Described herein are PKMYT1 (Myt1) inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of a disease or disorder associated with PKMYT1.

BACKGROUND

PKMYT1 (or Myt1) is a member of the Wee family and was first reported as a kinase capable of phosphorylating Cdc2 efficiently on both threonine-14 and tyrosine-15 in a Xenopus frog. PKMYT1 inhibits cell cycle progression by inhibiting the activities of cell cycle-associated proteins, such as Cyclin A, CDK1, and CDK2. PKMYT1 also drives the progression of a variety of tumors.

The inhibitory phosphorylation of cdc2 is important for the timing of entry into mitosis. Entry into mitosis is initiated by the M phase-promoting factor (MPF), a complex containing the cdc2 protein kinase and cyclin B. Proper regulation of MPF ensures that mitosis occurs only after earlier phases of the cell cycle are complete. Phosphorylation of cdc2 at Tyr-15 and Thr-14 suppresses this activity during interphase (G1, S, and G2). At G2-M transition, cdc2 is dephosphorylated at Tyr-15 and Thr-14 allowing MPF to phosphorylate its mitotic substrates.

Studies have shown that premature activation of cdc2 leads to mitotic catastrophe and cell death. Inhibition of Myt1 is predicted to cause premature activation of cdc2, and thus would kill rapidly proliferating cells. In addition, Myt1 inhibition is predicted to reduce resistance to conventional DNA-damaging chemotherapeutics, because the mechanisms by which cells avoid death involve arrest in the G2 phase of the cell cycle, and repair or DNA damage prior to division. That arrest should be prevented by blocking Myt1 inhibitory phosphorylation of cdc2. Thus forcing the cell to enter mitosis prematurely. Myt1 kinase is an important cell cycle regulator, particularly at the G2/M phase. This is due to cell cycle regulation and subsequent repair of damage to DNA or mitotic apparatus, the targets for most effective chemotherapeutic agents. Myt1 kinase offers a point of intervention downstream from these mechanisms by which tumor cells develop resistance. Inhibition of Myt1 could in and of itself have therapeutic benefit in reducing tumor proliferation, and in addition, could be used in conjunction with conventional chemotherapies to overcome drug resistance.

Based on the foregoing, there is a need to identify a potent PKMYT1 (Myt1) kinase inhibitor for the treatment of cancer.

SUMMARY

In some embodiments of a compound of Formula (I), the compound is of Formula (Ia):

In some embodiments of a compound of Formula (I), the compound is of Formula (Ib):

In some embodiments of a compound of Formula (I), the compound is of Formula (Ic):

Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of modulating PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of inhibiting PKMYT1 in a subject, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

Also disclosed herein is method of inhibiting PKMYT1 and WEE1 in a subject, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject has cancer. In some embodiments, the cancer depends on the activity of PKMYT1. In some embodiments, the cancer overexpresses CCNE1. In some embodiments, the cancer has an inactivating mutation in the FBXW7 gene. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, or uterine cancer.

INCORPORATION BY REFERENCE

DETAILED DESCRIPTION

Definitions

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 dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.

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

“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-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-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 “C1-C6 alkyl” or “C1-6alkyl”, 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 C1-10alkyl. In some embodiments, the alkyl is a C1-6alkyl. In some embodiments, the alkyl is a C1-5alkyl. In some embodiments, the alkyl is a C1-4alkyl. In some embodiments, the alkyl is a C1-3alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, the alkyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

“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 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” or “C2-6alkenyl”, 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 oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, the alkenyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

“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” or “C2-6alkynyl”, 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 oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, the alkynyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

“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 oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, —CN, —COOH, COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, the alkylene is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkylene is optionally substituted with halogen.

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

“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, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, the aryl is optionally substituted with halogen.

“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, 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 (C3-C15 cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (C3-C10 cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered 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, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

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

“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 include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

“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 include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

“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 (e.g., —NH—, —N(alkyl)-), 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 C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, phosphorus, or combinations thereof 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 optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

“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 fully saturated. 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 quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15 heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (C2-C6 heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-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 heterocycloalkyl is 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 may be optionally substituted as described below, for example, with 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 optionally substituted with oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, —CN, —CF3, —OH, or —OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

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 un-substituted (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.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

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

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.

The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.

As used herein, a “disease or disorder associated with PKMYT1” or, alternatively, “a PKMYT1-mediated disease or disorder” means any disease or other deleterious condition in which PKMYT1, or a mutant thereof, is known or suspected to play a role.

As used herein, a “disease or disorder associated with Myt1” or, alternatively, “a Myt1-mediated disease or disorder” means any disease or other deleterious condition in which Myt1, or a mutant thereof, is known or suspected to play a role.

Compounds

Described herein are compounds, or a pharmaceutically acceptable salt thereof useful in the treatment of a disease or disorder associated with PKMYT1.

In some embodiments of a compound of Formula (I), X is N. In some embodiments of a compound of Formula (I), X is CRX.

In some embodiments of a compound of Formula (I), Y is N. In some embodiments of a compound of Formula (I), Y is CRY.

In some embodiments of a compound of Formula (I), W is N. In some embodiments of a compound of Formula (I), W is CRW.

In some embodiments of a compound of Formula (I), Z is N. In some embodiments of a compound of Formula (I), Z is CRZ.

In some embodiments of a compound of Formula (I), the compound is of Formula (Ia):

In some embodiments of a compound of Formula (I), the compound is of Formula (Ib):

In some embodiments of a compound of Formula (I), the compound is of Formula (Ic):

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R3 is halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R3 is halogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R3 is C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R3 is C1-C3alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R3 is n-propyl or isopropyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R3 is ethyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R3 is methyl.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R4 is halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R4 is halogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R4 is C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R4 is C1-C3alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R4 is n-propyl or isopropyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R4 is ethyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R4 is methyl.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R5 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R5 is hydrogen, halogen, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R5 is hydrogen.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R6 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R6 is hydrogen, halogen, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R6 is hydrogen.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R2 is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R2 is hydrogen.

In some embodiments of a compound of Formula (I) or (Ia)-(Ib), RX is hydrogen, halogen, —CN, —C(═O)NRcRd, C1-C6alkyl, or C1-C6haloalkyl.

In some embodiments of a compound of Formula (I) or (Ia)-(Ib), RX is hydrogen, halogen, —CN, C1-C6alkyl, or C1-C6haloalkyl.

In some embodiments of a compound of Formula (I) or (Ia)-(Ib), RX is hydrogen, halogen, or —CN.

In some embodiments of a compound of Formula (I) or (Ia)-(Ib), RX is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl.

In some embodiments of a compound of Formula (I) or (Ia)-(Ib), RX is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ib), RX is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (Ia)-(Ib), RX is hydrogen. In some embodiments of a compound of Formula (I) or (Ia)-(Ib), RX is halogen. In some embodiments of a compound of Formula (T) or (Ia)-(Ib), RX is C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ib), RX is C1-C3alkyl. In some embodiments of a compound of Formula (T) or (1a)-(Ib), RX is —CN.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R1 is hydrogen, halogen, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments of a compound of Formula (T) or (Ia)-(Ic), RY is hydrogen, halogen, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), RY is hydrogen.

In some embodiments of a compound of Formula (I), RZ is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), RZ is hydrogen or halogen. In some embodiments of a compound of Formula (I), RZ is hydrogen.

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is hydrogen, halogen, —CN, —OH, —ORa, —SRa, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RWa.

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is hydrogen, halogen, —ORa, —SRa, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkynyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more RWa.

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is C2-C6alkynyl optionally substituted with one or more RWa.

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is hydrogen, halogen, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is hydrogen, halogen, —ORa, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is hydrogen, —ORa, C1-C6alkyl, or heterocycloalkyl; wherein the alkyl and heterocycloalkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R. In some embodiments, RW is 5 membered ring. In some embodiments, RW is 6 membered ring. In some embodiments, RW is

In some embodiments, RW is

In some embodiments, RW is

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is hydrogen. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is halogen. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is chloro. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is heterocycloalkyl optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is —ORa. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is —ORa, and Ra is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R. In some embodiments, Ra is 5 membered ring. In some embodiments, Ra is 5- or 6-membered cycloalkyl or heterocycloalkyl. In some embodiments, Ra is 6 membered ring. In some embodiments, Ra is 5- or 6-membered aryl or heteroaryl. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is C1-C6alkyl. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is C1-C3alkyl. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is C1-C6haloalkyl. In some embodiments of a compound of Formula (I) or (Ib)-(Ic), RW is C1-C3haloalkyl.

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), each RWa is independently halogen, —CN, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), each RWa is independently halogen, —CN, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ib)-(Ic), each RWa is independently halogen, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 5- or 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 6-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is tetrahydropyridinyl.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is heteroaryl.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 6-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is monocyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is 5-6, 6-5, 5-5, or 6-6 fused bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is fused bicyclic heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is pyridinyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is pyrimidyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is pyrazinyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring A is

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1 is independently halogen, —CN, —OH, —ORa, —S(═O)2Ra, —S(═O)2NRcRd, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a; or two R1 on the same atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1 is independently halogen, —CN, —OH, —ORa, —S(═O)2Ra, —NRcRd, —C(═O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R1a; or two R1 on the same atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1 is independently halogen, —CN, —OH, —ORa, —S(O)2Ra, —NRcRd, —C(═O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl; wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R1a; or two R1 on the same atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1 is independently halogen, —CN, —OH, —ORa, —S(O)2Ra, —NRcRd, —C(═O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, or C2-C6alkynyl; wherein each alkyl and alkynyl is independently optionally substituted with one or more R1a; or two R1 on the same atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1 is independently cycloalkyl, heterocycloalkyl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, and heteroaryl is independently optionally substituted with one or more R1a; or two R1 on the same atom are taken together to form an oxo.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1 is independently halogen, —CN, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally independently substituted with one or more R1a. In some embodiments, one or more R1 is —ORa. In some embodiments, one or more R1 is —NRcRd. In some embodiments, one or more R1 is —C(═O)Ra. In some embodiments, one or more R1 is optionally substituted C1-C6alkyl. In some embodiments, one or more R1 is optionally substituted C1-C6haloalkyl. In some embodiments, one or more R1 is optionally substituted C1-C6hydroxyalkyl. In some embodiments, one or more R1 is optionally substituted cycloalkyl. In some embodiments, one or more R1 is optionally substituted heterocycloalkyl. In some embodiments, one or more R1 is an optionally substituted 6-membered heterocycloalkyl containing 1-2 nitrogen.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1 is independently halogen, —ORa, —NRcRd, —C(═O)Ra, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally independently substituted with one or more R1a.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1 is independently halogen, —ORa, —NRcRd, —C(═O)Ra, C1-C6alkyl, C1-C6hydroxyalkyl, or heterocycloalkyl; wherein each alkyl, and heterocycloalkyl is independently optionally independently substituted with one or more R1a.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1a is independently halogen, —CN, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1a is independently halogen, —OH, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, or heterocycloalkyl is independently optionally substituted with one or more R.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1a is independently halogen, —CN, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1a is independently halogen, C1-C6alkyl, or C1-C6haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R1a is independently halogen, C1-C6alkyl, or C1-C6haloalkyl.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0-2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1 or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 2.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0.

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia) (Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula I or Ia-Ic,

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic)

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound of Formula (I) or (Ia)-(Ic),

In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently C1-C6alkyl.

In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rb is hydrogen. In some embodiments of a compound disclosed herein, each Rb is independently C1-C6alkyl.

In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C5alkylene(heteroaryl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6alkylene(cycloalkyl), C1-C6alkylene(heterocycloalkyl), C1-C6alkylene(aryl), or C1-C6alkylene(heteroaryl). In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are hydrogen. In some embodiments of a compound disclosed herein, each Rc and Rd are independently C1-C6alkyl.

In some embodiments of a compound disclosed herein, Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R.

In some embodiments of a compound disclosed herein, each R is independently halogen, —CN, —OH, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; 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, —NHCH3, —N(CH3)2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; 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, C1-C6alkyl, C1-C6alkoxy, or C1-C6haloalkyl; 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 C1-C6alkyl; or two R on the same atom form an oxo. In some embodiments of a compound disclosed herein, each R is independently halogen, —OH, or C1-C6alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen.

In some embodiments of a compound disclosed herein, one or more of R, R1, R1a, R2, R3, R4, R5, R6, RX, RY, RZ, RW, Ra, Rb, Rc, and Rd groups comprise deuterium at a percentage higher than the natural abundance of deuterium.

In some embodiments of a compound disclosed herein, one or more 1H are replaced with one or more deuteriums in one or more of the following groups R, R1, R1a, R2, R3, R4, R5, R6, RX, RY, RZ, RW, Ra, Rb, Rc, and Rd.

In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R, R1, R1a, R2, R3, R4, R5, R6, RX, RY, RZ, RW, Ra, Rb, Rc, and Rd is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% by molar.

In some embodiments of a compound disclosed herein, one or more hydrogens of Ring A are replaced with one or more deuteriums.

In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is one of the compounds in Table 1.

Example
Structure

(unknown cis or trans isomer)

(unknown cis or trans isomer)

In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is one of the compounds in Table 2.

Structure

Further Forms of Compounds Disclosed Herein

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 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 have distinct 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.

In some embodiments, the compounds described herein contain bonds with hindered rotation such that two separate rotamers or atropisomers can be isolated. In some embodiments the atropisomers are

In some embodiments, these atropisomer are separated and are found to have different biological activity which may be advantageous. In some embodiments the atropisomer is

In some embodiments the atropisomer is

In some embodiments the compound disclosed herein is a racemic mixture:

Labeled Compounds

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 chloride, such as 2H (D), 3H, 13C, 14C, 15N, 18O 17O, 31P, 32P, 35S, 8F, and 36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts 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 as 3H and 14C 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 for their ease of preparation and detectability.

In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of a total number of hydrogen and deuterium. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein.

Pharmaceutically Acceptable Salts

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.

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, to form 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 by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

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. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like.

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 quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

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

Disclosed herein are methods of treating a disease modulated at least in part by PKMYT1 in a subject in need thereof, comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.

Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.

In some embodiments, the cancer depends on the activity of PKMYT1.

In some embodiments, the cancer overexpresses CCNE1. In some embodiments cancers which have a high incidence of CCNE1 overexpression include e.g., breast cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, stomach cancer, and uterine cancer.

In some embodiments, the cancer has an inactivating mutation in the FBXW7 gene. In some embodiments cancers which have a deficiency in FBXW7 include, e.g., breast cancer, colorectal cancer, esophageal cancer, lung cancer, and uterine cancer.

In some embodiments, the cancer is a solid tumor.

Disclosed herein is a method of modulating PKMYT1 in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, disclosed herein. Disclosed herein is a method of inhibiting PKMYT1 in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, disclosed herein. Further disclosed herein is a method of selectively inhibiting PKMYT1 in a subject (e.g., selective over WEE1), the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.

WEE1 widely exists in human tissues and plays an important role in all phases of the cell cycle. It can be beneficial to use compounds that selectively inhibit PKMYT1 over WEE1 in methods of treatment described herein. In some embodiments, compounds disclosed herein do not inhibit WEE1. In some embodiments, a compound disclosed herein has a WEE1 IC50 value of at least about 100 nM, at least about 500 nM, at least about 1000 nM, or at least about 10,000 nM as determined in a WEE1 ADP-Glo assay. For example, the WEE1 IC50 value can be determined according to Example B.

Dosing

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 methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.

Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.

The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

In some embodiments, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In some embodiments, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

Routes of Administration

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. In specific embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.

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.

Combination

Disclosed herein are methods of treating a disease or disorder associated with PKMYT1 using a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent.

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.

In some embodiments, the additional therapeutic agent is an anti-cancer agent.

EXAMPLES

Example 1: Preparation of 2,4-dimethyl-3-(2-(2-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)phenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 1-2

Step 2: Preparation of Compound 1-4

Step 3: Preparation of Example 1

Example 2: Preparation of 2,4-dimethyl-3-(7-methyl-2-(2-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-6-yl)phenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 2-2

To a solution of compound 2-1 (60 mg, 0.104 mmol) in dioxane (2 mL) were added compound 1-3 (20 mg, 0.104 mmol), pd(dtbpf)Cl2 (67 mg, 0.104 mmol), Na2CO3 (10 mg, 0.104 mmol) and H2O (0.2 mL). The reaction was stirred at 90° C. for 2 h under N2. The reaction mixture was quenched with water (20 mL), and extracted with EA (3×20 mL). The organic layer was combined, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 2-2. LCMS: 573.3 [M+H]+.

Step 2: Preparation of Example 2

Example 3: Preparation of 2,4-dimethyl-3-(3-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 3-2

To a solution of compound 3-1 (1.0 g, 4.738 mmol) in THF (20 mL) was added NaH (0.38 g 9.476 mmol) at 0° C. The mixture was stirred at 0° C. under N2 for 0.5 h. Then TsCl (1.08 g, 1.780 mmol) was added. The mixture was stirred at 20° C. under N2 for 1 h. The reaction was quenched by NH4Cl (50 ml, sat. in water), extracted with EA (100 mL×3), washed with (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford compound 3-2 as a white solid. LCMS: 366.8 [M+H]+.

Step 2: Preparation of Compound 3-3

To a solution of compound 3-2 (500 mg, 1.369 mmol) in THF (10 mL) was added LDA (1.03 mL) at −78° C. under N2. The mixture was stirred at −78° C. under N2 for 0.5 h. Then I2 (451 mg, 1.780 mmol) was added. The mixture was stirred at −78° C. under N2 for 1 h. The reaction was quenched by NH4Cl (50 ml, sat. in water), which was extracted with EA (100 mL×3), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford compound 3-3 as a white solid. LCMS: 492.6 [M+H]+.

Step 3: Preparation of Compound 3-5

To a solution of compound 3-3 (200 mg, 0.407 mmol) in dioxane (6 mL) and H2O (1 mL) was added compound 3-4 (135 mg, 0.448 mmol), Pd(dppf)Cl2 (30 mg, 0.041 mmol) and CsF (186 mg, 1.221 mmol). The mixture was stirred at 90° C. under N2 for 1.5 h. The mixture was diluted with EA (100 mL), which was washed with brine (100 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford compound 3-5. LCMS: 542.2 [M+H]+.

Step 4: Preparation of Compound 3-6

Step 5: Preparation of Compound 3-7

Step 6: Preparation of Example 3

Example 4: Preparation of 2,4-dimethyl-3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 4-2

To a solution of compound 4-1 (3 g, 15.23 mmol) in THF (60 mL) was added NaH (0.73 g, 30.45 mmol) at 0° C. The mixture was stirred at 0° C. under N2 for 0.5 h. Then TsCl (3.48 g, 18.27 mmol) was added. The mixture was stirred at 20° C. under N2 for 1 h. The reaction was quenched by NH4Cl (50 mL, sat.), extracted with EA (100 mL×3), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford compound 4-2 as a white solid. LCMS: 352.7 [M+H]+.

Step 2: Preparation of Compound 4-3

To a solution of compound 4-2 (1 g, 2.390 mmol) in THF (10 mL) was added LDA (0.46 g, 4.271 mmol) at −78° C. The mixture was stirred at −78° C. under N2 for 0.5 h. Then I2 (1.64 g, 3.701 mmol) was added. The mixture was stirred at −78° C. under N2 for 1 h. The reaction was quenched by NH4Cl (50 ml, sat.), extracted with EA (100 mL×3), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to compound 4-3 as a white solid. LCMS: 476.9 [M+H]+.

Step 3: Preparation of Compound 4-4

Step 4: Preparation of Compound 4-5

Step 5: Preparation of Compound 4-6

Step 5: Preparation of Example 4

Example 5: Preparation of 2,4-dimethyl-3-(2-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 5-2

To a solution of compound 5-1 (150 mg, 0.339 mmol) in dioxane (6 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (172 mg, 0.678 mmol), Pd(dppf)Cl2 (25 mg, 0.034 mmol) and potassium acetate (100 mg, 1.017 mmol). The reaction mixture was stirred at 100. for 2 h. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with EA (30 mL×3), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The crude compound 5-2 was used directly in next step. LCMS: 408.2 [M+H]+.

Step 2: Preparation of Compound 5-3

To a solution of compound 5-2 (150 mg, 0.306 mmol) in dioxane (6 mL) and H2O (1 mL) were added compound 1-3 (62 mg, 0.306 mmol), K2CO3 (127 mg, 0.919 mmol) and Pd(dtbpf)Cl2 (20 mg, 0.031 mmol). The reaction mixture was stirred at 90. for 2 h. The reaction was diluted with DCM and water. The organic layer was separated and concentrated in vacuo. The crude material was purified by silica gel column to afford compound 5-3. LCMS: 484.2 [M+H]+.

Step 3: Preparation of Example 5

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 6-1

To a solution of compound 4-3 and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethan-1-one (579 mg, 2.306 mmol) in dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)Cl2 (153 mg, 0.209 mmol) and cesium fluoride (957 mg, 6.300 mmol). The mixture was stirred at 100° C. for 1 h under N2. The reaction mixture was cooled to room temperature and extracted with EA (20 mL×2). The organic layer was combined, dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel column chromatography to afford compound 6-1. LCMS: 448.9 [M+H]+.

Step 3: Preparation of Compound 6-2

Step 4: Preparation of Compound 6-3

Step 5: Preparation of Example 6

Example 7: Preparation of 2,4-dimethyl-3-(2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 7-2

Step 2: Preparation of Compound 7-3

Step 3: Preparation of Compound 7-4

Step 4: Preparation of Example 7

Example 8: Preparation of 3-(2-(5-methoxypyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,4-dimethylphenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 8-2

To a stirred solution of compound 4-3 (160 mg, 0.335 mmol) in dioxane (4 mL) were added Pd(dppf)Cl2 (24.54 mg, 0.034 mmol), compound 8-1 (61.55 mg, 0.402 mmol), potassium carbonate (139.04 mg, 1.006 mmol) and H2O (0.8 mL). The reaction was stirred at 100  for 2 h by microwave under argon and quenched with water (25 mL). The resulting mixture was extracted with EA (3×20 mL). The EA layer was combined, washed with brine (2×30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to compound 8-2. LCMS: 457.9 [M+H]+.

Step 2: Preparation of Compound 8-3

To a stirred solution of compound 8-2 (80 mg, 0.175 mmol) in dioxane (2 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (66.49 mg, 0.262 mmol), Pd(dppf)Cl2 (127.72 mg, 0.175 mmol) and KOAC (51.32 mg, 0.524 mmol). The reaction was stirred at 90  for 3 h and quenched with H2O (10 mL). The resulting mixture was extracted with EA (3×15 mL). The EA layer was combined, washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 8-3. LCMS: 506.2 [M+H]+.

Step 4: Preparation of Compound 8-4

To a stirred solution of compound 8-3 (70 mg, 0.139 mmol) in dioxane (2 mL) was added compound 1-3 (27.85 mg, 0.139 mmol), Cs2CO3 (173.19 mg, 0.532 mmol), Pd(dtbpf)Cl2 (9.14 mg, 0.014 mmol) and H2O (0.4 mL). The reaction was stirred at 90′C for 2 h under argon. The reaction mixture was quenched with water (15 mL). The resulting mixture was extracted with EA (3×15 mL). The EA layer was combined, washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 8-4. LCMS: 500.2 [M+H]+.

Step 5: Preparation of Example 8

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 9-2

To a solution of compound 4-3 (380 mg, 0.796 mmol) in dioxane (6 mL) and H2O (1 mL) was added compound 9-1 (187.24 mg, 0.796 mmol), cesium fluoride (362.95 mg, 2.389 mmol) and Pd(dppf)Cl2 (58.28 mg, 0.080 mmol). The resulting mixture was stirred at 90  under N2 for 2 h. The reaction mixture was quenched with water (20 mL), and extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified using silica gel column chromatography to afford compound 9-2. LCMS: 460.0 [M+H]+.

Step 2: Preparation of Compound 9-3

To a solution of compound 9-2 (200 mg, 0.436 mmol) in dioxane (6 mL) were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (132.97 mg, 0.524 mmol), KOAc (128.48 mg, 1.309 mmol) and Pd(dppf)Cl2 (31.93 mg, 0.044 mmol). The reaction was stirred at 100  under N2 for 3 h. The reaction mixture was diluted with water (20 mL), extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 9-3. LCMS: 506.1 [M+H]+.

Step 3: Preparation of Compound 9-4

To a solution of compound 9-3 (200 mg, 0.394 mmol) in dioxane (6 mL) and H2O (1 mL) were added compound 1-3 (79.25 mg, 0.394 mmol), Pd(dtbpf)Cl2 (25.77 mg, 0.039 mmol) and K2CO3 (163.42 mg, 1.182 mmol). The reaction was stirred at 90° C. under N2 for 2 h. The reaction mixture was diluted with water (20 mL), extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 9-4. LCMS: 500.2 [M+H]+.

Step 4: Preparation of Example 9

Example 10: Preparation of 3-(4-chloro-2-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,4-dimethylphenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 10-2

To a solution of compound 10-1 (950 mg, 4.104 mmol) in THF (20 mL) was added NaH (328.3 mg, 60% dispersion in mineral oil, 8.208 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then TsCl (935.72 mg, 4.925 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by sat. NH4Cl (aq., 20 mL), extracted with EA (150 mL). The organic layers were combined and dried over Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography to afford compound 10-2. LCMS: 387.0 [M+H]+.

Step 2: Preparation of Compound 10-3

To a solution of compound 10-2 (700 mg, 1.818 mmol) in THF (10 mL) was added LDA (1.09 mL, 2.182 mmol) at −78° C. The mixture was stirred at this temperature for 1 h. Then I2 (692.18 mg, 2.727 mmol) was added, and the resulting mixture was stirred at −78° C. for 1 h. The mixture was quenched with sat. NH4Cl (aq., 20 mL), extracted with EA (100 mL). The organic layer was washed with sat. Na2SO3 (aq., 30 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 10-3. LCMS: 512.9 [M+H]+.

Step 3: Preparation of Compound 10-5

Step 4: Preparation of Compound 10-7

Step 5: Preparation of Compound 10-8

To a solution of compound 10-7 (60 mg, 0.113 mmol) in DCM (3 mL) was added BBr3 (0.1 mL) at 0° C. The mixture was stirred for 0.5 h. The reaction was quenched with MeOH (1 mL). The mixture was concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 10-8. LCMS: 518.2 [M+H]+.

Step 6: Preparation of Example 10

Example 11: Preparation of 2,4-dimethyl-3-(6-(6-methylpyridin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 11-2

To a solution of compound 11-1 (500 mg, 3.256 mmol) in THF (10 mL) was added NaH (260.48 mg, 60% dispersion in mineral oil, 6.512 mmol) at 0° C. The mixture was stirred at this temperature for 0.5 h. Then TsCl (744.87 mg, 3.907 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with sat. NH4Cl (aq., 20 mL), extracted with EA (100 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 11-2. LCMS: 307.9 [M+H]+.

Step 2: Preparation of Compound 11-3

To a solution of compound 11-2 (1.1 g, 3.574 mmol) in THF (20 mL) was added LDA (2.32 mL, 4.647 mmol) at −78° C. The mixture was stirred at this temperature for 1 h. Then 12 (1.36 g, 5.361 mmol) was added and stirred at −78° C. for 1 h. The mixture was quenched with sat. NH4Cl (aq, 20 mL), extracted with EA (100 mL). The organic layer was washed with Na2SO3 (sat.aq, 30 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 11-3. LCMS: 434.0 [M+H]+.

Step 3: Preparation of Compound 11-4

Step 4: Preparation of Compound 11-5

Step 5: Preparation of Compound 11-6

To a solution of compound 11-5 (200 mg, 0.011 mmol) in DCM (10 mL) was added BBr3 (0.2 mL) at 0° C. The mixture was stirred for 0.5 h. The reaction was quenched with MeOH (1 mL). The mixture was concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 11-6. LCMS: 485.2 [M+H]+.

Step 6: Preparation of Example 11

Example 12: Preparation of 3-(7-fluoro-6-(2-methylpyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,4-dimethylphenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 12-2

To a solution of compound 12-1 (500 mg, 2.525 mmol) in HOAc (2 mL) and CH3CN (10 mL) was added selectfluor (1341.8 mg, 3.787 mmol). The solution was heated to 90  for 16 h under N2. The solution was quenched by sat.aq NaHCO3 (50 mL), extracted with EA (50 mL×3). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford compound 12-2 (100 mg, 0.463 mmol, 18.33%). LCMS: 215.9 [M+H]+.

Step 2: Preparation of Compound 12-3

To a solution of compound 12-2 (100 mg, 0.463 mmol) in DMF (2 mL) was added NaH (27.8 mg, 0.694 mmol) in portions at 0  The mixture was stirred at 0  for 30 min. Then TsCl (132.4 mg, 0.694 mmol) was added. The reaction mixture was stirred at 0  for 1 h and quenched by H2O (10 mL). The suspension was filtered and the solid was dried to afford compound 12-3 (150 mg, 0.405 mmol, 87.52%). LCMS: 370.1 [M+H]+.

Step 3: Preparation of Compound 12-4

Step 4: Preparation of Compound 12-6

To a solution of compound 12-4 (95 mg, 0.223 mmol) in THF (4 mL) was added LDA (0.22 mL, 0.447 mmol) in drops at −78 . The solution was stirred at −78  for 30 min. Then compound 12-5 (145.4 mg, 0.447 mmol) in THF (0.4 ml) was added. The reaction mixture was stirred at −78  for 1 h under N2. The mixture was quenched by sat.aq NH4Cl (20 mL), diluted with H2O (20 mL), extracted with EA (30 mL×3). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford compound 12-6 (90 mg, 0.178 mmol, 79.92%). LCMS: 505.6 [M+H]+.

Step 5: Preparation of Compound 12-7

A solution of compound 12-6 (200 mg, 0.397 mmol) and NaOH (4.0 mL, 3.965 mmol) in EtOH (4 mL) was heated to 50  for 1 h. The mixture was cooled to 0 , adjusted pH to 6 by 1N HCl, diluted with H2O (10 mL), extracted with EA (10 mL×3). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford compound 12-7. LCMS: 351.7 [M+H]+.

Step 6: Preparation of Compound 12-9

A mixture of compound 12-7 (100 mg, 0.286 mmol), compound 12-8 (81.7 mg, 0.371 mmol), K2CO3 (118.4 mg, 0.857 mmol) and Pd(dtbpf)Cl2 (18.7 mg, 0.029 mmol) in dioxane-water (5:1) (2 mL) was heated to 90  for 3 h under N2 atmosphere. The mixture was concentrated and the residue was diluted with H2O (10 mL), extracted with EA (10 mL×3). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford compound 12-9.

Step 7: Preparation of Example 12

Example 13: Preparation of 2,4-dimethyl-3-(7-methyl-6-(2-methylpyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol

The example 13 was synthesized from compound 13-1, which was prepared according to the methods described in example 12 with analogous starting material.

Step 1: Preparation of Compound 13-2

To a solution of compound 13-1 (200.0 mg, 0.579 mmol) in CH3CN (10.0 mL) was added NBS (103.1 mg, 0.579 mmol) at 0 . The mixture was stirred at room temperature for 2 h. The reaction mixture was purified by reversed-phase column chromatography to afford compound 13-2. LCMS: 426.0 [M+H]+.

Step 2: Preparation of Compound 13-4

A mixture of compound 13-2 (243.0 mg, 0.573 mmol), compound 13-3 (151.0 mg, 1.203 mmol), K2CO3 (336.4 mg, 2.434 mmol) and Pd(dtbpf)Cl2 (37.4 mg, 0.057 mmol) in dioxane-water (6 mL, 5:1) were stirred at 100° C. under N2 for 16 h. The reaction mixture was cooled to room temperature and diluted with water (20 mL), which was extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 13-4. LCMS: 360.2 [M+H]+.

Step 3: Preparation of Example 13

Example 14: Preparation of 3-(6-(2-aminopyrimidin-5-yl)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,4-dimethylphenol

The example 14 was synthesized from compound 14-1, which was prepared according to the methods described in example 12 with analogous starting material.

Step 1: Preparation of Compound 14-2

To a solution of compound 14-1 (320 mg, 0.963 mmol) in DMF (2 mL) was added Boc2O (0.2 mL, 1.059 mmol) and TEA (0.2 mL, 1.444 mmol) and DMAP (6 mg, 0.048 mmol). The mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EA (10 mL), which was washed with brine (10 mL×3). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 14-2 (255 mg, 0.590 mmol, 61.2%). LCMS: 433.4 [M+H]+.

Step 2: Preparation of Compound 14-3

To a solution of compound 14-2 (260 mg, 0.509 mmol) in CAN (10 mL) was added NIS (103 mg, 0.458 mmol). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (10 mL), which was extracted with EA (10 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 14-3. LCMS: 559.3 [M+H]+.

Step 3: Preparation of Compound 14-5

Step 4: Preparation of Example 14

The following examples 15-27 were prepared according to the methods described in examples 12-14 with analogous starting materials.

Example 29: Preparation of 2,4-dimethyl-3-(2-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

The example 29 was synthesized from compound 29-1, which was prepared according to the methods described in example 12 with analogous starting material.

Step 1: Preparation of Compound 29-2

To a solution of compound 29-1 (585 mg, 1.439 mmol) in THF (10 mL) was added LDA (1.1 mL, 2.159 mmol) at −78° C. The mixture was stirred at this temperature for 0.5 h. Then I2 (766.05 mg, 5.361 mmol) was added and stirred at −78° C. for 1 h. The mixture was quenched with NH4Cl (sat.aq, 20 mL) and extracted with EA (100 mL). The organic layer was washed with Na2SO3 (sat.aq, 30 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 29-2 (550 mg, 1.03 mmol, 71.78%). LCMS: 533.4 [M+H]+.

Step 2: Preparation of Compound 29-4

Step 3: Preparation of Compound 29-5

To a solution of compound 29-4 (48 mg, 0.096 mmol) in DCM (5 mL) was added BBr3 (0.241 mL, 2.0 M in DCM). The mixture was stirred at room temperature under N2 for 1 h. The reaction was quenched with MeOH (5 mL). The mixture was concentrated to dryness. The residue was purified by prep-TLC to afford compound 29-5. LCMS: 485.2 [M+H]+.

Step 4: Preparation of Example 29

Example 30: Preparation of 3-(4-amino-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,4-dimethylphenol

The example 30 was synthesized from compound 30-1, which was prepared according to the methods described in example 12 with analogous starting material.

Step 1: Preparation of Compound 30-2

To a solution of compound 30-1 (300.0 mg, 0.563 mmol) in DMSO (6.0 mL) were added CuI (750.6 mg, 3.940 mmol), L-proline (453.6 mg, 3.940 mmol) and NaN3 (512.2 mg, 7.880 mmol). The reaction mixture was stirred at 140  under N2 for 18 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC to afford compound 30-2. LCMS: 360.2 [M+H]+.

Step 2: Preparation of Example 30

Example 31: Preparation of (R)-2,4-dimethyl-3-(2-(2-methylpyrimidin-5-yl)-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

The example 31 was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 31-1

To a solution of compound 10-2 (4 g, 10.372 mmol) in CH3CN (60 mL) were added NaI (7.77 g, 51.859 mmol) and acetyl chloride (2.212 mL, 31.115 mmol). The mixture was stirred at 80° C. under N2 overnight. The reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL×3). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 31-1 (3.2 g, 6.707 mmol, 64.67%). LCMS: 476.8 [M+H]+.

Step 2: Preparation of Compound 31-2

To a solution of compound 31-1 (600 mg, 1.258 mmol) in DMF (20 mL) were added CuI (239.50 mg, 1.258 mmol) and methyl 2,2-difluoro-2-fluoro-sulfonyl acetate (965.82 mg, 5.030 mmol) at 80° C. The mixture was stirred at this temperature for 12 h. The mixture was quenched with H2O (20 mL) and extracted with EA (100 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 31-2 (450 mg, 1.073 mmol, 85.36%). LCMS: 418.9 [M+H]+.

Step 3: Preparation of Example 31

Example 32: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The example 32 was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 32-1

To a solution of compound 31-1 (23.5 g, 49.255 mmol) in DMF (235 mL) was added Zn(CN)2 (2.891 g, 24.627 mmol) and Pd(PPh3)4 (5.692 g, 4.925 mmol). The mixture was stirred at 110° C. for 16 h. The mixture was quenched by water (100 mL), which was extracted with EtOAc (500 mL×3). The organic layer was washed with brine, concentrated, and purified by silica gel column chromatography to afford compound 32-1 (25 g, 35.983 mmol, 73.1%). LCMS: 378.1 [M+H]+.

Step 2: Preparation of Compound 32-2

Step 3: Preparation of Compound 32-3

To a solution of compound 32-2 (27 g, 62.571 mmol) in THF (500 mL) was added LDA (62.57 mL, 125.142 mmol) in drops at −78 . The mixture was stirred at −78 for 30 min. Then compound 12-5 (40.7 g, 125.142 mmol) in THF (5 mL) was added. The mixture was stirred at −78  for 1 h and then warmed to rt for 16 h. The mixture was quenched by st.aq NH4Cl (100 mL), extracted with EA (50 mL×3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to afford compound 32-3 (18 g, 35.266 mmol, 56.4%). LCMS: 511.8 [M+H]+.

Step 4: Preparation of Compound 32-4

Step 5: Preparation of Example 32

Example 33: Preparation of (S)-3-chloro-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was synthesized from compound 33-1, which was prepared according to the methods described in example 32 with analogous starting materials.

Step 1: Preparation of Compound 33-2

To a solution of compound 33-1 (40 mg, 0.108 mmol) in CH3CN (2 mL) was added NCS (14.4 mg, 0.108 mmol). The mixture was stirred at 40° C. for 16 h. The mixture was diluted with H2O (15 mL) and extracted with DCM (10 mL×3). Combined organic layers were washed with brine (10 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 33-2. LCMS: 404.1 [M+H]+.

Step 2: Preparation of Example 33

Example 34: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carboxamide

The title compound was synthesized from compound 33-1, which was prepared according to the methods described in example 32 with analogous starting materials.

Step 1: Preparation of Compound 34-1

To a solution of compound 33-1 (50 mg, 0.135 mmol) in MeOH (1 mL) and H2O (0.5 mL) was added H2O2 (85.72 mg, 0.677 mmol) and NaOH (16.24 mg, 0.406 mmol). The mixture was stirred at 40° C. for 16 h. The mixture was filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 34-1. LCMS: 388.4 [M+H]+.

Step 2: Preparation of Example 34

The following examples 35-81 were prepared according to the methods described in examples 32-34 with analogous starting materials.

where

carboxylic acid

carboxylic acid

Example 82: Preparation of (R)-3-chloro-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(2-oxooxazolidin-3-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 82-3

To a solution of compound 82-1 (1.1 g, 5.687 mmol) in NMP (20 mL) was added compound 82-2 (449.14 mg, 5.158 mmol), and the reaction was stirred at 80° C. under N2 for 18 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL×3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford compound 82-3 (500 mg, 2.049 mmol, 37.74%). LCMS: 244.0 [M+H]+.

Step 2: Preparation of Compound 82-4

Step 3: Preparation of Example 82

Example 83: Preparation of (5R)-2-(2-(2,3-dihydroxypropoxy)pyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 83-2

To a solution of compound 83-1 (512.43 mg, 3.877 mmol) in THF (10 mL) was added NaH (124.08 mg, 3.102 mmol) at 0° C. for 0.5 h, then compound 82-1 (500 mg, 2.585 mmol) was added. The mixture was stirred at rt for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 83-2 (550 mg, 1.902 mmol, 73.6%). LCMS: 291.1 [M+H]+.

Step 2: Preparation of Compound 83-3

To a solution of compound 83-2 (300 mg, 1.038 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (790.4 mg, 3.113 mmol) in dioxane (5 mL) were added KOAc (305.4 mg, 3.113 mmol) and Pd(dppf)Cl2 (75.9 mg, 0.104 mmol). The reaction mixture was replaced gas three times. The reaction mixture was stirred at 90° C. under N2 overnight. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (50 mL×2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 83-3 (130 mg, 1.200 mmol, 26.0%). LCMS: 255.2 [M+H]+.

Step 3: Preparation of Example 83

Example 84: Preparation of (R)-3-chloro-2-(2-(1,1-dioxidothiomorpholino)pyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 84-3

To a solution of compound 84-1 (500 mg, 2.079 mmol) in ethanol (10 mL) were added compound 84-2 (843.1 mg, 6.237 mmol) and TEA (0.87 mL, 6.237 mmol), the reaction was stirred at 80 under N2 for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 84-3 (500 mg, 1.945 mmol, 93.55%). LCMS: 258.0 [M+H]+.

Step 2: Preparation of Example 84

Example 85: Preparation of 2-(2-(difluoromethoxy)pyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 85-2

A solution of compound 85-1 (5 g, 18.860 mmol) in TFA (20 mL, 18.860 mmol) was stirred at 40° C. for 16 h. The mixture was diluted with EA (100 mL) and water (100 mL) and stirred for 10 min. The mixture was filtered. The filtrate was dried under reduced pressure to afford compound 85-2 (2 g, 11.429 mmol, 60.60%).

Step 2: Preparation of Compound 85-4

To a solution of compound 85-2 (3 g, 17.144 mmol) and K2CO3 (7.11 g, 51.432 mmol) in DMF (40 mL) was added compound 85-3 (7.84 g, 51.432 mmol) at 80° C. The mixture was stirred at 100° C. for 2 h. The mixture was filtered. The filtrate was diluted with EA (50 mL), which was washed with brine (50 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 85-4 (300 mg, 1.333 mmol, 7.78%).

Step 3: Preparation of Compound 85-5

To a solution of compound 85-4 (65 mg, 0.289 mmol) in dioxane (2 mL) were added KOAc (85.06 mg, 0.867 mmol) and Pd(dppf)Cl2 (21.14 mg, 0.029 mmol). The mixture was stirred at 100° C. for 1 h. The reaction mixture was to be used directly in next step. LCMS: 190.9 [M+H]+.

Step 4: Preparation of Example 85

Example 86: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 86-2

To a solution of compound 86-1 (1 g, 4.608 mmol) in THF (10 mL) was added magnesium monobromide methanide (18.431 mL, 18.431 mmol). The mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with water (20 mL), which was extracted with EA (10 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford compound 86-2 (400 mg, 1.843 mmol, 39.99%). LCMS: 219.0 [M+H]+.

Step 2: Preparation of Compound 86-3

Step 3: Preparation of Example 86

Example 87: Preparation of (R)-2-(6-amino-5-ethynylpyridin-3-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 87-3

Step 2: Preparation of Compound 87-4

Step 3: Preparation of Compound 87-5

Step 4: Preparation of Example 87

Example 88: Preparation of 3-(2-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,4-dimethylphenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 88-3

To a solution of compound 88-1 (2 g, 4.192 mmol) and compound 88-2 (0.9 g, 4.192 mmol) in dioxane (20 mL) and water (4 mL) were added CsF (1.91 g, 12.576 mmol), Pd(dppf)Cl2 (0.31 g, 0.419 mmol). The reaction was stirred at 90  under N2 for 16 h. The reaction was diluted with EA (60 mL) and water (50 mL). The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford compound 88-3 (360 mg, 0.739 mmol, 17.62%). LCMS: 489.0 [M+H]+.

Step 2: Preparation of Compound 88-4

To a solution of compound 88-3 (360 mg, 0.739 mmol) in THF (5 mL) was added MeMgBr (3.7 mL, 0.739 mmol, 1M) at 0° C., and the reaction was stirred at 0° C. for 3 h. The reaction mixture was carefully added into water (30 mL) under ice-bath, which was extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The organic layer was separated and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford compound 88-4 (200 mg, 0.410 mmol, 55.55%). LCMS: 488.8 [M+H]+.

Step 3: Preparation of Example 88

Example 89: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(5-(4-hydroxypiperidin-1-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 89-3

To a solution of compound 89-1 (500 mg, 2.11 mmol) in DMF (10 mL) were added compound 89-2 (485 mg, 4.219 mmol) and K2CO3 (874 mg, 6.33 mmol) at rt. The mixture was stirred at 120° C. for 16 h. The mixture was quenched with H2O (50 mL) and extracted with EA (60 mL×3). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 89-3 (120 mg, 0.443 mmol, 21%). LCMS: 273.1 [M+H]+.

Step 2: Preparation of Compound 89-4

Step 3: Preparation of Example 89

Example 90: Preparation of 5-(2-ethyl-3-hydroxy-6-methylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 90-2

To a solution of compound 90-1 (8.0 g, 39.594 mmol) and ethylboronic acid (5.9 g, 79.188 mmol) in dioxane (100 mL) and H2O (20 mL) were added Pd(dppf)Cl2 (2.9 g, 3.959 mmol) and K2CO3 (16.4 g, 118.782 mmol). The mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 90-2 (2.4 g, 15.872 mmol, 40.09%). LCMS: 152.2 [M+H]+.

Step 2: Preparation of Compound 90-3

To a solution of compound 90-2 (7.0 g, 46.293 mmol) in DMF (20 mL) was added NIS (8.0 g, 46.293 mmol). The mixture was stirred at rt for 12 h. The reaction mixture was diluted with EA (30 mL) and washed with brine (20 mL×3). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 90-3 (8 g, 28.869 mmol, 62.36%). LCMS: 278.2 [M+H]+.

Step 3: Preparation of Compound 90-4

Step 4: Preparation of Compound 90-5

Step 5: Preparation of Compound 90-6

Step 6: Preparation of Example 90

The title compound was prepared from compound 90-6 according to the methods described in example 32-33. Spectrum data of example 90: LCMS: 370.4 [M+H]+.

Example 91: Preparation of (R)-5-(2-ethyl-3-hydroxy-6-methylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

Step 1: Preparation of Example 91

Example 92: Preparation of 2-(4-amino-2-methylpyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 92-2

Step 2: Preparation of Compound 92-4

Step 3: Preparation of Example 92

Example 93: Preparation of (R)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(pyrrolidin-1-ylmethyl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 93-2

Step 2: Preparation of Compound 93-3

Step 3: Preparation of Compound 93-4

To a solution of compound 32-4 (100 mg, 0.281 mmol) in dioxane (5 mL) were added compound 93-3 (253.9 mg, 0.561 mmol), LiCl (11.9 mg, 0.281 mmol) and Pd(PPh3)4 (32.4 mg, 0.028 mmol). The mixture was added at 100° C. for 16 h under N2 atmosphere. The reaction mixture was diluted with DCM (30 mL), which was washed with brine (10 mL×3). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 93-4. LCMS: 439.5 [M+H]+.

Step 4: Preparation of Example 93

The following examples 94-95 were prepared according to the methods described in example 93 with analogous starting materials.

Example 96: Preparation of (R)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(methyl(oxetan-3-yl)amino)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was synthesized from 96-1, which was prepared according to the methods described in example 32-33 with analogous starting materials.

Step 1: Preparation of Example 96

The following examples 97-103 were prepared according to the methods described in example 96 with analogous starting materials.

(cis or trans mixture of

hydroxycyclobutylamino part with 3-

(cis or trans mixture of

hydroxycyclobutylamino part with 3-

Example 104: Preparation of (R)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-(prop-1-yn-1-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was synthesized from compound 96-1, which was prepared according to the methods described in example 32 with analogous starting materials.

Step 1: Preparation of Example 104

Example 105: Preparation of (R)-5-(4-cyano-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyrimidine-2-carboxamide

The title compound was synthesized from compound 105-1, which was prepared according to the methods described in example 32 with analogous starting materials.

Step 1: Preparation of Compound 105-2

To a solution of compound 105-1 (120.0 mg, 0.308 mmol) in DMSO (1.5 mL) were added 4-azabicyclo[2.2.2]octan-7-ol (7.8 mg, 0.062 mmol) and KCN (40.1 mg, 0.616 mmol). The mixture was stirred at 50 I for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 105-2. LCMS: 381.2 [M+H]+.

Step 2: Preparation of Compound 105-3

To a solution of compound 105-2 (45.0 mg, 0.118 mmol) in MeOH (3.0 mL) were added NaOH (14.2 mg, 0.355 mmol) and H2O2 (12.1 mg, 0.355 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was washed with water. The residue was purified by prep-TLC to afford compound 105-3. LCMS: 399.2 [M+H]+.

Step 3: Preparation of Example 105

Example 106: Preparation of (R)-2-(2-aminopyrimidin-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 106-1

To a solution of compound 39 (100.0 mg, 0.281 mmol) in CH3CN (5 mL) was added NBS (44.9 mg, 0.252 mmol) at 0° C. The mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 106-1 (120.0 mg, 0.276 mmol, 98.2%). LCMS: 435.2 [M+H]+.

Step 2: Preparation of Compound 106-2

To a solution of compound 106-1 (120.0 mg, 0.276 mmol) in DMF (6 mL) were added (Boc)2O (60.2 mg, 0.276 mmol), DMAP (1.7 mg, 0.014 mmol) and TEA (41.8 mg, 0.1414 mmol). The mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (50 mL×3), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 106-2. LCMS: 535.2 [M+H]+.

Step 3: Preparation of Compound 106-3

To a solution of compound 106-2 (70.0 mg, 0.131 mmol) in H2O (0.5 mL) and dioxane (2.5 mL) were added compound 13-3 (32.9 mg, 0.262 mmol), K3PO4 (83.4 mg, 0.393 mmol) and Pd(dtbpf)Cl2 (8.6 mg, 0.0132 mmol). The mixture was stirred at 80° C. for 6 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 106-3. LCMS: 471.4 [M+H]+.

Step 4: Preparation of Example 106

The following examples 107-108 were prepared according to the methods described in example 106 using analogous starting materials.

Example 109: Preparation of (S)-3-ethynyl-5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 109-1

To a solution of compound 33-1 (141 mg, 0.382 mmol) in CAN/DMF (1:1, 5 mL) was added NIS (94.5 mg, 0.420 mmol) at 0 . The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EA (60 mL), which was washed with brine (30 mL×3). The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 109-1. LCMS: 496.4 [M+H]+.

Step 2: Preparation of Compound 109-2

To a solution of compound 109-1 (85 mg, 0.172 mmol) in DCM (5 mL) was added BBr3 (215.5 mg, 0.860 mmol). The mixture was stirred at rt for 1 h under N2 atmosphere. The mixture was quenched by MeOH (5 mL) and concentrated. The residue was purified by column chromatography on silica gel to afford compound 109-2. LCMS: 482.1[M+H]+.

Step 3: Preparation of Compound 109-3

Step 4: Preparation of Example 109

The following examples 110-111 were prepared according to the methods described in example 109 using analogous starting materials.

Example 112: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 112-1

To a solution of compound 109-1 (50 mg, 0.101 mmol) in DMF (2 mL) were added Cu (12.84 mg, 0.202 mmol) and diphenyl(trifluoromethyl)sulfonium (204.20 mg, 0.505 mmol) at rt. The mixture was stirred at 60° C. for 24 h. The mixture was quenched with H2O (5 mL) and extracted with EA (20 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 112-1. LCMS: 438.4 [M+H]+.

Step 2: Preparation of Example 112

Example 113: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(2-methylpyrimidin-5-yl)-3-(phenylthio)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 113-2

Step 2: Preparation of Example 113

Example 114: Preparation of 2,4-dimethyl-3-(2-(2-methylpyrimidin-5-yl)-3H-imidazo[4,5-b]pyridin-6-yl)phenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 114-2

To a solution of compound 114-1 (500 mg, 2.659 mmol) in dioxane (5 mL) and water (1 mL) were added compound 10-6 (836.5 mg, 3.191 mmol), Pd(dppf)Cl2 (194.6 mg, 0.266 mmol) and K2CO3 (1.102 g, 7.977 mmol). The mixture was stirred at 90° C. under N2 for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 114-2. LCMS: 244.2 [M+H]+.

Step 2: Preparation of Compound 114-4

To a solution of compound 114-2 (150 mg, 0.616 mmol) in AcOH (5 mL) was added compound 114-3 (75.29 mg, 0.616 mmol). The mixture was stirred at 90° C. under N2 for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 114-4. LCMS: 346.0 [M+H]+.

Step 3: Preparation of Example 114

Example 115: Preparation of 3-(2-(2-(cyclopropylamino)thiazol-5-yl)-3H-imidazo[4,5-b]pyridin-6-yl)-2,4-dimethylphenol

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 115-2

To a solution of compound 114-2 (100 mg, 0.41 mmol) in AcOH (1.5 mL) was added compound 115-1 (73 mg, 0.49 mmol). The mixture was stirred at 90° C. under N2 for 20 h. The reaction was diluted with EA (10 ml) and brine (10 ml). The aqueous layer was extracted with EA (10 mL×3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TCL to afford compound 115-2. LCMS: 371.0 [M+H]+.

Step 2: Preparation of Compound 115-4

To a solution of compound 115-2 (40 mg, 0.11 mmol) in CH3CN (1.5 mL) was added compound 115-3 (1 mL). The mixture was stirred at 100° C. for 3 h. The reaction was dried to afford the title crude compound 115-4. LCMS: 392.1 [M+H]+.

Step 3: Preparation of Example 115

Example 116: Preparation of (S)-2-(2-aminopyrimidin-5-yl)-6-(3-hydroxy-2,6-dimethylphenyl)-3H-imidazo[4,5-b]pyridine-7-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 116-2

To a solution of compound 116-1 (5 g, 19.802 mmol) in EtOH (150 mL) was added Fe (11.0 g, 198.020 mmol) and AcOH (22.67 mL, 396.040 mmol). The mixture was stirred at 90° C. for 2 h. The reaction mixture was carefully added into ice-water (150 mL) while stirring, the pH of which was adjusted to 8 with NaOH (4 M in water). The mixture was extracted with DCM (200 mL×3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 116-2 (3.5 g, 15.730 mmol, 79.4%). LCMS: 221.9 [M+H]+.

Step 2: Preparation of Compound 116-3

Step 3: Preparation of Compound 116-5

To a solution of compound 116-3 (200 mg, 0.720 mmol) in dioxane (4 mL) was added compound 116-4 (102.6 mg, 0.720 mmol) and AcOH (2 mL). The mixture was stirred at 75° C. for 8 h. The reaction mixture was carefully added into ice-water (20 mL) while stirring, the pH of which was adjusted to 8 with NaHCO3 (aq. sat). The mixture was extracted with EA (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 116-5 (67 mg, 0.167 mmol, 23.2%). LCMS: 400.1 [M+H]+.

Step 4: Preparation of Compound 116-6

A solution of compound 116-5 (60 mg, 0.150 mmol) in NH3/EtOH (1.5 mL) was stirred at 70  for 48 h. The reaction mixture was diluted with water (10 mL), which was extracted with EA (10 mL×3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 116-6. LCMS: 381.2 [M+H]+.

Step 5: Preparation of Compound 116-7

To a solution of compound 116-6 (45 mg, 0.118 mmol) in DCM (1 mL) was added BBr3 (0.4 mL). The mixture was stirred at rt under N2 for 2 h. The reaction mixture was carefully added into MeOH (10 mL). Then the pH of the mixture was adjusted to 7-8 with TEA. After filtration, the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 116-7. LCMS: 367.1 [M+H]+.

Step 6: Preparation of Example 116

Example 117: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 117-3

To a solution of compound 117-1 (1 g, 5.155 mmol) and compound 117-2 (1.2 g, 10.825 mmol) in DMF (10 mL) was added Cs2CO3 (4.2 g, 12.887 mmol). The mixture was stirred at 140° C. for 2.5 h by microwave. The reaction mixture was diluted with EA (20 mL), which was washed with brine (20 mL×3). The organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 117-3. LCMS: 266.6 [M+H]+.

Step 2: Preparation of Example 117

The following examples 118-122 were prepared according to the methods described in examples 117 with analogous starting materials.

Example 121: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Example 121

Example 122: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Example 122

Example 123: Preparation of (S)-5-(3-hydroxy-2,6-dimethylphenyl)-2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 123-2

Step 2: Preparation of Compound 123-3

Step 3: Preparation of Compound 123-4

Step 4: Preparation of Example 123

The following examples were prepared according to the methods described in examples 123 with analogous starting materials.

Example 126: Preparation of (S)-2-(2-aminothiazol-5-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 126-2

Step 2: Preparation of Compound 126-3

To a solution of compound 126-2 (190.0 mg, 0.388 mmol) in dioxane (5 mL) were added compound 32-4 (69.1 mg, 0.194 mmol), LiCl (16.4 mg, 0.387 mmol) and Pd(PPh3)4 (44.8 mg, 0.0388 mmol). The mixture was stirred at 100° C. for 5 h. The mixture was diluted with water (30 mL), which was extracted with EA (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep-TLC to afford compound 126-3. LCMS: 476.3 [M+H]+.

Step 3: Preparation of Example 126

The following examples 132 were prepared according to the methods described in examples 126 with analogous starting materials.

Example 127: Preparation of (S)-2-(3-amino-1,2,4-triazin-6-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Step 1: Preparation of Compound 127-1

Step 2: Preparation of Compound 127-3

To a solution of compound 127-1 (400.0 mg, 0.555 mmol) in toluene (6.0 mL) were added compound 127-2 (97.1 mg, 0.555 mmol), Pd(PPh3)4 (64.1 mg, 0.056 mmol) and CuI (21.1 mg, 0.111 mmol). The mixture was stirred at 120° C. under N2 for 1 h. The reaction mixture was diluted with water (20 mL), which was extracted with EA (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography to afford compound 127-3. LCMS: 526.3 [M+H]+.

Step 3: Preparation of Compound 127-4

A mixture of compound 127-3 (172.0 mg, 0.327 mmol) and NaOH (130.9 mg, 3.272 mmol) in EtOH (6.0 mL) was stirred at 60° C. under N2 for 1 h. The pH of the reaction mixture was adjusted to 7 with HCl (1 M in water) at 0 . The mixture was extracted with EA (20 mL×3). The combined organic layer was washed with brine (90 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography and further purified by SFC to afford compound 127-4. LCMS: 413.1 [M+H+CH3CN]+.

Step 4: Preparation of Example 127

Example 128: Preparation of 3-(6-(2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2,4-dimethylphenol

Step 1: Preparation of Example 128

Example 133: Preparation of (S)-2-(4-amino-1H-pyrazol-1-yl)-5-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

The title compound was prepared according to the following synthetic procedures.

Example 135: Preparation of 5-(3-hydroxy-2,6-dimethylphenyl)-2-(4H-1,2,4-triazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile

Step 1: Preparation of Compound 135-2

To a solution of Compound 29-1 (2000 mg, 4.635 mmol) in THF (50 mL) was added LDA (4.63 mL, 9.270 mmol) at −78 . The mixture was stirred for 0.5 h before adding a solution of methyl chloroformate (876.0 mg, 9.27 mmol) in THF (15 mL). The mixture was stirred at −78  for 2 h, quenched with NH4Cl. aq (50 mL), diluted with water (200 mL), and extracted with EA (100 mL×3). The combined organic phase was washed with brine (150 mL×2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to afford Compound 135-2 as a white solid (1.0 g, 44.1% yield). LCMS: 489.8 [M+H]+.

Step 2: Preparation of Compound 135-3

Step 3: Preparation of Compound 135-4

A solution of Compound 135-3 (100 mg, 0.312 mmol) in N,N-dimethylformamide dimethyl acetal (5 mL) was stirred at 90  for 1 h. The mixture was concentrated and dissolved in EtOH (10 mL) to fsi afford P1. To a solution of hydrazinium hydroxide (1 mL, 20.559 mmol) in AcOH (3 mL) in 0  was added P1. The mixture was stirred at rt for 1 h, and concentrated. The residue was purified by silica gel column chromatography to afford Compound 135-4. LCMS: 345.1 [M+H]+.

Step 3: Preparation of Example 135

Compound serial dilution is performed by Echo, and the final concentrations vary from 10 μM to 0.5 nM. This was filled by the addition of 5 μL/well of Enzyme solution to the assay plate containing the compound. The plate was centrifuged at 1000 rpm for 1 minute, and incubate 15 minutes at 25 . Then 5 μL/well of tracer solution (Tracer 178) was added to initiate the reaction, and incubate for 60 minutes at 25° C. Next 5 μL GST-Tb was added into the assay plate, the plate was centrifuged at 1000 rpm for 1 minute, and incubate for 15 minutes at 25 . The assay plate was read on Envision.

The data for Example A is shown in Table 3.

100
A

101
A

102
A

103
A

104
A

105
A

106
A

107
A

109
A

110
A

111
A

113
C

114
C

115
C

116
A

117
A

118
A

119
A

120
A

121
A

122
A

123
A

124
A

125
A

126
A

127
A

128
A

129
A

130
A

131
A

133
A

134
A

135
A

Compound serial dilution is performed by Echo, and the final concentrations vary from 10 μM to 0.5 nM. This was filled by the addition of 5 μL/well of Enzyme solution to the assay plate containing the compound. The plate was centrifuged at 1000 rpm for 1 minute, and incubate 15 minutes at 25, Then 5 μL/well of substrate solution was added to initiate the reaction, and incubate for 60 minutes at 25° C. Next 10 μL kinase detection reagent was added into the assay plate, the plate was centrifuged at 1000 rpm for 1 minute, and incubate for 60 minutes at 25. The assay plate was read on Envision for US LUM as RLU.