1H), 7.40 (br d, J= 3.2 Hz, 1H), 7.21 (d, J = 4.8 Hz, 1H), 6.81 (br s, 1H), 2.55 (br s, 3H), 1.97 - 1.92 (m, 1H), 0.94 - 0.87 (m, 4H). LCMS (ESI+): m / z 370.1 (M+H)+. Example 356:

[0249] To a mixture of the starting amine (500 mg, 3.86 mmol, 1.00 eq) and BOC2O (2.95 g, 13.5 mmol, 3.10 mL, 3.50 eq) in THF (10 mL) were added TEA (781 mg, 7.72 mmol, 1.07 mL, 2.00 eq) and DMAP (23.6 mg, 193 pmol, 0.0500 eq) at 25 °C. The mixture was stirred at 40 °C for 3 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by addition of H2O (30 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine (20 mL* 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product (1.10 g) as a solid.

[0250] To a mixture of cyclopropylboronic acid (820 mg, 9.55 mmol, 3.00 eq) and the chloropyridazine intermediate (1.05 g, 3.18 mmol, 1.00 eq) in toluene (15 mL) and H2O (1.5 mL) were added Pd(Amphos)2C12 (226 mg, 318 pmol, 225 pL, 0.100 eq) and Cs₂CO₃ (3.11 g, 9.55 mmol, 3.00 eq) at 25 °C. The mixture was stirred at 100 °C for 1 h under N2. LC-MS showed that the chloropyridazine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to afford the product (750 mg, 2.24 mmol, 70% yield) as a yellow solid.

[0251] To a solution of the Boc-protected intermediate (650 mg, 1.94 mmol, 1.00 eq) in DCM (10 mL) was added TFA (3.07 g, 26.9 mmol, 2.00 mL, 13.9 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. TLC (SiC>2, PE / EtOAc = 0 / 1) indicated formation of a product. The mixture was adjusted to pH = 7 by TEA, diluted with H2O (10 mL), and extracted with DCM (10 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product (260 mg) as a solid.

[0252] To a solution of the free amine intermediate (260 mg, 1.92 mmol, 1.00 eq) in THF (6 mL) was added NaHMDS (1.00 M, 2.31 mL, 1.20 eq) at 0 °C under N2 and stirred for 0.5 h. Then 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (436 mg, 1.93 mmol, 1.00 eq) was added into the mixture at 0 °C under N2. The mixture was stirred at 25 °C for 1 h under N2. LC-MS showed that the amine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched with saturated NH4CI (10 mL) under N2 at 0 °C and extracted with ethyl acetate (8 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product (400 mg) as a solid.

[0253] To a mixture of the chloropyridine intermediate (200 mg, 616 pmol, 1.00 eq) and lH-pyrazol-3-ylboronic acid (138 mg, 1.20 mmol, 2.00 eq) in H2O (1 mL) and EtOH (10 mL) were added Brettphos Pd G3 (55.8 mg, 61.6 pmol, 0.100 eq) and K3PO4 (261 mg, 1.23 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 80 °C for 16 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD01 - Phenomenex luna C18 150 * 25 mm * 10 um; mobile phase: [H2O (0.225% FA) - MeCN]; gradient: 0% - 28% B over 11.0 min) to afford the final product (20.1 mg, 53.8 pmol, 9% yield, 97.9% purity, 0.2 FA salt). ’HNMR DMSO-de 400 MHz 5 = ppm 13.13 (br s, 1H), 10.55 (s, 1H), 9.24 (s, 1H), 8.85 - 8.76 (m, 3H), 8.23 (s, 0.2H), 8.18 (br s, 1H), 8.01 (br d, J= 4.8 Hz, 1H), 7.86 - 7.80 (m, 2H), 6.93 (br s, 1H), 2.28 - 2.17 (m, 1H), 1.09 - 1.05 (m, 4H). LCMS (ESI+): m / z 357.1 (M+H)+.Example 357:

[0254] The reaction was set up in five parallel batches. Solution 1: The bromopyridine starting material (200 mg, 732 pmol, 1.00 eq) in DME (5 m ) and add 3-bromo-l,l-difluoro-cyclobutane (376 mg, 2.20 mmol, 3.00 eq), TTMSS (273 mg, 1.10 mmol, 339 ph, 1.50 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;dichloronickel (14.6 mg, 36.6 pmol, 0.0500 eq), Na₂CO₃ (155 mg, 1.46 mmol, 2.00 eq), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(l+);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (8.22 mg, 7.32 pmol, 0.0100 eq) under N2 The solution 1 was pumped by Pump 1 {SI, Pl, 40.4 mL / min}to flow reactor 1 {FLR1, FEP, Coils reactor, 3.18 (1 / 8”) mm, 55.0 mb, 395 nm, 200 W*2, 55 °C}. The residence time of flow reactor 1 was {FLR1, 1.36 min}. LC-MS showed that the bromopyridine starting material was not consumed completely and a peak with the desired mass was detected. Five batches were combined. The mixture was diluted with H2O (30 mb) and extracted with EtOAc (20 mb * 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to afford the product (490 mg, 1.72 mmol, 47% yield).

[0255] A solution of the obtained intermediate (490 mg, 1.72 mmol, 1.00 eq) in DCM (3 mb) and TFA (1.54 g, 13.5 mmol, 1.00 mb, 7.81 eq) was stirred at 25 °C for 12 h. EC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was dissolved with DCM (3 mb), adjusted to pH = 8 with Na₂CO₃ solid, filtered and the filtrate was concentrated under reduced pressure to afford the crude product (250 mg).

[0256] To a solution of the amine intermediate (240 mg, 1.30 mmol, 1.00 eq) and 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (353 mg, 1.56 mmol, 1.20 eq) in THF (5 mL) was added NaHMDS (1.00 M, 1.95 mb, 1.50 eq) at -10 °C under N2. The mixture was stirred at 25 °C for 1 h under N2. EC-MS showed that the amine starting material was not consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous NH4CI solution (10 mL) at 0 °C and extracted with EtOAc (5 mb * 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiC>2, PE / EtOAc = 1 / 2) to afford the product (210 mg, 562 pmol, 43% yield).

[0257] To a solution of the chloropyridine intermediate thus obtained (200 mg, 535 pmol, 1.00 eq) and lH-pyrazol-3-ylboronic acid (599 mg, 5.35 mmol, 10.0 eq) in EtOH (5 mL) and EEO (1 mL) were added K3PO4 (227 mg, 1.07 mmol, 2.00 eq) and Brettphos Pd G3 (48.5 mg, 53.5 pmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 2 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 40% B over 8.0 min) to afford the final product (43.5 mg, 99.1 pmol, 19% yield, 95.5% purity, 0.3 FA salt). ’H NMR DMSO-de 400 MHz 5 = ppm 10.35 (s, 1H), 8.78 (d, J= 5.1 Hz, 2H), 8.71 (br s, 1H), 8.40 (d, J= 5.6 Hz, 1H), 8.14 (s, 0.3H), 8.00 (dd, J= 5.0, 1.4 Hz, 1H), 7.90 (d, J= 1.6 Hz, 1H), 7.82 (br dd, J= 5.0, 2.0 Hz, 1H), 7.73 (d, J= 5.0 Hz, 1H), 7.68 (dd, J= 5.8, 2.0 Hz, 1H), 6.94 (s, 1H), 3.45 (td, J= 8.6, 3.4 Hz, 1H), 2.94 - 2.87 (m, 4H). LCMS (ESI+): m / z 406.1 (M+H)+.Example 358:

[0258] To a solution of the bromopyridine starting material (2.00 g, 10.4 mmol, 1.00 eq) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (3.04 g, 10.9 mmol, 1.05 eq) in dioxane (40 mL) and H2O (10 mL) were added Pd(dppf)C12. CH2C12 (849 mg, 1.04 mmol, 0.100 eq) and K3PO4 (4.41 g, 20.8 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Si O2- Petroleum ether / Ethyl acetate = 1 / 0 to 4 / 1) to afford the crude product (1.60 g).

[0259] To a solution of this crude material (350 mg, 1.33 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (674 mg, 2.65 mmol, 2.00 eq) in dioxane (5 mL) were added Pd(dppf)C12. CH2C12 (108 mg, 133 pmol, 0.100 eq) and KOAc (261 mg, 2.65 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the chloropyridinestarting material was consumed completely and a peak with the desired mass was detected. The crude product (470 mg) in dioxane (5 mL) was used into the next step without any work-up and purification.

[0260] To a solution of the crude boronic acid ester intermediate (470 mg, 1.32 mmol, 1.00 eq), 4-chloro-N-(2 -cyclopropyl -4-pyridyl)pyrimidin-2 -amine (345 mg, 1.32 mmol, 1.00 eq) in dioxane (5 mL) and H2O (1 mL) were added Pd(dppf)C12. CH2C12 (108 mg, 132 pmol, 0.100 eq) and Na₂CO₃ (280 mg, 2.65 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the boronic acid ester starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (15 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether / THF = 1 / 0 to 1 / 1) to afford the product (490 mg, 1.08 mmol, 82% yield).

[0261] To a solution of the THP -protected intermediate (480 mg, 1.06 mmol, 1.00 eq) in DCM (3 mL) was added TFA (4.61 g, 40.4 mmol, 3.00 mL, 38.2 eq) at 20 °C. The mixture was stirred at 20 °C for 12 h. LC-MS showed that the starting material was not consumed completely and a peak with the desired mass was detected. The mixture was adjusted to pH~8 with saturated aqueous NaHC’CF solution, then concentrated under reduced pressure to remove DCM and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (10 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) -MeCN]; gradient: 5% - 25% B over 8.0 min) to afford the final product (101 mg, 257 pmol, 24% yield, 98.3% purity, 0.4 FA salt). ’H NMR DMSO-d6400 MHz 5 = ppm 13.07 (br s, 1H), 10.09 (s, 1H), 8.75 (d, J= 4.8 Hz, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 8.16 (s, 0.4H), 8.14 (s, 1H), 7.86 - 7.72 (m, 2H), 7.61 (dd, J= 5.0, 1.6 Hz, 1H), 7.49 (dd, J= 5.6, 2.0 Hz, 1H), 6.92 (d, J= 2.0 Hz, 1H), 2.30 (s, 3H), 2.00 - 1.89 (m, 1H), 0.92 - 0.81 (m, 4H). LCMS (ESI+): m / z 370.2 (M+H)+.Example 359:

[0262] To a solution of the fluoropyridine starting material (2.00 g, 11.4 mmol, 1.00 eq) and cyclopropanol (990 mg, 17.1 mmol, 1.50 eq) in DMA (25 mL) was added Cs₂CO₃ (7.41 g, 22.7 mmol, 2.00 eq) at 20 °C under N2. The mixture was stirred at 90 °C for 4 h under N2. LC-MS showed that the fluoropyridine starting material was consumed completely and a peak with the desired mass wasdetected. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 5 / 1) to afford the crude product (2.00 g).

[0263] To a solution of the bromopyridine intermediate (1.98 g, 9.25 mmol, 1.00 eq) and tert-butyl carbamate (1.19 g, 10.2 mmol, 1.10 eq) in dioxane (20 mL) were added Xantphos (1.07 g, 1.85 mmol, 0.200 eq), Pd₂(dba)₃ (847 mg, 925 pmol, 0.100 eq) and Cs₂CO₃ (4.52 g, 13.9 mmol, 1.50 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 1 h under N2. LC-MS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (10 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 3 / 1) to afford the crude product (1.20 g) as a solid.

[0264] A solution of the Boc -protect amine intermediate (1.19 g, 4.75 mmol, 1.00 eq) in HCl / EtOAc (4.00 M, 20.0 mL) was stirred at 15 °C for 12 h. LC-MS showed that the starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was freed by alkaline resin to afford the crude product (800 mg) as a yellow solid.

[0265] To a solution of the aminopyridine intermediate (780 mg, 5.19 mmol, 1.00 eq) in THF (15 mL) was added NaHMDS (1.00 M, 6.23 mL, 1.20 eq) at -10 °C under N2. The mixture was stirred at -10 °C for 0.5 h under N2. Then 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (1.17 g, 5.19 mmol, 1.00 eq) was added at -10 °C under N2. The mixture was stirred at 15 °C for 0.5 h under N2. LC-MS showed that the aminopyridine starting material was not consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous NH4CI solution (10 mL) at 0 °C and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to afford the crude product (490 mg) as a solid.

[0266] To a solution of the crude chloropyridine intermediate (120 mg, 353 pmol, 1.00 eq) and 1H-pyrazol-3-ylboronic acid (395 mg, 3.53 mmol, 10.0 eq) in dioxane (4 mL) and H2O (1 mL) were added XPhos Pd G2 (27.8 mg, 35.3 pmol, 0.100 eq) and K₃PO₄ (150 mg, 706 pmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 1 h. LC-MS showed that the chloropyridine starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 5% - 35% B over 8.0 min) to afford the final product (24.0 mg, 61.9 pmol, 18% yield, 95.8% purity, 0.2 FA salt). 'H NMR DMSO-d6400 MHz 5 = ppm 13.17 (br s, 1H), 10.35 (s, 1H), 8.79 (br d, J= 4.8 Hz, 2H), 8.67 (m, 1H), 8.14 (s, 0.2H), 8.03 - 7.98 (m, 2H), 7.83 (m, 1H), 7.73 (d, J= 52 Hz, 1H), 7.59 (s, 1H), 7.39 (br d, J= 5.2 Hz, 1H), 6.93 (br s, 1H), 4.22 - 4.17 (m, 1H), 0.71 - 0.63 (m, 4H). LCMS (ESI+): m / z 372.1 (M+H)+.Example 360:

[0267] To a solution of the starting material (1.00 g, 5.78 mmol, 1.00 eq) in H2O (4 mL) and acetone (10 mL) were added NaOH (694 mg, 17.3 mmol, 3.00 eq), and CbzCl (1.18 g, 6.94 mmol, 990 pL, 1.20 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h under N2. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~8% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford the crude product (700 mg) as a solid.

[0268] To this crude intermediate (650 mg, 2.12 mmol, 1.00 eq) in DME (19.5 mL) were add tert-butyl 3 -iodoazetidine -1 -carboxylate (1.20 g, 4.23 mmol, 2.00 eq), TTMSS (631 mg, 2.54 mmol, 783 pL, 1.20 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;dichloronickel (8.42 mg, 21.2 pmol, 0.0100 eq), Na₂CO₃ (449 mg, 4.23 mmol, 2.00 eq), bis[3,5-difhroro-2-[5-(trifhroromethyl)-2-pyridyl]phenyl]iridium(l+);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (23.7 mg, 21.2 pmol, 0.0100 eq) at 25 °C under N2. The solution 1 was pumped by Pump 1 {Si, Pi, 0.611 mL / min}to flow reactor 1 {FLRi, FEP, Coils reactor, 3.175(1 / 8”) mm, 54.95 mL, 395 nm, 200 W * 2, 25 °C}. The residence time of flow reactor 1 was {FLRi, 90 min}. LC-MS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was filtered and the fdtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to afford the crude product (225 mg).

[0269] To a solution of this material (225 mg, 587 pmol, 1.00 eq) in EtOAc (2 mL) was added 10% Pd / C (200 mg, 50.0% purity) at 25 °C under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 1 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was filtered and the fdtrate was concentrated under reduced pressure to afford the crude product (HO mg).

[0270] To a solution of the crude amine (110 mg, 441 pmol, 1.00 eq) and 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (120 mg, 529 pmol, 1.20 eq) in THF (2 mL) was added NaHMDS (1.00 M, 662 pL, 1.50 eq) at -10 °C under N2. The mixture was stirred at 25 °C for 1 h. LC-MS showed that the amine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous solution NH4CI (5 mL) at 0 °C, and then extracted with EtOAc (5 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 0 / 1) to afford the product (192 mg, 408 pmol, 93% yield, 93.3% purity).

[0271] To a solution of the chloropyridine intermediate (3.47 g, 7.91 mmol, 1.00 eq) in dioxane (30 mL) and H2O (10 mL) were added l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (4.40 g, 15.8 mmol, 2.00 eq), XPhos Pd G2 (622 mg, 791 pmol, 0.100 eq) and K3PO4 (3.36 g, 15.8 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product of this batch was combined with another batch (from 300 mg of the chloropyridine starting material). The combined crude product was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 - 45% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford the crude product (4.98 g) as a solid.

[0272] A solution of the protected intermediate (100 mg, 180 pmol, 1.00 eq) in HCl / EtOAc (4 M, 2 mL) was stirred at 15 °C for 2 h. LC-MS showed that the starting material was consumed completely and a peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. To the residue was added EtOAc (2 mL), then DIPEA was added to adjust to pH = 8-9 and concentrated under reduced pressure to afford the crude product (80.0 mg).

[0273] To a solution of the starting material (100 mg, 270 pmol, 1.00 eq) in DCM (2 mL) were added DIPEA (105 mg, 810 pmol, 141 pL, 3.00 eq) and acetyl chloride (21.2 mg, 270 pmol, 19.2 pL, 1.00 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h under N2. LC-MS showed that the starting material was consumed completely and a peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25 mm * 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 10% - 50% B over 8.0 min). To thus obtained product were added H2O (2 mL), MeCN (0.5 mL)and FA (0.01 mL), then lyophilized to afford the final product (6.00 mg, 13.2 pmol, 5% yield, 100% purity, 0.9 FA salt) as a solid. 'H NMR DMSO-d6400 MHz 5 = ppm 10.37 (s, 1H), 8.79 (d, J= 5.0 Hz, 2H), 8.72 (br s, 1H), 8.43 (d, J= 5.6 Hz, 1H), 8.20 (s, 0.9H), 8.05 - 7.95 (m, 1H), 7.91 (s, 1H), 7.83 (br s, 1H), 7.74 (d, J= 5.2 Hz, 1H), 7.72 - 7.66 (m, 1H), 6.94 (d, J= 1.6 Hz, 1H), 4.52 - 4.42 (m, 1H), 4.31 -4.24 (m, 1H), 4.23 - 4.15 (m, 1H), 4.03 - 3.96 (m, 1H), 3.95 - 3.88 (m, 1H), 1.77 (s, 3H). LCMS (ESI+): m / z 413.1 (M+H)+.Example 361:

[0274] To a solution of the chloropyridine starting material (100 mg, 229 pmol, 1.00 eq) in dioxane (6 mL) and H2O (1 mL) were added l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (191 mg, 687 pmol, 3.00 eq), XPhos Pd G2 (18.0 mg, 22.9 pmol, 0.100 eq) and K3PO4 (146 mg, 687 pmol, 3.00 eq) at 25 °C. The mixture was stirred at 90 °C for 1 h under N2 atmosphere. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted by water (15 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 100 / 0 to 3 / 2) to afford the crude product (140 mg).

[0275] A solution of the protected intermediate (130 mg, 278 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 5.00 mL, 36.0 eq) was stirred at 25 °C for 0.5 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (CD24-WePure Biotech XPT C18 (150 * 25 mm, 7 um); flow rate: 25 mL / min; gradient: 16% - 46%, B over 12 min; mobile phase A: H2O (0.05% HC1), mobile phase B: MeCN) to afford the final product (24.3 mg, 57.3 pmol, 21% yield, 98.9% purity, 1.0 HC1 salt). 'HNMR DMSO-d6400 MHz 5 = ppm 10.80 (s, 1H), 8.88 (br d, J= 4.8 Hz, 1H), 8.81 (brd, J= 4.8 Hz, 1H), 8.74 (s, 1H), 8.58 (br d, J= 5.4 Hz, 1H), 8.43 (s, 1H), 8.07 (br s, 2H), 7.85 (br s, 2H), 6.99 (s, 1H). LCMS (ESI+): m / z 384.1 (M+H)+.Example 363:

[0276] To a solution of the starting material (1.00 g, 6.71 mmol, 1.00 eq) and l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (2.80 g, 10.1 mmol, 1.50 eq) in dioxane (20 mL) and H2O (5 mL) were added Pd(OAc)2 (150 mg, 671 pmol, 0.100 eq), dppf (744 mg, 1.34 mmol, 0.200 eq) and Cs₂CO₃ (4.37 g, 13.4 mmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 2 h under N2. LC-MS showed that the starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (10 mL) and extracted with EtOAc (50 mL * 3). The organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, hexane / Ethyl acetate = 1 / 0 to 2 / 1) to afford the crude product (1.70 g) as a solid.

[0277] To a solution of this crude material (206 mg, 778 pmol, 1.30 eq) and N-(2-cyclopropyl-4-pyridyl)-4-tributylstannyl-pyrimidin-2 -amine (300 mg, 598 pmol, 1.00 eq) in dioxane (4 mL) was added Pd(PPh3)4 (69.2 mg, 59.9 pmol, 0.100 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 12 h. LC-MS showed that the starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (2 mL) and extracted with EtOAc (10 mL * 3). The organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, DCM / MeOH = 10 / 1) to afford the crude product (140 mg).

[0278] A solution of this material (140 mg, 318 pmol, 1.00 eq) in HCl / EtOAc (4.00 M, 5.00 mL) was stirred at 15 °C for 2 h. LC-MS showed that the starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 100 * 40 mm * 5 um; mobile phase: [H2O (0.04 HC1) - MeCN]; gradient: 1% - 35% B over 8.0 min), followed by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25 mm * 10 um; mobile phase: [H2O (10 mMNELHCCL) - MeCN]; gradient: 10% - 50% B over 8.0 min) to afford the final product (13.6 mg, 36.3 pmol, 11% yield, 95.0% purity). 'HNMR DMSO-d6400 MHz 5 = ppm 13.40 (br s, 1H), 10.34 (s, 1H), 9.86 (s, 1H), 8.89 -8.83 (m, 2H), 8.23 (br d, J= 5.2 Hz, 1H), 7.98 (br s, 1H), 7.90 - 7.87 (m, 2H), 7.52 (br d, J= 4.4 Hz, 1H), 7.11 (br s, 1H), 2.07 (br s, 1H), 0.95 - 0.91 (m, 4H). LCMS (ESI+): m / z 357.1 (M+H)+.Example 364:

[0279] To a mixture of the bromopyridine starting material (2.60 g, 14.8 mmol, 1.00 eq) in NMP (100 mL) were added t-BuOK (1.99 g, 17.7 mmol, 1.20 eq) and 2-[tert-butyl(dimethyl)silyl]oxyethanol (3.13 g, 17.7 mmol, 1.20 eq) at 25 °C. The mixture was stirred at 60 °C for 16 h. LC-MS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched with water (300 mL) and extracted with EtOAc (300 mL * 3). The combined organic phase was washed with water (300 mL * 3), brine (500 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 100 / 0 to 98 / 2) to afford the product (1.30 g, 3.91 mmol, 27% yield).

[0280] To a mixture of this material (1.60 g, 4.81 mmol, 1.00 eq) in NMP (32 mL) and H2O (8 mL) were added trans-N, N'-dimethylcyclohexane-l,2-diamine (1.37 g, 4.81 mmol, 1.00 eq) and NaNs (680 mg, 10.5 mmol, 2.17 eq) at 25 °C, then stirred for 10 min under N2. Cui (183 mg, 963 pmol, 0.200 eq) and sodium; (2R)-2-[(lS)-l, 2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (191 mg, 963 pmol, 0.200 eq) were added to the mixture and it was stirred at 100 °C for 2 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. This batch was combined with another batch (in page EC25977-164, from 100 mg of the starting material). The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (50 mL * 4). The combined organic phase was washed with brine (100 mL * 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 100 / 0 to 65 / 35) to afford the product (1.10 g, 4.10 mmol) as a solid.

[0281] To a solution of the pyridylamine starting material (300 mg, 1.12 mmol, 1.00 eq) in THF (3 mL) was added dropwise NaHMDS (1.00 M, 1.34 mL, 1.20 eq) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 30 min. Then 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (278 mg, 1.23 mmol, 1.10 eq) in THF (3 mL) was added into the mixture at 0 °C. Then the mixture was allowed to warm to 25 °C and stirred for 1 h. LC-MS showed that the pyridylamine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated NH4CI (15 mL) andextracted with ethyl acetate (15 mL * 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (CD07-Daisogel SP -100-8-ODS-PK (150 * 25 mm, 10 um); flow rate: 25 mL / min; gradient: 64% - 94%, B over 10 min; mobile phase A: H2O (10 mM NH4HCO3), mobile phase B: MeCN) to afford the product (156 mg, 341 pmol, 31% yield) as a yellow solid.

[0282] To a solution of the chloropyridine intermediate (136 mg, 297 pmol, 1.00 eq) in dioxane (3 mL) and H2O (0.8 mL) were added l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (99.1 mg, 356 pmol, 1.20 eq), XPhos Pd G2 (23.4 mg, 29.7 pmol, 0.100 eq) and K3PO4 (158 mg, 742 pmol, 2.50 eq) at 25 °C. The mixture was stirred at 100 °C for 1 h under N2 atmosphere. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted by water (5 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1) to afford the product (150 mg, 261 pmol, 88% yield) as a yellow solid.

[0283] A mixture of the THP -protected intermediate ( 140 mg, 244 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 3.00 mL, 24.6 eq) was stirred for 0.5 h at 25 °C. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (CDOl-Phenomenex luna C18 (150 * 25 mm, 10 um); flow rate: 25 mL / min; gradient: 1% - 31%, B over 10 min; mobile phase A: H2O (0.225% FA), mobile phase B: MeCN) to afford the final product (65.7 mg, 163 pmol, 66.8% yield, 100% purity, 0.6 FA salt) as a solid. 'H DMSO-d6400 MHz 5 = ppm 10.33 (s, 1H), 8.79 (d, J= 5.0 Hz, 2H), 8.69 (br s, 1H), 8.15 (s, 0.6H), 8.01 - 7.97 (m, 2H), 7.82 (br s, 1H), 7.73 (d, J= 5.0 Hz, 1H), 7.45 (s, 1H), 7.39 (br d, J= 5.8 Hz, 1H), 6.94 (s, 1H), 4.84 (br s, 1H), 4.26 (t, J= 5.1 Hz, 2H), 3.70 (brt, J= 5.0 Hz, 2H). LCMS (ESI+): m / z 376.1 (M+H)+.Example 365:

[0284] To a mixture of the bromopyridine starting material (1.00 g, 4.84 mmol, 1.00 eq) and 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (2.02 g, 7.27 mmol, 1.50 eq in dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)C12 (354 mg, 484 pmol, 0.100 eq) and Na₂CO₃ (1.03 g, 9.69 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 80 °C for 16 h under N2. LC-MS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to afford the product (1.30 g, 4.68 mmol, 97% yield).

[0285] To a mixture of the chloropyridine intermediate (500 mg, 1.80 mmol, 1.00 eq) and ELPim (686 mg, 2.70 mmol, 1.50 eq) in dioxane (10 mL) were added Pd(dppf)C12 (132 mg, 180 pmol, 0.100 eq), XPhos (172 mg, 360 pmol, 0.200 eq) and KOAc (353 mg, 3.60 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 2 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD07 - Daisogel SP - 100 - 8 - ODS - PK 150 * 25 * 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 36% - 66% B over 10.0 min) to afford the product (240 mg, 650 pmol, 36% yield).

[0286] To a mixture of boronic acid ester intermediate (220 mg, 596 pmol, 1.00 eq) and 4-chloro-N-(2-cyclopropyl-4-pyridyl)pyrimidin-2 -amine (147 mg, 596 pmol, 1.00 eq) in dioxane (5 mL) and H2O (1 mL) were added Na₂CO₃ (126 mg, 1.19 mmol, 2.00 eq) and Pd(dppf)C12 (43.6 mg, 59.6 pmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 1 h under N2. LC-MS showed that the boronic acid ester starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH = 15 / 1) to afford the product (130 mg, 287 pmol, 48% yield).

[0287] A solution of the protected intermediate (120 mg, 265 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 4.00 mL, 30.2 eq) was stirred at 25 °C for 0.5 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD24 - WePure Biotech XPT C18 150 * 25 * 7 um; mobile phase: [H2O (0.05% HC1) - MeCN]; gradient: 0% - 29% B over 12.0 min) to afford the final product (60.9 mg, 148 pmol, 56% yield, 98.6% purity, 1.0 HC1 salt) as a solid. ’H NMR DMSO-de 400 MHz 5 = ppm 14.63 (br s, 1H), 11.42 (s, 1H), 8.94 (d, J = 5.2 Hz, 1H), 8.68 (d, J= 5.6 Hz, 1H), 8.42 (d, J = 6.8 Hz, 1H), 8.26 (s, 2H), 8.01 (br d, J = 5.2 Hz, 1H), 7.93 (br s, 1H), 7.56 (br d, J= 4.4 Hz, 1H), 7.49 (d, J= 5.2 Hz, 1H), 2.48 - 2.46 (m, 3H), 2.33 - 2.29 (m, 1H), 1.32 - 1.29 (m, 2H), 1.05 - 1.03 (m, 2H). LCMS (ESI+): m / z 370.2 (M+H)+.Example 367:

[0288] A mixture of the bromopyridine starting material (1.00 g, 4.84 mmol, 1.00 eq), 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (1.35 g, 4.84 mmol, 1.00 eq), Pd(dppf)C12 (354 mg, 484 pmol, 0.100 eq) and Na₂CO₃ (1.03 g, 9.69 mmol, 2.00 eq) in dioxane (8 mL) and H2O (2 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 80 °C for 2 h under N2 atmosphere. LCMS showed that the bromopyridine starting material was consumed completely and apeak with the desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (15 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 9 / 1 to 17 / 3) to afford the crude product (1.00 g).

[0289] A mixture of the chloropyridine intermediate (500 mg, 1.79 mmol, 99.6% purity, 1.00 eq), 4, 4, 5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (455 mg, 1.79 mmol, 1.00 eq), Pd(dppf)C12 (131 mg, 179 pmol, 0.100 eq), XPhos (85.5 mg, 179 pmol, 0.100 eq) and KOAc (352 mg, 3.58 mmol, 2.00 eq) in dioxane (10 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 100 °C for 12 h under N2 atmosphere. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: CD45 - Waters Xbridge BEH C18 150 * 40 mm * 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 18% - 48% B over 10.0 min) to afford the crude product (120 mg) as a white solid.

[0290] A mixture of this crude material (120 mg, 253 pmol, 78.0% purity, 1.00 eq), 4-chloro-N-(2-cyclopropyl-4-pyridyl)pyrimidin-2 -amine (62.5 mg, 253 pmol, 1.00 eq), K2CO3 (70.1 mg, 507 pmol, 2.00 eq) and Pd(dppf)C12 (18.6 mg, 25.4 pmol, 0.100 eq) in dioxane (4 mL) and H2O (1 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 100 °C for 2 h under N2 atmosphere. LC-MS showed that the boronic acid ester starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (15 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product (100 mg).

[0291] A mixture of the starting material (100 mg, 220 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 5.00 mL, 45.4 eq) was stirred at 25 °C for 2 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition; column: CD24 - WePure Biotech XPT Cl 8 150 * 25 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 18% - 48% B over 10.0 min) to afford the final product (15.0 mg, 40.2 pmol, 18% yield, 98.9% purity). 'H NMR DMSO-d6400 MHz 5 = ppm 13.05 (br s, 1H), 10.16 (s, 1H), 8.75 (d, J= 5.2 Hz, 1H), 8.52 (s, 1H), 8.36 (br s, 1H), 8.17 (d, J= 5.6 Hz, 1H), 8.09 (br s, 1H), 7.80 (s, 1H), 7.73 (d, J= 1.6 Hz, 1H), 7.52 (dd, J= 5.6, 2.0 Hz, 1H), 7.26 (d, J= 5.0 Hz, 1H), 2.38 (s, 3H), 1.93 (quin, J= 6.4 Hz, 1H), 0.87 - 0.86 (m, 4H). LCMS (ESI+): m / z 370.0 (M+H)+.Example 368:

[0292] A mixture ofthe bromopyridine starting material (1.00 g, 5.20 mmol, 1.00 eq), 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (1.45 g, 5.20 mmol, 1.00 eq), Pd(dppf)C12 (380 mg, 520 pmol, 0.100 eq) and Na₂CO₃ (1.10 g, 10.4 mmol, 2.00 eq) in dioxane (8 mL) and H2O (2 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 80 °C for 2 h under N2 atmosphere. LC-MS showed that the bromopyridine starting material was consumed completely and apeak with the desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (15 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 9 / 1 to 17 / 3) to afford the crude product (1.00 g, 88.3% purity).

[0293] A mixture of the crude chloropyridine (500 mg, 1.67 mmol, 88.3% purity, 1.00 eq), 4, 4, 5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (425 mg, 1.67 mmol, 1.00 eq), Pd(dppf)C12 (123 mg, 167 pmol, 0.100 eq), XPhos (79.8 mg, 167 pmol, 0.100 eq) and KO Ac (329 mg, 3.35 mmol, 2.00 eq) in dioxane (10 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 100 °C for 12 h under N2 atmosphere. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixturewas diluted with water (100 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition; column: CD24-WePure Biotech XPT C18 150 * 25 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 0% - 27% B over 12.0 min) to afford the crude product (160 mg, 96.2% purity) as a solid.

[0294] A mixture of the crude boronic acid ester (140 mg, 379 pmol, 96.2% purity, 1.00 eq), 4-chloro-N-(2-cyclopropyl-4-pyridyl)-5-methyl-pyrimidin-2-amine (113 mg, 379 pmol, 87.8%purity, 1.00 eq), K2CO3 (105 mg, 758 pmol, 2.00 eq) and Pd(dppf)C12 (27.8 mg, 37.9 pmol, 0.100 eq) in dioxane (4 mL) and H2O (1 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 100 °C for 2 h under N2 atmosphere. LC-MS showed that the boronic acid ester starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (15 mL * 3), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product (100 mg).

[0295] A mixture of the starting material (100 mg, 220 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 5.00 mL, 45.4 eq) was stirred at 25 °C for 2 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was filtered and the filter cake was dried under reduced pressure. The crude product was purified by prep-HPLC (column: CD24-WePure Biotech XPT C18 150 * 25 * 7 um; mobile phase: [H2O (0.05% HC1) - MeCN]; gradient: 0% - 25% B over 12.0 min) to afford the final product (62.1 mg, 151 pmol, 68.3% yield, 98.5% purity, 1.0 HC1 salt). ’H NMR DMSO-d6400 MHz 5 = ppm 14.56 (br s, 1H), 11.34 (s, 1H), 8.82 (s, 1H), 8.74 (d, J = 5.4 Hz, 1H), 8.44 (s, 2H), 8.37 (br d, J= 6.8 Hz, 1H), 8.15 (s, 1H), 8.04 (br s, 1H), 7.85 (br s, 1H), 7.61 (br d, J= 4.8 Hz, 1H), 2.38 (s, 3H), 2.28 - 2.25 (m, 1H), 1.26 - 1.22 (m, 2H), 1.02 - 1.00 (m, 2H). LCMS (ESI+): m / z 370.1 (M+H)+.Example 369:

[0296] To a solution of the boronic acid ester starting material (1.00 g, 4.18 mmol, 1.00 eq) and 2,4-dichloro-6-methoxy-pyrimidine (747 mg, 4.18 mmol, 1.00 eq) in dioxane (20 mL) and H2O (5 mL) were added Pd(dppf)C12 (306 mg, 418 pmol, 0.100 eq) and K3PO4 (1.77 g, 8.35 mmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 50 °C for 0.5 h under N2. LC-MS showed that the boronic acid ester starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixturewas concentrated under reduced pressure to remove solvent. The residue was diluted with water (10 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexane / Ethyl acetate = 1 / 0 to 3 / 1) to afford the product (120 mg, 447 pmol, 11% yield, 95.3%purity) as a solid.

[0297] To a solution of 2-cyclopropylpyridin-4-amine (75.5 mg, 562 pmol, 1.20 eq) in THF (2 mL) was added NaHMDS (1.00 M, 1.17 mL, 2.50 eq) at -10 °C under N2. The mixture was stirred at -10 °C for 0.5 h. Then the chloropyrimidine reactant obtained in the previous step (120 mg, 469 pmol, 1.00 eq) was added at -10 °C under N2, the mixture was stirred at 15 °C for 0.5 h. LC-MS showed that the chloropyrimidine reagent was consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous NH4CI solution (2 mL) at 0 °C and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiC hexane / EtOAc = 0 / 1) to afford the crude product (100 mg) as a solid.

[0298] To a solution of the chloropyridine intermediate thus obtained (65.0 mg, 184 pmol, 1.00 eq) and lH-pyrazol-3-ylboronic acid (411 mg, 3.67 mmol, 20.0 eq) in H2O (1 mL) and EtOH (4 mL) were added Brettphos Pd G3 (16.7 mg, 18.4 pmol, 0.100 eq) and K3PO4 (78.0 mg, 367 pmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 12 h. LC-MS showed that the chloropyridine starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% -40% B over 8.0 min) to afford the final product (2.30 mg, 5.53 pmol, 3% yield, 97.1% purity, 0.4 FA salt). 'H NMR DMSO-d6400 MHz 5 = ppm 13.12 (br s, 1H), 10.15 (s, 1H), 8.77 - 8.74 (m, 2H), 8.20 (d, J = 5.6 Hz, 1H), 8.18 (s, 0.4H), 7.98 - 7.93 (m, 2H), 7.83 - 7.82 (m, 1H), 7.53 (dd, J= 5.6, 2.0 Hz, 1H), 7.19 (s, 1H), 6.92 (br s, 1H), 4.05 (s, 3H), 2.08 - 2.06 (m, 1H), 0.96 - 0.89 (m, 4H). LCMS (ESI+): m / z 386.1 (M+H)+.Example 370:15-100 °C, 12 h

[0299] To a solution of the chloropyrimidine starting material ( 1.00 g, 5.59 mmol, 1.00 eq) and 2-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.07 g, 4.47 mmol, 0.800 eq) in H2O (20 mL) and dioxane (100 mL) were added Pd(dppf)C12 (408 mg, 558 pmol, 9.98e-2 eq) and K3PO4 (2.37 g, 11.2 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 60 °C for 0.5 h under N2. LC-MS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to afford the product (330 mg, 1.29 mmol, 23% yield) as a solid.

[0300] To a solution of 2-cyclopropylpyridin-4-amine (179 mg, 1.33 mmol, 1.10 eq) in THF (5 mL) was added NaHMDS (1.00 M, 3.03 mL, 2.50 eq) at -10 °C under N2. The mixture was stirred at -10 °C for 0.5 h under N2. The chloropyridine starting intermediate from the previous step (310 mg, 1.21 mmol, 1.00 eq) was added to the mixture at -10 °C. The mixture was stirred at 15 °C for 0.5 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous NH4CI solution (10 mL) at 0 °C and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO₂, PE / THL = 1 / 2) to afford the product (150 mg, 424 pmol, 35% yield).

[0301] To a solution of the material thus obtained (140 mg, 396 pmol, 1.00 eq) and lH-pyrazol-3-ylboronic acid (443 mg, 3.96 mmol, 10.0 eq) in EtOH (5 mL) and H2O (1 mL) were added K3PO4 (168 mg, 791 pmol, 2.00 eq) and Brettphos Pd G3 (35.9 mg, 39.6 pmol, 0.100 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with H2O (30 mL) and extracted with EtOAc / THL (10 mL * 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 urn; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 35% B over 8.0 min) to give the final product (62.3 mg, 152 pmol, 38% yield, 97.7% purity, 0.5 FA salt). 'H NMR DMSO-d6400 MHz 5 = ppm 10.01 (s, 1H), 8.74 (d, J= 5.4 Hz, 1H), 8.69 (s, 1H), 8.62 (br s, 1H), 8.16 - 8.15 (m, 1.5H), 7.92 (dd, J= 5.0, 1.6 Hz, 1H), 7.81 - 7.78 (m, 2H), 7.46 (dd, J= 5.6, 2.0 Hz, 1H), 6.89 (d, J= 2.0 Hz, 1H), 3.99 (s, 3H), 2.02 - 1.96 (m, 1H), 0.89 - 0.87 (m, 4H). LCMS (ESI+): m / z 386.1 (M+H)+.

[0302] To a solution of the bromopyridine starting material (1.00 g, 4.75 mmol, 1.00 eq) in dioxane (20 mL) and H2O (4 mL) were added l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (1.45 g, 5.23 mmol, 1.10 eq), Pd(dppf)C12 (348 mg, 475 pmol, 0.100 eq) and K2CO3 (1.64 g, 11.9 mmol, 2.50 eq) at 25 °C. The mixture was stirred at 100 °C for 1 h under N2 atmosphere. LC-MS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted by water (30 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 100 / 0 to 95 / 5) to afford the crude product (770 mg).1) B2Pin2, Pd(dppf)CI2,

[0303] To a solution of this crude material (300 mg, 1.06 mmol, 1.00 eq) in dioxane (6 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (325 mg, 1.28 mmol, 1.20 eq), Pd(dppf)C12 (77.9 mg, 106 pmol, 0.100 eq), KOAc (209 mg, 2.13 mmol, 2.00 eq) and XPhos (102 mg, 213 pmol, 0.200 eq) at 25 °C. The mixture was stirred at 100 °C for 2 h under N2 atmosphere. Then 4-chloro-N-(2-cyclopropyl-4-pyridyl)pyrimidin-2 -amine (263 mg, 1.06 mmol, 1.00 eq), H2O (1 mL) and K2CO3 (294 mg, 2.13 mmol, 2.00 eq) were added into the reaction mixture at 25 °C. The mixture was stirred at 100 °C for 1 h under N2 atmosphere. LC-MS showed that 4-chloro-N-(2-cyclopropyl-4-pyridyl)pyrimidin-2 -amine was consumed and a peak with the desired MS was detected. The reaction was diluted by water (30 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 100 / 0 to 60 / 40) to afford the product (120 mg, 262 pmol, 25% yield) as a solid.

[0304] The THP-protected intermediate (110 mg, 240 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 4.00 mL, 33.3 eq) was stirred for 0.5 h at 25 °C. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC: (CD24-WePure Biotech XPT C18 (150 * 25 mm, 7 um); flow rate: 25 mL / min; gradient: 8% - 38%, B over 12 min; mobile phase A: H2O (0.1% TFA), mobile phase B: MeCN) to afford the final product (14.9 mg, 29.4 pmol, 12% yield, 96.0% purity, 1.0 TFA salt). 'H NMR DMSO-d6400 MHz 5 = ppm 14.26 (br s, 1H), 11.40 (s, 1H), 8.96 (d, J = 5.0 Hz, 1H), 8.70 (d, J= 4.8 Hz, 1H), 8.44 (d, J= 6.8 Hz, 1H), 8.03 (br s, 1H), 7.93 - 7.90 (m, 2H), 7.81(brs, 1H), 7.75 (dd, J= 5.0, 1.4 Hz, 1H), 6.91 (t, J= 2.4 Hz, 1H,), 2.30 - 2.25 (m, 1H), 1.33 - 1.29 (m, 2H), 1.08 - 1.05 (m, 2H). LCMS (ESI+): m / z 374.1 (M+H)+.Example 372 and 373:Note: the absolute stereochemistry was assigned arbitrarily.

[0305] To a solution of the bromopyridine starting material (3.30 g, 12.1 mmol, 1.00 eq) in dioxane (40 m ) were added tributyl(l-ethoxyvinyl)stannane (7.75 g, 21.5 mmol, 7.25 m, 1.78 eq) and Pd(PPh₃)₄ (1.40 g, 1.21 mmol, 0.100 eq) at 25 °C under N2. The mixture was stirred at 105 °C for 12 h. Then HCI (1.00 M, 24.0 mb, 2.00 eq) was added to the solution, and the mixture was stirred at 50 °C for 2 h. LCMS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by addition of KF (4 M, 30 mb) at 25 °C and stirred for 2 h. H2O (30 mb) was added to the solution and extracted with EtOAc (40 mb * 3). The combined organic layers were dried over Na2SC>4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 2 / 1) to afford the product (800 mg, 3.39 mmol, 28% yield) as a solid.

[0306] To a solution of the ketone intermediate (800 mg, 3.39 mmol, 1.00 eq) in MeOH (10 mL) was added NaBH₄ (430 mg, 11.4 mmol, 3.36 eq) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h. LCMS showed that the starting material was consumed completely and a peak with the desired mass was detected. H2O (10 mL) was added to the solution, and it was extracted with EtOAc (10 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to afford the crude product (800 mg) as a solid.

[0307] A solution of the Boc-protected amino alcohol intermediate (800 mg, 3.36 mmol, 1.00 eq) in HCI / EtOAc (4.00 M, 9.00 mL, 10.7 eq) was stirred at 25 °C for 12 h. LCMS showed that the startingmaterial was consumed completely and a peak with the desired mass was detected. The mixture was concentrated to dryness under a stream of nitrogen to afford the crude product (580 mg, HC1 salt) as a solid. To a solution of this crude material (580 mg, 3.32 mmol, 1.00 eq, HC1 salt) in DMF (10 mL) were added imidazole (678 mg, 9.96 mmol, 3.00 eq) and TBSC1 (751 mg, 4.98 mmol, 613 pL, 1.50 eq) at 25 °C under N2. The mixture was stirred at 25 °C for 1 h. LCMS showed that the starting material was consumed completely and a peak with the desired mass was detected. H2O (30 mL) was added to the solution, then it was extracted with EtOAc (30 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 2 / 1) to afford the product (400 mg, 1.58 mmol, 48% yield) as a solid.

[0308] To a solution of the pyridylamine intermediate (300 mg, 1.19 mmol, 1.00 eq) and 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (269 mg, 1.19 mmol, 1.00 eq) in THF (6 mL) was added NaHMDS (1.00 M, 1.78 mL, 1.50 eq) at -10 °C under N2. The mixture was stirred at 25 °C for 2 h. LCMS showed that the pyridylamine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (10 mL) at 0 °C, diluted with H2O (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to afford the crude product (250 mg) as a solid.

[0309] To a solution of the chloropyridine intermediate (240 mg, 543 pmol, 1.00 eq) in dioxane (4 mL) and H2O (1 mL) were added l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (227 mg, 814 pmol, 1.50 eq), K3PO4 (231 mg, 1.09 mmol, 2.00 eq) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (42.7 mg, 54.3 pmol, 0.100 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 2 h. LCMS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc(10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 1 / 1) to afford the product (140 mg, 251 pmol, 46% yield).

[0310] A solution of the THP -protected intermediate (140 mg, 251 pmol, 1.00 eq) in HCl / EtOAc (4.00 M, 2.00 mL, 31.9 eq) was stirred at 15 °C for 1 h. LCMS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated to dryness under a stream of nitrogen. The residue was purified by prep-HPLC (Phenomenex Gemini C18 75 * 40 mm * 5 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 10% - 40% B over 8.0 min) to afford the product (30.0 mg, 83.5 pmol, 33% yield).

[0311] The racemic material thus obtained (20.0 mg, 55.7 pmol, 1.00 eq) was separated by SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 um); mobile phase: [CO2- EtOH (0.1% NH3H2O)]; B%: 38%, isocratic elution mode) to afford the final product (3.90 mg, 10.8 pmol, 30% yield, 99.9% purity)as a solid and the final product (1.70 mg, 4.54 pmol, 8% yield, 95.9% purity) as a solid. Note: the absolute stereochemistry assignment was made arbitrarily.

[0312] 'H NMR DMSO-d6400 MHz 5 = ppm 13.24 (br s, 1H), 10.50 - 10.36 (m, 1H), 8.90 - 8.82 (m, 3H), 8.40 - 8.37 (m, 1H), 8.15 (s, 1H), 7.95 (s, 1H), 7.80 - 7.75 (m, 2H), 6.98 (s, 1H), 5.43 (br d, J= 4.0 Hz, 1H), 4.82 - 4.76 (m, 1H), 1.45 (d, J= 6.4 Hz, 3H). LCMS (ESI+): m / z 360.1 (M+H)+.

[0313] H NMR DMSO-d6400 MHz 5 = ppm 13.18 (m, 1H), 10.36 (br s, 1H), 8.82 - 8.78 (m, 3H), 8.32 (d, J= 5.6 Hz, 1H), 8.09 (br s, 1H), 7.89 (br s, 1H), 7.74 - 7.71 (m, 2H), 6.92 (br s, 1H), 5.37 (br d, J= 3.2 Hz, 1H), 4.75 - 4.70 (m, 1H), 1.40 (d, J= 6.4 Hz, 3H). LCMS (ESI+): m / z 360.1 (M+H)+.Example 374:

[0314] To a solution of the bromopyridine starting material (2.50 g, 12.3 mmol, 1.00 eq) and cyclopropylboronic acid (5.29 g, 61.6 mmol, 5.00 eq) in dioxane (50 m ) were added K2CO3 (5.11 g, 36.9 mmol, 3.00 eq) and Pd(dppf)C12 (901 mg, 1.23 mmol, 0.100 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the bromopyridine starting material was not consumed completely and a peak with the desired mass was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, DCM / MeOH = 1 / 0 to 0 / 1) to afford the product (1.20 g, 7.31 mmol, 59% yield).

[0315] To a solution of this amine intermediate (1.10 g, 6.70 mmol, 1.00 eq) in THF (30 m ) was added NaHMDS (1.00 M, 10.1 mb, 1.50 eq) at -10 °C under N2. The mixture was stirred at -10 °C for 0.5 h under N2. 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (1.82 g, 8.04 mmol, 1.20 eq) was added to the mixture at -10 °C. The mixture was stirred at 15 °C for 0.5 h under N2. LC-MS showed that the amine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous NH4CI solution (50 mL) at 0 °C and extracted with EtOAc / THF (30 mb * 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc (20 mL * 2), filtered, and the filter cake was collected to afford the product (1.40 g, 3.96 mmol, 59% yield) as a solid.

[0316] To a solution of the chloropyridine intermediate (500 mg, 1.41 mmol, 1.00 eq) and lH-pyrazol-3-ylboronic acid (1.58 g, 14.1 mmol, 10.0 eq) in EtOH (20 mL) and H2O (4 mL) were added K3PO4 (600 mg, 2.83 mmol, 2.00 eq) and Brettphos Pd G3 (128 mg, 141 pmol, 0.100 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the chloropyridine starting material was consumedcompletely and a peak with the desired mass was detected. The mixture was diluted with H2O (30 mL) and extracted with EtOAc / THF (10 mL * 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 urn; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 40% B over 8.0 min) to afford the final product (102 mg, 258 pmol, 18% yield, 97.4% purity). 'H NMR DMSO-d6400 MHz 5 = ppm 13.12 (br s, 1H), 10.19 (s, 1H), 8.79 - 8.70 (m, 3H), 7.99 (br d, J= 3.6 Hz, 1H), 7.86 (br s, 1H), 7.70 (br d, J= 4.6 Hz, 1H), 7.44 (br s, 1H), 7.15 (br s, 1H), 6.92 (br s, 1H), 3.77 (s, 3H), 2.00 (br s, 1H), 0.96 - 0.89 (m, 4H). LCMS (ESI+): m / z 386.1 (M+H)+.Example 375:

[0317] To a solution of the bromopyridine starting material (2.50 g, 12.3 mmol, 1.00 eq) and cyclopropylboronic acid (4.23 g, 49.3 mmol, 4.00 eq) in dioxane (50 m ) were added K2CO3 (5.11 g, 36.9 mmol, 3.00 eq) and Pd(dppf)C12 (901 mg, 1.23 mmol, 0.100 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 8 h under N2. LC-MS showed that the bromopyridine starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (50 m ) and extracted with EtOAc (20 mb * 5). The combined organic layers were washed with brine (10 mb * 2), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, DCM / MeOH = 1 / 0 to 100 / 3) to afford the crude product (600 mg) as a solid.

[0318] To a solution of this amine intermediate (291 mg, 1.77 mmol, 0.800 eq) in THF (8 mb) was added NaHMDS (1.00 M, 2.65 mb, 1.20 eq) at -10 °C under N2. The mixture was stirred at -10 °C for 0.5 h under N2. Then 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (500 mg, 2.21 mmol, 1.00 eq) was added at -10 °C under N2, the mixture was stirred at 15 °C for 0.5 h under N2. LC-MS showed that the reaction was incomplete. NaHMDS (1.00 M, 2.65 mb, 1.20 eq) was added into reaction mixture at -10 °C under N2, the mixture was stirred at 15 °C for 0.5 h under N2. LC-MS showed that the amine starting material was not consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous NLLC1 solution (10 mL) at 0 °C under N2 and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 5 / 1) to afford the crude product (100 mg).

[0319] To a solution of this crude material (90.0 mg, 254 pmol, 1.00 eq) and lH-pyrazol-3-ylboronic acid (142 mg, 1.27 mmol, 5.00 eq) in EtOH (4 mL) and H2O (0.8 mL) were added Brettphos Pd G3 (23.1 mg, 25.4 pmol, 0.100 eq) and K3PO4 (108 mg, 509 pmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 8 h under N2. LC-MS showed that the chloropyridine starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 30% B over 8.0 min) to afford the final product (2.10 mg, 4.74 pmol, 2% yield, 97.5% purity, 1.0 FA salt). ’H NMR DMSO-de 400 MHz 5 = ppm 13.11 (br s, 1H), 8.80 (t, J= 5.2 Hz, 2H), 8.72 (br s, 1H), 8.43 (br d, J= 7.8 Hz, 2H), 8.27 (br d, J= 1.6 Hz, 1H), 8.12 (s, 1H), 8.02 (br d, J= 5.2 Hz, 1H), 7.82 (br s, 1H), 7.77 (d, J= 5.2 Hz, 1H), 6.94 (br s, 1H), 3.95 (s, 3H), 2.15 (br d, J= 7.0 Hz, 1H), 0.92 - 0.85 (m, 4H). LCMS (ESI+): m / z 386.2 (M+H)+.Example 377:

[0320] A mixture of the bromopyridine starting material (1.00 g, 4.75 mmol, 1.00 eq), 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (1.32 g, 4.75 mmol, 1.00 eq), Pd(dppf)C12 (348 mg, 475 pmol, 0.100 eq) and ISfeCCE (1.01 g, 9.50 mmol, 2.00 eq) in dioxane (8 mL) and H2O (2 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 70 °C for 2 h under N2 atmosphere. LC-MS showed that the bromopyridine starting material was consumed completely and apeak with the desired mass was detected. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition; column: CD45 - Waters Xbridge BEH C18 150 * 40 mm * 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 33% - 63% B over 10.0 min) to afford the product (300 mg, 1.01 mmol, 95.0% purity, 21% yield) as a solid.

[0321] A mixture of the material thus obtained (300 mg, 1.01 mmol, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (257 mg, 1.01 mmol, 1.00 eq), Pd(dppf)C12 (74.0 mg, 101 pmol, 0.100 eq), XPhos (48.2 mg, 101 pmol, 0.100 eq) and KOAc (198 mg, 2.02 mmol, 2.00 eq) in dioxane (5 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 100 °C for 2 h under N2 atmosphere. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The crude product (200 mg, in5 mL dioxane) was used to next step directly. Note: The amount of the product was estimated based on the LCMS.

[0322] A mixture of the material from the previous step (200 mg, 536 pmol, 1.00 eq), 4-chloro-N-(2-cyclopropylpyridin-4-yl)pyrimidin-2-amine (132 mg, 536 pmol, 1.00 eq), Pd(dppf)C12 (39.2 mg, 53.6 pmol, 0.100 eq) and Na₂CO₃ (114 mg, 1.07 mmol, 2.00 eq) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 100 °C for 2 h under N2 atmosphere. LC-MS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (15 mL * 3), dried overNa2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition; column: CD45 - Waters Xbridge BEH C 18 150 * 40 mm * 10 um; mobile phase: [H2O (10 mMNELHCOs) - MeCN]; gradient: 32% - 62% B over 15.0 min) to afford the product (50.0 mg, 99.1 pmol, 90.7% purity, 18% yield) as a solid.

[0323] A solution of the THP -protected material (50.0 mg, 99.1 pmol, 90.7% purity, 1.00 eq) in HCl / EtOAc (2.00 M, 4.53 mL, 91.5 eq) was stirred at 25 °C for 2 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD24 -WePure Biotech XPT C18 150 * 25 * 7 um; mobile phase: [H2O (0.05% HC1) - MeCN]; gradient: 10% -40% B over 12.0 min) to afford the final product (14.3 mg, 34.9 pmol, 35% yield, 99.9% purity, 1.0 HC1 salt). 'H NMR DMSO-d6400 MHz 5 = ppm 14.68 (br s, 1H), 11.46 (s, 1H), 8.96 (d, J= 5.2 Hz, 1H), 8.81 (d, J= 2.6 Hz, 1H), 8.60 (d, J= 6.4 Hz, 1H), 8.40 (br d, J= 6.8 Hz, 1H), 8.13 (br s, 1H), 7.92 (br d, J= 6.2 Hz, 1H), 7.84 (d, J= 2.2 Hz, 1H), 7.76 (dd, J= 5.0, 1.4 Hz, 1H), 6.88 (d, J= 2.2 Hz, 1H), 2.38 - 2.35 (m, 1H), 1.29 - 1.26 (m, 2H), 1.11 - 1.08 (m, 2H). LCMS (ESI+): m / z 374.0 (M+H)+.Example 379:

[0324] The reaction was set up in two parallel batches. To a solution of the bromide starting material (20.0 g, 104 mmol, 1.00 eq) and l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (23.8 g, 114 mmol, 1.10 eq) in dioxane (300 mL) and H2O (60 mL) were added Pd(dppf)C12 (7.60 g, 10.4 mmol, 0.100 eq) and K2CO3 (28.7 g, 208 mmol, 2.00 eq) at 15 °C under N2. The reaction mixture was stirred at 70 °C for 4 h. LCMS showed that the bromide starting material was not consumed completely and a peak withthe desired MS was detected. The two batches were combined, diluted with water (100 mL), and extracted with EtOAc (150 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Commercial hexanes: Ethyl acetate = 1 / 0 to 1 / 1) to give the product (39.0 g, 197 mmol, 95% yield, 98.0% purity).

[0325] To a solution of the chloropyridine intermediate (39.0 g, 201 mmol, 1.00 eq) and 4, 4, 5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (61.4 g, 242 mmol, 1.20 eq) in dioxane (400 mL) were added Pd(dppf)C12. CH2C12 (16.5 g, 20.1 mmol, 0.100 eq), KOAc (40.0 g, 403 mmol, 2.00 eq) and XPhos (19.2 g, 40.3 mmol, 0.200 eq) at 15 °C under N2. The reaction mixture was stirred at 80 °C for 2 h. LCMS showed that the chloride starting material was consumed completely and a peak with the desired MS was detected. The crude product (40.0 g) was used in the next step without further work-up and purification.

[0326] To a solution of the crude boronic acid ester intermediate (40.0 g, 140 mmol, 1.00 eq) and 2,4-dichloro-5 -methyl -pyrimidine (27.4 g, 168 mmol, 1.20 eq) in dioxane (400 mL) and H2O (100 mL) were added Pd(dppf)C12. CH2C12 (11.5 g, 14.0 mmol, 0.100 eq) and Na₂CO₃ (29.7 g, 280 mmol, 2.00 eq) at 15 °C under N2. The reaction mixture was stirred at 80 °C for 2 h. LCMS showed that the boronic acid ester starting material was not consumed completely and a peak with the desired MS was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (100 mL) and extracted with EtOAc (500 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / Tetrahydrofuran = 1 / 0 to 1 / 3) to give the product (20.0 g, 53.7 mmol, 38% yield, 76.7% purity) as a solid.

[0327] The reaction was set up in two parallel batches. To a solution of the chloropyrimidine intermediate from the previous step (10.0 g, 35.0 mmol, 1.00 eq) and 2-cyclopropylpyridin-4-amine (5.64 g, 42.0 mmol, 1.20 eq) in dioxane (150 mL) were added diacetoxypalladium (786 mg, 3.50 mmol, 0.100 eq), BINAP (4.36 g, 7.00 mmol, 0.200 eq) and Cs₂CO₃ (22.8 g, 70.0 mmol, 2.00 eq) at 15 °C under N2. The reaction mixture was stirred at 100 °C for 0.5 h. LCMS showed that the chloropyrimidine starting material was not consumed completely and a peak with the desired MS was detected. The two batches were combined and concentrated under reduced pressure to remove solvent. The residue was diluted with water (100 mL) and extracted with EtOAc (500 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 * 150 mm * 15 urn; mobile phase: [H2O (0.2% PA) - MeCN]; gradient: 5% - 35% B over 20.0 min) to afford the final product (9.13 g, 23. 8 mmol, 34.0% yield, 99.9% purity). 'H NMR DMSO-d6400 MHz 5 = ppm 10.08 (s, 1H), 8.74 (d, J= 5.2 Hz, lH), 8.60 (s, lH), 8.19 (s, 1H), 8.14 (d, J = 5.6 Hz, 1H), 7.81 (d, J= 2.2 Hz, 1H), 7.77 (d, J= 1.8 Hz, 1H), 7.61 (dd, J= 5.2, 1.6 Hz, 1H), 7.49 (dd, J= 5.6, 2.0 Hz, 1H), 6.87 (d, J= 2.2 Hz, 1H), 3.92 (s, 3H), 2.30 (s, 3H), 1.99 - 1.92 (m, 1H), 0.86 (d, J = 6.4 Hz, 4H). LCMS (ESI+): m / z 384.2(M+H)+.Example 380:

[0328] A mixture of the chloropyridine starting material (2.00 g, 7.42 mmol, 1.00 eq), 2,4-dichloropyrimidine (884 mg, 5.94 mmol, 0.800 eq), Na₂CO₃ (1.57 g, 14.8 mmol, 2.00 eq) and Pd(dppf)C12 (271 mg, 371 pmol, 0.0500 eq) in dioxane (40 mL) and H2O (2 mL) was stirred at 60 °C for 2 h under N2 atmosphere. LCMS showed that the chloropyridine starting material was consumed completely and apeak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 1 / 0 to 4 / 1) to afford the crude product (1.85 g).

[0329] To a solution of 2-cyclopropylpyridin-4-amine (825 mg, 6.15 mmol, 1.05 eq) in THF (20 mL) was added NaHMDS (1.00 M, 15 mL, 2.56 eq) at -10 °C under N2. The mixture was stirred at -10 °C for 0.5 h under N2. Then the crude material from the previous step (1.50 g, 5.86 mmol, 1.00 eq) in THF (5 mL) was added into the reaction mixture at -10 °C under N2, the reaction mixture was stirred at 15 °C for 0.5 h under N2. LC-MS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous NH4CI solution (30 mL) at 0 °C and extracted with EtOAc (15 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes / Ethyl acetate = 1 / 0 to 0 / 1) to afford the product (550 mg, 1.55 mmol, 26% yield) as a solid.

[0330] To a solution of the chloropyridine intermediate (550 mg, 1.55 mmol, 1.00 eq), 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (1.30 g, 4.66 mmol, 3.00 eq) and K2CO3 (430 mg, 3.11 mmol, 2.00 eq) in dioxane (10 mL) and H2O (1 mL) was added Brettphos Pd G3 (141 mg, 155 pmol, 0.100 eq) at 15 °C under N2. The reaction mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes / Ethyl acetate = 1 / 0 to 0 / 1) to afford the product (550 mg, 1.17 mmol, 75% yield) as a solid.

[0331] A solution of the THP -protected intermediate (50.0 mg, 106 pmol, 1.00 eq) in pyridine hydrochloride (1.00 g, 8.65 mmol, 27.1 eq) was stirred at 170 °C for 1 h. LC-MS showed that the starting material not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: PhenomenexlunaC18 100 * 40 mm * 5 um; mobile phase: [H2O (0.04% HC1) - MeCN]; gradient: 1% - 30% B over 8.0 min) to afford the final product (40.9 mg, 88.9 pmol, 28% yield, 96.6% purity, 2.0 HC1 salt). 'H NMR DMSO-d6400 MHz 5 = ppm 14.59 (br s, 1H), 11.51 (br s, 1H), 11.45 (s, 1H), 8.91 (d, J= 5.2 Hz, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.41 (d, J= 6.8 Hz, 1H), 8.10 (br s, 1H), 8.02 (d, J= 5.6 Hz, 1H), 7.94 (br d, J= 6.0 Hz, 1H), 7.78 (d, J= 2.0 Hz, 1H), 6.84 (d, J= 2.0 Hz, 1H), 2.38 - 2.34 (m, 1H), 1.30 - 1.26 (m, 2H), 1.11 - 1.09 (m, 2H). LCMS (ESI+): m / z 372.1 (M+H)+.Example 381:

[0332] A solution of example 374 (90.0 mg, 234 pmol, 1.00 eq) in pyridine hydrochloride (270 mg, 2.34 mmol, 10.0 eq) was stirred at 170 °C for 0.5 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was triturated with MeOH (5 mL * 2), filtered, and the filter cake was collected to afford the final product (37.9 mg, 81.3 pmol, 35% yield, 95.3% purity, 2.0 HC1 salt). ’H NMR DMSO-de 400 MHz 5 = ppm 10.31 (br s, 1H), 8.81 (t, J= 5.6 Hz, 2H), 8.66 (s, 1H), 8.01 (dd, J= 5.2, 1.6 Hz, 1H), 7.83 (br s, 1H), 7.80 (d, J= 5.2 Hz, 1H), 7.12 (s, 1H), 6.96 (s, 1H), 6.59 (br s, 1H), 1.95 - 1.89 (m, 1H), 1.05 - 1.01 (m, 2H), 0.84 - 0.81 (m, 2H). LCMS (ESI+): m / z 372.1 (M+H)+.Example 382:

[0333] To a mixture of the chloropyrimidine starting material (1.11 g, 7.42 mmol, 1.00 eq) and 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (2.00 g, 7.42 mmol, 1.00 eq) in dioxane (10 mL) and H2O (2 mL) were added K3PO4 (3.15 g, 14.8 mmol, 2.00 eq) and Pd(dppf)C12 (543 mg, 742 pmol, 0.100 eq) at 15 °C under N2. The mixture was stirred at 60 °C for 0.5 h under N2. LC-MS showed that the chloropyrimidine starting material was consumed completely and a peak with the desiredmass was detected. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Commercial hexanes / tetrahydrofuran = 1 / 0 to 1 / 2) to afford the product (1.10 g, 4.30 mmol, 58% yield) as a solid.

[0334] To a mixture of the material thus obtained (500 mg, 1.95 mmol, 1.00 eq) and 2-cyclopropylpyridin-4-amine (262 mg, 1.95 mmol, 1.00 eq) in THF (5 mL) was added NaHMDS (1.00 M, 4.88 mL, 2.50 eq) at -10 °C under N2. The mixture was stirred at 15 °C for 1 h under N2. LC-MS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by H2O (5 mL) at 0 °C. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Commercial hexanes / tetrahydrofuran = 1 / 2) to afford the product (165 mg, 466 pmol, 24% yield) as a solid.

[0335] To a mixture of the chloropyridine intermediate from the previous step (155 mg, 439 pmol, 1.00 eq) and l-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (609 mg, 2.19 mmol, 5.00 eq) in dioxane (3 mL) and H2O (0.6 mL) were added Brettphos Pd G3 (39.7 mg, 43.8 pmol, 0.100 eq) and K3PO4 (186 mg, 876 pmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 12 h. LC-MS showed that chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with H2O (15 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product (350 mg) as a yellow solid.

[0336] To a solution of the THP-protected intermediate (340 mg, 724 pmol, 1.00 eq) in THF (3 mL) was added HC1 (1.00 M, 724 pL, 1.00 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. Part of the crude material was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 3 um; mobile phase: [H2O (0.04% HC1) - MeCN]; gradient: 15% - 40% B over 18.0 min) to afford the final product (2.50 mg, 5.43 pmol, 99.5 % purity, 2.0 HC1). 'HNMR DMSO-d6400 MHz 5 = ppm 14.59 (br d, J= 0.8 Hz, 1H), 11.40 (s, 1H), 8.92 (d, J= 5.0 Hz, 1H), 8.43 (br d, J= 6.8 Hz, 1H), 8.29 (s, 1H), 8.12 (br s, 1H), 7.96 (d, J= 5.0 Hz, 1H), 7.93 (br d, J = 6.4 Hz, 1H), 7.81 (br s, 1H), 7.47 (s, 1H), 6.93 (s, 1H), 4.03 (s, 3H), 2.37 - 2.33 (m, 1H), 1.34 - 1.29 (m, 2H), 1.12 (br dd, J= 4.2, 2.2 Hz, 2H). LCMS (ESI+): m / z 386.2 (M+H)+.Example 384:

[0337] To a solution ofthe starting material (900 mg, 4.48 mmol, 1.00 eq) in dioxane (18 mL) were added tert-butyl carbamate (629 mg, 5.37 mmol, 1.20 eq), Pd₂(dba)₃ (410 mg, 448 pmol, 0.100 eq), Cs₂CO₃ (2.92 g, 8.95 mmol, 2.00 eq) and Xantphos (518 mg, 895 pmol, 0.200 eq) at 25 °C. The mixture was stirred at 100 °C for 16 h under N2 atmosphere. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was quenched by water (30 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 40 / 60) to afford the crude product (1.00 g).

[0338] To a solution of the Boc-protected intermediate (900 mg, 3.79 mmol, 1.00 eq) in DCM (10 mL) was added TFA (4.61 g, 40.4 mmol, 3.00 mL, 10.7 eq) at 25 °C. The mixture was stirred at 40 °C for 16 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (CD16-Waters Atlantis T3 (150 * 30 mm, 5 um); flow rate: 25 mL / min; gradient: 5% - 35%, B over 10 min; mobile phase A: H2O (10 mM NH4HCO3), mobile phase B: MeCN) to afford the product (350 mg, 2.55 mmol, 67% yield) as a solid.

[0339] To a solution ofthe aminopyridine intermediate (300 mg, 2.19 mmol, 1.00 eq) in THF (4 mL) was added dropwise NaHMDS (1.00 M, 2.62 mL, 1.20 eq) at 0 °C under N2 atmosphere. The mixture was stirred for 30 min at 0 °C. Then 2-chloro-4-(2-chloro-4-pyridyl)pyrimidine (593 mg, 2.62 mmol, 1.20 eq) in THF (4 mL) was added into the reaction mixture at 0 °C. Then the mixture was allowed to warm to 25 °C and stirred for another 1 h. LC-MS showed that the aminopyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by water (10 mL), then extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (Commercial hexanes / Ethyl acetate = 0 / 1) to afford the product (150 mg, 459 pmol, 21% yield) as a solid.

[0340] To a solution of the chloropyridine intermediate (140 mg, 428 pmol, 1.00 eq) in dioxane (4 mL) and H2O (1 mL) were added l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)pyrazole (132 mg, 471 pmol, 1.10 eq), XPhos Pd G2 (33.7 mg, 42.8 pmol, 0.100 eq) and K3PO4 (182 mg, 857 pmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 1 h under N2 atmosphere. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product (150 mg) as a solid.

[0341] The THP-protected intermediate (140 mg, 316 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 5.00 mL, 31.6 eq) was stirred at 25 °C for 1 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (CD04-Welch Ultimate C18 (150 * 25 mm, 7 um); flow rate: 25 mL / min; gradient: 1% - 31%, B over 10 min; mobile phase A: H2O (0.225% PA), mobile phase B: MeCN) to afford the final product (36.2 mg, 83.9 pmol, 27% yield, 94.9% purity, 1.1 FA salt). ’H NMR DMSO-d6400 MHz 5 = ppm 10.01 (s, 1H), 8.76 (dd, J= 10.0, 5.0 Hz, 2H), 8.67 (s, 1H), 8.14 (s, 1.1H), 7.99 (d, J = 5.0 Hz, 1H), 7.93 (d, J = 5.6 Hz, 1H), 7.81 (br s, 1H), 7.66 (d, J = 5.2 Hz, 1H), 7.40 (s, 1H), 6.99 (d, J= 5.6 Hz, 1H), 6.91 (d, J= 1.8 Hz, 1H), 3.02 (s, 6H). LCMS (ESI+): m / z 359.2 (M+H)+.Example 388:,

[0342] To a mixture of example 18 (200 mg, 515 pmol, 1.00 eq, 0.9 HC1 salt) and tert-butyl-(2-iodoethoxy)-dimethyl-silane (177 mg, 618 pmol, 1.20 eq) in DMF (2 mL) was added Cs₂CO₃ (336 mg, 1.03 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 16 h. LC-MS showed that the starting material consumed completely and a peak with the desired mass was detected. The suspension was filtered, the filter cake was washed with DMF (1 mL), and the filtrate was purified by prep-HPLC (column: CD24 - WePure Biotech XPT C18 150 * 25 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 21% - 41% B over 10.0 min) to afford the final product (40.3 mg, 98.2 pmol, 19% yield, 97.4% purity). 'H NMR DMSO-d6400 MHz 5 = ppm 10.22 (s, 1H), 8.77 (d, J= 5.2 Hz, 2H), 8.68 (s, 1H), 8.22 (d, J= 5.6 Hz, 1H), 7.98 (dd, J= 5.2, 1.6 Hz, 1H), 7.85 (dd, J= 10.0, 2.0 Hz, 2H), 7.69 (d, J= 5.2 Hz, 1H), 7.59 (dd, J= 5.6, 2.0 Hz, 1H), 6.88 (d, J= 2.4 Hz, 1H), 4.98 (br s, 1H), 4.23 (t, J= 5.6 Hz, 2H), 3.82 (br s, 2H), 2.05 (quin, J = 6.4 Hz, 1H), 0.97 - 0.87 (m, 4H). LCMS (ESI+): m / z 400.2 (M+H)+.Example 387:

[0343] To a mixture of example 18 (200 mg, 515 pmol, 1.00 eq, 0.9 HCI salt) and tert-butyl-(3-iodopropoxy)-dimethyl-silane (186 mg, 618 pmol, 1.20 eq) in DMF (2 mL) was added Cs₂CO₃ (336 mg, 1.03 mmol, 2.00 eq) at 25 °C. The mixture was stirred at 100 °C for 16 h. LC-MS showed that the starting material consumed completely and a peak with the desired mass was detected. The reaction was quenched by H2O (5 mL) and extracted with ethyl acetate (3 mL * 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced to afford the product (200 mg, 379 pmol, 74% yield).

[0344] A mixture of the TBS-protected material (200 mg, 379 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 6.00 mL, 31.7 eq) was stirred at 25 °C for 16 h. LC-MS showed that the starting material consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD24 - WePure Biotech XPT C18 150 * 25 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN; gradient: 23% -43%B over 10.0 min) to afford the final product (18.7 mg, 44.6 pmol, 12% yield, 98.6% purity). ’HNMR DMSO-d6400 MHz 5 = ppm 10.22 (s, 1H), 8.77 (d, J= 5.2 Hz, 2H), 8.66 (s, 1H), 8.22 (d, J= 5.6 Hz, 1H), 7.98 (dd, J= 5.2, 1.6 Hz, 1H), 7.86 - 7.85 (m, 2H), 7.70 (d, J = 5.2 Hz, 1H), 7.60 (dd, J = 5.6, 2.0 Hz, 1H), 6.88 (d, J= 2.0 Hz, 1H), 4.65 (br s, 1H), 4.25 (t, J= 7.2 Hz, 2H), 3.46 - 3.40 (m, 2H), 2.07 - 1.97 (m, 3H), 0.91 (d, J= 6.4 Hz, 4H). LCMS (ESI+): m / z 414.2 (M+H)+.Example 389:

[0345] To a solution of 4-methoxypyrazole (0.900 g, 9.17 mmol, 1.00 eq) in THF (10 mL) were added PPTS (2.31 g, 9.17 mmol, 1.00 eq) and DHP (2.32 g, 27.5 mmol, 2.52 mL, 3.00 eq) at 15 °C. The mixture was stirred at 60 °C for 2 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. Theresidue was diluted with H2O (30 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 15% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to afford the product (1.75 g, 9.00 mmol, 98% yield, 93.8% purity).

[0346] To a solution of THP -protected 4-methoxypyrazole (1.00 g, 5.49 mmol, 1.00 eq) in THF (10 mL) was added dropwise n-BuLi (2.50 M, 3.29 mL, 1.50 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h under N2. Then triisopropyl borate (2.06 g, 11.0 mmol, 2.52 mL, 2.00 eq) was added, the mixture was stirred at -78 °C for 1 h under N2. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by H2O (20 mL) at 0 °C and extracted with EtOAc (10 mL * 3). The aqueous phase was lyophilization, then solid was washed by THF (30 mL), filtered and the cake was discarded. The filtrate was concentrated to afford the crude product (960 mg, 4.25 mmol, 77% yield) as a solid.

[0347] To a solution of (4-methoxy-2-tetrahydropyran-2-yl-pyrazol-3-yl)boronic acid (419 mg, 1.85 mmol, 1.20 eq) in dioxane (4 mL) and H2O (1 mL) were added the 4-(2-chloropyridin-4-yl)-N-(2-cyclopropylpyridin-4-yl)pyrimidin-2 -amine (500 mg, 1.54 mmol, 1.00 eq), XPhos Pd G2 (122 mg, 154 pmol, 0.100 eq) and K3PO4 (983 mg, 4.63 mmol, 3.00 eq) at 15 °C. The mixture was stirred at 100 °C for 2 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 37% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to afford the product (320 mg, 554 pmol, 36% yield, 81.3% purity).

[0348] To a solution ofthus obtained intermediate (50.0 mg, 106 pmol, 1.00 eq) in THF (2 mL) was added HC1 (1.00 M, 0.500 mL, 4.70 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. LC-MS showed that the starting material was consumed completely and a peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 urn; mobile phase: [H2O (0.04% HC1) - MeCN]; gradient: 1% -30% B over 8.0 min) to afford the final product (10.7 mg, 23.0 pmol, 22% yield, 98.7% purity, 2.0 HC1 salt). 'H NMR DMSO-d6400 MHz 5 = ppm 14.70 (br s, 1H), 11.42 (s, 1H), 8.97 (d, J= 5.2 Hz, 1H), 8.84 (d, J= 5.6 Hz, 1H), 8.63 (s, 1H), 8.43 (d, J= 7.0 Hz, 1H), 8.09 - 8.05 (m, 1H), 8.03 (br s, 2H), 7.92 (d, J= 5.2 Hz, 1H), 7.69 (s, 1H), 3.87 (s, 3H), 2.38 - 2.32 (m, 1H), 1.34 - 1.24 (m, 2H), 1.13 - 1.05 (m, 2H). LCMS (ESI+): m / z 386.1 (M+H)+.Example 390:

[0349] To a solution of the boronic ester starting material (3.70 g, 10.0 mmol, 1.00 eq), 2,4-dichloro-5-methylpyrimidine (1.63 g, 10.0 mmol, 1.00 eq) in dioxane (30 mL) and H2O (6 mL) were added K2CO3 (2.77 g, 20.0 mmol, 2.00 eq) and Pd(dppf)C12. CH2C12 (818 mg, 1.00 mmol, 0.100 eq) at 15 °C. The mixture was stirred at 80 °C for 2 h under N2. LC-MS showed that the boronic acid ester starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Commercial hexanes / Ethyl acetate= 1 / 0 to 1 / 2) to afford the product (1.40 g, 3.79 mmol, 38% yield).

[0350] To a solution of 2-cyclopropylpyridin-4-amine (254 mg, 1.89 mmol, 1.00 eq) in THF (3 mL) was added NaHMDS (1.00 M, 5.68 mL, 3.00 eq) at -78 °C under N2. The mixture was stirred at 15 °C for 0.25 h under N2. The chloropyrimidine intermediate from the previous step (700 mg, 1.89 mmol, 1.00 eq) in THF (3 mL) was added to the mixture at -78 °C under N2. The mixture was stirred at 15 °C for 0.25 h under N2. LC-MS showed that the chloropyrimidine starting material was not consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous NH4CI solution (30 mL) at 0 °C and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Commercial hexanes / THF = 1 / 0 to 1 / 3) to afford the product (200 mg, 428 pmol, 23% yield).

[0351] A solution of the THP -protected intermediate (200 mg, 428 pmol, 1.00 eq) and TFA (3.07 g, 26.9 mmol, 2.00 mL, 62.9 eq) in DCM (2 mL) was stirred at 15 °C for 12 h. LC-MS showed that the starting material was not consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure and then adjusted to pH = 8 with saturated aqueous Na₂CO₃ solution. The resulting mixture was purified by prep-HPLC (column: Phenomenex luna Cl 8 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 30% B over 8.0 min) to afford the final product (27.6 mg, 67.2 pmol, 16% yield, 98.9% purity, 0.5 FA salt). NMR DMSO-d6400 MHz 5 = ppm 13.05 (br s, 1H), 10.12 (s, 1H), 8.66 - 8.56 (m, 2H), 8.15 (s, 0.5H), 8.14 (s, 1H), 7.77 (br s, 1H), 7.61 (d, J= 1.6 Hz, 1H), 7.51 (dd, J= 5.6, 1.8 Hz, 1H), 7.26 (br d, J= 4.4 Hz, 1H), 6.83 (br s, 1H), 2.35 (br s, 3H), 1.98 (s, 3H), 1.95 - 1.85 (m, 1H), 0.92 - 0.79 (m, 4H). LCMS (ESI+): m / z 384.3 (M+H)+.Example 391:

[0352] To a mixture of example 18 (100 mg, 281 pmol, 1.00 eq) and 2-chloro-N-methyl-acetamide (39.3 mg, 366 pmol, 1.30 eq in DMF (1 mL) were added Cs₂CO₃ (183 mg, 563 pmol, 2.00 eq) and Nal (4.22 mg, 28.1 pmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 16 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The suspension was filtered, the filter cake was washed with DMF (1 mL) and the filtrate was purified by prep-HPLC (CD04 - Welch Ultimate C18 150 * 25 mm * 7 um; mobile phase: [H2O (0.225% FA) - MeCN]; gradient: 0% - 30% B over 10.0 min) to afford the final product (13.7 mg, 28.3 pmol, 10% yield, 96.8% purity, 0.9 FA salt). 'H NMR DMSO-d6400 MHz 5 = 10.23 (s, 1H), 8.79 - 8.76 (m, 2H), 8.65 (s, 1H), 8.22 (d, J = 5.6 Hz, 1H), 8.16 (s, 0.9H), 8.06 (br d, J= 4.4 Hz, 1H), 7.99 (dd, J= 5.2, 1.6 Hz, 1H), 7.83 (dd, J= 10.8, 2.0 Hz, 2H), 7.69 (d, J= 5.2 Hz, 1H), 7.60 (dd, J= 5.6, 2.0 Hz, 1H), 6.92 (d, J= 2.4 Hz, 1H), 4.88 (s, 2H), 2.65 (d, J= 4.4 Hz, 3H), 2.02 (quin, J= 6.4 Hz, 1H), 0.90 (d, J= 6.4 Hz, 4H). LCMS (ESI+): m / z 427.1 (M+H)+.Note: two isomers were assigned arbitrarily.

[0353] To a solution of the chloropyridine starting material (210 mg, 618 pmol, 1.00 eq) and (4-methylsulfmylphenyl)boronic acid (114 mg, 618 pmol, 1.00 eq) in dioxane (5 mL) and H2O (1 mL) were added K2CO3 (171 mg, 1.24 mmol, 2.00 eq) and Pd(dppf)C12 (45.2 mg, 61.8 pmol, 0.100 eq) at 25 °C. The mixture was stirred at 100 °C for 1 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with H2O (15 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD50 - unihybrid C18 150 * 25 * 10 um; mobile phase: [H2O (0.225% FA) -MeCN]; gradient: 2% - 32% B over 13.0 min) to afford the product (115 mg, 235 pmol, 38% yield, 96.1% purity, 0.6 FA salt)

[0354] The racemate was separated by SFC: (Chiral - Whelk - 30 - (s, s) WHELK - 01 (250 mm * 30 mm, 10 um); mobile phase: [CO2 - EtOH / MeCN = 7 / 3 (0.1%NH3H2O)]; B%: 45%, isocratic elution mode)to afford a 1stisomer (34.3 mg, 76.2 pmol, 29% yield, 98.6% purity) and a second isomer (25.0 mg, 55.3 pmol, 21% yield, 98.1% purity). Note: the absolute stereochemistry configuration was assigned arbitrarily. 'H NMR DMSO-d6400 MHz 5 = ppm 10.33 (s, 1H), 8.92 (d, J= 5.2 Hz, 1H), 8.82 (d, J= 5.2 Hz, 1H), 8.69 (s, 1H), 8.47 - 8.36 (m, 3H), 8.14 (d, J= 4.8 Hz, 1H), 7.92 - 7.83 (m, 4H), 7.71 (br d, J= 4.4 Hz, 1H), 4.90 - 4.77 (m, 4H), 4.33 (quin, J= 7.6 Hz, 1H), 2.82 (s, 3H). LCMS (ESI+): m / z 444.1 (M+H)+.’H NMR DMSO-d6400 MHz 5 = ppm 10.33 (s, 1H), 8.92 (d, J= 5.2 Hz, 1H), 8.82 (d, J= 5.2 Hz, 1H), 8.68 (s, 1H), 8.44 - 8.39 (m, 3H), 8.14 (br d, J= 4.8 Hz, 1H), 7.90 - 7.86 (m, 4H), 7.71 (br d, J= 4.4 Hz, 1H), 4.89 - 4.78 (m, 4H), 4.33 (quin, J= 7.6 Hz, 1H), 2.82 (s, 3H). LCMS (ESI+): m / z 444.2 (M+H)+. Example 395:

[0355] To a solution of 2-bromopyridin-4-amine (5.00 g, 28.9 mmol, 1.00 eq) in THF (100 mL) were added the chloropyridine starting material (7.84 g, 34.7 mmol, 1.20 eq) and NaHMDS (1.00 M, 43.4 mL, 1.50 eq) at -10 °C. The mixture was stirred at 15 °C for 1 h under N2. LCMS showed that the chloropyridine starting material was consumed completely, and a peak with the desired mass was detected. The reaction was quenched by saturated NH4CI solution (100 mL) at 0 °C and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 20-30% Dichloromethane / Petroleum ether gradient @ 60 mL / min) to afford the product (4.20 g, 9.37 mmol, 34% yield, 80.9% purity) as a solid.

[0356] To a solution of the bromopyridine intermediate (1.80 g, 4.96 mmol, 1.00 eq) in dioxane (20 mL) were added Pd(PPh₃)₄ (574 mg, 496 pmol, 0.100 eq) and tributyl(l-ethoxyvinyl)stannane (7.17 g, 19.9 mmol, 6.71 mL, 4.00 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LCMS showed that the bromopyridine starting material was not consumed completely, and a peak with the desired mass was detected. The reaction was quenched by saturated KF solution (50 mL) at 15 °C, stirred at 15 °C for 0.5 h, and extracted with EtOAc (50 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / THF = 1 / 0 to 1 / 1) to afford the product (700 mg, 1.98 mmol, 40% yield).

[0357] To a solution of the enol ether intermediate (690 mg, 1.95 mmol, 1.00 eq) in THF (7 mL) was added HC1 (5.05 g, 12.0 M, 71.0 eq at 15 °C. The mixture was stirred at 15 °C for 1 h. LCMS showed that the starting material was consumed completely, and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and lyophilized to afford the crude product (550 mg) as a solid.

[0358] To a solution of the crude material from the previous step (540 mg, 1.66 mmol, 1.00 eq) and 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (692 mg, 2.49 mmol, 1.50 eq) in dioxane (8 mL) and H2O (2 mL) were added XPhos Pd G2 (130 mg, 166 pmol, 0.100 eq) and K3PO4 (704 mg, 3.32 mmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 4 h. LCMS showed that the chloropyridine starting material was consumed completely, and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Commercial hexanes / THF = 99 / 1 to 1 / 1) to afford the product (450 mg, 1.02 mmol, 64% yield) as a solid.

[0359] A solution of the THP -protected intermediate (80.0 mg, 181 pmol, 1.00 eq) in HCl / EtOAc (4.00 M, 2.00 mL) was stirred at 15 °C for 1 h. LCMS showed that the starting material was consumed completely, and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with the saturated Na₂CO₃ to adjust to pH = 10 at 0 °C. The resulting solution was purified by prep-HPLC (column: Phenomenex luna Cl 8 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 30% B over 8.0 min) to afford the final product (4.20 mg, 11.5 pmol, 6% yield, 97.7% purity). 'H NMR DMSO-d6400 MHz 5 = ppm 13.17 (br s, 1H), 10.63 (br s, 1H), 8.84 - 8.74 (m, 3H), 8.56 (d, J= 5.6 Hz, 1H), 8.52 - 8.43 (m, 1H), 8.18 - 7.98 (m, 2H), 7.93 - 7.78 (m, 2H), 6.94 - 6.89 (m, 1H), 2.64 (s, 3H). LCMS (ESI+): m / z 358.2 (M+H)+.Example 394:

[0360] To a solution of the starting material (400 mg, 906 pmol, 1.00 eq) in THF (5 mL) was added MeMgBr (3.00 M, 906 pL, 3.00 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h under N2. LCMS showed that the starting material was consumed completely, and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (5 mL) at 0 °C, and it was concentrated under reduced pressure to afford the crude product (500 mg) as a solid.

[0361] A mixture of the THP -protected intermediate (200 mg, 437 pmol, 1.00 eq) in HCI / EtOAc (4.00 M, 5.00 mL) was stirred at 15 °C for 1 h. LCMS showed that the starting material was not consumed completely, and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was diluted with saturated Na₂CO₃ to adjust to pH = 10 at 0 °C. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 25% B over 8.0 min) to afford the final product (22.2 mg, 52.9 pmol, 12% yield, 95.6% purity, 0.6 FA salt). 'HNMR DMSO-d6400 MHz 5 = ppm 13.14 - 13.05 (m, 1H), 10.32 (s, 1H), 8.79 (d, J= 5.2 Hz, 2H), 8.69 (br s, 1H), 8.32 (d, J= 5.6 Hz, 1H), 8.26 (s, 1H), 8.14 (s, 0.6H), 8.08 (br d, J= 4.4 Hz, 1H), 7.82 (br s, 1H), 7.73 (d, J= 4.8 Hz, 1H), 7.68 (dd, J= 5.4, 1.8 Hz, 1H), 6.95 (br s, 1H), 5.23 (br s, 1H), 1.46 (s, 6H). LCMS (ESI+): m / z 374.3 (M+H)+.

[0362] To a solution of the starting material (2.00 g, 12.2 mmol, 1.00 eq) in DMF (30 mL) were added Mel (2.60 g, 18.3 mmol, 1.14 mL, 1.50 eq) and K2CO3 (3.38 g, 24.5 mmol, 2.01 eq) at 15 °C. The mixture was stirred at 60 °C for 2 h. LC-MS showed the starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (20 mL * 3). The organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to afford the product (1.60 g, 8.99 mmol, 74% yield).

[0363] To a solution of the intermediate thus obtained (1.40 g, 7.86 mmol, 1.00 eq) and 1-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (3.94 g, 14.2 mmol, 1.80 eq) in dioxane (20 mL) and H2O (4 mL) were added Pd(dppf)C12 (575 mg, 786 pmol, 0.100 eq) and Na₂CO₃ (1.67 g, 15.7 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 80 °C for 12 h under N2. LC-MS showed that the dichloropyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (50 mL) and extracted with EtOAc (50 mL * 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 1 / 0 to 88 / 12) to afford the product (1.50 g, 5.11 mmol, 65% yield).

[0364] To a solution of the material from the previous step (100 mg, 340 pmol, 1.00 eq) and 4, 4, 5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (346 mg, 1.36 mmol, 4.00 eq) in dioxane (5 m ) were added Pd(dppf)C12 (24.9 mg, 34.0 pmol, 0.100 eq), KO Ac (100 mg, 1.02 mmol, 3.00 eq) and Xphos (16.2 mg, 34.0 pmol, 0.100 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The crude product (130 mg) was used into the next step without further purification.

[0365] To a solution of the crude boronic acid ester intermediate (104 mg, 270 pmol, 1.00 eq) and 4-chloro-N-(2-cyclopropyl-4-pyridyl)pyrimidin-2-amine (73.3 mg, 297 pmol, 1.10 eq) in dioxane (8 m ) and H2O (2 mb) were added Pd(dppf)C12 (19.8 mg, 27.0 pmol, 0.100 eq) and Na₂CO₃ (57.2 mg, 540 pmol, 2.00 eq) at 15 °C. The mixture was stirred at 80 °C for 12 h under N2. EC-MS showed that the boronic acid ester starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mb * 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous ISfeSCh, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / THb = 1 / 0 to 0 / 1) to afford the crude product (120 mg).

[0366] A solution of the THP-protected intermediate (100 mg, 213 pmol, 1.00 eq) in HCl / EtOAc (4.00 M, 2.00 mb, 37.6 eq) was stirred at 15 °C for 1 h. EC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.04% HC1) - MeCN]; gradient: 1% - 30% B over 8.0 min) to afford the final product (22.4 mg, 47.7 pmol, 22% yield, 97.6% purity, 2.0 HC1 salt). ’H NMR DMSO-d6400 MHz d = ppm 14.97 (br s, 1H), 11.45 (s, 1H), 8.95 (d, J= 5.0 Hz, 1H), 8.64 (d, J= 5.0 Hz, 1H), 8.42 (br d, J= 7.0 Hz, 1H), 8.07 (br s, 1H), 7.98 (br d, J= 6.0 Hz, 1H), 7.82 (d, J= 5.0 Hz, 1H), 7.79 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 5.0 Hz, 1H), 7.00 (d, J= 2.0 Hz, 1H), 3.61 (s, 3H), 2.43 - 2.31 (m, 1H), 1.36 -1.27 (m, 2H), 1.15 - 1.06 (m, 2H). ECMS (ESI+): m / z 386.1 (M+H)+.Example 397:

[0367] A mixture of the 2-bromo-4-chloropyridine (2.00 g, 10.4 mmol, 1.00 eq), l-tetrahydropyran-2-yl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (2.89 g, 10.4 mmol, 1.00 eq), Pd(dppf)C12 (760 mg, 1.04 mmol, 0.100 eq) and Na₂CO₃ (2.20 g, 20.8 mmol, 2.00 eq) in dioxane (16 mL) and H2O (4 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 70 °C for 2 h under N2 atmosphere. LCMS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / Ethyl acetate = 9 / 1 to 17 / 3) to afford the crude product (1.50 g, 61.8% purity).

[0368] A mixture of the crude material from the previous step (1.35 g, 3.17 mmol, 61.8% purity, 1.00 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (804 mg, 3.17 mmol, 1.00 eq), Pd(dppf)C12 (232 mg, 317 pmol, 0.100 eq), XPhos (151 mg, 317 pmol, 0.100 eq) and KOAc (621 mg, 6.33 mmol, 2.00 eq) in dioxane (10 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 100 °C for 2 h under N2 atmosphere. LCMS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The crude product (1.00 g, in 10 mL dioxane) was used in next step directly. Note: The amount of the product was estimated based on LCMS.

[0369] A mixture of the boronic acid ester from the previous step (1.00 g, 2.82 mmol, 1.00 eq), 2,4-dichloro-5 -fluoro-pyrimidine (470 mg, 2.82 mmol, 1.00 eq), Pd(dppf)C12 (206 mg, 282 pmol, 0.100 eq), Na₂CO₃ (597 mg, 5.63 mmol, 2.00 eq) in dioxane (20 mL) and H2O (5 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 100 °C for 2 h under N2 atmosphere. LCMS showed that the boronic acid ester starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The residue was purified by column chromatography (SiCE, Commercial hexanes / Ethyl acetate = 9 / 1 to 17 / 3) to afford the crude product (620 mg, 91.7% purity) as a solid.

[0370] A mixture of the chloropyrimidine intermediate (620 mg, 1.58 mmol, 91.7% purity, 1.00 eq), 2-cyclopropylpyridin-4-amine (212 mg, 1.58 mmol, 1.00 eq), Pd₂(dba)₃ (145 mg, 158 pmol, 0.100 eq), Cs₂CO₃ (1.03 g, 3.16 mmol, 2.00 eq) and XPhos (75.3 mg, 158 pmol, 0.100. e ) in dioxane (10 mL) was degassed and purged with N2 three times at 25 °C, and it was stirred at 100 °C for 2 h under N2 atmosphere. LCMS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried overNa2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Commercial hexanes / Ethyl acetate = 9 / 1) to afford the crude product (550 mg, 85.1% purity) as a white solid.

[0371] A mixture of the THP-protected intermediate (100 mg, 85.1% purity, 186 pmol, 1.00 eq) in HCl / EtOAc (2.00 M, 2.00 mL, 21.5 eq) was stirred at 25 °C for 2 h. LCMS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: CD24 - WePure Biotech XPT C18 150 * 25 * 7 um; mobile phase: [H2O (0.05% HC1) - MeCN]; gradient: 7% - 37% B over 11.0 min) to afford the final product (53.6 mg, 120 pmol, 65%yield, 100% purity, 2.0 HC1 salt). ’HNMR DMSO-d6400 MHz 5 = ppm 11.52 (s, 1H), 9.05 (d, J= 2.8 Hz, 1H), 8.85 (d, J= 5.4 Hz, 1H), 8.61 (s, 1H), 8.42 (d, J= 6.8 Hz, 1H), 8.02 (br s, 1H), 7.91 - 7.86 (m, 3H), 6.95 (d, J= 2.2 Hz, 1H), 2.38 - 2.33 (m, 1H), 1.32 - 1.28 (m, 2H), 1.10 - 1.07 (m, 2H). LCMS (ESI+): m / z 374.0 (M+H)+.Example 427:

[0372] A solution of the starting material (200 mg, 426 pmol, 1.00 eq) in pyridine hydrochloride (984 mg, 8.52 mmol, 20.0 eq) was stirred at 170 °C for 1 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% PA) - MeCN]; gradient: 1% - 35% B over 8.0 min) to afford the final product (26.8 mg, 60.7 pmol, 14% yield, 93.5% purity, 0.9 FA salt) as a solid. ’H NMR DMSO-d6400 MHz 5 = ppm 10.32 (br s, 1H), 8.79 (d, J= 5.4 Hz, 1H), 8.33 (d, J= 5.0 Hz, 1H), 8.24 (d, J= 5.6 Hz, 1H), 8.20 (s, 0.9H), 7.95 (d, J= 5.0 Hz, 1H), 7.93 (br s, 1H), 7.83 (d, J= 5.2 Hz, 1H), 7.76 (d, J= 1.8 Hz, 1H), 7.57 (dd, J= 1.8, 5.6 Hz, 1H), 7.06 (d, J= 2.2 Hz, 1H), 2.07 - 1.96 (m, 1H), 0.96 - 0.91 (m, 4H). LCMS (ESI+): m / z 372.1 (M+H)+.Example 428:

[0373] The reaction was set up in seven parallel batches. To a solution of starting material (10.0 mg, 28.1 pmol, 1.00 eq) in DMF (1 mL) were added tert-butyl N-(2-chloroethyl)-N-methyl-carbamate (10.9 mg, 56.3 pmol, 2.00 eq), Nal (4.22 mg, 28.1 pmol, 1.00 eq) and Cs₂CO₃ (27.5 mg, 84.4 pmol, 3.00 eq) at 25 °C. The mixture was stirred at 100 °C for 16 h. LC-MS showed that the pyrazole starting material was consumed completely and a peak with the desired mass was detected. The parallel batches were combined. The reaction was quenched by water (20 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with water (20 mL * 3), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (Dichloromethane / Methanol = 10 / 1) to afford the crude product (26.0 mg).

[0374] The Boc-protected intermediate (26.0 mg, 50.7 pmol, 1.00 eq) was dissolved in HCI / EtOAc (2.00 M, 1.00 mL, 39.4 eq) at 25 °C. The mixture was stirred at 25 °C for 30 min. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was filtered, and the filter cake was dried under reduced pressure to afford the crude product (25.0 mg, 1.0 HC1 salt).

[0375] To a solution of the amine intermediate (20.0 mg, 44.6 pmol, 1.00 eq, 1.0 HC1 salt) in THF (1 mL) and H2O (0.2 mL) was added Na₂CO₃ (14.2 mg, 134 pmol, 3.00 eq) at 25 °C. Then acetyl chloride (3.50 mg, 44.6 pmol, 3.17 pL, 1.00 eq) was added into the mixture at 0 °C under N2. The mixture was stirred at 25 °C for 1 h under N2. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (CD03 -Welch Xtimate C18 (150 * 25 mm, 5 um); flow rate: 25 mL / min; gradient: 1% - 31%, B over 10 min; mobile phase A: H2O (0.225% FA), mobile phase B: MeCN) to afford the final product (9.70 mg, 20.3 pmol, 46% yield, 95.2% purity). ’H NMR DMSO-d6400 MHz 5 = ppm 10.22 (br d, J= 2.2 Hz, 1H), 8.77 (br d, J= 4.0 Hz, 2H), 8.65 (br d, J = 2.4 Hz, 1H), 8.23 (br d, J= 5.4 Hz, 1H), 7.99 (br t, J= 3.2 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.68 (dd, J = 5.0, 2.8 Hz, 1H), 7.65 - 7.62 (m, 1H), 6.89 (t, J= 2.6 Hz, 1H), 4.40 (brt, J= 5.2 Hz, 1H), 4.30 (br t, J = 6.0 Hz, 1H), 3.75 (brt, J= 5.4 Hz, 1H), 3.70 (brt, J= 5.8 Hz, 1H), 2.78 (s, 3H), 2.03 (td, J= 12.8, 6.4 Hz, 1H), 1.95 (s, 1.5H), 1.61 (s, 1.5H), 0.91 (br d, J= 6.2 Hz, 4H). LCMS (ESI+): m / z 455.2 (M+H)+.Example 429:

[0376] To a solution of the dichloropyrimidine starting material (2.50 g, 14.0 mmol, 1.00 eq) in dioxane (16 mL) and H2O (4 mL) were added 2-chloro-3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (4.71 g, 18.3 mmol, 1.31 eq), Na₂CO₃ (4.43 g, 41.8 mmol, 3.00 eq) and Pd(dppf)C12. CH2C12 (571 mg, 699 pmol, 0.05) at 15 °C under N2. The mixture was stirred at 80 °C for 12 h. LC-MS showed that the dichloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The mixture was diluted with saturated aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Hexane / Ethyl acetate = 1 / 0 to 2 / 1) to afford the product (800 mg, 2.92 mmol, 21% yield).

[0377] To a solution ofthe chloropyrimidine intermediate (760 mg, 2.77 mmol, 1.00 eq) in THF (10 mL) were added 2-cyclopropylpyridin-4-amine (744 mg, 5.55 mmol, 2.00 eq) andNaHMDS (1.00 M, 6.93 mL, 2.50 eq) at -15 °C under N2. The mixture was stirred at 15 °C for 2 h. LC-MS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous ammonium chloride solution (5 mL) at 0 °C under N2, diluted with H2O (5 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (5 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Commercial hexanes / Ethyl acetate = 1 / 1) to afford the product (300 mg, 807 pmol, 29% yield).

[0378] To a solution of the intermediate obtained in the previous step (220 mg, 592 pmol, 1.00 eq) in dioxane (4 mL) and H2O (1 mL) were added l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (246 mg, 1.18 mmol, 2.00 eq), Na₂CO₃ (125 mg, 1.18 mmol, 2.00 eq) and Pd(dppf)C12. CH2C12 (48.3 mg, 59.2 pmol, 0.100 eq) at 15 °C under N2. The mixture was stirred at 90 °C for 2 h. LC-MS showed that the chloropyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (2 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 200 mg of crude product. 100 mg of the crude product was purified by prep-HPLC (column: WePure Biotech XP tC18 150 * 40 * 7 urn; mobile phase: [H2O (10 mM NH4HCO3) -MeCN]; gradient: 30% - 60% B over 8.0 min) to afford the final product (23.8 mg, 57.0 pmol, 99.9%purity) as a solid. 'HNMR DMSO-d6400 MHz 5 = ppm 10.06 (s, 1H), 8.68 (s, 1H), 8.59 (d, J= 4.8 Hz, 1H), 8.14 (d, J= 5.6 Hz, 1H), 7.85 (d, J= 2.4 Hz, 1H), 7.67 (d, J= 2.0 Hz, 1H), 7.58 (t, J= 4.8 Hz, 1H), 7.46 - 7.44 (m, 1H), 6.85 - 6.84 (m, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 1.94 - 1.91 (m, 1H), 0.88 - 0.86 (m, 4H). LCMS (ESI+): m / z 418.1 (M+H)+.Example 430:

[0379] The reaction was set up in two parallel batches. To a mixture of the boronic ester starting material (17.2 g, 60.2 mmol, 1.00 eq) and 2,4-dichloropyrimidine (10.8 g, 72.3 mmol, 1.20 eq) in dioxane (500 mb) and H2O (100 mb) were added Na₂CO₃ (12.8 g, 120 mmol, 2.00 eq) and Pd(dppf)C12 (4.41 g, 6.02 mmol, 0.100 eq) under N2 at 15 °C. The mixture was stirred at 90 °C for 12 h. LC-MS showed that the borate ester starting material was consumed completely and a peak with the desired mass was detected. Two batches were combined. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (I L) and extracted with EtOAc (1 L * 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiCE, Petroleum ether / Ethyl acetate = 1 / 0 to 0 / 1) to afford the product (11.0 g, 40.5 mmol, 34% yield) as a solid.

[0380] To a solution of the chloropyrimidine intermediate (100 mg, 368 pmol, 1.00 eq) and 4-aminopyridine-2 -carbonitrile (57.0 mg, 478 pmol, 1.30 eq) in dioxane (4 mL) were added Cs₂CO₃ (240 mg, 737 pmol, 2.00 eq), Xantphos (42.6 mg, 73.6 pmol, 0.200 eq) and Pd(OAc)2 (8.26 mg, 36.8 pmol, 0.100 eq) at 15 °C. The mixture was stirred at 100 °C for 2 h under N2. LC-MS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 100 * 40 mm * 5 urn; mobile phase: [H2O (0.2% PA) - MeCN]; gradient: 10% - 50% B over 8.0 min) to afford the final product (43.2 mg, 118 pmol, 32% yield, 96.7% purity). 'HNMR DMSO-d6400 MHz 5 = ppm 8.86 (d, J = 5.2 Hz, 1H), 8.78 (d, J= 5.2 Hz, 1H), 8.67 (d, J= 0.8 Hz, 1H), 8.56 (d, J= 5.8 Hz, 1H), 8.45 (d, J= 2.0 Hz, 1H), 8.09 (dd, J= 5.8, 2.4 Hz, 1H), 8.00 (dd, J= 52, 1.8 Hz, 1H), 7.83 - 7.82 (m, 2H), 6.88 (d, J= 2.4 Hz, 1H), 3.97 (s, 3H). LCMS (ESI+): m / z 355.1 (M+H)+.Example 431:

[0381] To a solution of the chloropyrimidine starting material (100 mg, 368 pmol, 1.00 eq) and 2-(4-amino-2-pyridyl)-2-methyl-propanenitrile (77.1 mg, 478 pmol, 1.30 eq) in dioxane (4 mL) were added Cs₂CO₃ (240 mg, 737 pmol, 2.00 eq), Xantphos (42.6 mg, 73.6 pmol, 0.200 eq) and Pd(OAc)2 (8.26 mg, 36.8 pmol, 0.100 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex lima Cl 8 100 * 40 mm * 5 urn; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 40% B over 8.0 min) to afford the final product (44.6 mg, 113 pmol, 31% yield, 100% purity) as a solid. 'H NMR DMSO-d6400 MHz 5 = ppm 10.50 (s, 1H), 8.80 (d, J= 5.2 Hz, 1H), 8.76 (d, J = 5.2 Hz, 1H), 8.64 (s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.19 (d, J= 1.8 Hz, 1H), 8.04 (dd,.7= 5.4, 1.8 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 5.6, 2.0 Hz, 1H), 7.75 (d, J = 5.0 Hz, 1H), 6.87 (d, J= 2.2 Hz, 1H), 3.96 (s, 3H), 1.71 (s, 6H). LCMS (ESI+): m / z 397.3 (M+H)+.Example 432:

[0382] To a solution ofthe bromopyridine starting material (1.00 g, 4.84 mmol, 1.00 eq) and l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.01 g, 4.84 mmol, 1.00 eq) in dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)C12 (354 mg, 484 pmol, 0.100 eq) and K3PO4 (2.06 g, 9.69 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 80 °C for 12 h under N2. LC-MS showed that the bromide starting material was not consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Commercial hexanes / Ethyl acetate = 1 / 0 to 1 / 3) to afford the product (1.00 g, 4.82 mmol, 99.4% yield).

[0383] To a solution of the 4 -chloropyridine intermediate (500 mg, 2.41 mmol, 1.00 eq), 4, 4, 5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.83 g, 7.22 mmol, 3.00 eq) in dioxane (6 mL) were added Pd(dppf)C12. CH2C12 (197 mg, 241 pmol, 0.100 eq) and KOAc (473 mg, 4.82 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the chloride starting material was not consumed completely and a peak with the desired mass was detected. The crude product (720 mg, 2.41 mmol, 100% yield) in dioxane (6 mL) was used directly in the next step.

[0384] To a solution of the crude boronic acid ester thus obtained (360 mg, 1.20 mmol, 1.00 eq) and 2,4-dichloro-5 -methylpyrimidine (196 mg, 1.20 mmol, 1.00 eq) in dioxane (3 mL) and H2O (0.6 mL) were added Pd(dppf)Ch (88.1 mg, 120 pmol, 0.100 eq) and K2CO3 (333 mg, 2.41 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 80 °C for 2 h under N2. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, commercial hexane / THF = 1:3) to afford the product (160 mg, 534 pmol, 44.4% yield).

[0385] To a solution of 2-cyclopropylpyridin-4-amine (35.8 mg, 267 pmol, 1.00 eq) in THF (1 mL) was added NaHMDS (1.00 M, 534 pL, 2.00 eq) at -15 °C under N2. The mixture was stirred at -15 °C for 0.5 h. The chloropyrimidine intermediate (80.0 mg, 267 pmol, 1.00 eq) in THF (1 mL) was added to the mixture at -15 °C under N2. The mixture was stirred at 15 °C for another 0.5 h. LC-MS showed that the chloropyrimidine reagent was consumed completely and a peak with the desired mass was detected. The reaction was quenched by dropwise addition of saturated NH4CI (5 mL) solution at 0 °C and extracted with EtOAc (5 mL * 4). The combined organic layers were washed with brine (10 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 urn; mobile phase: [H2O (0.2% PA) - MeCN]; gradient: 1% - 27% B over 8.0 min) to afford the final product (12.7 mg, 29.1 pmol, 5.5% yield, 97.4% purity, 0.6 FA salt). ’H NMR DMSO-d6400 MHz 5 = ppm 10.08 (s, 1H), 8.60 (s, 1H), 8.57 (d, J= 4.8 Hz, 1H), 8.16 (s, 0.6 H), 8.13 (d, J= 5.6 Hz, 1H), 7.78 (d, J= 2.1 Hz, 1H), 7.60 (d, J= 1.8 Hz, 1H), 7.50 (dd, J= 5.6, 2.0 Hz, 1H), 7.22 (d, J= 4.8 Hz, 1H), 6.83 (d, J= 2.1 Hz, 1H), 3.93 (s, 3H), 2.38 (s, 3H), 1.97 (s, 3H), 1.93 - 1.87 (m, 1H), 0.89 - 0.79 (m, 4H). LCMS (ESI+): m / z 398.3 (M+H)+.Example 601:

[0386] To a solution of the chloropyrimidine starting material (4.00 g, 16.2 mmol, 1.00 eq) in dioxane (100 mL) were added LiCl (2.06 g, 48.6 mmol, 997 pL, 3.00 eq), PC, (909 mg, 3.24 mmol, 1.05 mL, 0.200 eq), Pd₂(dba)₃ (1.48 g, 1.62 mmol, 0.100 eq) and tributyl(tributylstannyl)stannane (21.5 g, 37.1 mmol, 18.6 mL, 2.29 eq) at 25 °C. The mixture was stirred at 90 °C for 12 h under N2. LCMS showed that the chloropyrimidine starting material was consumed completely, and the desired mass was detected. The reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (600 mL * 3). The combined organic layers were washed with brine (600 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Petroleum ether / Ethyl acetate = 5 / 1 to 3 / 1) to afford the product (4.00 g, 7.98 mmol, 49% yield).

[0387] To a solution of the stannane intermediate (4.00 g, 7.98 mmol, 1.00 eq) and 2-bromo-4-iodo-pyridine (2.72 g, 9.58 mmol, 1.20 eq) in toluene (60 mL) were added Pd(PPh3)2C12 (560 mg, 798 pmol, 0.100 eq) and LiCl (677 mg, 16.0 mmol, 327 pL, 2.00 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiC>2, Petroleum ether / THF = 1 / 0 to 65 / 35) to afford the product (800 mg, 2.17 mmol, 27% yield) as a solid.

[0388] The reaction was set up in two parallel batches. To a solution of the bromopyridine intermediate (400 mg, 1.09 mmol, 1.00 eq) and ethynyl(trimethyl) silane (1.07 g, 10.9 mmol, 1.50 mL, 10.0 eq) in THF (5 mL) were added Cui (20.7 mg, 109 pmol, 0.100 eq), TEA (330 mg, 3.26 mmol, 454 pL, 3.00 eq) and Pd(PPh3)2Cl2(76.3 mg, 109 pmol, 0.100 eq) at 15 °C. The mixture was stirred at 60 °C for 12 h under N2. LC-MS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. Two batches were combined. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiC>2, Commercial hexanes / THF = 1 / 0 to 70 / 30 ) to afford the product (810 mg, 2.10 mmol, 97% yield) as a solid.

[0389] To a solution of the TMS-alkyne intermediate (810 mg, 2.10 mmol, 1.00 eq) in MeOH (10 mL) was added K2CO3 (145 mg, 1.05 mmol, 0.500 eq) at 15 °C. The mixture was stirred at 15 °C for 0.5 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiC>2, Commercial hexanes / THF = 1 / 0 to 1 / 1) to afford the desired compound (360 mg, 1.15 mmol, 55% yield). 'HNMR DMSO-de 400 MHz 5 = ppm 10.21 (s, 1H), 8.79 (t, J= 5.6 Hz, 2H), 8.31 (s, 1H), 8.22 (d, J= 5.6 Hz, 1H), 8.15 (br d, J= 5.0 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 5.0 Hz, 1H), 7.52 (br d, J= 5.6 Hz, 1H), 4.48 (s, 1H), 2.05 - 1.94 (m, 1H), 0.99 - 0.83 (m, 4H). LCMS (ESI+): m / z 314.1 (M+H)+.Example 434:

[0390] To a solution of the alkyne (150 mg, 479 pmol, 1.00 eq) in / -B11OH (1.5 mL) and H2O (1.5 mL) were added CUSO4.5H2O (120 mg, 479 pmol, 1.00 eq) and sodium; (2R)-2-[(lS)-l,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (94.8 mg, 479 pmol, 1.00 eq) and azidomethylcyclopropane (48.8 mg, 503 pmol, 1.05 eq) at 15 °C. The mixture was stirred at 40 °C for 2 h. LC-MS showed that the alkyne starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was filtered to give the filter cake. The filter cake was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 10% -50% B over 8.0 min) to afford the final product (5.10 mg, 12.4 pmol, 3% yield, 100% purity). 'H NMR DMSO-de 400 MHz 5 = ppm 10.27 (br s, 1H), 8.89 (br s, 1H), 8.81 (br d, J= 1.8 Hz, 2H), 8.74 (br s, 1H),8.22 (br s, 1H), 8.08 (br s, 1H), 7.97 (br s, 1H), 7.77 (br s, 1H), 7.53 (br s, 1H), 4.34 (br d, J= 5.0 Hz, 2H), 2.15 (br s, 1H), 1.46 - 1.30 (m, 1H), 0.92 (br s, 4H), 0.61 (br d, J= 5.2 Hz, 2H), 0.50 (br s, 2H). LCMS (ESI+): m / z 411.3 (M+H)+.Example 435:

[0391] A mixture of example 18 (20.0 mg, 56.3 pmol, 1.00 eq), ethyl 2-bromoacetate (9.40 mg, 56.3 pmol, 6.23 pL, 1.00 eq) and K2CO3 (77.8 mg, 566 pmol, 10.0 eq) in DMF (2 mL) was stirred at 15 °C for 4 h. LC-MS showed that the starting material was not consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 * 30 mm * 5 urn; mobile phase:[H2O (0.2% FA) - MeCN]; gradient: 5% - 40% B over 8.0 min) to afford the final product (6.70 mg, 13.7 pmol, 24% yield, 100% purity, 1.0 FA salt) as a solid. ’HNMR DMSO-de400 MHz 5 = ppm 10.30 (br s, 1H), 8.84 (dd, J= 8.8, 5.2 Hz, 2H), 8.72 (s, 1H), 8.28 (br d, J= 5.2 Hz, 1H), 8.20 (s, 1H), 8.07 (br d, J = 4.8 Hz, 1H), 7.95 (d, J= 2.4 Hz, 1H), 7.90 (d, J= 1.4 Hz, 1H), 7.76 (d, J= 5.2 Hz, 1H), 7.66 (br d, J= 4.6 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 5.23 (s, 2H), 4.25 (q, J= 6.8 Hz, 2H), 2.11 - 2.08 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 0.98 - 0.97 (m, 4H). LCMS (ESI+): m / z 442.2 (M+H)+.Example 436:

[0392] To a solution of 2-cyclopropylpyridin-4-amine (1.43 g, 10.7 mmol, 1.00 eq) in THF (20 mL) was added NaHMDS (1.00 M, 21.4 mL, 2.00 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 0.5 h under N2. Then sulfone starting material (2.2 g, 10.7 mmol, 1.00 eq) in THF (20 mL) was added to the solution at -78 °C. The resulting mixture was stirred at -78 °C for 0.5 h under N2. LCMS showed that the sulphone starting material was consumed completely and a peak with the desired mass was detected. H2O (100 mL) was added to the solution at 0 °C, then the mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Commercial hexanes / Ethyl acetate = 99 / 1 to 1 / 1) to afford the product (1.70 g, 6.52 mmol, 61% yield) as a solid.

[0393] To a solution of this material (1.70 g, 6.52 mmol, 1.00 eq) in dioxane (50 mL) were added LiCI (829 mg, 19.6 mmol, 401 pL, 3.00 eq), PCy3 (366 mg, 1.30 mmol, 423 µL, 0.200 eq), Pd₂(dba)₃ (597 mg,652 pmol, 0.100 eq) and tributyl(tributylstannyl)stannane (9.95 g, 17.2 mmol, 8.59 mL, 2.63 eq) at 15 °C. The mixture was stirred at 90 °C for 12 h under N2. LCMS showed that the reaction was incomplete. Then tributyl(tributylstannyl)stannane (44.7 g, 77.1 mmol, 38.6 mL, 11.8 eq) and Pd₂(dba)₃ (597 mg, 652 pmol, 0.100 eq) were added at 15 °C. The mixture was stirred at 90 °C for another 12 h under N2. LCMS showed that the reaction was complete. The reaction was diluted with H2O (50 mL) and extracted with ethyl acetate (60 mL * 3). The combined organic layers were washed with brine (60 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Commercial hexanes / Ethyl acetate = 99 / 1 to 3 / 1) to afford the product ( 1.50 g, 2.91 mmol, 45% yield).

[0394] To a solution of the stannane intermediate (600 mg, 1.16 mmol, 1.00 eq) in dioxane (10 mL) were added 2,4-dichloropyrimidine (260 mg, 1.75 mmol, 1.50 eq), LiCl (148 mg, 3.49 mmol, 71.6 pL, 3.00 eq) and palladium tritert-butylphosphane (59.5 mg, 116 pmol, 0.100 eq) at 15 °C. The reaction mixture was stirred at 110 °C for 2 h under N2. LCMS showed that the tin starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (20 mL) at 0 °C and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiCE, hexane: THF = 1:2) to afford the product (100 mg, 295 pmol, 25% yield) as solid.

[0395] To a solution of the material from the previous step (90.0 mg, 266 pmol, 1.00 eq) in dioxane (2 mL) and H2O (0.5 mL) were added XPhos Pd G2 (20.9 mg, 26.6 pmol, 0.100 eq), l-methyl-3-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (111 mg, 531 pmol, 2.00 eq) and K3PO4 (113 mg, 531 pmol, 2.00 eq) at 15 °C. The reaction mixture was stirred at 100 °C for 2 h under N2. LCMS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 100 * 25 mm * 10 um; mobile phase: [H2O (10 mM NH4HCO3) -MeCN]; gradient: 25% - 70% B over 8.0 min) to afford the final product (30.1 mg, 78.3 pmol, 30% yield, 100% purity). 'HNMR DMSO-d6400 MHz 5 = ppm 10.10 (s, 1H), 9.07 (d, J = 4.8 Hz, 1H), 8.66 (s, 1H), 8.18 (d, J= 5.6 Hz, 1H), 7.96 (d, J= 4.8 Hz, 1H), 7.84 (d, J= 2.0 Hz, 1H), 7.71 (d, J= 1.6 Hz, 1H), 7.54 (dd, J= 5.6, 2.0 Hz, 1H), 6.97 (d, J= 2.4 Hz, 1H), 3.96 (s, 3H), 2.53 (s, 3H), 2.00 - 1.94 (m, 1H), 0.90 -0.88 (m, 4H). LCMS (ESI+): m / z 385.2 (M+H)+.Example 440:

[0396] To a solution of the bromopyrazole starting material (1.40 g, 8.00 mmol, 1.00 eq) and 4, 4, 5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (6.09 g, 24.0 mmol, 3.00 eq) in dioxane (60 mL) were added KOAc (2.36 g, 24.0 mmol, 3.00 eq) and Pd(dppf)C12. CH2C12 (653 mg, 800 pmol, 0.100 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 12 h under N2. LC-MSshowed that the bromopyrazole starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (column: Phenomenex luna C18250 * 150 mm * 15 um; mobile phase: [H2O (0.1% TFA) - MeCN]; gradient: 1% -30% B over 30.0 min) to afford the crude product (800 mg) as solid.

[0397] To a solution of the chloropyrimidine starting material (260 mg, 767 pmol, 1.00 eq) and (1,4-dimethyl-lH-pyrazol-3-yl)boronic acid from the previous step (107 mg, 767 pmol, 1.00 eq) in dioxane (2 mL) and H2O (0.4 mL) were added K3PO4 (326 mg, 1.53 mmol, 2.00 eq) and XPhos Pd G2 (60.4 mg, 76.7 pmol, 0.100 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 0.5 h under N2. LC-MS showed that the chloropyrimidine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 40% B over 8.0 min) to afford the final product (17.6 mg, 42.9 pmol, 6% yield, 97.1% purity). 'HNMR DMSO-d6400 MHz 5 = ppm 10.10 (s, 1H), 9.07 (d, J= 5.2 Hz, 1H), 8.65 (s, 1H), 8.17 (d, J= 5.6 Hz, 1H), 7.87 (d, J= 4.8 Hz, 1H), 7.71 (d, J= 2.0 Hz, 1H), 7.63 (s, 1H), 7.54 (dd, J= 5.6, 2.0 Hz, 1H), 3.88 (s, 3H), 2.46 (s, 3H), 2.35 (s, 3H), 1.97 - 1.94 (m, 1H), 0.89 - 0.87 (m, 4H). LCMS (ESI+): m / z 399.3 (M+H)+.Example 437:

[0398] To a solution of the bromopyridine starting material (2.00 g, 10.7 mmol, 1.00 eq) in dioxane (50 mL) were added cyclopropylboronic acid (3.67 g, 42.8 mmol, 4.00 eq), Pd(dppf)C12 (782 mg, 1.07 mmol, 0.100 eq) and K2CO3 (4.43 g, 32.1 mmol, 3.00 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 2 h under N2. LC-MS showed that the bromopyridine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250 * 70 mm, 15 um); mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 10% - 40% B over 22.0 min) to afford the product (680 mg, 3.77 mmol, 35% yield, 82.1% purity).

[0399] To a solution of the intermediate thus obtained (104 mg, 700 pmol, 2.00 eq) in dioxane (3 mL) were added 2-chloro-5-methyl-4-[2-(l-methylpyrazol-3-yl)-4-pyridyl]pyrimidine (100 mg, 350 pmol, 1.00 eq), Pd(OAc)2 (7.86 mg, 35.0 pmol, 0.100 eq), Xantphos (40.5 mg, 70.0 pmol, 0.200 eq) and Cs₂CO₃ (228 mg, 700 pmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 80 °C for 1 h under N2. LC-MS showed that the amine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 3 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 45% B over 8.0 min) to afford the final product (52.7 mg, 126 pmol, 36% yield, 99.3% purity, 0.4 FA salt).1H NMR DMSO-d6400 MHz 5 = ppm 9.98 (s, 1H), 8.76 - 8.69 (m, 1H), 8.60 (s, 1H),8.26 - 8.20 (m, 1H), 8.14 (s, 0.4H), 7.81 (d, J= 2.0 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.55 (d, J= 1.6 Hz, 1H), 7.42 (d, J= 1.6 Hz, 1H), 6.87 (d, J= 2.2 Hz, 1H), 3.91 (s, 3H), 2.31 (s, 6H), 1.96 - 1.88 (m, 1H), 0.87 -0.79 (m, 4H). LCMS (ESI+): m / z 398.2 (M+H)+.Example 438:

[0400] The compound was synthesized using the same general procedure as example 437. ’H NMR DMSO-d6400 MHz 5 = ppm 8.83 (s, 1H), 8.71 (d, J= 5.2 Hz, 1H), 8.57 (s, 1H), 8.17 (d, J= 0.8 Hz, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.80 (d, J= 2.4 Hz, 1H), 7.58 (dd, J = 5.2, 1.6 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H), 2.00 - 1.95 (m, 1H), 0.84 - 0.82 (m, 4H). LCMS (ESI+): m / z 398.2 (M+H)+.Example 439:

[0401] The compound was synthesized using the same general procedure as example 437. ’H NMR DMSO-d6400 MHz 5 = ppm 12.77 (br s, 1H), 9.04 (s, 1H), 8.73 - 8.67 (m, 1H), 8.50 (s, 1H), 8.14 (s, 1H), 8.12 - 8.09 (m, 2H), 7.80 (d, J= 2.0 Hz, 1H), 7.58 (d, J= 5.6 Hz, 1H), 7.55 (dd, J= 5.2, 2.0 Hz, 1H), 6.85 (d, J= 2.4 Hz, 1H), 3.92 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H), 2.22 - 2.16 (m, 1H), 0.97 - 0.80 (m, 4H). LCMS (ESI+): m / z 398.3 (M+H)+.Example 441:

[0402] To a solution of the ketone starting material (1.00 g, 5.00 mmol, 1.00 eq) in DCM (10 mL) were added TEA (1.52 g, 15.0 mmol, 2.09 mL, 3.00 eq) and TBSOTf (1.59 g, 6.00 mmol, 1.38 mL, 1.20 eq) at 0 °C. The mixture was stirred at 15 °C for 1 h. TLC (SiO2, hexane: EtOAc = 5:1) indicated formation of a product. The reaction mixture diluted with H2O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes / Ethyl acetate = 1 / 0 to 5 / 1) to afford the product (1.40 g, 4.40 mmol, 88% yield, 98.8% purity).

[0403] To a solution of ZnEt2 (2.00 M, 7.64 mL, 6.00 eq) in DCM (10 mL) was added chloroiodomethane (2.69 g, 15.3 mmol, 1.11 mL, 6.00 eq) in DCM (10 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. The intermediate from the previous step (800 mg, 2.55 mmol, 1.00 eq) in DCM (10 mL) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 h under N2. LCMS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by addition of H2O (50 mL) at 0 °C, filtered and the filtrate was extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by column chromatography (SiC>2, Commercial hexanes / THF = 1 / 0 to 10 / 1) to afford the product (780 mg, 2.28 mmol, 90% yield, 96.0% purity).

[0404] To a solution of this bromo intermediate (740 mg, 2.25 mmol, 1.00 eq), diphenylmethanimine (408 mg, 2.25 mmol, 378 µL, 1.00 eq) in dioxane (10 mL) were added Pd₂(dba)₃ (206 mg, 225 pmol, 0.100 eq), Cs₂CO₃ (1.47 g, 4.51 mmol, 2.00 eq) and Xantphos (130 mg, 225 pmol, 0.100 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the bromide starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Commercial hexanes / Ethyl acetate = 1 / 0 to 5 / 1) to afford the crude product (1.00 g).

[0405] To a solution of this crude material (300 mg, 700 µmol, 1.00 eq) in THF (3 mL) was added HCl (1.00 M, 6.00 mL, 8.57 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. ECMS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (2 mb) and extracted with EtOAc (5 mb * 3). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford the crude product (75.0 mg, HC1 salt) as a solid.

[0406] The reaction was set up in two parallel batches. To a solution of 2-chloro-5-methyl-4-(2-(l-methyl-lH-pyrazol-3-yl)pyridin-4-yl)pyrimidine (105 mg, 366 pmol, 1.00 eq) and the amine intermediate (55.0 mg, 366 pmol, 1.00 eq) in dioxane (3 mb) were added Xantphos Pd G4 (35.3 mg, 36.6 pmol, 0.100 eq) and / -BuONa (70.4 mg, 732 pmol, 2.00 eq) at 15 °C. The mixture was stirred at 90 °C for 12 h under N2. LC-MS showed that the amine starting material was consumed completely and a peak with the desired mass was detected. Two batches were combined, diluted with H2O (5 mL), and extracted with EtOAc (5 mL * 4). The combined organic layers were washed with brine (10 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 40% B over 8.0 min) to afford the final product (29.8 mg, 74.6 pmol, 20% yield, 100% purity). ’H NMR DMSO-de 400 MHz 5 = ppm 10.44 (s, 1H), 8.74 (d, J= 5.0 Hz, 1H), 8.65 (s, 1H), 8.48 (d, J= 5.6 Hz, 1H), 8.37 (d, J = 2.0 Hz, lH), 8.16 (s, 1H), 8.05 (dd, J= 5.6, 2.0 Hz, 1H), 7.81 (d, J= 2.0 Hz, 1H), 7.60 (d, J = 5.0 Hz, 1H), 6.87 (d, J= 2.0 Hz, 1H), 3.93 (s, 3H), 3.14 (q, J= 7.4 Hz, 2H), 2.30 (s, 3H), 1.07 (t, J= 7.4 Hz, 3H). LCMS (ESI+): m / z 400.2 (M+H)+.Example 444:

[0407] To a solution of the starting material (1.00 g, 2.33 mmol, 1.00 eq) in THF (10 mL) was added HC1 (1.00 M, 20.0 mL, 8.57 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous Na₂CO₃ solution (20 mL) at 0 °C and extracted with EtOAc (20 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Commercial hexanes / THF = 1 / 0 to 1 / 1) to afford the product (300 mg, 1.13 mmol, 49% yield) as a solid.

[0408] To a solution of the amine intermediate (300 mg, 1.13 mmol, 1.00 eq), 2-chloro-5-methyl-4-[2-(l-methylpyrazol-3-yl)-4-pyridyl]pyrimidine (324 mg, 1.13 mmol, 1.00 eq) in dioxane (6 mL) were added Cs₂CO₃ (739 mg, 2.27 mmol, 2.00 eq) and Xantphos Pd G4 (109 mg, 113 pmol, 0.100 eq) at 15 °C. The mixture was stirred at 100 °C for 12 h under N2. LC-MS showed that the amine starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL * 4). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Commercial hexanes / Ethyl acetate = 1 / 1) to afford the product (270 mg, 526 pmol, 46% yield) as a solid.

[0409] To a solution of the TBS-protected intermediate (100 mg, 195 pmol, 1.00 eq) in THF (1 mL) was added HC1 (1.00 M, 667 pL, 3.42 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. LC-MS showed that the starting material was not consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure to remove THF, adjusted to pH~8 with saturated aqueous Na₂CO₃ solution, filtered and the filter cake was dried in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100 * 40 mm * 5 um; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 1% - 35% B over 8.0 min) to afford the final product (25.2 mg, 62.2 pmol, 32% yield, 98.5% purity). NMR DMSO-d6400 MHz 5 = ppm 10.14 (s, 1H), 8.72 (d, J= 5.2 Hz, 1H), 8.60 (s, 1H), 8.18 - 8.11 (m, 3H), 7.81 (d, J= 2.0 Hz, 1H), 7.66 - 7.59 (m, 2H), 6.87 (d, J= 2.0 Hz, 1H), 5.99 (s, 1H), 3.93 (s, 3H), 2.30 (s, 3H), 1.23 - 1.13 (m, 2H), 1.04 - 0.96 (m, 2H). LCMS (ESI+): m / z 400.3 (M+H)+.Example 442:

[0410] To a solution ofthe bromopyridine starting material (10.0 g, 36.6 mmol, 1.00 eq) in THF (100 mL) was added n-BuLi (2.50 M, 30.8 mL, 2.10 eq) at -78 °C under N2. The mixture was stirred at -78 °C for 2 h. Then thietan-3-one (6.13 g, 69.6 mmol, 1.90 eq) was added to the solution, and the mixture was stirred at 15 °C for 2 h under N2. LC-MS showed that the bromopyridine starting material was consumedcompletely and a peak with the desired mass was detected. The reaction was quenched by saturated aqueous ammonium chloride solution (100 mL) at 0 °C, diluted with H2O (100 mL) and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Commercial hexanes / Ethyl acetate = 1 / 0 to 2 / 1) to afford the product (6.60 g, 23.4 mmol, 64% yield) as a solid.

[0411] To a solution of this material (300 mg, 1.06 mmol, 1.00 eq) in DCM (2 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at 40 °C for 1.5 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The mixture was concentrated under reduced pressure. To the residue was added MeCN (3 mL), adjusted to pH = 8 by DIPEA, and it was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: WePure Biotech XP tC18 150 * 40 * 10 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 1% - 11% B over 8.0 min) to afford the product (90.0 mg, 494 pmol, 47% yield).

[0412] To a solution of 3-(4-amino-2-pyridyl)thietan-3-ol (72.4 mg, 397 pmol, 1.20 eq) in dioxane (2 mL) were added the chloropyrimidine starting material (90.0 mg, 331 pmol, 1.00 eq), Xantphos Pd G4 (31.9 mg, 33.1 pmol, 0.100 eq) and / -BuONa (2.00 M, 331 pL, 2.00 eq) at 15 °C under N2. The mixture was stirred at 80 °C for 12 h. LC-MS showed that the chloropyrimidine starting material was consumed completely and two peaks with the desired mass were detected. The mixture was concentrated to dryness under a stream of nitrogen. The crude product was purified by prep-HPLC (column: WePure Biotech XP tC18 100 * 30 * 7 um; mobile phase: [H2O (10 mM NH4HCO3) - MeCN]; gradient: 20% - 50% B over 8.0 min) to afford the final product (3.50 mg, 7.74 pmol, 2% yield, 92.3% purity, peak 1). ’H NMR DMSO-d6400 MHz 5 = ppm 10.47 (s, 1H), 8.85 (t, J= 5.6 Hz, 2H), 8.70 (s, 1H), 8.50 (d, J= 5.6 Hz, 1H), 8.33 (s, 0.4H), 8.31 (d, J= 1.6 Hz, 1H), 8.13 - 8.08 (m, 1H), 7.90 - 7.88 (m, 2H), 7.79 (d, J = 5.2 Hz, 1H), 6.95 (d, J= 2.0 Hz, 1H), 4.03 (s, 3H), 3.85 (d, J= 9.6 Hz, 2H), 3.47 (br d, J= 9.6 Hz, 2H). LCMS (ESI+): m / z 418.1 (M+H)+.Example 443:

[0413] To a solution of the starting material (6.00 g, 26.1 mmol, 1.00 eq) in DMF (100 mL) was added NaH (2.61 g, 65.2 mmol, 60.0% purity, 2.50 eq) at -20 °C under N2. The mixture was stirred at -20 °C for 0.5 h. Then Mel (3.33 g, 23.5 mmol, 1.46 mL, 0.900 eq) was added at -20 °C, the mixture was stirred at -20 °C for 1 h under N2. LC-MS showed that the starting material was not consumed completely and a peak with desired mass was detected. The reaction was quenched by saturated aqueous NH4CI solution (100 mL) at 0 °C, diluted with H2O (50 mL), and extracted with EtOAc (100 mL * 3). The combined organic layers were washed by brine (40 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 10-15% Ethyl acetate / Commercial hexanes @ 100 mL / min) to afford the crude product (2.70 g).

[0414] The reaction was set up in two parallel batches. To a mixture of the crude material from the previous step (1.30 g, 5.33 mmol, 1.00 eq) in dioxane (20 mL) were added diphenylmethanimine (869 mg, 4.79 mmol, 804 pL, 0.900 eq), Xantphos (308 mg, 533 pmol, 0.100 eq), Pd₂(dba)₃ (488 mg, 533 pmol, 0.100 eq) and Cs₂CO₃ (3.47 g, 10.7 mmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 100 °C for 2 h under N2. LC-MS showed that the bromopyridine starting material was consumed completely and a peak with desired mass was detected. Two batches were combined. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-15% Ethyl acetate / Commercial hexanes @ 120 mL / min) to afford the crude product (2.60 g).

[0415] To a solution of the material thus obtained (1.00 g, 2.90 mmol, 1.00 eq) in THF (10 mL) was added HC1 (1.00 M, 10.0 mL, 3.44 eq) at 15 °C. The mixture was stirred at 15 °C for 1 h. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (20 mL) and extracted with EtOAc (10 mL * 3). The organic phase was discarded, and the water phase was concentrated under reduced pressure to afford the product (510 mg, 2.35 mmol, 81% yield, 1.0 HC1 salt).

[0416] To a solution of the primary amine intermediate (140 mg, 646 pmol, 1.20 eq, 1.0 HC1 salt) in DME (4 mL) were added dicyclohexyl-(2-phenylphenyl)phosphane (18.9 mg, 53.9 pmol, 0.100 eq), 2-chloro-4-[2-(2-tetrahydropyran-2-ylpyrazol-3-yl)-4-pyridyl]pyrimidine (184 mg, 538 pmol, 1.00 eq), Pd(OAc)2 (12.1 mg, 53.9 pmol, 0.100 eq) and / -BuONa (103 mg, 1.08 mmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 90 °C for 12 h under N2. LC-MS showed that the primary amine starting material was consumed completely and a peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (3 mL) and extracted with EtOAc (3 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Commercial hexanes / Ethyl acetate = 0 / 1) to afford the product (68.0 mg, 140 pmol, 26% yield).

[0417] A solution of the THP -protected intermediate (80.0 mg, 165 pmol, 1.00 eq) in HCl / EtOAc (4.00 M, 2.00 mL) was stirred at 15 °C for 1 h. LC-MS showed that the starting material was consumedcompletely and a peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (3 mL) and extracted with EtOAc (3 mL * 3). The organic phase was discarded. The aqueous phase was adjusted to pH = 8-9 by Na₂CO₃ and extracted with EtOAc (3 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford the product (40.0 mg, 99.7 pmol, 61% yield).

[0418] To a solution of the obtained ester intermediate (40.0 mg, 99.7 pmol, 1.00 eq) in THF (1 mL) was added LiAlEL (2.50 M, 23.9 pL) at 0 °C. The mixture was stirred at 15 °C for 1 h under N2. LC-MS showed that the starting material was consumed completely and a peak with the desired mass was detected. The reaction was quenched by aqueous potassium sodium tartrate solution (5 mL) at 0 °C under N2. The resulting mixture was purified by prep-HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 urn; mobile phase: [H2O (0.2% FA) - MeCN]; gradient: 5% - 35% B over 8.0 min) to afford the final product (5.10 mg, 11.8 pmol, 12% yield, 95.8% purity, 0.9 FA salt). 'HNMR DMSO-d6400 MHz 5 = ppm 10.25 (s, 1H), 8.82 - 8.75 (m, 2H), 8.70 (br s, 1H), 8.32 (d, J= 5.6 Hz, 1H), 8.17 (s, 1H), 8.06 - 7.98 (m, 1H), 7.90 - 7.77 (m, 2H), 7.72 (d, J= 5.2 Hz, 1H), 7.69 - 7.64 (m, 1H), 6.93 (br s, 1H), 3.72 - 3.66 (m, 1H), 3.53 (br d, J= 3.2 Hz, 1H), 2.95 - 2.89 (m, 1H), 1.22 (d, J= 7.2 Hz, 3H). LCMS (ESI+): m / z 374.2 (M+H)+.Example 445:

[0419] To a solution of the bromopyridine starting material (1.50 g, 7.27 mmol, 1.00 eq) in dioxane (10 mL) and H2O (2.5 mL) were added l-(difluoromethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (1.77 g, 7.27 mmol, 1.00 eq), K2CO3 (2.01 g, 14.5 mmol, 2.00 eq) and Pd(dppf)C12 (532 mg, 727 pmol, 0.100 eq) at 15 °C. The mixture was stirred at 95 °C for 2 h under N2. LCMS showed that the bromopyridine starting material was consumed completely, and a peak with the desired mass was detected. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, Commercial hexanes / Ethyl acetate = 99 / 1 to 3 / 1) to afford the product (1.40 g, 5.75 mmol, 79% yield) as a solid.

[0420] To a solution of the chloropyridine intermediate thus obtained (500 mg, 2.05 mmol, 1.00 eq) in dioxane (10 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (625 mg, 2.46 mmol, 1.20 eq), Pd(dppf)C12 (150 mg, 205 pmol, 0.100 eq), XPhos (196 mg, 410 pmol, 0.200 eq) and KOAc (403 mg, 4.10 mmol, 2.00 eq) at 15 °C. The mixture was stirred at 100 °C for 1 h under N2. LCMS showed that the chloropyridine starting material was consumed completely, and apeak with the desired mass was detected. The mixture was concentrated under reduced pressure to afford the crude product ...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I);wherein:X1is N or CR1;R1is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;X2is N or CR2;R2is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;X3is N or CR3;R3is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;Ring A is aryl or heteroaryl;each R4is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -NRbS(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R4on the same atom form an oxo;n is 0, 1, 2, 3, or 4;Y is N or CR5;R5is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;R6is hydrogen, halogen, -CN, -NO2, -OH, -0Ra, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, or - L-heterocycloalkyl;Ring B is heteroaryl;each R7is independently halogen, -CN, -NO2, -OH, -0Ra, -OC(=O)Ra, -OC(=O)ORb, -0C(=0)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, - NRbC(=0)0Rb, -NRbS(=O)2Ra, -NRbS(=0)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=0)NRcRd, Ci- Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;and / or two R7on the same atom form an oxo;m is 0, 1, 2, 3, or 4;each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl,Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl,Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; andL is absent or Ci-Csalkylene independently optionally substituted with one or more R;each Ris independently halogen, -CN, -OH, -S(=0)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, -S(=O)2NH2, - S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -C(=O)Ci- C3alkyl, -C(=0)0H, -C(=O)OCi-C3alkyl, -C(=0)NH2, -C(=O)NHCi-C3alkyl, -C(=O)N(Ci-C3alkyl)2, Ci-Cealkyl. Ci-Csalkoxy, Ci-Cehaloalkyl. Ci-Cehaloalkoxy. Ci-Cehydroxyalkyl. Ci-Csaminoalkyl, Ci-Cehctcroalkyl. C3-C, cycloalkyl. or 3- to 6-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more halogen;and / or two R on the same atom form an oxo;provided that the compound. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X1is N.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X1is CR1.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X2is N.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X2is CR2.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X3is N.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X3is CR3.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is N.

9. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is CR5.

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (la):Formula (la).

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R1is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R1is hydrogen.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is hydrogen.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R3is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R3is hydrogen.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R5is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R5is hydrogen.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R6is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R6is hydrogen.

21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (lb):Formula (lb).

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl, a 5- to 6-membered monocyclic heteroaryl, or a 8- to 12-membered bicyclic heteroaryl.

23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl.

24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5- to 6-membered monocyclic heteroaryl.

25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5- to 6-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

26. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 6-membered monocyclic heteroaryl comprising one or two heteroatoms that are N.

27. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is pyridinyl, pyrimidinyl, or pyrazinyl.

28. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is pyridinyl or pyrimidinyl.

29. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5 -membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

30. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is 5 -membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N and O.

31. The compound of any one of claims 1 -21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, or triazolyl.

32. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is pyrazolyl.

33. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is a 8- to 12-membered bicyclic heteroaryl.

34. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is a 8- to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

35. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is a 8- to 10-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

36. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is a 8- to 10-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N and O.

37. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is a 9-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms that are N.

38. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is indazolyl, pyrrolopyridinyl, 3,4-dihydropyridooxazinyl, or dioxolopyridinyl.

39. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R4is independently halogen, -CN, -OH, -ORa, -SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R4is independently halogen, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)ORb, Ci-Cealkyl, Ci-C6haloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R4is independently -0Ra, -S(=O)Ra, -S(=0)2Ra, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)ORb, Ci-Cealkyl, Ci-Cehaloalkyl, or -L-heterocycloalkyl; wherein each alkyl and heterocycloalkyl is independently optionally substituted with one or more R.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R4is independently -ORa, -S(=O)Ra, -NRbC(=O)NRcRd, Ci-Cealkyl, or heterocycloalkyl.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0 or 1.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0.

46. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 1.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5- or 6-membered monocyclic heteroaryl or a 8- to 12-membered bicyclic heteroaryl.

48. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5- or 6-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S or a 8 - to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of O, S, and N.

49. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5- or 6-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S or a 8 - to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of O andN.

50. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5- or 6-membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

51. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 6-membered monocyclic heteroaryl comprising one or two heteroatoms that are N.

52. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is pyridinyl, pyrimidinyl, or pyrazinyl.

53. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is pyridinyl or pyrimidinyl.

54. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5 -membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

55. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5 -membered monocyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N and O.

56. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, or triazolyl.

57. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is pyrazolyl.

58. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is a 8- to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

59. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is a 8- to 12-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of O and N.

60. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is a 8- to 10-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N, O, and S.

61. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is a 8- to 10-membered bicyclic heteroaryl comprising one, two, three, or four heteroatoms selected from the group consisting of N and O.

62. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

63. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R7is independently halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R7is independently halogen, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R7is independently -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, or cycloalkyl.

66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:m is 0 or 1.

67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:m is 0.

68. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:m is 1.

69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a compound found in table 1.

70. A pharmaceutical composition comprising a compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

71. A method of modulating MY C activity in a subject in need thereof, the method comprising administering to the subject in need thereof a compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

72. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject in need thereof a compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

73. The method of claim 72, wherein the disease or disorder is cancer.

74. The method of claim 73, wherein the cancer is triple -negative breast cancer, ovarian cancer, or lung cancer.

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