KINASE ANTAGONISTS AND METHODS FOR MAKING AND USING THEM Inventors: Stephen Todd Meyer, Warren S. Wade, James W. Zapf, János Gerencsér, and Balázs

Gyimóthy CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of United States Provisional Patent Application No. 62/702,064, filed July 23, 2018, which is incorporated by reference in its entirety.

FIELD

This disclosure generally relates to kinase inhibitors and their applications. BACKGROUND

The serum and glucocorticoid-regulated kinases (also known as serum and glucocorticoid- induced kinases), commonly abbreviated as SGK, are members of a family of related serine/threonine kinases. Currently known isoforms in this family include SGK1, SGK2 and SGK3. The SGK enzymes are collectively members of the larger AGC group of serine/threonine kinases, so named for three of its most-studied families. Other kinase families in the AGC group include AKT, RSK, DMPK, GRK, RSKR and MAST.

Another important member of the AGC kinase group is PDK1, which is known as a“master regulator” because it serves to phosphorylate and thereby activate several other AGC kinases, including SGK1 and Akt1. PDK1 is itself regulated by phosphoinositide-3-kinase (PI3K), which is activated by various signaling molecules, including growth factors. Consequences of PDK1- dependent signaling in tumor cells include increased cell growth and motility, leading subsequently to cancer progression.

The SGK family of enzymes, and SGK1 in particular, are relevant in multiple biochemical processes that, when improperly regulated in vivo, can lead to pathologies. SGK1 activity has been found to be increased in several cancer cell lines, including cells derived from thyroid cancer, head and neck cancer, prostate cancer, colorectal cancer, cervical cancer, or breast cancer. In patients, therapeutic inhibition of SGK1 suppresses colorectal cancer. Overexpression of SGK1 can also improperly stimulate the epithelial-to-mesenchymal transition in cells, enhancing invasiveness of cancer. SGK1 thus promotes survival of tumor initiating cells (also known as cancer stem cells), cells that also cause radio- and chemo-resistance. Activation of the PI3K/mTOR/Akt axis is the most frequent aberration in cancer. SGK1 has been found to be activated in cancer cells that are resistant to inhibitors of PI3K or AKT kinases alone, particularly Akt1 inhibitor-resistant triple-negative breast cancer cells or claudin-low breast cancer cells. Inhibition of SGK1 does not instigate an adaptive resistance response in cells, allowing sustained, powerful growth inhibition, an advantage over inhibiting PI3K or AKT alone.

Activation of SGK1 is also implicated in immunomodulatory processes. SGK1 modulates the immune system and some inflammatory diseases, in part, by maintaining inflammatory leukocytes such as neutrophils in inflamed tissue. SGK1 mediates induction of CD4(+) helper T cells (Th17 cells), which produce pathogenic interleukin (IL)-17. Th17 cells are associated with multiple different autoimmune and inflammatory disorders, including rheumatoid arthritis, multiple sclerosis (MS), psoriasis and asthma.

SGK1 promotes pathology of hypertension, and cardiac hypertrophy, in part, by mediating hypertensive responses to angiotensin, corticosteroids, and sodium. Further, kinases of the SGK family play a key role in regulating sodium balance, blood volume and blood pressure values through regulation of sodium transport in the kidney.

Inhibitors of SGK enzymes, and inhibitors of SGK1 in particular, can be useful in the treatment of disease mediated by aberrant or excessive SGK activity. SGK inhibitors can be used, alone or in combination with other therapies, in the treatment of cancer, including but not limited to thyroid cancer, head and neck cancer, prostate cancer, colorectal cancer, cervical cancer or breast cancer, and preferably triple-negative breast cancer (TNBC), anaplastic thyroid cancer or radioiodine treatment-resistant thyroid cancer. SGK1 inhibitors, and compositions thereof, can also be used for the treatment of autoimmune, inflammatory or fibrotic disorders, including but not limited to osteoarthritis, rheumatoid arthritis, lung fibrosis, liver fibrosis, scleroderma, or cystic fibrosis. SGK1 inhibitors, and compositions thereof, may also inhibit other enzymes of the AGC kinase group and can be useful in the treatment of disease mediated by aberrant or excessive AGC kinase activity. Compounds that inhibit both SGK1 and one or all other isoforms of SGK enzymes, including SGK2 and SGK3, and preferably SGK3, can be useful in the treatment of diseases mediated by SGK family activity. Compounds that inhibit both SGK1 and one or all of the Akt family kinases, including Akt1, Akt2, and Akt3, and preferably Akt1, can provide an effective approach to the treatment of cancer.

There exists a need for SGK inhibitors with acceptable drug-like properties that would enable such compounds to enter clinical development. Compounds of different chemical classes are well known to be unsuitable for development due to poor physical properties including low solubility, low cell permeability, low selectivity against other kinases, or a combination of these factors. Together or alone, these properties are inherently limiting for studies in patients and thus clinical development. Inhibitors of an AGC kinase, preferably SGK1, that combine potency against the enzyme with desirable physical properties and efficacy in patients, are needed to address unmet medical needs.

SUMMARY

Disclosed herein are compounds and compositions that are small molecule inhibitors of kinases, including kinase enzymes of the AGC group of kinases, including SGK1, that can inhibit proliferation of cancer cells, enable apoptosis, and impair proliferation and metastasis of cancer cells, and methods of making and using them. These small molecule compounds can be used for treating, ameliorating or preventing, or slowing the progress of, any disease, condition or infection responsive to the inhibition of a kinase, including for example, thyroid cancer, head and neck cancer, prostate cancer, colorectal cancer, cervical cancer, or breast cancer. These small molecule compounds can be used for treating, ameliorating or preventing, or slowing the progress of, any disease, condition or infection responsive to the inhibition of a kinase, including for example, autoimmune, inflammatory or fibrotic disorders, including but not limited to osteoarthritis, rheumatoid arthritis, lung fibrosis, scleroderma or cystic fibrosis.

This disclosure relates to compounds represented by Formula 1:

Formula 1

or a pharmaceutically acceptable salt thereof; wherein the dashed line represents the presence or absence of a direct bond; R ¹ is CN, optionally substituted C1-12 alkyl, an optionally substituted C _3-12 carbocycle, an optionally substituted phenyl, an optionally substituted C _1-12 heterocycle, or an optionally substituted C5-12 bicyclic ring system; W is N or CR ² ; U is N or CR ⁵ ; V is N or CR ⁶ ; wherein R ² , R ⁵ , and R ⁶ are independently H, F, Cl, Br, I, CN, OH, R ^A , -OR ^A , -NR ^A R ^B , -SR ^A , -S(O)R ^A , - SO ₂ R ^A , -NR ^A SO ₂ R ^B , or -SO ₂ NR ^A R ^B ; L is a direct bond or a linking group, wherein the total number of C, N, O, and S atoms in L is 0, 1, 2, or 3; R ³ and R ⁴ are independently H, F, Cl, CN, , R ^A , OH, -OR ^A , or -NR ^A R ^B , wherein R ³ and R ⁴ are optionally linked to form a ring; each R ^A and R ^B is independently H or C _1-12 organyl, wherein R ^A and R ^B are optionally linked to form a ring; and A is an optionally substituted C3-12 cycloalkyl or an optionally substituted C3-12 heterocycle.

Some embodiments include a method of treating any disease, condition, or infection responsive to the inhibition of a kinase, such as kinase enzymes of the AGC group of kinases, including SGK1, for example, thyroid cancer, head and neck cancer, prostate cancer, colorectal cancer, cervical cancer, or breast cancer comprising administering a therapeutically effective amount of a compound described herein, or any optionally substituted compound represented in Formula 1, Table 1 below, or any compound described herein, or a pharmaceutically acceptable salt thereof (referred to collectively herein as a“subject compound”), to a patient in need thereof.

Some embodiments include a method of treating a cancer responsive to the inhibition of a kinase, such as kinase enzymes of the AGC group of kinases, including SGK1, wherein the cancer is a breast cancer, preferably triple-negative breast cancer or claudin-low breast cancer comprising administering a therapeutically effective amount of a subject compound to a patient in need thereof.

Some embodiments include a method of treating a cancer responsive to the inhibition of a kinase, such as kinase enzymes of the AGC group of kinases, including SGK1, wherein the cancer is a thyroid cancer, preferably anaplastic thyroid cancer or a radioiodine treatment-resistant thyroid cancer comprising administering a therapeutically effective amount of a subject compound to a patient in need thereof.

Some embodiments include a method of treating a disease, a condition, or an infection, for example, autoimmune, inflammatory, or fibrotic disorders, such as osteoarthritis, rheumatoid arthritis, lung fibrosis, liver fibrosis, scleroderma or cystic fibrosis comprising administering a therapeutically effective amount of a subject compound described herein to a patient in need thereof.

Some embodiments include use of a compound described herein, such as a compound of Formula 1, a subject compound described herein in the manufacture of a medicament for the treatment of any disease, condition, or infection responsive to the inhibition of a kinase, such as kinase enzymes of the AGC group of kinases, including SGK1, for example, thyroid cancer, head and neck cancer, prostate cancer, colorectal cancer, cervical cancer, or breast cancer.

Some embodiments include use of a compound described herein, such as a compound of Formula 1, a subject compound described herein in the manufacture of a medicament for the treatment of autoimmune, inflammatory, or fibrotic disorders, such as osteoarthritis, rheumatoid arthritis, lung fibrosis, scleroderma or cystic fibrosis.

Some embodiments include a pharmaceutical composition comprising a therapeutically effective amount of a subject compound described herein, or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable vehicle, diluent, or carrier.

Some embodiments include a process for making a pharmaceutical composition comprising combining a subject compound described herein and at least one pharmaceutically acceptable carrier.

Some embodiments include a medicament comprising a composition comprising a therapeutically effective amount of a subject compound.

Some embodiments include a kit comprising a medicament of above and a label indicating that the medicament is for treating any disease, condition, or infection responsive to the inhibition of a kinase, such as kinase enzymes of the AGC group of kinases, including SGK1, for example, thyroid cancer, head and neck cancer, prostate cancer, colorectal cancer, cervical cancer, or breast cancer.

Some embodiments include a kit comprising a medicament of above and a label indicating that the medicament is for treating autoimmune, inflammatory, or fibrotic disorders, such as osteoarthritis, rheumatoid arthritis, lung fibrosis, liver fibrosis, scleroderma or cystic fibrosis. DETAILED DESCRIPTION

Provided are compounds, including formulations and pharmaceutical compositions, and methods of making and using them, for treating, ameliorating, preventing, reversing or slowing the progression of: a cancer, a tumor, a metastasis or a dysplastic or a dysfunctional cell condition responsive to inhibition of a kinase enzyme, by administration of an AGC kinase inhibitor or antagonist, for example, by administration of an inhibitor or antagonist of serum and glucocorticoid-regulated kinase 1 (SGK1). In alternative embodiments, the type of cancer or proliferative disorder includes breast cancer, including a triple-negative breast cancer (TNBC); breast cancer metastasis; thyroid cancer, including anaplastic thyroid cancer or a radioiodine treatment-resistant thyroid cancer; or, a cancer, tumor, metastasis or dysplastic or dysfunctional cell condition responsive to inhibition of an AGC kinase enzyme by an AGC kinase antagonist. In alternative embodiments, provided are compounds, and methods of making and using them, for: reducing mortality associated with cancer; inhibiting or reducing survival ability, or radio- and/or chemo-resistance, of tumor initiating cells or cancer stem cells, or inhibiting epithelial to mesenchymal transition (EMT) of cells; potentiating cancer chemotherapy; or, treating, ameliorating, preventing or reversing, slowing the progression of, or decreasing the severity of: an autoimmune disease or condition, an inflammatory disease or condition, an inherited or genetic disease or condition, a neurodegenerative disease or condition, or an infection responsive to inhibition of a kinase enzyme.

Unless otherwise indicated, any reference to a compound herein by structure, name, or any other means, includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts, or HCl, H2SO4, HCO2H, and CF3CO2H salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

If stereochemistry is not indicated, a name or structural depiction includes any stereoisomer or any mixture of stereoisomers.

Unless otherwise indicated, when a compound or chemical structural feature such as aryl is referred to as being“optionally substituted,” it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is“substituted,” meaning that the feature has one or more substituents. The term“substituent” is broad, and includes a moiety that occupies a position normally occupied by one or more hydrogen atoms attached to a parent compound or structural feature. In some embodiments, a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g. the sum of the atomic masses of the atoms of the substituent) of 15 g/mol to 50 g/mol, 15 g/mol to 100 g/mol, 15 g/mol to 150 g/mol, 15 g/mol to 200 g/mol, 15 g/mol to 300 g/mol, or 15 g/mol to 500 g/mol. In some embodiments, a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight of 15 g/mol to 200 g/mol. In some embodiments, a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, P, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, S, P, Si, F, Cl, Br, or I atom. Examples of substituents include, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, phosphonic acid, etc.

For convenience, the term“molecular weight” is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.

The term“treating” or“treatment” includes the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.

A hydrogen atom in any position of a compound of Formula 1 may be replaced by a deuterium. In some embodiments, a compound of Formula 1 contains a deuterium atom or multiple deuterium atoms.

Some embodiments include a compound of Formula 2, 3, 4, 5, 6, 7, 8, 9, or 10.

With respect to any relevant structural representation, such as Formula 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, a dashed line represents the presence or absence of a bond. With respect to any relevant structural representation, such as Formula 1, 4, 5, 6, 7 or 10, W is N or CR ² . In some embodiments, W is N. In some embodiments, W is CR ² . In some embodiments, W is CH.

With respect to any relevant structural representation, such as Formula 1, 5, 6, or 7, U is N or CR ⁵ . In some embodiments, U is N. In some embodiments, U is CR ⁵ . In some embodiments, U is CH.

With respect to any relevant structural representation, such as Formula 1, 5, 6, or 7, V is N or CR ⁶ . In some embodiments, V is N. In some embodiments, V is CR ⁶ . In some embodiments, V is CH.

With respect to any relevant structural representation, such as Formula 1, 4, 5, 6, 7 or 10, W is CR ² , U is CR ⁵ , or V is CR ⁶ , wherein R ² , R ⁵ , and R ⁶ are independently H or any substituent, such as, F, Cl, Br, I, CN, CF3, NO2, NH2, R ^A , OH, -OR ^A , -NR ^A R ^B , -SR ^A , -S(O)R ^A , -SO2R ^A , -NR ^A SO2R ^B , or - SO2NR ^A R ^B , etc. Some of the structures with attachment points are shown below.

-NR ^A COR ^B -CONR ^A R ^B With respect to any relevant structural representation, R ^A or R ^B is independently H or organyl, such as C1-30 organyl, including any organic substituent group, regardless of functional type, having a free valence at a carbon, such as optionally substituted alkyl, e.g. optionally substituted C _1-30 , C _1-12 , C _1-6 , or C _1-3 alkyl, including methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, C ₆ alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl, C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, C18 alkyl, C19 alkyl, C20 alkyl, C21 alkyl, C22 alkyl, C23 alkyl, C24 alkyl, C25 alkyl, C26 alkyl, C27 alkyl, C ₂₈ alkyl, C ₂₉ alkyl, C ₃₀ alkyl, C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, C8 cycloalkyl, C9 cycloalkyl, C10 cycloalkyl, C11 cycloalkyl, C12 cycloalkyl, etc.; optionally substituted alkenyl, e.g. optionally substituted C _2-12 or C _2-6 , alkenyl, including ethenyl, C ₃ alkenyl, C ₄ alkenyl, C ₅ alkenyl, C ₆ alkenyl, C ₇ alkenyl, C ₈ alkenyl, C ₉ alkenyl, C ₁₀ alkenyl, C ₁₁ alkenyl, C ₁₂ alkenyl, C ₄ cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C7 cycloalkenyl, C8 cycloalkenyl, C9 cycloalkenyl, C10 cycloalkenyl, C ₁₁ cycloalkenyl, C ₁₂ cycloalkenyl, etc.; optionally substituted alkynyl, e.g. optionally substituted C _2-12 or C _2-6 alkynyl, including ethynyl, C ₃ alkynyl, C ₄ alkynyl, C ₅ alkynyl, C ₆ alkynyl, C ₇ alkynyl, C8 alkynyl, C9 alkynyl, C10 alkynyl, C11 alkynyl, C12 alkynyl, C5 cycloalkynyl, C6 cycloalkynyl, C7 cycloalkynyl, C8 cycloalkynyl, C9 cycloalkynyl, C10 cycloalkynyl, C11 cycloalkynyl, C12 cycloalkynyl, etc.; optionally substituted aryl, such as optionally substituted phenyl, optionally substituted naphthyl, etc.; optionally substituted heterocyclyl, e.g. optionally substituted C3-12 heterocycloalkyl, where C3-12 refers to the number of carbon atoms in the ring, such as optionally substituted C ₃ azetidine, optionally substituted C ₃ oxetane, optionally substituted C ₄ pyrrolidine, optionally substituted C ₄ tetrahydrofuran, optionally substituted C ₄ piperazine, optionally substituted C5 piperidine, optionally substituted C5 tetrahydropyran, optionally substituted C5 diazepane, optionally substituted C ₆ azepane, optionally substituted C _1-5 heteroaryl, where C _1-5 refers to the number of carbon atoms in the ring, such as optionally substituted C ₁ tetrazole, optionally substituted C2 1,2,3-triazole, optionally substituted C2 1,2,4-triazole, optionally substituted C21,2,4-oxadiazole, optionally substituted C21,3,4-oxadiazole, optionally substituted C ₃ pyrazole, optionally substituted C ₃ imidazole, optionally substituted C ₃ oxazole, optionally substituted C3 thiazole, optionally substituted C4 pyrrole, optionally substituted C4 furan, optionally substituted C4 thiophene, optionally substituted C4 pyrimidine, optionally substituted C ₄ pyrazine, optionally substituted C ₄ pyridazine, optionally substituted C ₅ pyridine, etc.; organyl also includes CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NHR ^a , -C(O)NR ^a R ^b , -C(O)-Z-organyl, wherein Z is a bond, O, S, -NR ^a -, -C(R ^a R ^b )O-, or -C(R ^a R ^b )NR ^a -. In some embodiments, R ^a or R ^b is independently H or C1- ₃₀ organyl, such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl, etc. In some embodiments, C _1-30 organyl can be substituted by halogen, hydroxyl, amines, alkoxyl, aryl, heteroaryl, sulfone, sulfonamide, carboxylic acid, amide, reversed amide, ester, cycloalkyl, heterocycloalkyl, carbonyl, alkyl, alkenyl, alkynyl, phosphonamidic acid, phosphinic amide, or phosphine oxide.

With respect to any relevant structural representation, each R ^A may be H, or C _1-12 organyl, for example, C _1-12 hydrocarbyl, such as C _1-12 alkyl, C _1-12 alkenyl, C _1-12 alkynyl, phenyl, etc., including: linear or branched alkyl having a formula CaH2a+1, or cycloalkyl having a formula CaH2a- ₁ , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl with a formula: CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , C ₅ H ₁₁ , C ₆ H ₁₃ , C ₇ H ₁₅ , C ₈ H ₁₇ , C ₉ H ₁₉ , C ₁₀ H ₂₁ , etc., or cycloalkyl with a formula: C3H5, C4H7, C5H9, C6H11, C7H13, C8H15, C9H17, C10H19, etc. In some embodiments, R ^A may be H or C1- ₆ alkyl. In some embodiments, R ^A may be H or C _1-3 alkyl. In some embodiments, R ^A may be H or CH ₃ . In some embodiments, R ^A may be H.

With respect to any relevant structural representation, each R ^B may be H, or C1-12 organyl, for example, C _1-12 hydrocarbyl, such as C _1-12 alkyl, C _1-12 alkenyl, C _1-12 alkynyl, phenyl, etc., including: linear or branched alkyl having a formula CaH2a+1, or cycloalkyl having a formula CaH2a- 1, wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl with a formula: CH ₃ , C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , C ₅ H ₁₁ , C ₆ H ₁₃ , C ₇ H ₁₅ , C ₈ H ₁₇ , C ₉ H ₁₉ , C ₁₀ H ₂₁ , etc., or cycloalkyl with a formula: C3H5, C4H7, C5H9, C6H11, C7H13, C8H15, C9H17, C10H19, etc. In some embodiments, R ^B may be H or C1- 6 alkyl. In some embodiments, R ^B may be H or C1-3 alkyl. In some embodiments, R ^B may be H or CH ₃ . In some embodiments, R ^B may be H.

With respect to any relevant structural representation, such as Formula 1, 5, 6, 7, 10 (when W is CR ² , U is CR ⁵ , or V is CR ⁶ ), 2, 3, 4, 8, or 9, R ² , R ⁵ , and R ⁶ are independently H or any substituent, such as, F, Cl, Br, I, CN, CF ₃ , NO ₂ , NH ₂ , R ^A , OH, -OR ^A , -NR ^A R ^B , -SR ^A , -S(O)R ^A , -SO ₂ R ^A , - NR ^A SO2R ^B , or -SO2NR ^A R ^B , etc. In some embodiments, R ² , R ⁵ , and R ⁶ may be independently H; F; Cl; CN; CF3; C1-6 alkyl, such as methyl, ethyl, any one of the propyl isomers (e.g. n-propyl and isopropyl), cyclopropyl, any one of the butyl isomers, any one of the cyclobutyl isomers (e.g. cyclobutyl and methylcyclopropyl), any one of the pentyl isomers, any one of the cyclopentyl isomers, any one of the hexyl isomers, or any one of the cyclohexyl isomers, etc.; or C1-6 alkoxy, such as -O-methyl, -O-ethyl, any one of the isomers of -O-propyl, -O-cyclopropyl, any one of the isomers of -O-butyl, any one of the isomers of -O-cyclobutyl, any one of the isomers of -O-pentyl, any one of the isomers of -O-cyclopentyl, any one of the isomers of -O-hexyl, or any one of the isomers of -O-cyclohexyl, etc.; or C _3-8 heterocycle, for example, C _3-8 heterocycloalkyl, such as oxetanyl, pyrrolidinyl, piperidinyl, or piperazinyl, etc; C1-5 heteroaryl, such as furyl, pyrazolyl, pyridinyl, etc. or -C(O)NR ^A R ^B . In some embodiments, R ² , R ⁵ , and R ⁶ are independently H, F, or– CH ₃ . In some embodiments, R ² , R ⁵ , and R ⁶ are all H.

With respect to any relevant structural representation, such as Formula 1, 4, 5, 6, 7, 10 (when W is CR ² , U is CR ⁵ , or V is CR ⁶ ), 2, or 8, R ² is independently H or any substituent, such as, F, Cl, Br, I, CN, CF ₃ , NO ₂ , NH ₂ , R ^A , OH, -OR ^A , -NR ^A R ^B , -SR ^A , -S(O)R ^A , -SO ₂ R ^A , -NR ^A SO ₂ R ^B , or -SO ₂ NR ^A R ^B , etc. In some embodiments, R ² is H, F, Cl, CN, R ^A , OH, -OR ^A , -NR ^A R ^B , -SR ^A , -S(O)R ^A , -SO ₂ R ^A , - NR ^A SO ₂ R ^B , or -SO ₂ NR ^A R ^B . In some embodiments, R ² is H.

With respect to any relevant structural representation, such as Formula 1, 5, 6, 7 (when W is CR ² , U is CR ⁵ , or V is CR ⁶ ), 2, 3, 4, 8, 9, or 10, R ⁵ is independently H or any substituent, such as, F, Cl, Br, I, CN, CF3, NO2, NH2, R ^A , OH, -OR ^A , -NR ^A R ^B , -SR ^A , -S(O)R ^A , -SO2R ^A , -NR ^A SO2R ^B , or - SO2NR ^A R ^B , etc. In some embodiments, R ⁵ is H, F, Cl, CN, R ^A , OH, -OR ^A , -NR ^A R ^B , -SR ^A , -S(O)R ^A , - SO ₂ R ^A , -NR ^A SO ₂ R ^B , or -SO ₂ NR ^A R ^B . In some embodiments, R ⁵ is H. In some embodiments, R ⁵ is optionally substituted C1-6 alkyl. In some embodiments, R ⁵ is optionally substituted C1-6 carbocycle. In some embodiments, R ⁵ is optionally substituted C1-6 heterocycle. In some embodiments, R ⁵ is optionally substituted C _3-8 heterocycloalkyl. In some embodiments, R ⁵ is– C(O)NR ^A R ^B . In some embodiments, R ⁵ is:

In some embodiments, R ⁵ is–C(O)NH2. In some embodiments, R ⁵ is–C(O)NHCH3. In some embodiments, R ⁵ is–C(O)N(CH3)2. In some embodiments, R ⁵ is cyclohexyl. In some embodiments, R ⁵ is–CH ₃ .

With respect to any relevant structural representation, such as Formula 1, 5, 6, 7 (when W is CR ² , U is CR ⁵ , or V is CR ⁶ ), 2, 3, 8, or 9, R ⁶ is independently H or any substituent, such as, F, Cl, Br, I, CN, CF ₃ , NO ₂ , NH ₂ , R ^A , OH, -OR ^A , -NR ^A R ^B , -SR ^A , -S(O)R ^A , -SO ₂ R ^A , -NR ^A SO ₂ R ^B , or -SO ₂ NR ^A R ^B , etc. In some embodiments, R ⁶ is H, F, Cl, CN, R ^A , OH, -OR ^A , -NR ^A R ^B , -SR ^A , -S(O)R ^A , -SO2R ^A , - NR ^A SO2R ^B , or -SO2NR ^A R ^B . In some embodiments, R ⁶ is H.

With respect to any relevant structural representation, such as Formula 1, 2, 3, 4, 6, 7, 8, 9, or 10, R ¹ is H or any substituent, such as CN, optionally substituted C1-12 alkyl, an optionally substituted C _3-12 carbocycle, an optionally substituted C _1-12 heterocycle, or an optionally substituted C6-12 bicyclic ring system. In some embodiments, R ¹ is H. In some embodiments, R ¹ is CN. In some embodiments, R ¹ is optionally substituted C1-12 alkyl, such as–CH3. In some embodiments, R ¹ is optionally substituted C _3-12 carbocycle. For example, in some embodiments, R ¹ is optionally substituted C _3-12 cycloalkyl, such as cyclohexyl. In some embodiments, R ¹ is optionally substituted bicyclic ring system. In some embodiments, R ¹ is optionally substituted phenyl. In some embodiments, R ¹ is optionally substituted C _1-12 heterocycle. For example, in some embodiments, R ¹ is optionally substituted pyridine. In some embodiments, R ¹ is optionally substituted 5-membered heterocycle. In some embodiments, R ¹ is optionally substituted pyrazole. In some embodiments, R ¹ is optionally substituted piperidine.

In some embodiments, R ¹ is unsubstituted phenyl. In some embodiments, R ¹ is substituted phenyl as represented by Formula 5, having 1, 2, 3, 4, or 5 R ⁷ substituents, which may be the same or different, and may be substituted at any position of the phenyl ring. Each R ⁷ may independently be any substituent, such as F, Cl, Br, I, CN, CHF2, CF3, NO2, NH2, R ^A , OH, -OR ^A , - NR ^A R ^B , -SR ^A , -S(O)R ^A , -SO ₂ R ^A , -NR ^A SO ₂ R ^B , or -SO ₂ NR ^A R ^B , etc. In some embodiments, R ⁷ may be F, Cl, Br, I, CN, CHF2, C1-6 alkyl, C1-6 alkoxy, or -SO2NR ^A R ^B . Possible R ⁷ groups include for example, but are not limited to, those listed below:

In some embodiments, R ⁷ may be F, Cl, Br, I, CN, CHF ₂ , -OCH ₃ , -OCHF ₂ , -S(O) ₂ NCH ₃ , or a combination thereof. In some embodiments, R ⁷ is F. In some embodiments, R ⁷ is Cl. In some embodiments, R ⁷ is CN. In some embodiments, R ⁷ is CHF ₂ . In some embodiments, R ⁷ is -OCH ₃ . In some embodiments, R ⁷ is -OCHF ₂ . In some embodiments, R ⁷ is -S(O) ₂ NCH ₃ .

In some embodiments, R ¹ is optionally substituted 5-membered heterocycle. In some embodiments, R ¹ is optionally substituted pyrazole. In some embodiments, R ¹ is unsubstituted pyrazole. In some embodiments, R ¹ is substituted pyrazole. The substituent of pyrazole may be any substituent. In some embodiments, the substituted pyrazole contains one or more substituents. In some embodiments, the substituent may be substituted at any available position of the pyrazole ring. Possible substituents of R ¹ when R ¹ is pyrazole, include for example, but are not limited to, those listed below: In some embodiments, R ¹ is optionally substituted piperidine. In some embodiments, R ¹ is unsubstituted piperidine. In some embodiments, R ¹ is substituted piperidine. The substituent of piperidine may be any substituent. In some embodiments, the substituted piperidine contains one or more substituents. In some embodiments, the substituent may be substituted at any available position of the piperidine ring. Possible substituents of R ¹ when R ¹ is piperidine, include for example, but are not limited to, those listed below:

In some embodiments, R ¹ is optionally substituted C3-12 carbocycle. In some embodiments, R ¹ is optionally substituted cycloalkyl. In some embodiments, R ¹ is unsubstituted cycloalkyl. In some embodiments, R ¹ is substituted cycloalkyl. The substituent of cycloalkyl may be any substituent. In some embodiments, the substituted cycloalkyl contains one or more substituents. In some embodiments, the substituent may be substituted at any available position of the cycloalkyl ring. Possible substituents of R ¹ when R ¹ is cycloalkyl, for example, include for example, but are not limited to, those listed below:

In some embodiments, R ¹ is an optionally substituted C6-12 bicyclic ring system. In some embodiments, R ¹ is an optionally substituted C6-12 spirobicyclic ring system. In some embodiments, R ¹ is an unsubstituted C _6-12 spirobicyclic ring system. In some embodiments, R ¹ is spiro[2.5]octan-6-yl.

In some embodiments, R ¹ is any one of the groups listed below, which may be optionally substituted:

In some embodiments, R ¹ is optionally substituted pyridine. In some embodiments, R ¹ is unsubstituted pyridine. In some embodiments, R ¹ is substituted pyridine. The substituent of pyridine may be any substituent. In some embodiments, the substituted pyridine contains one or more substituents. In some embodiments, the substituent may be substituted at any available position of the pyridine ring. A possible substituent of R ¹ when R ¹ is pyridine includes, but is not limited to,–CH3.

In some embodiments, R ¹ is optionally substituted C _1-4 heteroaryl. In some embodiments, R ¹ is optionally substituted 1,3,4-oxadiazole. In some embodiments, R ¹ is unsubstituted oxadiazole, such as 1,3,4-oxadiazole. In some embodiments, R ¹ is substituted 1,3,4-oxadiazole. The substituent of 1,3,4-oxadiazole may be any substituent. A possible substituent of R ¹ when R ¹ is 1,3,4-oxadiazole includes, but is not limited to,–CH ₂ NHS(O) ₂ CH ₃ . With respect to any relevant structural representation, such as Formula 1, 2, 3, 4, 5, 6, 7, 8, or 9, L is a direct bond or a linking group, wherein the total number of C, N, O, and S atoms in the linear chain of L is 0, 1, 2, or 3. In some embodiments, L is a direct bond. In some embodiments, L is a linking group, wherein the total number of C, N, O, and S atoms in the linear chain of L is 0, 1, 2, or 3. In some embodiments, L is O. In some embodiments, L is S. In some embodiments, L is -CH2CH2O-, wherein–CH2 is directly linked to A. In some embodiments, L is , , wherein X is C, CH, CH2, O, N, NH, S, S(O), S(O)2, SO2CH2, or S(O)CH2. In some embodiments, X is O. In some embodiments, X is CH2. In some embodiments, X is S. In some embodiments, X is -S(O) ₂ -. In some embodiments, L is CH ₂ O, wherein the CH ₂ is directly linked to A. In some embodiments, L is CH2CH2. In some embodiments, L is -CH2S-, wherein the -CH2 is directly linked to A. In some embodiments, L is -CH2SO2-, wherein the -CH2 is directly linked to A.

With respect to any relevant structural representation, such as Formula 1, 2, 3, 4, 5, 6, 7,

, , , , , , , , .

embodiments, when

In some embodiments, when . In some embodiments, R ³ may be H or any substituent, such as F, Cl, C , , R ^A , -OR ^A , or -NR ^A R ^B . In some embodiments, R ³ is H. In some embodiments, R ⁴ may be H or any substituent, such as F, Cl, CN, , R ^A , -OR ^A , or -NR ^A R ^B . In some embodiments, R ⁴ is H.

In some embodiments, R ³ and R ⁴ are both H. In some embodiments, R ³ and R ⁴ can be directly linked and, together with L, form a ring. In some embodiments, R ³ and R ⁴ together form , as in a carbonyl. In some embodiments, R ³ and R ⁴ are each , as in a sulfonyl. With respect to any relevant structural representation, such as Formula 1, 2, 3, 4, or 5, A is optionally substituted C3-12 cycloalkyl, or optionally substituted C3-12 heterocycle. In some embodiments, A is optionally substituted C _3-12 cycloalkyl. In some embodiments, A is optionally substituted C _3-12 heterocycle. In some embodiments, A is optionally substituted C5-12 spirocyclic heterocycle or C5- 12 bridged bicyclic heterocycle. In some embodiments, A is optionally substituted C5-12 spirocycloalkyl, C _5-12 fused bicyclic cycloalkyl, or C _5-12 bridged bicyclic cycloalkyl. In some embodiments, A is optionally substituted C5-12 spirocyclic heterocycle. In some embodiments, A is optionally substituted C5-12 fused bicyclic heterocycle. In some embodiments, A is optionally substituted C _5-12 bridged bicyclic heterocycle. In some embodiments, A is unsubstituted C _5-12 spirocyclic heterocycle. In some embodiments, A is unsubstituted C _5-12 bridged bicyclic heterocycle.

In some embodiments, represented by Formula 6, wherein G is N, or C-Y, and wherein m or n is independently 0, 1, 2, 3, 4, or 5 with total ring atoms of 4 to 7. In some embodiments G is N. In some embodiments G is C-Y. In some embodiments, A is an optionally substituted 4-membered ring. In some embodiments, A is an optionally substituted 5- membered ring. In some embodiments, A is an optionally substituted 6-membered ring. In some embodiments, A is an optionally substituted 7-membered ring. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

In some embodiments, , represented by Formula 7, 8, 9 or 10. With respect to any relevant structural representation, such as Formula 6, 7, 8, 9, or 10, Y is H, F, Cl, CN, R ^A , OH, -OR ^A , -NR ^A R ^B , -SO ₂ R ^A , -NR ^A SO ₂ R ^B , or -SO ₂ NR ^A R ^B . In some embodiments, Y is F, C _1-6 alkyl, OH, C _1-6 alkyoxyl, NH ₂ , amide, ketone, or sulfonyl. In some embodiments, Y is C _1- 6 alkyl, such as methyl or ethyl. In some embodiments, Y is F. In some embodiments, Y is OH. In some embodiments, Y is CH ₂ OH. In some embodiments, Y is NH ₂ . In some embodiments, Y is amide. In some embodiments, Y is ketone. In some embodiments, Y is sulfonyl.

With respect to any relevant structural representation, such as Formula 7, 8, 9, or 10, each R ⁸ is independently H or any substituent, such as R ^A , F, Cl, CN, -OR ^A , -NR ^A R ^B , -SO ₂ R ^A , - NR ^A SO ₂ R ^B , or -SO ₂ NR ^A R ^B , etc. In some embodiments, R ⁸ may be H, F, Cl, CN, OH, NH ₂ , C _1-6 alkyl, or C1-6 alkoxy. In some embodiments, R ⁸ may be H.

With respect to any relevant structural representation, such as Formula 7, 8, 9, or 10, each R ⁹ is independently H or any substituent, such as R ^A , F, Cl, CN, -OR ^A , -NR ^A R ^B , -SO ₂ R ^A , - NR ^A SO2R ^B , or -SO2NR ^A R ^B , etc. In some embodiments, R ⁹ may be H, F, Cl, CN, OH, NH2, C1-6 alkyl, or C1-6 alkoxy. In some embodiments, R ⁹ may be H.

With respect to Formula 1, 2, 3, 4, or 5, in some embodiments, A is: optionally substituted piperidine, optionally substituted piperidin-4-yl, optionally substituted piperazin-1-yl, optionally substituted 2-oxopiperidin-4-yl, optionally substituted pyrrolidine, optionally substituted pyrrolidin-3-yl, optionally substituted azetidine, optionally substituted azetidin-3-yl, optionally substituted tetrahydro-2H-pyran-4-yl, optionally substituted tetrahydrofuran-3-yl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, or optionally substituted cyclohexyl. For example, A may be unsubstituted piperidin-4-yl, or substituted piperidin-4-yl. In some embodiments, the piperidin-4-yl may be substituted by one or more methyl groups. In some embodiments, the piperidin-4-yl may be substituted by one or more methyl groups, and one methyl group is at the ring N atom. In some embodiments, A is any one of the groups listed below, which may be optionally substituted:

, , , , ,

, _{, , , o} ^cyclohexyl _. In some embodiments, A is unsubstituted.

In some embodiments, A may be substituted with any substituent.

In some embodiments, A has a CH ₃ substituent.

In some embodiments, A has two CH3 substituents.

In some embodiments, A has a CH ₂ CH ₃ substituent.

In some embodiments, A has an F substituent.

In some embodiments, A has an OH substituent.

In some embodiments, A has a CH2OH substituent.

In some embodiments, A has an NH ₂ substituent.

In some embodiments, A has a C(O)NH2 substituent.

In some embodiments, A has a C(O)NHCH3 substituent.

In some embodiments, A has a C(O)NH(CH ₃ ) ₂ substituent.

In some embodiments, A has an acetyl substituent.

In some embodiments, A has a C(O)CH3 substituent.

In some embodiments, A has a C(O)CH ₂ CH ₃ substituent.

In some embodiments, A has a C(O)CH(CH3)2 substituent.

In some embodiments, A has a C(O)CH2CH(CH3)2 substituent.

In some embodiments, A has a S(O) ₂ CH ₃ substituent. In some embodiments, A has multiple substituents with any combination of the above substituents.

Some embodiments include one of the compounds in Table 1, wherein any of the compounds in Table 1 below may be optionally substituted.

Table 1

2- 2- 2-

Alternatively, the compounds described above may be described as following, wherein R8 represents a single substituent of R8, not 8 substituents of an R group, and so on. Table A lists some examples of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , or Y of Formula 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 that correlates to the group of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ , R ₄₆ , R ₄₇ , R ₄₈ , R ₄₉ , R ₅₀ , R ₅₁ , R ₅₂ , R ₅₃ , R ₅₄ , R ₅₅ , R ₅₆ , R ₅₇ , R ₅₈ , R ₅₉ , R ₆₀ , R ₆₁ , R ₆₂ , R ₆₃ , R ₆₄ , R ₆₅ , R ₆₆ , or R ₆₇ , of Formula A or Formula B. This list shows the same or close to position at which the substituent group is located for different formula. This list is not intended to be exhaustive or complete, but rather to show some examples of different substituents that may be used to describe the specific substitution position in the compounds described herein. This list is not to be construed as any limitation of the scope of any substituent described herein. Additionally, the definitions used for the alternative description of the compounds of Formula A and B below, such as “alkyl”, “alkenyl”, “alkynyl”, “alkyloxy”, “alkylamino”, “alkylthio”, “cycloalkyl”, “heterocycloalkyl”,“phenyl”,“heteroaryl”,“acyl ”,“lactam”,“sultam”,“cyano”,“halogen”, “carbonyl” or“hydroxyl”, etc. are the same as that described in the U.S. provisional application 62/702,064, which is hereby incorporated by reference for the definitions of these terms. These definitions do not apply to Formulas 1-10.

Table A

In alternative embodiments, provided are compounds having one of the following structures or compositions having one or more compounds of the following structures, or equivalents thereof, or an isomer, optical isomer or stereoisomer thereof, a racemate or racemic mixture thereof, an enantiomer, an individual diastereomer or a diastereomeric mixture thereof, or an analog, thereof, or a crystalline product or crystalline intermediate thereof, or a pharmaceutically acceptable salt thereof, or prodrug or a bioisostere thereof; or

a composition comprising an isolated or synthetic compound consisting essentially of, or consisting of:

(a) a compound having the formula A:

Formula A

wherein U is independently selected from N and CR3;

V is independently selected from N and CR ₄ ;

W is independently selected from N and CH;

L is a linker of 0-3 atoms independently selected from C, N, O and S, where the atoms of L may be optionally substituted as CR ₅ R ₆ , NR ₇ , S(O) or SO ₂ ;

A is independently selected from: C _3-12 cycloalkyl optionally substituted independently at any position with 1-2 R8; C3-12 heterocycloalkyl optionally independently substituted on each carbon with 1-2 R ₈ and on each nitrogen with R ₉ ;

R ₁ is independently selected from: cyano; a phenyl optionally independently substituted with 1-3 R10; a 5 or 6 membered heteroaryl ring optionally independently substituted with 1-3 R11; C1-6 alkyl optionally substituted independently at any position with 1-3 R12; C3-12 cycloalkyl optionally substituted independently at any position with 1-2 R ₁₂ ; C _3-12 heterocycloalkyl optionally independently substituted on each carbon with 1-2 R12 and independently on each nitrogen with R13;

R ₃ is independently selected from: a hydrogen; a cyano; C _1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₁₄ ; C ₃ - ₈ cycloalkyl; C ₄ - ₈ heterocycloalkyl; OR15; NR16R17; SR18; C(O)NR16R17; OC(O)NR16R17; NR16C(O)R15; NR16C(O)OR18; NR ₁₆ SO ₂ R ₁₈ ; SO ₂ NR ₁₆ R ₁₇ ; C(O)R ₁₅ ; S(O)R ₁₈ ; and SO ₂ R ₁₈ ;

R ₄ is independently selected from: a hydrogen; a cyano; C _1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R19; C3-8 cycloalkyl; C4-8 heterocycloalkyl; OR20; NR21R22; SR23; C(O)NR21R22; OC(O)NR21R22; NR21C(O)R20; NR21C(O)OR23; NR ₂₁ SO ₂ R ₂₃ ; SO ₂ NR ₂₁ R ₂₂ ; C(O)R ₂₀ ; S(O)R ₂₃ ; and SO ₂ R ₂₃ ;

R5 and R6 are independently selected from, at each occurrence: a hydrogen; a cyano; a halogen; C1-6 alkyl optionally substituted independently at any position with 1-3 R24; OR25; NR ₂₆ R ₂₇ ; or R ₅ and R ₆ together are a carbonyl;

R7 is independently selected from, at each occurrence: a hydrogen; C1-6 alkyl optionally substituted independently at any position with 1-3 R28; C3-8 cycloalkyl; C4-8 heterocycloalkyl; C(O)R ₂₉ ; C(O)OR ₂₉ ; and SO ₂ R ₂₉ ;

R ₈ is independently selected from, at each occurrence: a hydrogen; a cyano; a carbonyl; a halogen; a phenyl optionally independently substituted with 1-3 R30; a 5 or 6 membered heteroaryl ring optionally independently substituted with 1-3 R ₃₁ ; C _1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₃₂ ; C ₃ - ₈ cycloalkyl; C ₄ - ₈ heterocycloalkyl; OR33; NR34R35; SR36; C(O)NR34R35; OC(O)NR34R35; NR34C(O)R33; NR34SO2R36; SO2NR35R36; C(O)R33; S(O)R36; and SO2R36;

R ₉ is independently selected from, at each occurrence: a hydrogen; a phenyl optionally independently substituted with 1-3 R30; a 5 or 6 membered heteroaryl ring optionally independently substituted with 1-3 R ₃₁ ; C _1-6 alkyl optionally substituted independently at any position with 1-3 R ₃₂ ; C ₃ - ₈ cycloalkyl; C ₄ - ₈ heterocycloalkyl; C(O)NR ₃₄ R ₃₅ ; SO ₂ NR ₃₄ R ₃₅ ; C(O)R ₃₃ ; C(O)OR36; and SO2R36;

R ₁₀ is independently selected from, at each occurrence: a hydrogen; a halogen; a cyano; C _1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₃₇ ; C _1- 6 alkyloxy, alkylamino or alkylthio; C3-8 cycloalkyl; C4-8 heterocycloalkyl; OR38; NR39R40; SR41; C(O)NR39R40; OC(O)NR39R40; NR39C(O)R38; NR39SO2R41; SO2NR39R40; C(O)R38; S(O)R41; and SO2R41;

R ₁₁ is independently selected from, at each occurrence: a hydrogen; a halogen; a cyano; C1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R37; C1- 6 alkyloxy, alkylamino or alkylthio; C3-8 cycloalkyl; C4-8 heterocycloalkyl; OR38; NR39R40; SR41; C(O)NR ₃₉ R ₄₀ ; OC(O)NR ₃₉ R ₄₀ ; NR ₃₉ C(O)R ₃₈ ; NR ₃₉ SO ₂ R ₄₁ ; SO ₂ NR ₃₉ R ₄₀ ; C(O)R ₃₈ ; S(O)R ₄₁ ; and SO ₂ R ₄₁ ;

R ₁₂ is independently selected from, at each occurrence: a hydrogen; a cyano; a carbonyl; a halogen; C1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₄₂ ; C _1-6 alkyloxy, alkylamino or alkylthio; C ₃ - ₈ cycloalkyl; C ₄ - ₈ heterocycloalkyl; OR ₄₃ ; NR ₄₄ R ₄₅ ; SR ₄₆ ; C(O)NR ₄₄ R ₄₅ ; OC(O)NR ₄₄ R ₄₅ ; NR ₄₄ C(O)R ₄₃ ; NR ₄₄ SO ₂ R ₄₆ ; SO ₂ NR ₄₄ R ₄₅ ; C(O)R ₄₃ ; S(O)R ₄₆ ; and SO2R46;

R13 is independently selected from, at each occurrence: a hydrogen; C1-6 alkyl optionally substituted independently at any position with 1-3 R ₄₂ ; C _1-6 alkyloxy, alkylamino or alkylthio; C ₃ - ₈ cycloalkyl; C4-8 heterocycloalkyl; C(O)NR44R45; SO2NR44R45; C(O)R43; C(O)OR46; and SO2R46;

R14 is independently selected from, at each occurrence: a hydrogen; a halogen; a cyano; C _1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₄₇ ; C _1- 6 alkyloxy, alkylamino or alkylthio; OR48; NR49R50; and SR51;

R15 is independently selected from, at each occurrence: hydrogen; C1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₄₇ ; C _3-8 cycloalkyl; and C _{4- 8} heterocycloalkyl;

R16 and R17 are independently selected from, at each occurrence: a hydrogen; C1-6 alkyl, alkenyl or alkynyl; C _1-6 alkyloxy, alkylamino or alkylthio, or R ₁₆ and R ₁₇ together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring;

R18 is independently selected from, at each occurrence: C1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R47; C3-8 cycloalkyl; and C4-8 heterocycloalkyl; R ₁₉ is independently selected from, at each occurrence: a hydrogen; a halogen; a cyano; C _1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₅₃ ; C _1- 6 alkyloxy, alkylamino or alkylthio; OR54; NR55R56; and SR57;

R ₂₀ is independently selected from, at each occurrence: hydrogen, C _1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₅₃ ; C _3-8 cycloalkyl; and C _4- 8 heterocycloalkyl;

R21 and R22 are independently selected from, at each occurrence: a hydrogen; C1-6 alkyl, alkenyl or alkynyl; C _1-6 alkyloxy, alkylamino or alkylthio, or R ₂₁ and R ₂₂ together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring;

R23 is independently selected from, at each occurrence: C1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₅₃ ; C _3-8 cycloalkyl; and C _4-8 heterocycloalkyl;

R24 is independently selected from, at each occurrence: a hydrogen; a cyano; a halogen; and C _1-6 alkyl;

R ₂₅ is independently selected from, at each occurrence: a hydrogen; and C _1-6 alkyl;

R26 and R27 are independently selected from, at each occurrence: a hydrogen; C1-6 alkyl; C(O)R29; C(O)OR29; and SO2R29

R ₂₈ is independently selected from, at each occurrence: a hydrogen; a cyano; a halogen; and C1-6 alkyl;

R29 is independently selected from, at each occurrence: C1-6 alkyl; C3-8 cycloalkyl; and C4-8 heterocycloalkyl;

R30 and R31 are independently selected from, at each occurrence: a hydrogen; a cyano; a halogen; C1-6 alkyl, alkenyl, or alkynyl, optionally substituted independently at any position with 1-3 R ₅₈ C _1-6 alkyloxy, alkylamino or alkylthio; C ₃ - ₈ cycloalkyl; C ₄ - ₈ heterocycloalkyl; OR ₅₉ ; NR ₆₀ R ₆₁ ; SR ₆₂ ; C(O)NR ₆₀ R ₆₁ ; OC(O)NR ₆₀ R ₆₁ ; NR ₆₀ C(O)R ₆₁ ; NR ₆₀ SO ₂ R ₆₂ ; SO ₂ NR ₆₀ R ₆₁ ; C(O)R ₆₂ ; S(O)R ₆₂ ; and SO2R62

R ₃₂ is independently selected from, at each occurrence: a hydrogen; a cyano; a halogen; C _1-6 alkyl; and C _1-6 alkyloxy, alkylamino or alkylthio;

R33 is independently selected from, at each occurrence: a hydrogen; C1-6 alkyl; C3-8 cycloalkyl; and C4-8 heterocycloalkyl; R ₃₄ and R ₃₅ are independently selected from, at each occurrence: a hydrogen; C _1-6 alkyl; _; or R ₃₄ and R ₃₅ together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring;

R ₃₆ is independently selected from, at each occurrence: C _1-6 alkyl; C ₃ - ₈ cycloalkyl; and C ₄ - ₈ heterocycloalkyl;

R37 is independently selected from, at each occurrence: a hydrogen; a halogen; a cyano; C1-6 alkyl; C3-8 cycloalkyl; and C4-8 heterocycloalkyl;

R ₃₈ is independently selected from, at each occurrence: a hydrogen; C _1-6 alkyl; C _3-8 cycloalkyl; and C4-8 heterocycloalkyl;

R39 and R40 are independently selected from, at each occurrence: a hydrogen; C1-6 alkyl;; or R ₃₉ and R ₄₀ together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring;

R41 is independently selected from, at each occurrence: C1-6 alkyl; C3-8 cycloalkyl; and C4-8 heterocycloalkyl;

R ₄₂ is independently selected from, at each occurrence: a hydrogen; a cyano; a halogen; C1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R63; C1- 6 alkyloxy, alkylamino or alkylthio; C3-8 cycloalkyl; C4-8 heterocycloalkyl; OR64; NR65R66; SR67; C(O)NR ₆₅ R ₆₆ ; OC(O)NR ₆₅ R ₆₆ ; NR ₆₅ C(O)R ₆₆ ; NR ₆₅ SO ₂ R ₆₇ ; SO ₂ NR ₆₅ R ₆₆ ; C(O)R ₆₇ ; S(O)R ₆₇ ; and SO ₂ R ₆₇ R43 is independently selected from, at each occurrence: a hydrogen; C1-6 alkyl; C3-8 cycloalkyl; and C4-8 heterocycloalkyl;

R ₄₄ and R ₄₅ are independently selected from, at each occurrence: a hydrogen; C _1-6 alkyl; _; or R44 and R45 together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring;

R ₄₆ is independently selected from, at each occurrence: C _1-6 alkyl; C _3-8 cycloalkyl; and C _4-8 heterocycloalkyl;

R47 is independently selected from, at each occurrence: a hydrogen; a cyano; a halogen; and C _1-6 alkyl;

R ₄₈ is independently selected from, at each occurrence: a hydrogen; C _1-6 alkyl; C _3-8 cycloalkyl; and C4-8 heterocycloalkyl;

R49 and R50 are independently selected from, at each occurrence: a hydrogen; C1-6 alkyl;; or R ₄₉ and R ₅₀ together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring; R ₅₁ is independently selected from, at each occurrence: C _1-6 alkyl; C _3-8 cycloalkyl; and C _4-8 heterocycloalkyl;

R53 is independently selected from, at each occurrence: a hydrogen; a cyano; a halogen; and C _1-6 alkyl;

R ₅₄ is independently selected from, at each occurrence: a hydrogen; C _1-6 alkyl; C _3-8 cycloalkyl; and C4-8 heterocycloalkyl;

R55 and R56 are independently selected from, at each occurrence: a hydrogen; C1-6 alkyl;; or R ₄₉ and R ₅₀ together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring;

R57 is independently selected from, at each occurrence: C1-6 alkyl; C3-8 cycloalkyl; and C4-8 heterocycloalkyl;

R ₅₈ is independently selected from, at each occurrence: a hydrogen; a cyano; a halogen and C1-6 alkyl;

R ₅₉ is independently selected from, at each occurrence: a hydrogen; C _1-6 alkyl; C _3-8 cycloalkyl; and C _4-8 heterocycloalkyl;

R60 and R61 are independently selected from, at each occurrence: a hydrogen; C1-6 alkyl;; or R60 and R61 together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring;

R62 is independently selected from, at each occurrence: C1-6 alkyl; C3-8 cycloalkyl; and C4-8 heterocycloalkyl;

R ₆₃ is independently selected from, at each occurrence: a hydrogen; a cyano; a halogen; and C1-6 alkyl;

R64 is independently selected from, at each occurrence: a hydrogen; C1-6 alkyl; C3-8 cycloalkyl; and C _4-8 heterocycloalkyl;

R ₆₅ and R ₆₆ are independently selected from, at each occurrence: a hydrogen; C _1-6 alkyl; _; or R65 and R66 together with the nitrogen to which they are attached form a 4 to 8 membered heterocycloalkyl ring;

R ₆₇ is independently selected from, at each occurrence: C _1-6 alkyl; C _3-8 cycloalkyl; and C _4-8 heterocycloalkyl.

In alternative embodiments, L is selected from CR5R6X and XCR5R6, where X is independently selected from CR ₅ R ₆ ; O; NR ₇ ; S; SO ₂ and S(O); or, L is selected from CR ₅ R ₆ CR ₅ R ₆ X and XCR ₅ R ₆ CR ₅ R ₆ , wherein X is independently selected from CR ₅ R ₆ ; O; NR ₇ ; S; SO ₂ or S(O).

In alternative embodiments: U is CR3; V is CR4; and/or W is CH; or, U is CR3 and V is CR4; or, U is CR ₃ and W is CH.

In alternative embodiments: A is selected from C _3-12 heterocycloalkyl containing at least one nitrogen atom and optionally independently substituted on each carbon with 1-2 R12 and independently on each nitrogen with 1-2 R13.

In alternative embodiments, X is O.

In alternative embodiments, a compound as provided herein has formula B:

Formula B

wherein Y is R8.

In alternative embodiments, L is selected from CR ₅ R ₆ X and XCR ₅ R ₆ , where X is independently selected from CR5R6; O; NR7; S; SO2 and S(O), and optionally X is O.

In alternative embodiments, Y is selected from a cyano; a halogen; C1-6 alkyl, alkenyl or alkynyl, optionally substituted independently at any position with 1-3 R ₃₂ ; OR ₃₃ ; NR ₃₄ R ₃₅ ; SR ₃₆ ; C(O)NR ₃₄ R ₃₅ ; OC(O)NR ₃₄ R ₃₅ ; NR ₃₄ C(O)R ₃₃ ; NR ₃₄ SO ₂ R ₃₆ ; SO ₂ NR ₃₅ R ₃₆ ; C(O)R ₃₃ ; S(O)R ₃₆ ; and SO ₂ R ₃₆ . In alternative embodiments, L is selected from CR5R6X and XCR5R6, where X is independently selected from CR ₅ R ₆ ; O; NR ₇ ; S; SO ₂ and S(O), and optionally X is O.

In alternative embodiments, provided are formulations comprising a compound or composition as provided herein, wherein optionally the formulation is a solid, liquid, aerosol, powder, lyophilized, gel, hydrogel, semi-solid or emulsion formulation.

In alternative embodiments, provided are pharmaceutical compositions comprising a compound or compositions as provided herein, wherein optionally the pharmaceutical composition is formulated for enteral or parenteral administration, or is formulated for administration by inhalation, intravenously (IV), intradermally, intrathecally, sub- or intra- dermally, topically or intramuscularly (IM); and optionally the compound is formulated for administration in vivo; or for enteral or parenteral administration, or as a tablet, pill, capsule, lozenge, gel, geltab, liquid, lotion, aerosol, patch, spray, or implant, and optionally the compound is formulated as a liposome, a microparticle, a nanoparticle or a nanolipoparticle.

In alternative embodiments, provided are kits, implants, a pump, a device, a subcutaneous infusion device, a continuous subcutaneous infusion device, an infusion pen, a needles, a reservoir, an ampoules, a vial, a syringe, a cartridge, a pen, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi-chambered pump, comprising a compound as provided herein, or a formulation as provided herein, or a pharmaceutical composition as provided herein.

In alternative embodiments, provided are methods for inhibiting a kinase, wherein optionally the kinase is a kinase in the AGC group of kinases, and optionally the kinase in the AGC group is a kinase selected from the group consisting of:

a Protein Kinase A/cyclic AMP-dependent protein kinase (cAPK), or PKA kinase, a Protein Kinase C (PKC),

a Protein Kinase G (PKG), or cGMP-dependent protein kinase,

a Protein Kinase N (PKN),

a PDK1 kinase,

an AKT kinase (also known as Protein Kinase B, PKB),

a RSK, RSKR or RSKL ribosomal protein S6 Kinase,

a G-protein-coupled receptor (GRK) kinase,

a MAST kinase,

a Myotonic Dystrophy Protein Kinase (DMPK); and,

a Serum and Glucocorticoid-induced Kinase (SGK), wherein optionally the SGK kinase is an SGK1 kinase;

the method comprising:

(a) providing or having provided a compound as provided herein, or a formulation as provided herein, or a pharmaceutical composition as provided herein; and

(b) contacting or having contacted, or administering or having administered, the enzyme with the compound, formulation or pharmaceutical composition,

wherein optionally the contacting or administering is in vitro, ex vivo or in vivo.

In alternative embodiments, provided are methods for: (a) treating, ameliorating, preventing, reversing or slowing the progression of: a cancer, a tumor, a metastasis or a dysplastic or a dysfunctional cell condition responsive to inhibition of a kinase enzyme,

wherein optionally the kinase is a kinase in the AGC group of kinases, and optionally the kinase in the AGC group is a kinase selected from the group consisting of:

a Protein Kinase A/cyclic AMP-dependent protein kinase (cAPK), or PKA kinase, a Protein Kinase C (PKC),

a Protein Kinase G (PKG), or cGMP-dependent protein kinase,

a Protein Kinase N (PKN),

a PDK1 kinase,

an AKT kinase (also known as Protein Kinase B, PKB), wherein optionally the AKT kinase is an Akt1 or an Akt2 kinase,

a RSK, RSKR or RSKL ribosomal protein S6 Kinase,

a G-protein-coupled receptor (GRK) kinase,

a MAST kinase,

a Myotonic Dystrophy Protein Kinase (DMPK); and,

a Serum and Glucocorticoid-induced Kinase (SGK), wherein optionally the SGK kinase is an SGK1 kinase;

wherein optionally the cancer or tumor is: a breast cancer or a breast cancer metastasis, optionally a triple-negative breast cancer or breast cancer metastasis; a thyroid cancer, optionally a radioiodine treatment-resistant thyroid cancer; a thyroid cancer metastasis, optionally a thyroid cancer metastasis resistant to radioiodine treatment; a colorectal or colon cancer; a prostate cancer; a head and neck cancer; a skin cancer or a melanoma; a kidney or renal cancer or a renal cell carcinoma; an ovarian cancer; a leukemia or lymphoma, Hodgkin's lymphoma, an acute lymphoblastic leukemia (ALL) or a childhood ALL, an acute lymphoid leukemia or an acute myeloid leukemia (AML); a lung cancer, a non-small cell lung cancer or a small cell lung cancer; a sarcoma or a histiocytic sarcoma; a bladder tumor; a tumor of the reticuloendothelial tissue; a Wilm’s tumor; a bone cancer, a rhabdomyosarcoma or an osteosarcoma; an oral cancer; a laryngeal cancer; an oropharyngeal cancer; a liver cancer or a hepatocarcinoma; a mastocytoma or a mast cell tumor; a cervical cancer; a pancreatic cancer; or, a neuroblastoma or a brain cancer;

(b) reducing mortality associated with the cancer or tumor; (c) inhibiting or reducing survival ability, or radio- and/or chemo-resistance, of tumor initiating cells or cancer stem cells, or inhibiting epithelial to mesenchymal transition (EMT) of cells;

(d) potentiating cancer chemotherapy, optionally a chemotherapy for breast, thyroid, head and neck, colorectal or colon, prostate, brain or cervical cancer;

(e) treating, ameliorating, preventing or reversing, slowing the progression of, or decreasing the severity of: an autoimmune disease or condition, an inflammatory disease or condition, an inherited or genetic disease or condition, a neurodegenerative disease or condition, or an infection responsive to inhibition of a kinase enzyme,

wherein optionally the inflammatory disease or condition or inherited or genetic disease or condition is: osteoarthritis, rheumatoid arthritis, lung fibrosis or cystic fibrosis; or

(f) inhibiting the kinase enzyme in vivo,

the method comprising:

administering or having administered to a patient or an individual in need thereof, a compound as provided herein, or a formulation as provided herein, or a pharmaceutical composition as provided herein,

wherein optionally the compound or formulation is administered enterally or parenterally,

wherein optionally the compound or formulation is administered orally, parenterally, by inhalation spray, nasally, topically, intrathecally, intracerebrally, epidurally, intracranially or rectally.

In alternative embodiments of methods as provided herein, the AGC group kinase is selected from a serum and a glucocorticoid-regulated kinase 1 (SGK1), a serum and a glucocorticoid-regulated kinase 2 (SGK2), a serum and a glucocorticoid-regulated kinase 3 (SGK3), and, an Akt1 and Akt2.

In alternative embodiments of methods as provided herein:

the pharmaceutical composition or the formulation is administered as a solid, liquid, aerosol, powder, lyophilized, gel or emulsion formulation, or

the pharmaceutical composition or the formulation is administered enterally or parenterally, or intravenously (IV), intradermally, intrathecally, sub- or intra-dermally, topically or intramuscularly (IM), and optionally the compound is administered in vivo; or as a tablet, pill, capsule, lozenge, gel, geltab, liquid, lotion, aerosol, patch, spray, or implant, or as a liposome, a nanoparticle or a nanolipoparticle.

In alternative embodiments, methods as provided herein further comprise:

administering to the patient or individual in need thereof a (or an additional) cancer therapy or cancer therapeutic, optionally formulated with or administered together with a compound as provided herein, or a formulation as provided herein, or a pharmaceutical composition as provided herein,

wherein optionally the cancer therapy or cancer therapeutic comprises drug or chemotherapy or radiation therapy, and optionally the drug or chemotherapy comprises administration (or co-administration) of a taxane, paclitaxel, TAXOL™, ONXOL™, an albumin- bound paclitaxel (nab- paclitaxel) or ABRAXANE™, docetaxel, carboplatin, an anthracycline, bevacizumab, an epothilone (optionally ixabepilone), cetuximab, a PARP inhibitor (optionally olaparib) or any equivalent thereof, or

administering or having administered a compound as provided herein, or a formulation as provided herein, or a pharmaceutical composition as provided herein, before, with or during, or after a cancer surgery.

In alternative embodiments, provided are uses of a compound as provided herein, or a formulation as provided herein, or a pharmaceutical composition as provided herein, in the manufacture of a medicament,

and optionally the use is for:

(a) treating, ameliorating, preventing, reversing or slowing the progression of: a cancer, a tumor, a metastasis or a dysplastic or a dysfunctional cell condition responsive to inhibition of a kinase enzyme,

wherein optionally the kinase is a kinase in the AGC group of kinases, and optionally the kinase in the AGC group is a serine/threonine kinase, or a kinase selected from the group consisting of:

a Protein Kinase A/cyclic AMP-dependent protein kinase (cAPK), or PKA kinase, a Protein Kinase C (PKC),

a Protein Kinase G (PKG), or cGMP-dependent protein kinase,

a Protein Kinase N (PKN),

a 3-phosphoinositide-dependent protein kinase-1 (PDPK1) kinase, a Pyruvate Dehydrogenase Kinase 1 (PDK1) kinase,

an AKT kinase (also known as Protein Kinase B, PKB),

a RSK, RSKR or RSKL ribosomal protein S6 Kinase,

a G-protein-coupled receptor (GRK) kinase,

a MAST kinase,

a Myotonic Dystrophy Protein Kinase (DMPK); and,

a Serum and Glucocorticoid-induced Kinase (SGK), wherein optionally the SGK kinase is an SGK1 kinase;

wherein optionally the cancer or tumor is: a breast cancer or a breast cancer metastasis, optionally a triple-negative breast cancer or breast cancer metastasis; a thyroid cancer, optionally a radioiodine treatment-resistant thyroid cancer; a thyroid cancer metastasis, optionally a thyroid cancer metastasis resistant to radioiodine treatment; a colorectal or colon cancer; a prostate cancer; a head and neck cancer; a skin cancer or a melanoma; a kidney or renal cancer or a renal cell carcinoma; an ovarian cancer; a leukemia or lymphoma, Hodgkin's lymphoma, an acute lymphoblastic leukemia (ALL) or a childhood ALL, an acute lymphoid leukemia or an acute myeloid leukemia (AML); a lung cancer, a non-small cell lung cancer or a small cell lung cancer; a sarcoma or a histiocytic sarcoma; a bladder tumor; a tumor of the reticuloendothelial tissue; a Wilm’s tumor; a bone cancer, a rhabdomyosarcoma or an osteosarcoma; an oral cancer; a laryngeal cancer; an oropharyngeal cancer; a liver cancer or a hepatocarcinoma; a mastocytoma or a mast cell tumor; a cervical cancer; a pancreatic cancer; or, a neuroblastoma or a brain cancer;

(b) reducing mortality associated with the cancer or tumor;

(c) inhibiting or reducing survival ability, or radio- and/or chemo-resistance, of tumor initiating cells or cancer stem cells, or inhibiting epithelial to mesenchymal transition (EMT) of cells;

(d) potentiating cancer chemotherapy, optionally a chemotherapy for breast, thyroid, head and neck, colorectal or colon, prostate, brain or cervical cancer;

(e) treating, ameliorating, preventing or reversing, slowing the progression of, or decreasing the severity of: an autoimmune disease or condition, an inflammatory disease or condition, an inherited or genetic disease or condition, a neurodegenerative disease or condition, or an infection responsive to inhibition of a kinase enzyme; or

(f) inhibiting the kinase enzyme in vivo. In alternative embodiments, provided are compounds, formulas, products of manufacture or compositions for use as a medicament,

and optionally the medicament is used for:

(a) treating, ameliorating, preventing, reversing or slowing the progression of: a cancer, a tumor, a metastasis or a dysplastic or a dysfunctional cell condition responsive to inhibition of a kinase enzyme,

wherein optionally the kinase is a kinase in the AGC group of kinases, and optionally the kinase in the AGC group is a serine/threonine kinase, or a kinase selected from the group consisting of:

a Protein Kinase A/cyclic AMP-dependent protein kinase (cAPK), or PKA kinase, a Protein Kinase C (PKC),

a Protein Kinase G (PKG), or cGMP-dependent protein kinase,

a Protein Kinase N (PKN),

a 3-phosphoinositide-dependent protein kinase-1 (PDPK1) kinase,

a Pyruvate Dehydrogenase Kinase 1 (PDK1) kinase,

a AKT kinase (also known as Protein Kinase B, PKB),

a RSK, RSKR or RSKL ribosomal protein S6 Kinase,

a G-protein-coupled receptor (GRK) kinase,

a MAST kinase,

a Myotonic Dystrophy Protein Kinase (DMPK); and,

a Serum and Glucocorticoid-induced Kinase (SGK), wherein optionally the SGK kinase is an SGK1 kinase;

wherein optionally the cancer or tumor is: a breast cancer or a breast cancer metastasis, optionally a triple-negative breast cancer or breast cancer metastasis; a thyroid cancer, optionally a radioiodine treatment-resistant thyroid cancer; a thyroid cancer metastasis, optionally a thyroid cancer metastasis resistant to radioiodine treatment; a colorectal or colon cancer; a prostate cancer; a head and neck cancer; a skin cancer or a melanoma; a kidney or renal cancer or a renal cell carcinoma; an ovarian cancer; a leukemia or lymphoma, Hodgkin's lymphoma, an acute lymphoblastic leukemia (ALL) or a childhood ALL, an acute lymphoid leukemia or an acute myeloid leukemia (AML); a lung cancer, a non-small cell lung cancer or a small cell lung cancer; a sarcoma or a histiocytic sarcoma; a bladder tumor; a tumor of the reticuloendothelial tissue; a Wilm’s tumor; a bone cancer, a rhabdomyosarcoma or an osteosarcoma; a head and neck cancer; an oral cancer; a laryngeal cancer; an oropharyngeal cancer; a liver cancer of a hepatocarcinoma; a mastocytoma or a mast cell tumor; a cervical cancer; a pancreatic cancer; or, a neuroblastoma or a brain cancer;

(b) reducing mortality associated with the cancer or tumor;

(c) inhibiting or reducing survival ability, or radio- and/or chemo-resistance, of tumor initiating cells or cancer stem cells, or inhibiting epithelial to mesenchymal transition (EMT) of cells;

(d) potentiating cancer chemotherapy, optionally a chemotherapy for breast, thyroid, head and neck, colorectal or colon, prostate, brain or cervical cancer;

(e) treating, ameliorating, preventing or reversing, slowing the progression of, or decreasing the severity of: an autoimmune disease or condition, an inflammatory disease or condition, an inherited or genetic disease or condition, a neurodegenerative disease or condition, or an infection responsive to inhibition of a kinase enzyme; or

(f) inhibiting the kinase enzyme in vivo; and

the compound, formula, product of manufacture or composition comprises at least one compound as provided herein, or a formulation as provided herein, or a pharmaceutical composition as provided herein. An example, not as an attempt to limit the scope of the disclosure, of a useful composition for a dosage form containing about 0.1-1000 mg or about 10-1000 mg of compound 7-1 is shown in Table 2 below: Table 2. Example of dosage form of compound 7-1

)

A pharmaceutical composition comprising a compound of Formula 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 may be adapted for oral, or parenteral, such as intravenous, intramuscular, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder. The dosage of a compound of Formula 1 may vary depending on the route of administration, body weight, age, the type and condition of the disease being treated. A pharmaceutical composition provided herein may optionally comprise two or more compounds of Formula 1 without an additional therapeutic agent, or may comprise an additional therapeutic agent (i.e., a therapeutic agent other than a compound provided herein). For example, the subject compounds can be administered simultaneously, sequentially, or separately in combination with at least one other therapeutic agent. The other therapeutic agent can be a small molecule, an antibody-drug conjugate, or a biologic. Therapeutic agents suitable for combination with a subject compound include, but are not limited to antibiotics, antiemetic agents, antidepressants, and antifungal agents, anti-inflammatory agents, antiviral agents, and anticancer agents that are known in the art. In some embodiments, the other therapeutic agents are chemotherapy agents, for example, mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel; or tyrosine kinase inhibitors, for example Erlotinib; ALK inhibitors such as Crizotinib; BRAF inhibitors such as Vemurafanib; MEK inhibitors such as trametinib; or other anticancer agents, i.e. cisplatin, flutamide, gemcitabine, CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors. Such combination may offer significant advantages, including synergistic activity, in therapy. The pharmaceutical composition may be used for the treatment of cancer, autoimmune diseases, inflammatory diseases, autoinflammatory conditions, and other SGK1-mediated disorders in patients. The term "patient" herein means a mammal (e.g., a human or an animal). In some embodiments, the patient has cancer.

The pharmaceutical composition described herein can be prepared by combining a compound of Formula 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 with at least one pharmaceutical acceptable inert ingredient, such as a carrier, excipient, filler, lubricant, flavoring agent, buffer, etc., selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated herein by reference, in its entirety. The relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.

Some embodiments include a method of treating a cancer, a tumor, a metastasis or a dysplastic or a dysfunctional cell condition responsive to inhibition of a kinase enzyme, comprising administering a therapeutically effective amount of a compound of Formula 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any compound described herein, or a pharmaceutically acceptable salt thereof (“subject compound”), or a pharmaceutical composition comprising a subject compound to a patient in need thereof. The subject compounds are inhibitors of kinases, including kinase enzymes of the AGC group of kinases, including SGK1, which can inhibit proliferation of cancer cells, enable apoptosis, and impair proliferation and metastasis of cancer cells. In some embodiments, the type of cancer or proliferative disorder includes breast cancer, including a triple-negative breast cancer (TNBC); breast cancer metastasis; thyroid cancer, including radioiodine treatment-resistant thyroid cancer; or, a cancer, tumor, metastasis or dysplastic or dysfunctional cell condition responsive to inhibition of an AGC kinase enzyme by an AGC kinase antagonist.

Some embodiments include a method of reducing mortality associated with metastatic breast cancer; inhibiting or reducing survival ability, or radio- and/or chemo-resistance, of tumor initiating cells or cancer stem cells, or inhibiting epithelial to mesenchymal transition (EMT) of cells; potentiating cancer chemotherapy; or, treating, ameliorating, preventing or reversing, slowing the progression of, or decreasing the severity of: an autoimmune disease or condition, an inflammatory disease or condition, an inherited or genetic disease or condition, a neurodegenerative disease or condition, or an infection responsive to inhibition of a kinase enzyme.

The term a "therapeutically effective amount" herein refers to an amount of a subject compound, or a pharmaceutical composition containing a subject compound, sufficient to be effective in inhibiting a kinase enzyme, such as AGC kinase and thus providing a benefit in the treatment of cancer, a metastasis or a dysplastic or a dysfunctional cell condition in patients, such as to delay or minimize symptoms associated with a disease, a condition, or a disorder, or to ameliorate a disease or cause thereof, or to prevent the further development of a disorder, or reducing the severity of symptoms that are otherwise expected to develop without treatment.

In alternative embodiments, provided are selective antagonists of kinases, including kinases in the AGC group of kinases, such as a SGK (Serum and Glucocorticoid-regulated Kinase) for example. In alternative embodiments, provided are small molecule compounds for treating, ameliorating or preventing triple-negative breast cancers, which have the worst prognoses among human breast cancers. Triplenegative breast cancer (sometimes abbreviated TNBC) refers to any breast cancer that does not express the genes for estrogen receptor (ER) or progesterone receptor (PR) and does not amplify expression of Her2/neu. In alternative embodiments, provided are small molecule compounds for treating, ameliorating or preventing thyroid cancers, optionally radioiodine treatment-resistant thyroid cancers. In alternative embodiments, provided are small molecule compounds for treating, ameliorating or preventing, or slowing the progress of, any disease, condition or infection responsive to the inhibition of a kinase, including for example, autoimmune, inflammatory or fibrotic disorders, including but not limited to osteoarthritis, rheumatoid arthritis, lung fibrosis, scleroderma or cystic fibrosis.

In alternative embodiments, SGK1 inhibitors as provided herein are used as single agents and/or in combination with standard chemotherapies or immunotherapies. In alternative embodiments, SGK1 inhibitors can enhance the effectiveness of a cancer therapy, e.g., a radiation therapy, an immunotherapy or a chemotherapy, e.g., for eliminating a cancer cell such as a TNBC cells, e.g., while reducing toxicities of chemotherapy. In alternative embodiments, SGK1 inhibitors as provided herein are administered with (in conjunction with, or administered before, during or after):

- a chemotherapeutic agent, wherein optionally the chemotherapeutic agent comprises a doxorubicin or a carboplatin, or comprises an inducer of apoptosis or a mitotic inhibitor or anti- microtubule inhibitor, or an alkylating agent, or a topoisomerase inhibitor, or a glycopeptide antibiotic, or steroid receptor inhibitor, or a matrix metalloproteinase (MMP) inhibitor, or an mTOR (mammalian target of rapamycin) inhibitor, or a macrolide or a composition comprising a macrolide ring, or an aromatase inhibitor;

- a cytokine, wherein optionally the cytokine is an immunomodulator, and optionally the immunomodulator comprises an Interleukin-2 (IL-2) or an interferon (IFN), and optionally the interferon is an alpha-IFN (interferon-a) or a gamma-IFN; and optionally the IL-2 is a recombinant IL-2, an aldesleukin, or a PROLEUKIN (Prometheus Laboratories);

- a H2-receptor antagonist (H2RA), a melatonin (or an N-acetyl-5-methoxytryptamine), a metformin or an N,N-Dimethylimidodicarbonimidic diamide, or a quinoline (e.g., chloroquine);

- an immune checkpoint blockade agent, or an agent that blocks the interaction between a transmembrane programmed cell death 1 protein (PD-1; also known as CD279) and its ligand, PD-1 ligand 1 (PD-L1), or an ipilumumab (CTLA-4 mAb) or nivolumab (PD-1 mAb), or pembrolizumab (PD-1 mAb), or a lambrolizumab (a PD-L1 mAb);

- a radiotherapy enhancing agent; - an anti-cancer or anti-tumor antibody, and optionally the anti-cancer or anti-tumor antibody is an alemtuzumab, a brentuximab vedotin, a cetuximab, a gemtuzumab ozogamicin, an abritumomab tiuxetan, a nimotuzumab, an ofatumumab, a panitumumab, a rituximab, a tositumomab, or a trastuzumab, or

- an immunomodulator, wherein optionally the immunomodulator is a lenalidomide (e.g., REVLIMID™), a pomalidamide (e.g., POMALYST™, IMNOVID™), or an apremilast (e.g., OTEZLA™).

Exemplary compounds provided herein are drug-like and show cellular penetration in Caco-2 permeability assays. Inhibitors of SGK1 provided herein block proliferation of MDA-MB- 231 triple-negative breast cancer cells and T683 thyroid cancer cells.

In alternative embodiments, compounds, compositions and methods as provided herein can be used to inhibit or block SGK1 and potentiate chemotherapy for various cancers, e.g., breast, thyroid, head and neck, colon and cervical cancer. SGK1 inhibitors can be used to treat cancer as a single agent and combined with standard chemotherapy to enhance treatment, e.g., by enabling apoptosis.

Accordingly, compounds, compositions and methods as provided herein solve a problem in the art by providing small molecule inhibitors of SGK1 that can inhibit proliferation of cancer cells, enable apoptosis, and impair proliferation and metastasis of cancer cells.

While many embodiments are not limited by any particular mechanism of action, it is hypothesized that certain tumor types, including TNBC and thyroid tumors, are dependent on SGK1 for proliferation, metastasis and drug resistance. Inhibitors of SGK1 as provided herein can offer a new targeted therapy for TNBC patients and for thyroid cancer patients. Further, SGK1 inhibitors as provided herein can enhance the effectiveness of existing chemotherapies in combination therapy. Inhibitors of SGK1 as provided herein exhibit the drug-like properties consistent with compounds that would be suitable for clinical development. Compounds as provided herein thus address limitations that have heretofore prevented identification of therapeutically valuable SGK1 inhibitors. Inhibitors of SGK1 as provided herein are suitable for development as the first targeted therapy for human diseases that are mediated by SGK1 activity.

In alternative embodiments, compounds as provided herein contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all of the possible optical isomers and diastereomers in mixtures, as pure or partially purified compounds, are provided herein. In alternative embodiments, compounds provided herein encompass any and all existing isomers and mixtures thereof in any proportion. In alternative embodiments, compounds herein are provided as isomers in pure form or as part of a mixture with other isomers in any proportion.

In alternative embodiments, provided are independent syntheses of diastereomers or their chromatographic separations, and their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

In alternative embodiments, racemic mixtures are separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. In alternative embodiments, a coupling reaction comprises formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

In alternative embodiments, a compound is made using stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

In alternative embodiments, a compound is isotopically labeled with one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundant in nature. Examples of isotopes that can be incorporated into compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, for example ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O or ¹⁸ F. In alternative embodiments, compounds provided herein may be substituted with an alternative isotope, e.g., a ² H (deuterium) in place of a hydrogen, to, e.g., increase metabolic stability and/or in vivo half-life. In alternative embodiments, a compound is selectively modified, e.g., selectively deuterated, to modify all or only part of a reactive site, or a portion of the compound that is a site of chemical modification in vivo, e.g. for the purpose of changing its solubility or pharmacokinetics, e.g., metabolic profile or half-life. In alternative embodiments, compounds as provided herein, prodrugs thereof, and pharmaceutically acceptable salts of these compounds may contain the aforementioned isotopes and/or isotopes of other atoms.

Products of Manufacture, Kits

Also provided are products of manufacture and kits for practicing the methods as provided herein. In alternative embodiments, provided are products of manufacture and kits comprising all the components needed to practice a method as provided herein.

Provided are kits comprising compositions and/or instructions for practicing methods as provided herein. In alternative embodiments, provided are kits comprising: a composition used to practice a method as provided herein, optionally comprising instructions for use thereof.

Disclosed herein is a kit comprising a therapeutically effective amount of a compound of Formula 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any compound described herein, or a pharmaceutically acceptable salt thereof (“subject compound”), or a pharmaceutical composition comprising a subject compound for treating a cancer, a tumor, a metastasis or a dysplastic or a dysfunctional cell condition responsive to inhibition of a kinase enzyme of SGK1. EXAMPLES

These specific examples are to be construed as merely illustrative, and not limitative of the remainder of the disclosure or other embodiments provided herein in any way whatsoever. General synthesis schemes for exemplary compositions

Compounds of Formula S1-8 as provided herein may be prepared according to the following general schemes, using techniques and procedures known to a person skilled in the art. In alternative embodiments, a bicyclic ring system of an exemplary compound may be elaborated from a compound of Formula S1-1 as shown in the following schemes. Other compounds of Formula S1-8 may be prepared from related derivatives of a compound of Formula S1-1, as this heterocyclic ring system represents the core structure of the compounds as provided herein.

A person having ordinary skill in the art will recognize that different types of chemical bonds may be formed through selective reactivity on the core structure of Formula S1-8, and that a protecting group (represented in the following schemes as“PG”) may be desirable or necessary to enable reactivity. It may also be desirable or necessary to incorporate protecting groups into other reacting partners for introduction onto the core structure of Formula S1-8. The choice of an appropriate protecting group for certain reaction conditions and conditions for introduction or removal of said protecting group will be well known to a person having ordinary skill in the art. Conventional protecting groups are described in Greene, T.M. and Wuts, P.G.M., Third Edition, John Wiley & Sons, 1999, and are hereby incorporated by reference.

General Scheme 1

A general route to certain compounds of Formula S1-8 is shown in Scheme 1 below.

A compound of Formula S1-1 may undergo halogenation selectively at the 3-position to give a compound of Formula S1-2, as shown in Scheme 1, through the action of an electrophilic halogenating agent, such as N-bromosuccinimide, in an appropriate solvent such as N,N- dimethylformamide. Reactions typically proceed at temperatures between 0 °C and 40 °C, with reaction times from 1 h to 12 h.

Subsequent to halogenation, it may be desirable to introduce a protecting group on the NH of the core structure to furnish a compound of Formula S1-3. Treatment of the compound of Formula S1-2 with an appropriate electrophile, such as di-tert-butyldicarbonate or p- toluenesulfonyl chloride, in the presence of a base such as triethylamine or sodium hydroxide in an appropriate solvent such as dichloromethane, introduces a protecting group onto the molecule. Such reactions may be accelerated by using a catalyst, such as 4- dimethylaminopyridine or tetrabutylammonium hydrogen sulfate. Reactions typically proceed at temperatures between 0 °C and 100 °C, with reaction times from 1 h to 72 h. Alternative protecting groups may be introduced under similar conditions using appropriate electrophiles, such as 2-(trimethylsilyl)ethoxymethyl chloride, chloromethyl methyl ether, or triisopropylsilyl chloride. Reactions with such electrophiles typically proceed in the presence of a base such as triethylamine or sodium hydride, in an appropriate solvent such as dichloromethane, at temperatures between 0 °C and 100 °C, with reaction times from 1 h to 72 h.

A compound of Formula S1-5 may be prepared from a compound of Formula S1-3 by reaction with an appropriate nucleophile S1-4, through a nucleophilic aromatic substitution reaction. Typical nucleophiles of type S1-4 include alcohols, amines, thiols and carbon nucleophiles. Such reactions can proceed using an appropriate base, such as a hydride, carbonate or tertiary amine, and in an appropriate solvent, such as 1,4-dioxane or dimethyl sulfoxide. Reactions may also be performed in the absence of solvent. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h. A compound of Formula S1-7 may be prepared by a cross-coupling reaction between S1- 5 and an alkyl or aromatic reagent S1-6 containing a boron atom, such as a boronic acid, boronic acid ester, or trifluoroborate salt, to form a carbon-carbon bond through a Suzuki reaction. These reactions proceed using an appropriate metal precatalyst, such as palladium(0), in the presence of a ligand, typically a phosphine compound, and in an appropriate solvent, such as 1,4-dioxane. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h. Such carbon-carbon bonds may alternatively be formed under similar conditions where the boron atom is replaced by another metal, such as magnesium or zinc.

Finally, removal of the protecting group (deprotection) will afford a compound of Formula S1-8. The appropriate deprotection conditions are chosen based on the nature of the protecting group in each case, as protecting groups are orthogonal to certain reaction conditions by design. Treatment of the protected compound of Formula S1-7 with an appropriate reagent, such as trifluoroacetic acid, hydrochloric acid, sodium hydroxide, or tetrabutylammonium fluoride, removes the protecting group and reveals the NH moiety. Deprotection reactions may occur without solvent, or may proceed in an appropriate solvent such as tetrahydrofuran or methanol, at temperatures between -40 °C and 100 °C, with reaction times from 1 h to 72 h.

Scheme 1

General Scheme 2

A person having ordinary skill in the art will recognize that it may, at times, be desirable to perform a Suzuki reaction in such a way that the borylated and brominated species are reversed from those shown in Scheme 1. A general example of such an approach is shown in Scheme 2 below.

A compound of Formula S1-5 may be converted to a corresponding borylated compound of Formula S2-1 through a reaction with bis(pinacolato)diboron under Miyaura borylation conditions. Such reactions proceed using an appropriate metal precatalyst, such as palladium(0), in the presence of a ligand, typically a phosphine compound, and in an appropriate solvent, such as 1,4-dioxane. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h. Compounds of Formula S2-1 may be isolated from such reactions as the boronic ester, boronic acid, or a mixture of these species. A compound of Formula S2-1 may also be prepared through metal-halogen exchange and reaction with an appropriate electrophile, such as triisopropylborate. Metal-halogen exchange typically occurs in the presence of an appropriate metalating agent, such as n-butyllithium or magnesium, in a solvent such as tetrahydrofuran or diethyl ether, at temperatures typically between -78 °C and 40 °C, with reaction times between 1 h and 12 h. Treatment of the metalated intermediate with an appropriate boron electrophile, such as triisopropylborate or 2-methoxy-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane, furnishes the borylated compound of Formula S2-1. Borylation typically takes place at temperatures between -78 °C and 100 °C, with reaction times between 1 h and 24 h. Compounds of Formula S2-1 may be isolated from such reactions as the boronic ester, boronic acid, or a mixture of these species.

A compound of Formula S2-1 may then undergo a Suzuki coupling reaction with an appropriate alkyl or aryl bromide of Formula S2-2 to furnish a compound of Formula S1-7. These reactions proceed using an appropriate metal precatalyst, such as palladium(0), in the presence of a ligand, typically a phosphine compound, and in an appropriate solvent, such as 1,4-dioxane. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h.

Removal of the protecting group (deprotection) from a compound of Formula S1-7, by such methods as described previously in Scheme 1, will afford a compound of Formula S1-8. Scheme 2

General Scheme 3

Another general route to certain compounds of Formula S1-8 is shown in Scheme 3 below.

A compound of Formula S3-1 may be prepared by a cross-coupling reaction between S1- 3 and an alkyl or aromatic reagent S1-6 containing a boron atom, such as a boronic acid, boronic acid ester, or trifluoroborate salt, to form a carbon-carbon bond through a Suzuki reaction. These reactions proceed using an appropriate metal precatalyst, such as palladium(0), in the presence of a ligand, typically a phosphine compound, and in an appropriate solvent, such as 1,4-dioxane. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h. Such carbon-carbon bonds may alternatively be formed under similar conditions where the boron atom is replaced by another metal, such as magnesium or zinc.

Treatment of a compound of Formula S3-1 with an appropriate nucleophile of Formula S1-4, such as an alcohol, amine, thiol or carbon nucleophile, may give rise to a compound of Formula S1-7 through a nucleophilic aromatic substitution reaction. Such reactions can proceed using an appropriate base, such as a hydride, carbonate or tertiary amine, and in an appropriate solvent, such as 1,4-dioxane or dimethyl sulfoxide. Reactions may also be performed in the absence of solvent. Reactions typically proceed at temperatures between 0 °C and 100 °C, with reaction times from 1 h to 72 h.

A subsequent deprotection step would then furnish the compound of Formula S1-8. Treatment of the protected compound of Formula S1-7 with an appropriate reagent, such as trifluoroacetic acid, hydrogen chloride, hydrochloric acid or tetrabutylammonium fluoride, removes the protecting group and reveals the NH moiety. Deprotection reactions may occur without solvent, or may proceed in an appropriate solvent such as tetrahydrofuran or methanol, at temperatures between -40 °C and 100 °C, with reaction times from 1 h to 72 h.

Scheme 3

General Scheme 4

As described above in Scheme 2, a person having ordinary skill in the art will recognize that it may, at times, be desirable to perform a Suzuki reaction in such a way that the borylated and brominated species are reversed from those shown in Scheme 3. A general example of such an approach is shown in Scheme 4 below.

A compound of Formula S1-3 may be converted to a corresponding borylated compound of Formula S4-1 through a reaction with bis(pinacolato)diboron under Miyaura borylation conditions. Such reactions proceed using an appropriate metal precatalyst, such as palladium(0), in the presence of a ligand, typically a phosphine compound, and in an appropriate solvent, such as 1,4-dioxane. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h. Compounds of Formula S4-1 may be isolated from such reactions as the boronic ester, boronic acid, or a mixture of these species. A compound of Formula S4-1 may also be prepared through metal-halogen exchange and reaction with an appropriate electrophile, such as triisopropylborate. Metal-halogen exchange typically occurs in the presence of an appropriate metalating agent, such as n-butyllithium or magnesium, in a solvent such as tetrahydrofuran or diethyl ether, at temperatures typically between -78 °C and 40 °C, with reaction times between 1 h and 12 h. Treatment of the metalated intermediate with an appropriate boron electrophile, such as triisopropylborate or 2-methoxy-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane, furnishes the borylated compound of Formula S4-1. Borylation typically takes place at temperatures between -78 °C and 100 °C, with reaction times between 1 h and 24 h. Compounds of Formula S4-1 may be isolated from such reactions as the boronic ester, boronic acid, or a mixture of these species.

A compound of Formula S4-1 may then undergo a Suzuki coupling reaction with an appropriate alkyl or aryl bromide of Formula S2-2 to furnish a compound of Formula S3-1. These reactions proceed using an appropriate metal precatalyst, such as palladium(0), in the presence of a ligand, typically a phosphine compound, and in an appropriate solvent, such as 1,4-dioxane. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h.

Treatment of a compound of Formula S3-1 with an appropriate nucleophile, such as an alcohol, amine, thiol or carbon nucleophile, may give rise to a compound of Formula S1-7 through a nucleophilic aromatic substitution reaction, as described previously in Scheme 3.

Removal of the protecting group (deprotection) from a compound of Formula S1-7, by such methods as described previously in Scheme 1, will afford a compound of Formula S1-8. Scheme 4

General Scheme 5

In certain cases, it may be desirable to perform a nucleophilic substitution reaction using a bifunctional reagent where it is necessary to discriminate between two possible nucleophiles in the same molecule. A person having ordinary skill in the art will appreciate that it may at times not be possible to discriminate completely between the reactive sites under typical reaction conditions, and that in such cases it may be desirable to use a reagent where one of the possible nucleophiles has been masked with a protecting group. A general example of such an approach is shown in Scheme 5 below.

A compound of Formula S5-2 may be prepared from a compound of Formula S3-1 through a reaction with an appropriate reagent S5-1, which may contain an alcohol, amine, thiol or carbon nucleophile. Such reactions can proceed using an appropriate base, such as a hydride, carbonate or tertiary amine, and in an appropriate solvent, such as 1,4-dioxane or dimethyl sulfoxide. Reactions may also be performed in the absence of solvent. Reactions typically proceed at temperatures between 0 °C and 100 °C, with reaction times from 1 h to 72 h.

A person having ordinary skill in the art will recognize that most common protecting groups are stable to certain reaction conditions and not to others, and that a compound such as that of Formula S5-2 bearing two protecting groups (PG ₁ and PG ₂ ) may be deprotected in stages. For example, PG2 may be deprotected under strongly acidic conditions while PG1 is not. Scheme 5 below shows a sequence in which PG ₂ is removed under conditions where PG ₁ does not react, furnishing a compound of Formula S5-3. It may be desirable to purify a compound of Formula S5- 3, or it may be possible to carry it over to a subsequent second deprotection step without purification.

Treatment of a compound of Formula S5-3 with appropriate alternative reaction conditions, under which PG1 is reactive, would then remove PG1 to reveal a compound of Formula S1-8.

Scheme 5

General Scheme 6

A person having ordinary skill in the art will recognize that in some cases a compound such as that of Formula S5-2, bearing two protecting groups (PG1 and PG2), may be deprotected in stages where the sequence of deprotection steps is reversed from that shown in Scheme 5. For example, PG ₁ may be deprotected under strongly basic conditions while PG ₂ is not. Scheme 5 below shows a sequence in which PG1 is removed under conditions where PG2 does not react, furnishing a compound of Formula S6-1. It may be desirable to purify a compound of Formula S6- 1, or it may be possible to carry it over to the subsequent second deprotection step without purification.

Treatment of a compound of Formula S6-1 with appropriate alternative reaction conditions would then remove PG ₁ to reveal a compound of Formula S1-8. A general example of such an approach is shown in Scheme 6 below.

Scheme 6

General Scheme 7

A person having ordinary skill in the art will recognize that in some cases a compound such as that of Formula S5-2, bearing two protecting groups (PG ₁ and PG ₂ ), may be deprotected under conditions that remove all protecting groups in a single reaction step (global deprotection). In some cases, PG ₁ and PG ₂ will be removed under the same conditions (e.g., treatment with strong acid). In other cases, the reaction will proceed in a stepwise fashion in such a way that it is not necessary to isolate a partially deprotected intermediate. A general example of such an approach is shown in Scheme 7 below.

Scheme 7

General Scheme 8

In certain cases, it may be desirable to introduce functionality at the 3-position of the heterocyclic core by means other than standard palladium-mediated reactivity. Photoredox catalysis can enable coupling between aryl bromides and alkyl bromides to form carbon-carbon bonds. A general example is shown in Scheme 8 below. A compound of Formula S1-3 may undergo a reaction with a compound of Formula S2-2, where R ¹ is an alkyl, cycloalkyl or heterocycloalkyl group. Such reactions typically proceed in the presence of an iridium catalyst, typically containing bipyridyl ligands to the iridium atom, such as Ir[dF(CF3)ppy]2(dtbbpy)PF6. Such reactions are also typically performed in the presence of a second metal precatalyst, such as nickel(II), and may also be performed in the presence of an additive such as tris(trimethylsilyl)silane. Such reactions are conducted with continuous exposure to a light source, typically blue LED light (wavelength range ca.400 nm to 500 nm). Photoredox reactions are performed in an appropriate solvent, such as ethylene glycol dimethyl ether, acetonitrile or diethyl ether. Reactions typically proceed at temperatures between 20 °C and 60 °C, with reaction times from 1 h to 72 h.

Subsequent reaction between a compound of Formula S3-1 and a nucleophile of Formula S5-1, under appropriate conditions as described herein, will furnish a compound of Formula S5- 2. Deprotection of an intermediate of Formula S5-2, as described herein, will afford a product of Formula S1-8.

Scheme 8

General Scheme 9

In certain cases, it may be desirable to introduce functionality at the 5-position of the heterocyclic core, such that U is a carbon atom and is substituted with R ⁵ . An appropriate protecting group, must first be introduced onto a compound of Formula S9-1, by reaction with an electrophile such as triisopropylsilyl chloride or 2-(trimethylsilyl)ethoxymethyl chloride, to generate an intermediate of Formula S9-2. A compound of Formula S9-2 may then be deprotonated specifically at the 5-position with a suitable strong base, such as sec-butyllithium or tert-butyllithium, and treated with an electrophile to furnish a compound of Formula S9-3. Suitable electrophiles may include methyl iodide, methyl chloroformate, methyl cyanoformate, carbon tetrabromide, or other such electrophiles known to one having ordinary skill in the art. Such reactions are performed in an appropriate solvent, such as tetrahydrofuran or diethyl ether, and typically proceed at temperatures between -78 °C and 0 °C, with reaction times from 1 h to 24 h. A general example of such site-selective alkylation is shown in Scheme 9 below. A person having ordinary skill in the art will understand that a compound of Formula S9-3 is a suitable intermediate for reactions of types shown in other general schemes as described herein. In one general example, shown in Scheme 9 below, a compound of Formula S9-2 is reacted with a nucleophile of Formula S5-1 to generate an intermediate of Formula S9-3. Subsequent selective bromination and reaction with a boronic acid or ester of Formula S1-6 will generate a protected intermediate of Formula S9-5. Deprotection of such an intermediate, as described herein, will afford a compound of Formula S9-7.

Scheme 9

General Scheme 10

A person having ordinary skill in the art will understand that, for a given compound of formula S10-1 bearing two reactive halogens, it may be possible to effect selective reactivity to distinguish between the two reactive sites. A general example of such selectivity is shown in Scheme 10 below.

A suitable protecting group may be introduced on a dichloride compound of Formula S10- 1 by methods described in previous general schemes. Subsequent reaction with a nucleophile of Formula S5-1, in an appropriate solvent and in the presence of a suitable base, will afford a compound of Formula S10-3 as the predominant product, as shown in Scheme 10.

Treatment of a compound of Formula S10-3 with an appropriate iodinating agent, such as N- iodosuccinimide, will lead to selective iodination to furnish a compound of Formula S10-4. A person having ordinary skill in the art will recognize that a reaction between an intermediate of Formula S10-4 and an electrophile of Formula S1-6 will occur predominantly at the iodinated site to afford a product of Formula S10-5. Subsequent deprotection of a compound of Formula S10- 5, as described herein, will furnish a compound of Formula S10-6.

Scheme 10

General Scheme 11

One having ordinary skill in the art will understand that an intermediate of Formula S10- 5 may be converted by reaction with a suitable nucleophile of Formula S11-1, such as a boronic acid or ester, to form a carbon-carbon bond and furnish a compound of Formula S11-2, as shown in Scheme 11 below, to form a carbon-carbon bond through a Suzuki reaction. These reactions proceed using an appropriate metal precatalyst, such as palladium(0), in the presence of a ligand, typically a phosphine compound, and in an appropriate solvent, such as 1,4-dioxane. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h. Such carbon-carbon bonds may alternatively be formed under similar conditions where the boron atom is replaced by another metal, such as magnesium or zinc. Subsequent deprotection of a compound of Formula S11-2, as described herein, will furnish a compound of Formula S11- 3.

Scheme 11

General Scheme 12

One having ordinary skill in the art will understand that an intermediate of Formula S10- 5 may be converted by reaction with a suitable nitrogen nucleophile of Formula S12-1 to form a carbon-nitrogen bond and generate a compound of Formula S12-2. Such reactions may be performed in the presence of a metal precatalyst, such as palladium(0), in the presence of a ligand, typically a phosphine compound, and in an appropriate solvent, such as 1,4-dioxane. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h.

Alternatively, a compound of Formula S12-2 may be prepared by a reaction between a compound of Formula 10-5 and an amine of Formula S12-1 under nucleophilic aromatic substitution conditions. Such reactions can proceed using an appropriate base, such as a hydride, carbonate or tertiary amine, and in an appropriate solvent, such as 1,4-dioxane or dimethyl sulfoxide. Reactions may also be performed in the absence of solvent. Reactions typically proceed at temperatures between 40 °C and 200 °C, with reaction times from 1 h to 72 h.

Subsequent deprotection of a compound of Formula S12-2, as described herein, will furnish a compound of Formula S12-3.

Scheme 12

E erimental Procedures

All synthetic chemistry was performed in standard laboratory glassware unless indicated otherwise in the examples. Commercial reagents were used as received. ¹ H NMR was performed on a Bruker Avance 300™ at 300 MHz or a Bruker Avance DRX™ 500 at 500 MHz. For complicated splitting patterns, the apparent splitting is tabulated. Microwave reactions were performed in a Biotage Initiator using the instrument software to control heating time and pressure. Analytical thin layer chromatography was performed on silica (Macherey-Nagel ALUGRAM Xtra SIL G, 0.2 mm, UV254 indicator or EMD TLC Silica Gel 60G, F254 indicator) and was visualized under UV light or by staining as indicated. Silica gel chromatography was performed manually, or with an Isco COMBIFLASH™ for gradient elutions. Preparative HPLC was performed using a Wufeng LC- 100™ instrument equipped with a Gemini™ 5 µm NX-C18 column, 100 x 30 mm.

Analytical LCMS Method A: Agilent 1200™ system with a variable wavelength detector and Agilent 6140™ single quadrupole mass spectrometer, alternating positive and negative ion scans. Retention times were determined from the extracted 220 nm UV chromatogram. HPLC column: Kinetex™, 2.6 µm, C18, 50 x 2.1 mm, maintained at 40 °C. HPLC Gradient: 1.0 mL/min, 95:5:0.1 water:acetonitrile:formic acid to 5:95:0.1 water:acetonitrile:formic acid in 2.0 min, maintaining for 0.5 min.

Analytical LCMS Method B: Shimadzu™ system with a variable wavelength detector and Shimadzu LCMS-2020™ single quadrupole mass spectrometer, alternating positive and negative ion scans. Retention times were determined from the extracted 220 nm UV chromatogram. HPLC column: Kinetex™, 2.6 µm, C18, 50 x 2.1 mm, maintained at 40 °C. HPLC Gradient: 1.0 mL/min, 95:5 water:acetonitrile (with 20 mM ammonium bicarbonate) to 20:80 water:acetonitrile (with 20 mM ammonium bicarbonate) in 2.0 min, maintaining for 0.5 min.

Analytical LCMS Method C: Shimadzu™ system with a variable wavelength detector and Shimadzu LCMS-2020 single quadrupole mass spectrometer, alternating positive and negative ion scans. Retention times were determined from the extracted 220 nm UV chromatogram. HPLC column: Kinetex™, 2.6 µm, C18, 50 x 2.1 mm, maintained at 40 °C. HPLC Gradient: 1.0 mL/min, 95:5 water:acetonitrile (with 10 mM ammonium carbonate) to 20:80 water:acetonitrile (with 10 mM ammonium carbonate) in 2.0 min, maintaining for 0.5 min.

Analytical LCMS Method D: Shimadzu™ system with a variable wavelength detector and Shimadzu LCMS-2020 single quadrupole mass spectrometer, alternating positive and negative ion scans. Retention times were determined from the extracted 220 nm UV chromatogram. HPLC column: Kinetex™, 2.6 µm, C18, 50 x 2.1 mm, maintained at 40 °C. HPLC Gradient: 1.0 mL/min, 95:5 water:acetonitrile (with 20 mM ammonium bicarbonate) to 20:80 water:acetonitrile (with 20 mM ammonium bicarbonate) in 1.5 min, maintaining for 3.0 min.

Analytical LCMS Method E: Shimadzu™ system with a variable wavelength detector and Shimadzu LCMS-2020™ single quadrupole mass spectrometer, alternating positive and negative ion scans. Retention times were determined from the extracted 220 nm UV chromatogram. HPLC column: Kinetex™, 2.6 µm, C18, 50 x 2.1 mm, maintained at 40 °C. HPLC Gradient: 1.0 mL/min, 95:5:0.1 water:acetonitrile:formic acid to 5:95:0.1 water:acetonitrile:formic acid in 2.0 min, maintaining for 0.5 min.

Analytical LCMS Method F: Shimadzu™ system with a variable wavelength detector and Shimadzu LCMS-2020™ single quadrupole mass spectrometer, alternating positive and negative ion scans. Retention times were determined from the extracted 220 nm UV chromatogram. HPLC column: Kinetex™, 2.6 µm, C18, 50 x 2.1 mm, maintained at 40 °C. HPLC Gradient: 1.0 mL/min, 95:5 water:acetonitrile (with 10 mM ammonium formate) to 20:80 water:acetonitrile (with 10 mM ammonium formate) in 2.0 min, maintaining for 0.5 min.

Analytical LCMS Method G: Agilent 1200™ system with a variable wavelength detector and Agilent 6140™ single quadrupole mass spectrometer, alternating positive and negative ion scans. Retention times were determined from the extracted 220 nm UV chromatogram. HPLC column: Kinetex™, 2.6 µm, C18, 50 x 2.1 mm, maintained at 40 °C. HPLC Gradient: 1.0 mL/min, 95:5 water:acetonitrile (with 10 mM ammonium formate) to 20:80 water:acetonitrile (with 10 mM ammonium formate) in 2.0 min, maintaining for 0.5 min.

Analytical LCMS Method H: Shimadzu™ system with a variable wavelength detector and Shimadzu LCMS-2020™ single quadrupole mass spectrometer, alternating positive and negative ion scans. Retention times were determined from the extracted 220 nm UV chromatogram. HPLC column: Kinetex™, 2.6 µm, C18, 50 x 2.1 mm, maintained at 40 °C. HPLC Gradient: 1.0 mL/min, 95:5 water:acetonitrile (with 10 mM ammonium formate) to 20:80 water:acetonitrile (with 10 mM ammonium formate) in 1.5 min, maintaining for 3.0 min.

Preparation 1: 3-Bromo-4-fluoro-1-((2-(trimethylsily dine

Step 1

3-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (P1-1a)

To a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (4.07 g, 29.9 mmol) in N,N- dimethylformamide (250 mL) was added N-bromosuccinimide (6.20 g, 34.8 mmol) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with water (200 mL) and the precipitate was collected to afford the title compound (4.06 g, 18.9 mmol, 63%) as an off-white solid.

LCMS Method A: 99%, t _R 1.328 min, m/z = 215.0 [M+H] ⁺

Step 2

3-Bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyr rolo[2,3-b]pyridine (P1-1) To a solution of 3-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (800 mg, 3.73 mmol) in dry N,N- dimethylformamide (8 mL) was added sodium hydride (60% dispersion in mineral oil, 224 mg, 5.59 mmol) in portions. To the reaction mixture was added 2-(trimethylsilyl)ethoxymethyl chloride (724 µL, 4.11 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. To the reaction mixture was added water (20 mL) and the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n- heptane: ethyl acetate (4:1) to afford the title compound (1.10 g, 3.19 mmol, 85%) as a pale yellow solid.

LCMS Method A: 95%, tR 2.067 min, m/z = 345.0 [M+H] ⁺ Preparation 2: N-(4-(4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrro lo[2,3-b]pyridin-3- yl)benzyl)methanesulfonamide

N-(4-(4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py rrolo[2,3-b]pyridin-3- yl)benzyl)methanesulfonamide (P2-1)

A mixture of 3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyr rolo[2,3- b]pyridine (766 mg, 2.26 mmol), (4-methanesulfonylaminomethylphenyl)boronic acid (554 mg, 2.42 mmol), [1,1¢-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80 mg, 0.109 mmol) and sodium bicarbonate (924 mg, 11.0 mmol) in a mixture of 1,4-dioxane (15.2 mL) and water (5 mL) was stirred at 100 °C for 20 h under argon atmosphere. The reaction mixture was evaporated and the residue was purified by silica gel chromatography eluting with dichloromethane:n- hexane (50:50 ^ 100:0). The crude product was purified by preparative HPLC to afford the title compound (400 mg, 0.890 mmol, 40%) as a colorless oil.

LCMS Method A: 100%, tR 1.874 min, m/z = 450.1 [M+H] ⁺ The following compounds were prepared by the same general method:

Preparation 3: 4-[4-Fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]py ridin-3-yl]-N- methylsulfonylbenzamide

Step 1

2-[[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrrolo[2,3-b]pyridin-1- yl]methoxy]ethyltrimethylsilane (P3-1a)

A mixture of 2-[(3-bromo-4-fluoropyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl - trimethylsilane (1.30 g, 3.76 mmol), bis(pinacolato)diboron (3.80 g, 15.1 mmol), 2- dicyclohexylphosphino-2¢,4¢,6¢-triisopropylbiphenyl (570 mg, 1.20 mmol), palladium(II) acetate (194 mg, 0.864 mmol) and triethylamine (2.1 mL, 15.0 mmol) in toluene (31 mL) was stirred at 120 °C for 16 h under argon. The reaction mixture was evaporated. The residue was purified by silica gel column chromatography eluting with heptanes:ethyl acetate (100:0 ^90:10) to give the title compound (1.15 g.2.93 mmol, 78%) as a pale yellow semi-solid.

LCMS Method D: 90%, tR=2.582 min, m/z = 393.3 [M+H] ⁺

Step 2 4-[4-Fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]py ridin-3-yl]-N- methylsulfonylbenzamide (P3-1)

A mixture of 2-[[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrrolo[2,3- b]pyridin-1-yl]methoxy]ethyltrimethylsilane (180 mg, 0.459 mmol), 2-(4-bromophenyl)-N- methylsulfonylacetamide (106 mg, 0.381 mmol), [1,1¢-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (15 mg, 0.021 mmol) and 2 M aqueous potassium carbonate (572 µL, 1.14 mmol) in 1,4-dioxane (3 mL) was stirred at 100 °C for 4 h under argon. The reaction mixture was evaporated. The residue was purified by silica gel column chromatography eluting with chloroform:methanol (100:2 ^10:1) to give the title compound (164 mg.0.354 mmol, 76%) as a brown oil.

LCMS Method B: 84%, t _R =1.972 min, m/z = 464.2 [M+H] ⁺ . The following compounds were prepared by the same general method:

Preparation 4: 2-[[3-Bromo-4-[(1,4-dimethyl-4-piperidyl)methoxy]pyrrolo[2,3 -b]pyridin-1- yl]methoxy]ethyltrimethylsilane

2-[[3-Bromo-4-[(1,4-dimethyl-4-piperidyl)methoxy]pyrrolo[ 2,3-b]pyridin-1- yl]methoxy]ethyltrimethylsilane (P4-1)

To a solution of (1,4-dimethyl-4-piperidyl)methanol (288 mg, 2.01 mmol) in dry dimethyl sulfoxide (6 mL) was added sodium hydride (60% dispersion in mineral oil, 88 mg, 2.20 mmol) and the reaction mixture was stirred at room temperature for 15 min. To the mixture was added a solution of 2-[(3-bromo-4-fluoropyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl trimethylsilane (347 mg, 1.00 mmol) in dry dimethyl sulfoxide (4 mL) and the reaction mixture was stirred at room temperature for 7 h. The reaction mixture was poured into ice water (100 mL). The mixture was extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with chloroform:methanol:triethylamine (100:2:1). The residue was partitioned between dichloromethane (20 mL) and water (10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound (290 mg, 0.619 mmol, 61%) as a pale yellow oil.

LCMS Method A: 93%, tR=1.307 min, m/z = 468.1 [M+H] ⁺

1H NMR (500 MHz, DMSO-d ₆ ) d 8.17 (d, J = 5.6 Hz, 1H), 7.65 (s, 1H), 6.78 (d, J = 5.6 Hz, 1H), 5.55 (s, 2H), 3.91 (s, 2H), 3.54– 3.45 (m, 2H), 2.47– 2.40 (m, 2H), 2.28– 2.20 (m, 2H), 2.18 (s, 3H), 1.69 (ddd, J = 13.2, 9.4, 3.8 Hz, 2H), 1.52– 1.44 (m, 2H), 1.12 (s, 3H), 0.81 (t, J = 8.0 Hz, 2H), -0.09 (s, 9H). The following compounds were prepared by the same general method:

Preparation 5: N-[(4-Bromophenyl)methylsulfonyl]acetamide

Step 1

(4-Bromophenyl)methanesulfonamide (P5-1a)

To a solution of (4-bromophenyl)methanesulfonyl chloride (250 mg, 0.927 mmol) in tetrahydrofuran (10 mL) was added 25% aqueous ammonium hydroxide (20 mL) at 0 °C. The reaction mixture was stirred at 5 °C for 1 h. The reaction mixture was concentrated to 20 mL under vacuum. The precipitate was collected and the solid was washed with water (2 x 2 mL) to give the title compound (206 mg, 0.823 mmol, 88%) as a white powder.

LCMS Method A: 100%, t _R =1.089 min, m/z = 248.0 [M-H]- Step 2

N-[(4-Bromophenyl)methylsulfonyl]acetamide (P5-1)

To a solution of (4-bromophenyl)methanesulfonamide (180 mg, 0.720 mmol) in pyridine (4.5 mL) was added acetic anhydride (204 µL, 2.16 mmol) and 4-(dimethylamino)pyridine (4.4 mg, 0.036 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated and the residue was triturated with water (10 mL) to give the title compound (182 mg, 0.625 mmol, 86%) as a white powder.

LCMS Method A: 100%, tR=1.183 min, m/z = 290.0 [M-H]- Preparation 6: 2-(4-Bromophenyl)-N-methylsulfonylacetamide

2-(4-Bromophenyl)-N-methylsulfonylacetamide (P6-1)

To a solution of 2-(4-bromophenyl)acetic acid (914 mg, 4.25 mmol) in dichloromethane (18 mL) was added 1,1¢-carbonyldiimidazole (1.38 g, 8.50 mmol). The reaction mixture was stirred at room temperature for 1 h. To the reaction mixture was added methanesulfonamide (808 mg, 8.50 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.27 mL, 8.50 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane (20 mL), washed with water (1 x 20 mL), 10% aqueous potassium bisulfate (1 x 20 mL) and water (1 x 20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was triturated with diethyl ether (10 mL) to give the title compound (798 mg, 2.73 mmol, 64%) as a white powder.

LCMS Method A: 100%, t _R =1.203 min, m/z = 290.0 [M-H]-.

Preparation 7: 1-[4-(Hydroxymethyl)-1-piperidyl]-3-methylbutan-1-one

1-[4-(Hydroxymethyl)-1-piperidyl]-3-methylbutan-1-one (P7-1)

To a solution of 4-piperidylmethanol (500 mg, 4.34 mmol) and N,N-diisopropylethylamine (1.50 mL, 8.68 mmol) in dichloromethane (20 mL) was added isovaleryl chloride (550 µL, 4.56 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The mixture was washed with water (1 x 20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound (823 mg, 4.12 mmol, 94%) as a yellow oil.

LCMS Method B: 96%, t _R =1.364 min, m/z = 200.1 [M+H] ⁺ . The following compounds were prepared by the same general method:

Preparation 8: (1,4-Dimethyl-4-piperidyl)methanol

(1,4-Dimethyl-4-piperidyl)methanol (P8-1)

To a solution of ethyl N-Boc-4-methylpiperidine-4-carboxylate (3.90 g, 14.4 mmol) in freshly distilled tetrahydrofuran (40 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran, 17.2 mL, 17.2 mmol) dropwise at room temperature under argon. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was heated to 60 °C for 16 h. The reaction was quenched by dropwise addition of 10% aqueous sodium carbonate (10 mL) at 10 °C. The mixture was filtered and the layers of the filtrate were separated. The organic layer was washed with brine (1 x 30 mL), dried over sodium sulfate, filtered and evaporated to give the title compound (1.79 g, 12.5 mmol, 87%) as a colorless oil.

LCMS Method B: low UV absorption, 100%, tR=0.209 min, m/z = 144.2 [M+H] ⁺

TLC: Rf=0.29, CHCl ₃ :MeOH:TEA = 100:10:1 (visualized by PMA)

1H NMR (300 MHz, Chloroform-d) d 3.39 (s, 2H), 2.65– 2.54 (m, 2H), 2.39– 2.24 (m, 2H), 2.34 (s, 3H), 1.70– 1.56 (m, 2H), 1.46– 1.35 (m, 2H), 0.96 (s, 3H). Preparation 9: 1-[4-(2-Hydroxyethyl)-1-piperidyl]ethanone

Step 1

Ethyl 2-(1-acetyl-4-piperidyl)acetate (P9-1a)

To a solution of ethyl 2-(4-piperidyl)acetate (500 mg, 2.92 mmol) in freshly distilled tetrahydrofuran (10 mL) was added pyridine (353 µL, 4.38 mmol) at room temperature. To the mixture was added a solution of acetyl chloride (310 µL, 4.38 mmol) in freshly distilled tetrahydrofuran (10 mL) dropwise while maintaining the temperature between 0-5 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound (560 mg, 2.62 mmol, 89%) as a colorless oil.

LCMS Method C: 97%, t _R =1.479 min, m/z = 214.2 [M+H] ⁺

Step 2

1-[4-(2-Hydroxyethyl)-1-piperidyl]ethanone (P9-1)

To a solution of ethyl 2-(1-acetyl-4-piperidyl)acetate (506 mg, 2.37 mmol) in freshly distilled tetrahydrofuran (13 mL) was added lithium borohydride (415 mg, 19.05 mmol) in three equal portions. The reaction mixture was stirred at 50 °C for 6 h. The reaction was quenched with 10% aqueous sodium carbonate (2 mL) and the mixture was stirred at room temperature for 1 h and evaporated. The residue was taken up in water (10 mL) and the mixture was neutralized by addition of acetic acid. The aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with chloroform:methanol (100:0 ^100:2) to give the title compound (190 mg.1.11 mmol, 47%) as a colorless oil.

LCMS Method C: 96%, tR=0.419 min, m/z = 172.3 [M+H] ⁺

The following compounds were prepared by the same general method:

Preparation 10: Ethyl 1-acetyl-4-methylpiperidine-4-carboxylate

Ethyl 1-acetyl-4-methylpiperidine-4-carboxylate (P10-1)

A solution of ethyl N-Boc-4-methylpiperidine-4-carboxylate (10.0 g, 36.8 mmol) and hydrogen chloride (4.2 M in 1,4-dioxane, 100 mL, 420 mmol) was stirred at room temperature for 1 h. The reaction mixture was evaporated and the residue was taken up in pyridine (150 mL). To the solution was added acetic anhydride (7.0 mL, 73.7 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated and the residue was partitioned between ethyl acetate (250 mL) and brine (100 mL). The aqueous layer was extracted with ethyl acetate (1 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (8.38 g, 39.3 mmol) as a pale yellow oil, which was used without purification.

LCMS Method B: 97%, tR=1.587 min, m/z = 214.1 [M+H] ⁺ Preparation 11: 1-[4-(Hydroxymethyl)-4-methyl-1-piperidyl]ethanone

1-[4-(Hydroxymethyl)-4-methyl-1-piperidyl]ethanone (P11-1)

To a solution of ethyl 1-acetyl-4-methylpiperidine-4-carboxylate (500 mg, 2.34 mmol) in freshly distilled tetrahydrofuran (13 mL) was added lithium borohydride (408 mg, 18.7 mmol) in three equal portions. The reaction mixture was stirred at 50 °C for 40 h. The reaction was quenched with 10% aqueous sodium carbonate (3 mL) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated to remove tetrahydrofuran, acidified to pH 4 by addition of 5% aqueous acetic acid (20 mL), and extracted with chloroform:isopropanol (3:1, 3 x 15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (350 mg.2.04 mmol, 87%) as a colorless oil.

LCMS Method B: 98%, tR=0.527 min, m/z = 172.2 [M+H] ⁺ Preparation 12: (1-Ethyl-4-methyl-4-piperidyl)methanol

(1-Ethyl-4-methyl-4-piperidyl)methanol (P12-1)

To a solution of ethyl 1-acetyl-4-methylpiperidine-4-carboxylate (100 mg, 0.583 mmol) in abs. tetrahydrofuran (1 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran, 670 µL, 0.670 mmol) dropwise at 0 °C under argon atmosphere. The reaction mixture was stirred at 0 °C for 30 min. The reaction was quenched by dropwise addition of 10% aqueous sodium carbonate (2 mL) at 10 °C. The mixture was diluted with water (5 mL) and ethyl acetate (5 mL) and filtered. The layers of the filtrate were separated. The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound (47 mg, 0.299 mmol, 51%) as a yellow oil, which was used without purification.

LCMS Method B: low UV absorption, 42%, t _R =0.229 min, m/z = 158.2 [M+H] ⁺ . Preparation 13: 2-[(5-Bromo-4-fluoropyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl trimethylsilane

Step 1

(4-Fluoropyrrolo[2,3-b]pyridin-1-yl)-triisopropylsilane (P13-1a)

To a suspension of sodium hydride (60% dispersion in mineral oil, 2.14 g, 53.5 mmol) in dry N,N-dimethylformamide (30 mL) was added a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (5.77 g, 42.46 mmol) in dry N,N-dimethylformamide (58 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 15 min. To the mixture was added a solution of triisopropylsilyl chloride (10 mL, 46.71 mmol) in dry N,N-dimethylformamide (12 mL) dropwise at 0 °C over 30 min. The reaction mixture was allowed to warm to room temperature and the mixture was stirred at room temperature for 42 h. The reaction mixture was poured into ice water (800 mL) and the mixture was extracted with dichloromethane (4 x 200 mL). The combined organic layers were washed with water (2 x 200 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (8.51 g, 29.14 mmol, 68%) as a pale yellow liquid. LCMS Method A: 99%, tR=2.242 min, m/z = 293.2 [M+H] ⁺ .

Step 2

(5-Bromo-4-fluoropyrrolo[2,3-b]pyridin-1-yl)-triisopropyl silane (P13-1b)

To a solution of (4-fluoropyrrolo[2,3-b]pyridin-1-yl)-triisopropylsilane (1.0 g, 3.43 mmol) in distilled tetrahydrofuran (25 mL) was added sec-butyllithium (1.4 M in cyclohexane, 5.38 mL, 7.53 mmol) dropwise at -78 °C over 15 min under argon. The mixture was stirred at -78 °C for 30 min. To the reaction mixture was added a solution of carbon tetrabromide (2.84 g, 8.46 mmol) in distilled tetrahydrofuran (12.5 mL) dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and the mixture was extracted with n-heptane (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n-heptane to afford the title compound (1.11 g, 3.00 mmol, 87%) as a white crystalline solid.

LCMS Method H: 100%, t _R =3.850 min, m/z = 371.0 [M+H] ⁺

Step 3

5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (P13-1c)

To a solution of (5-bromo-4-fluoropyrrolo[2,3-b]pyridin-1-yl)-triisopropylsil ane (2.40 g, 6.49 mmol) in distilled tetrahydrofuran (24 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 6.50 mL, 6.50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (1.19 g, 5.53 mmol, 85%) as a pale yellow crystalline solid.

LCMS Method A: 99%, tR=1.319 min, m/z = 215.0 [M+H] ⁺

Step 4

2-[(5-Bromo-4-fluoropyrrolo[2,3-b]pyridin-1-yl)methoxy]et hyltrimethylsilane (P13-1)

To a suspension of sodium hydride (60% dispersion in mineral oil, 129 mg, 3.22 mmol) in dry N,N-dimethylformamide (2 mL) was added a solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3- b]pyridine (552 mg, 2.58 mmol) in dry N,N-dimethylformamide (5.5 mL) dropwise at 0 °C over 5 min. The mixture was stirred at 0 °C for 20 min. To the mixture was added a solution of (2- chloromethoxyethyl)trimethylsilane (500 µL, 2.84 mmol) in dry N,N-dimethylformamide (1 mL) dropwise at 0 °C over 10 min. The reaction mixture was stirred at 0 °C for 2 h. The mixture was poured into ice water (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 85:15) to afford the title compound (703 mg, 2.04 mmol, 79%) as a colorless liquid. LCMS Method A: 98%, t _R =1.972 min, m/z = 345.1 [M+H] ⁺

1H NMR (500 MHz, DMSO-d ₆ ) d 8.45 (d, J = 8.9 Hz, 1H), 7.77 (d, J = 3.6 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 5.63 (s, 2H), 3.51 (t, J = 7.9 Hz, 2H), 0.81 (t, J = 8.0 Hz, 2H), -0.11 (s, 9H). Preparation 14: 4-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyra zolo[3,4-b]pyridine

Step 1

4-Chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (P14-1a)

To a solution of 4-chloro-1H-pyrazolo[3,4-b]pyridine (2.00 g, 13.07 mmol) in dry N,N- dimethylformamide (17 mL) was added a solution of N-iodosuccinimide (3.24 g, 14.38 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was poured into water (300 mL). The precipitate was collected and the solid was washed with water (100 mL) to afford the title compound (3.08 g, 11.04 mmol, 85%) as a yellow powder.

LCMS Method F: 88%, tR=1.780 min, m/z = 279.1 [M+H] ⁺

Step 2

4-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-p yrazolo[3,4-b]pyridine (P14-1)

To a suspension of sodium hydride (60% dispersion in mineral oil, 560 mg, 13.98 mmol) in dry N,N-dimethylformamide (14 mL) was added a solution of 4-chloro-3-iodo-1H-pyrazolo[3,4- b]pyridine (3.00 g, 10.75 mmol) in dry N,N-dimethylformamide (50 mL) dropwise at 5 °C. The mixture was stirred at 5 °C for 30 min. To the mixture was added a solution of (2- (chloromethoxy)ethyl)trimethylsilane (2.1 mL, 11.83 mmol) in dry N,N-dimethylformamide (7 mL) the reaction mixture was stirred at 5 °C for 2 h. The reaction was quenched with water (720 mL) and the mixture was extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over magnesium sulfate and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (2.26 g, 5.52 mmol, 51%) as an off-white powder. LCMS Method F: 90%, tR=2.932 min, m/z = 410.0 [M+H] ⁺ Preparation 15: t Butyl 4-[[3-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]py ridin-4-

yl]methoxy]piperidine-1-carboxylate

Step 1

Methyl 1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-4-car boxylate (P15-1a)

To a suspension of sodium hydride (60% dispersion in mineral oil, 198 mg, 4.95 mmol) in dry N,N-dimethylformamide (2 mL) was added a solution of methyl 1H-pyrrolo[2,3-b]pyridine-4- carboxylate (700 mg, 3.97 mmol) in dry N,N-dimethylformamide (7 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 20 min. To the mixture was added a solution of (2- (chloromethoxy)ethyl)trimethylsilane (770 mL, 4.37 mmol) in dry N,N-dimethylformamide (2 mL) and the reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (100 mL) and the mixture was extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 80:20) to afford the title compound (1.05 g, 3.43 mmol, 86%) as a pale yellow oil.

LCMS Method A: 89%, tR=1.750 min, m/z = 307.2 [M+H] ⁺

Step 2

[1-(2-Trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4- yl]methanol (P15-1b)

To a solution of methyl 1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-4- carboxylate (1.05 g, 3.43 mmol) in freshly distilled tetrahydrofuran (10 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran, 3.95 mL, 3.95 mmol) dropwise at 0 °C under argon. The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with 10% aqueous sodium carbonate solution (1.5 mL). The mixture was diluted with ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (1 x 10 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (460 mg, 1.65 mmol, 48%) as a pale yellow oil.

LCMS Method A: 100%, tR=1.379 min, m/z = 279.2 [M+H] ⁺

Step 3

2-[[4-(Bromomethyl)pyrrolo[2,3-b]pyridin-1-yl]methoxy]eth yltrimethylsilane (P15-1c)

To a solution of [1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl] methanol (460 mg, 1.66 mmol) and triphenylphosphine (434 mg, 1.66 mmol) in anhydrous dichloromethane (12 mL) was added carbon tetrabromide (823 mg, 2.48 mmol) and the reaction mixture was stirred at room temperature for 18 h. To the reaction mixture was added carbon tetrabromide (274 mg, 0.83 mmol) and triphenylphosphine (217 mg, 0.83 mmol) and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (372 mg, 1.09 mmol, 66%) as a pale yellow oil.

LCMS Method A: 97%, t _R =1.814 min, m/z = 341.1 [M+H] ⁺

Step 4 tert-Butyl 4-[[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4- yl]methoxy]piperidine-1- carboxylate (P15-1d)

To a suspension of sodium hydride (60% dispersion in mineral oil, 117 mg, 2.92 mmol) in dry N,N-dimethylformamide (4 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (401 mg, 1.99 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. To the mixture was added a solution of 2-[[4-(bromomethyl)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethylt rimethylsilane (452 mg.1.33 mmol) in dry N,N-dimethylformamide (4.5 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (90 mL) and the mixture was extracted with a mixture of chloroform:isopropyl alcohol (3:1, 3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 80:20) to afford the title compound (375 mg, 0.81 mmol, 61%) as a yellow oil.

LCMS Method A: 96%, tR=1.959 min, m/z = 462.4 [M+H] ⁺

Step 5

tert-Butyl 4-[[3-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]py ridin-4- yl]methoxy]piperidine-1-carboxylate (P15-1)

To a solution of tert-butyl 4-[[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4- yl]methoxy]piperidine-1-carboxylate (375 mg, 0.810 mmol) in dry N,N-dimethylformamide (4 mL) was added a solution of N-bromosuccinimide (159 mg, 0.89 mmol) in dry N,N- dimethylformamide (1.5 mL) dropwise at -10 °C. The reaction mixture was allowed to warm to room temperature and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water (60 mL) and the mixture was extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford the title compound (300 mg, 0.550 mmol, 68%) as a pale yellow oil.

LCMS Method A: 92%, t _R =2.112 min, m/z = 540.2 [M+H] ⁺ Preparation 16: tert-Butyl 4-[[6-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)pyrrolo[ 2,3- b]pyridin-4-yl]oxymethyl]piperidine-1-carboxylate

Step 1

2-[(4,6-Dichloropyrrolo[2,3-b]pyridin-1-yl)methoxy]ethylt rimethylsilane (P16-1a)

To a suspension of sodium hydride (60% dispersion in mineral oil, 1.07 g, 26.80 mmol) in dry N,N-dimethylformamide (10 mL) was added a solution of 4,6-dichloro-1H-pyrrolo[2,3- b]pyridine (4.0 g, 21.39 mmol) in dry N,N-dimethylformamide (40 mL) dropwise at 0 °C over 20 min. The mixture was stirred at 0 °C for 20 min. To the mixture was added a solution of (2- chloromethoxyethyl)trimethylsilane (4.15 mL, 23.53 mmol) in dry N,N-dimethylformamide (4 mL) dropwise at 0 °C over 10 min. The reaction mixture was stirred at 0 °C for 4 h. The reaction mixture was poured into ice water (600 mL) and the mixture was extracted with dichloromethane (4 x 100 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 80:20) to afford the title compound (3.85 g, 12.18 mmol, 57%) as a colorless oil.

LCMS Method A: 99%, t _R =2.051 min, m/z = 317.1 [M+H] ⁺

Step 2

tert-Butyl 4-[[6-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]p yridin-4- yl]oxymethyl]piperidine-1-carboxylate (P16-1b)

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.04 g, 9.49 mmol) in anhydrous dimethyl sulfoxide (20 mL) was added sodium hydride (60% dispersion in mineral oil, 401 mg, 10.0 mmol) and the mixture was stirred at room temperature for 30 min. To the mixture was added a solution of 2-[(4,6-dichloropyrrolo[2,3-b]pyridin-1- yl)methoxy]ethyltrimethylsilane (1.5 g, 4.75 mmol) in anhydrous dimethyl sulfoxide (15 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (350 mL) and the mixture was extracted with a mixture of chloroform:isopropyl alcohol (3:1, 4 x 80 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 75:25) to afford the title compound (2.32 g, 4.69 mmol, 98%) as a white semi-solid.

LCMS Method A: 90%, tR=2.161 min, m/z = 496.2 [M+H] ⁺

Step 3

tert-Butyl 4-[[6-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)pyrrolo[ 2,3-b]pyridin-4- yl]oxymethyl]piperidine-1-carboxylate (P16-1)

To a solution of tert-butyl 4-[[6-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridin-4-yl]oxymethyl]piperidine-1-carboxylate (1.0 g, 2.02 mmol) in dry N,N- dimethylformamide (10 mL) was added a solution of N-iodosuccinimide (500 mg, 2.22 mmol) in dry N,N-dimethylformamide (5 mL) dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and the mixture was stirred at room temperature for 2 h. To the reaction mixture was added a solution of N-iodosuccinimide (227 mg, 1.01 mmol) in dry N,N- dimethylformamide (1 mL) dropwise at room temperature and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (150 mL) and the mixture was extracted with dichloromethane (3 x 60 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 90:10) to afford the title compound (1.01 g, 1.63 mmol, 81%) as a pale yellow crystalline solid.

LCMS Method A: 98%, tR=2.274 min, m/z = 622.1 [M+H] ⁺ Preparation 17: t Butyl 4-[[3-bromo-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrrolo [2,3-

b]pyridin-4-yl]oxymethyl]-4-methylpiperidine-1-carboxylat e

Step 1

4-Fluoro-5-methylpyrrolo[2,3-b]pyridin-1-yl)-triisopropyl silane (P17-1a)

To a solution of (4-fluoropyrrolo[2,3-b]pyridin-1-yl)-triisopropylsilane (3.00 g, 10.27 mmol) in freshly distilled tetrahydrofuran (75 mL) was added sec-butyllithium (1.4 M in cyclohexane, 16.14 mL, 22.6 mmol) dropwise at -78 °C over 30 min. To the mixture was added a solution of iodomethane (3.2 mL, 51.4 mmol) in freshly distilled tetrahydrofuran (30 mL) dropwise at -78 °C over 30 min. The reaction mixture was stirred at -78 °C for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and the mixture was extracted with n-heptane (3 x 80 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n-heptane to afford the title compound (2.69 g, 8.78 mmol, 85%) as a white crystalline solid.

LCMS Method A: 93%, tR=2.320 min, m/z = 307.3 [M+H] ⁺

Step 2

4-Fluoro-5-methyl-1H-pyrrolo[2,3-b]pyridine (P17-1b)

To a solution of 4-fluoro-5-methylpyrrolo[2,3-b]pyridin-1-yl)-triisopropylsil ane (2.69 g, 8.79 mmol) in freshly distilled tetrahydrofuran (30 mL) was added tetrabutylammonium fluoride (2.30 g, 8.79 mmol) and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (1.27 g, 8.447 mmol, 96%) as an off-white crystalline solid.

LCMS Method A: 93%, t _R =0.830 min, m/z = 151.1 [M+H] ⁺

1H NMR (500 MHz, DMSO-d ₆ ) d 11.82 (s, 1H), 8.10 (d, J = 10.0 Hz, 1H), 7.45 (d, J = 3.5 Hz, 1H), 6.46 (d, J = 3.4 Hz, 1H), 2.30 (s, 3H).

Step 3

3-Bromo-4-fluoro-5-methyl-1H-pyrrolo[2,3-b]pyridine (P17-1c)

To a solution of 4-fluoro-5-methyl-1H-pyrrolo[2,3-b]pyridine (1.00 g, 6.67 mmol) in dry N,N-dimethylformamide (10 mL) was added a solution of N-bromosuccinimide (1.31 g, 7.33 mmol) in dry N,N-dimethylformamide (10 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The mixture was poured into water (300 mL) and the precipitate was collected. The solid was washed with water (2 x 30 mL) and dried under air to afford the title compound (1.37 g, 6.02 mmol, 90%) as a pale yellow crystalline solid.

LCMS Method A: 95%, t _R =1.351 min, m/z = 229.0 [M+H] ⁺

Step 4

2-[(3-Bromo-4-fluoro-5-methylpyrrolo[2,3-b]pyridin-1-yl)m ethoxy]ethyltrimethylsilane (P17-1d) To a suspension of sodium hydride (60% dispersion in mineral oil, 301 mg, 7.52 mmol) in dry N,N-dimethylformamide (6 mL) was added a solution of 3-bromo-4-fluoro-5-methyl-1H- pyrrolo[2,3-b]pyridine (1.37 g, 6.02 mmol) in dry N,N-dimethylformamide (13 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 20 min. To the mixture was added a solution of (2- (chloromethoxy)ethyl)trimethylsilane (1.17 mL, 6.62 mmol) in dry N,N-dimethylformamide (3 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h and then poured into water (250 mL). The mixture was extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 90:10) to afford the title compound (1.62 g, 4.53 mmol, 75%) as a pale yellow crystalline solid.

LCMS Method A: 96%, tR=1.985 min, m/z = 359.1 [M+H] ⁺

Step 5

tert-Butyl 4-[[3-bromo-5-methyl-1-(2-trimethylsilylethoxymethyl)pyrrolo [2,3-b]pyridin-4- yl]oxymethyl]-4-methylpiperidine-1-carboxylate (P17-1)

To a solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (287 mg, 1.25 mmol) in anhydrous dimethyl sulfoxide (2.8 mL) was added sodium hydride (60% dispersion in mineral oil, 53 mg, 1.32 mmol) and the reaction mixture was stirred at room temperature for 30 min. To the mixture was added a solution of 2-[(3-bromo-4-fluoro-5-methylpyrrolo[2,3- b]pyridin-1-yl)methoxy]ethyltrimethylsilane (224 mg, 0.630 mmol) in anhydrous dimethyl sulfoxide (2.2 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and the mixture was extracted with a mixture of chloroform:isopropyl alcohol (3:1, 3 x 100 mL). The combined organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 80:20) to afford the title compound (173 mg, 0.305 mmol, 49%) as a colorless oil.

LCMS Method A: 98%, tR=2.251 min, m/z = 568.2 [M+H] ⁺

1H NMR (500 MHz, DMSO-d6) d 8.17 (s, 1H), 7.77 (s, 1H), 5.56 (s, 2H), 3.81 (s, 2H), 3.74– 3.65 (m, 2H), 3.54– 3.48 (m, 2H), 3.20– 3.06 (m, 2H), 2.31 (s, 3H), 1.74– 1.65 (m, 2H), 1.48– 1.42 (m, 2H), 1.41 (s, 9H), 1.19 (s, 3H), 0.84– 0.79 (m, 2H), -0.09 (s, 9H). Preparation 18: Methyl 3-bromo-4-[(1-tert-butoxycarbonyl-4-pip ]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxyl ate

Step 1

Methyl 4-fluoro-1-triisopropylsilylpyrrolo[2,3-b]pyridine-5-carboxy late (P18-1a)

To a solution of 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.93 g, 20.31 mmol) in distilled tetrahydrofuran (120 mL) was added sec-butyllithium (1.4 M in cyclohexane, 32 mL, 44.8 mmol) dropwise at -78 °C over 30 min under argon. The mixture was stirred at -78 °C for 30 min. To the mixture was added a solution of methyl chloroformate (4.7 mL, 60.7 mmol) in distilled tetrahydrofuran (50 mL) dropwise at -78 °C over 45 min. The reaction mixture was stirred at -78 °C for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (120 mL) and the mixture was extracted with n-heptane (2 x 120 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 95:5) to afford the title compound (3.26 g, 9.30 mmol, 46%) as a pale yellow oil.

LCMS Method A: 81%, tR=2.183 min, m/z = 351.2 [M+H] ⁺

Step 2

Methyl 4-fluoro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (P18-1b)

To a solution of methyl 4-fluoro-1-triisopropylsilylpyrrolo[2,3-b]pyridine-5-carboxy late (527 mg, 1.50 mmol) in distilled tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 1.50 mL, 1.50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The mixture was poured into water (50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 30 mL) and the combined organic layers were washed with brine (3 x 30 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 0:100) to afford the title compound (244 mg, 1.25 mmol, 83%) as an off-white crystalline solid.

LCMS Method A: 96%, tR=1.110 min, m/z = 195.1 [M+H] ⁺

Step 3

Methyl 3-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (P18-1c)

To a suspension of methyl 4-fluoro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.10 g, 5.67 mmol) in dry N,N-dimethylformamide (11 mL) was added a solution of N-bromosuccinimide (1.11 g, 6.24 mmol) in dry N,N-dimethylformamide (11 mL) dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and the mixture was stirred for 1 h. The reaction mixture was poured into ice water (300 mL) and the mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n- heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (1.16 g, 4.26 mmol, 75%) as an off-white crystalline solid.

LCMS Method A: 93%, tR=1.293 min, m/z = 273.0 [M+H] ⁺

Step 4

Methyl 3-bromo-4-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3 -b]pyridine-5-carboxylate (P18-1d)

To a suspension of sodium hydride (60% dispersion in mineral oil, 218 mg, 5.45 mmol) in dry N,N-dimethylformamide (2 mL) was added a solution of methyl 3-bromo-4-fluoro-1H- pyrrolo[2,3-b]pyridine-5-carboxylate (1.19 g, 4.38 mmol) in dry N,N-dimethylformamide (12 mL) dropwise at 0 °C over 5 min. The mixture was stirred at 0 °C for 20 min. To the mixture was added a solution of (2-chloromethoxyethyl)trimethylsilane (848 µL, 4.81 mmol) in dry N,N- dimethylformamide (2 mL) dropwise at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into ice water (200 mL) and the mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 90:10) to afford the title compound (1.22 g, 3.04 mmol, 69%) as an off-white crystalline solid.

LCMS Method A: 98%, tR=1.903 min, m/z = 403.1 [M+H] ⁺

Step 5

Methyl 3-bromo-4-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxyl ate (P18-1)

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (980 mg, 4.55 mmol) in anhydrous dimethyl sulfoxide (10 mL) was added sodium hydride (60% dispersion in mineral oil, 256 mg, 6.40 mmol) at room temperature and the mixture was stirred at room temperature for 30 min. To the mixture was added a solution of methyl 3-bromo-4-fluoro-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxyl ate (1.22 g, 3.04 mmol) in anhydrous dimethyl sulfoxide (12 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (220 mL) and the mixture was extracted with a mixture of chloroform:isopropyl alcohol (3:1, 3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (370 mg, 0.62 mmol, 20%) as a pale yellow oil. LCMS Method A: 94%, t _R =2.312 min, m/z = 681.3 [M+H] ⁺

1H NMR (300 MHz, DMSO-d6) d 8.63 (s, 1H), 7.90 (s, 1H), 5.59 (s, 2H), 4.18 (d, J = 6.4 Hz, 2H), 3.99 (t, J = 9.3 Hz, 4H), 3.52 (dd, J = 8.5, 7.4 Hz, 2H), 2.73 (s, 2H), 2.20– 1.87 (m, 2H), 1.84– 1.67 (m, 2H), 1.45– 1.35 (m, 9H), 1.27– 1.20 (m, 2H), 0.84– 0.77 (m, 2H), -0.10 (s, 9H). Preparation 19: t Butyl 4-[2-[3-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b] pyridin-

4-yl]ethyl]piperidine-1-carboxylate

Step 1

tert-Butyl 4-[2-[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 4-yl]ethyl]piperidine-1- carboxylate (P19-1a)

A solution of nickel(II) chloride ethylene glycol dimethyl ether complex (40 mg, 0.18 mmol) and 4,4’-di-tert-butyl-2,2’-bipyridine (49 mg, 0.18 mmol) in 1,2-dimethoxyethane (16 mL) was stirred at room temperature for 10 min under argon.

To a solution of 4-bromo-1-(2-trimethylsilylethoxymethyl)-1H-pyrrolo[2,3-b]py ridine (600 mg, 1.84 mmol) in 1,2-dimethoxyethane (28 mL) was added tert-butyl 4-(2-bromoethyl)piperidine-1- carboxylate (803 mg, 2.76 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (41 mg, 0.04 mmol), anhydrous lithium hydroxide (88 mg, 3.68 mmol) and tris(trimethylsilyl)silane (568 µL, 1.84 mmol). To the mixture was added the solution of nickel(II) chloride ethylene glycol dimethyl ether complex and 4,4’-di-tert-butyl-2,2’-bipyridine in 1,2-dimethoxyethane via cannula. The reaction mixture was stirred at room temperature for 18 h irradiated by blue LED light (Optonica ST4825 blue LED strip, 35W, cooled with a fan). The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (516 mg, 1.12 mmol, 61%) as a colorless oil.

LCMS Method A: 90%, t _R =2.072 min, m/z = 460.4 [M+H] ⁺

Step 2 tert-Butyl 4-[2-[3-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b] pyridin-4- yl]ethyl]piperidine-1-carboxylate (P19-1)

To a solution of tert-butyl 4-[2-[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin- 4- yl]ethyl]piperidine-1-carboxylate (490 mg, 1.07 mmol) in dry N,N-dimethylformamide (4.9 mL) was added a solution of N-bromosuccinimide (209 mg, 1.17 mmol) in dry N,N- dimethylformamide (2 mL) dropwise at -10 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into water (70 mL) and the mixture was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford the title compound (337 mg, 2.24 mmol, 59%) as a pale yellow oil.

LCMS Method A: 91%, t _R =2.242 min, m/z = 538.2 [M+H] ⁺ Preparation 20: tert-Butyl 4-[[3-bromo-5-cyclohexyl-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]-4-methylpiperidine-1- carboxylate

Step 1

2-[(5-Cyclohexyl-4-fluoropyrrolo[2,3-b]pyridin-1-yl)metho xy]ethyltrimethylsilane (P20-1a)

A solution of nickel(II) chloride ethylene glycol dimethyl ether complex (38 mg, 0.17 mmol) and 4,4’-di-tert-butyl-2,2’-bipyridine (47 mg, 0.17 mmol) in 1,2-dimethoxyethane (16 mL) was stirred at room temperature for 10 min under argon.

To a solution of 2-[(5-bromo-4-fluoropyrrolo[2,3-b]pyridin-1- yl)methoxy]ethyltrimethylsilane (600 mg, 1.74 mmol) in 1,2-dimethoxyethane (28 mL) was added bromocyclohexane (320 µL, 2.62 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (39 mg, 0.04 mmol), anhydrous lithium hydroxide (84 mg, 3.49 mmol) and tris(trimethylsilyl)silane (538 µL, 1.74 mmol). To the mixture was added the solution of nickel(II) chloride ethylene glycol dimethyl ether complex and 4,4’-di-tert-butyl-2,2’-bipyridine in 1,2-dimethoxyethane via cannula. The reaction mixture was stirred at room temperature for 18 h irradiated by blue LED light (Optonica ST4825 blue LED strip, 35W, cooled with a fan). The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 80:20) to afford the title compound (395 mg, crude) as a pale yellow oil, which was used without further purification.

LCMS Method A: 45%, tR=2.195 min, m/z = 349.2 [M+H] ⁺

Step 2

tert-Butyl 4-[[5-cyclohexyl-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3 -b]pyridin-4- yl]oxymethyl]-4-methylpiperidine-1-carboxylate (P20-1b)

To a solution of crude tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (390 mg) in anhydrous dimethyl sulfoxide (4 mL) was added sodium hydride (60% dispersion in mineral oil, 96 mg, 2.40 mmol) at room temperature and the mixture was stirred at room temperature for 30 min. To the mixture was added a solution of 2-[(5-cyclohexyl-4- fluoropyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyltrimethylsilan e (395 mg, 1.14 mmol) in anhydrous dimethyl sulfoxide (4 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (80 mL) and the mixture was extracted with a mixture of dichloromethane:isopropyl alcohol (3:1, 3 x 80 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 60:40) to afford the title compound (75 mg, 0.14 mmol, 8% over two steps) as a colorless oil.

LCMS Method A: 95%, tR=2.176 min, m/z = 558.4 [M+H] ⁺

Step 3

tert-Butyl 4-[[3-bromo-5-cyclohexyl-1-(2-trimethylsilylethoxymethyl)pyr rolo[2,3-b]pyridin-4- yl]oxymethyl]-4-methylpiperidine-1-carboxylate (P20-1)

To a solution of tert-butyl 4-[[5-cyclohexyl-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3 - b]pyridin-4-yl]oxymethyl]-4-methylpiperidine-1-carboxylate (75 mg, 0.13 mmol) in dry N,N- dimethylformamide (750 µL) was added a solution of N-bromosuccinimide (26 mg, 0.15 mmol) in dry N,N-dimethylformamide (250 µL) dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and the mixture was stirred for 1 h at room temperature. The reaction mixture was poured into ice water (10 mL) and the mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 90:10) to afford the title compound (44 mg, 0.07 mmol, 52%) as a pale yellow oil.

LCMS Method A: 92%, t _R =2.440 min, m/z = 636.3 [M+H] ⁺ Preparation 21: tert-Butyl 4-[[3-bromo-5-(1-methylsulfonyl-4-piperidyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]-4-methylpiperidine-1- carboxylate

Step 1

2-[[4-Fluoro-5-(1-methylsulfonyl-4-piperidyl)pyrrolo[2,3- b]pyridin-1- yl]methoxy]ethyltrimethylsilane (P21-1a) A solution of nickel(II) chloride ethylene glycol dimethyl ether complex (44 mg, 0.20 mmol) and 4,4’-di-tert-butyl-2,2’-bipyridine (54 mg, 0.20 mmol) in 1,2-dimethoxyethane (10 mL) was stirred at room temperature for 10 min under argon.

To a solution of 2-[(5-bromo-4-fluoropyrrolo[2,3-b]pyridin-1- yl)methoxy]ethyltrimethylsilane (693 mg, 2.01 mmol) in 1,2-dimethoxyethane (50 mL) was added 4-bromo-1-(methylsulfonyl)piperidine (728 mg, 3.02 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (45 mg, 0.04 mmol), anhydrous lithium hydroxide (96 mg, 4.03 mmol) and tris(trimethylsilyl)silane (621 µL, 2.01 mmol). To the mixture was added the solution of nickel(II) chloride ethylene glycol dimethyl ether complex and 4,4’-di-tert-butyl-2,2’-bipyridine in 1,2-dimethoxyethane via cannula. The reaction mixture was stirred at room temperature for 18 h irradiated by blue LED light (Optonica ST4825 blue LED strip, 35W, cooled with a fan). The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (306 mg, 0.72 mmol, 36%) as a yellow crystalline solid.

LCMS Method A: 99%, t _R =1.745 min, m/z = 428.3 [M+H] ⁺

Step 2

2-[[3-Bromo-4-fluoro-5-(1-methylsulfonyl-4-piperidyl)pyrr olo[2,3-b]pyridin-1- yl]methoxy]ethyltrimethylsilane

To a solution of 2-[[4-fluoro-5-(1-methylsulfonyl-4-piperidyl)pyrrolo[2,3-b]p yridin-1- yl]methoxy]ethyltrimethylsilane (296 mg, 0.69 mmol) in dry N,N-dimethylformamide (2 mL) was added a solution of N-bromosuccinimide (136 mg, 0.76 mmol) in dry N,N-dimethylformamide (2 mL) dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and the mixture was stirred for 1 h. The reaction mixture was poured into ice water (40 mL) and the mixture was extracted with dichloromethane (3 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 60:40) to afford the title compound (220 mg, 0.44 mmol, 63%) as a pale yellow oil.

LCMS Method A: 99%, t _R =1.872 min, m/z = 506.1 [M+H] ⁺

Step 3

tert-Butyl 4-[[3-bromo-5-(1-methylsulfonyl-4-piperidyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]-4-methylpiperidine-1- carboxylate (P21-1) To a solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (150 mg, 0.650 mmol) in anhydrous dimethyl sulfoxide (1.5 mL) was added sodium hydride (60% dispersion in mineral oil, 37 mg, 0.92 mmol) at room temperature. The mixture was stirred at room temperature for 30 min. To the mixture was added a solution of 2-[[3-bromo-4-fluoro-5- (1-methylsulfonyl-4-piperidyl)pyrrolo[2,3-b]pyridin-1-yl]met hoxy]ethyltrimethylsilane (220 mg, 0.440 mmol) in anhydrous dimethyl sulfoxide (2 mL) and the reaction mixture was stirred at room temperature for 5 h. The mixture was poured into ice water (40 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (167 mg, 0.230 mmol, 54%) as a pale yellow oil.

LCMS Method: 96%, t _R =2.109 min, m/z = 715.3 [M+H] ⁺ Preparation 22: 4-Bromo-1-(difluoromethyl)-2-methoxybenzene

4-Bromo-1-(difluoromethyl)-2-methoxybenzene (P22-1)

To a solution of 4-bromo-2-methoxybenzaldehyde (1.0 g, 4.6 mmol) in anhydrous dichloromethane (4.7 mL) was added N-ethyl-N-(trifluoromethylsulfanyl)ethanamine (1.84 mL, 13.91 mmol) and anhydrous ethanol (500 µL) and the reaction mixture was stirred at room temperature for 48 h. The reaction was quenched with 2M aqueous sodium hydroxide (4.5 mL) at 0 °C. The mixture was extracted with dichloromethane (3 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with n-heptane to afford the title compound (529 mg, 2.24 mmol, 48%) as a colorless oil.

LCMS Method F: 100%, tR=2.348 min, no ion

1H NMR (300 MHz, Chloroform-d) d 7.44 (d, J = 8.1 Hz, 1H), 7.31– 7.14 (m, 1H), 7.13– 7.09 (m, 1H), 6.80 (t, J = 55.5 Hz, 1H), 4.11– 3.64 (m, 3H). The following compounds were prepared by the same general method:

*TLC: Rf=0.85, heptane:EtOAc = 9:1 (visualized by PMA) Preparation 23: 4-Bromo-N,2-dimethylbenzenesulfonamide

4-Bromo-N,2-dimethylbenzenesulfonamide (P23-1)

To a suspension of methylamine hydrochloride (500 mg, 7.42 mmol) in anhydrous dichloromethane (15 mL) was added triethylamine (2.58 mL, 18.55 mmol) at 0 °C and the mixture was stirred at 0 °C for 10 min. To the mixture was added a solution of 4-bromo-2- methylbenzenesulfonyl chloride (1.0 g, 3.7 mmol) in anhydrous dichloromethane (10 mL) dropwise over 15 min at 0 °C. The reaction mixture was allowed to warm to room temperature and the stirring was continued for 1 h. The reaction mixture was washed with saturated aqueous sodium bicarbonate (3 x 15 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title compound (998 mg, crude) as a yellow crystalline solid, which was used without purification.

LCMS Method F: 93%, tR=1.921 min, m/z = 264.0 [M-H]- The following compounds were prepared by the same general method:

Preparation 24: N-[(4-Bromo-2-fluorophenyl)methyl]methanesulfonamide

N-[(4-Bromo-2-fluorophenyl)methyl]methanesulfonamide (P24-1)

To a solution of (4-bromo-2-fluorophenyl)methanamine (1.0 g, 4.9 mmol) and triethylamine (2.0 mL, 14.7 mmol) in anhydrous dichloromethane (15 mL) was added a solution of methanesulfonyl chloride (455 µL, 5.88 mmol) in anhydrous dichloromethane (10 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The mixture was washed with saturated aqueous sodium bicarbonate (2 x 10 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to afford the title compound (1.17 g, 4.16 mmol, 85%) as an off-white solid.

LCMS Method F: 98%, t _R =1.701 min, m/z = 281.9 [M-H]- The following compounds were prepared by the same general method:

Preparation 25: 2-[4-(1,1-Difluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-di oxaborolane

2-[4-(1,1-Difluoroethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-di oxaborolane (P25-1)

To a mixture of 1-bromo-4-(1,1-difluoroethyl)benzene (500 mg, 2.26 mmol), bis(pinacolato)diboron (2.87 g, 11.31 mmol) and potassium acetate (1.33 g, 13.56 mmol) in 1,4- dioxane (10 mL) was added tetrakis(triphenylphosphine)palladium (261 mg, 0.23 mmol) and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 20:80) to afford the title compound (483 mg, crude) as a white crystalline solid, which was used without further purification.

LCMS Method A: 50%, t _R =1.787 min, m/z = 269.2 [M+H] ⁺ .

The following compounds were prepared by the same general method:

*[M-H-C6H12+HCOOH]- †[M+NH4] ⁺ Preparation 26: 3-Fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2- yl)benzenesulfonamide

3-Fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)benzenesulfonamide (P26-1) To a mixture of 4-bromo-3-fluoro-N-methylbenzenesulfonamide (500 mg, 1.87 mmol), bis(pinacolato)diboron (1.90 g, 7.49 mmol) and triethylamine (1.0 mL, 7.49 mmol) in toluene (12.5 mL) was added XPhos palladacycle G3 (159 mg, 0.19 mmol) and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with chloroform:methanol (100:0 to 50:50) to afford the tile compound (333 mg, crude) as a colorless oil, which was used without further purification.

LCMS Method H: 75%, t _R =0.496 min, m/z = 278.0 [M-H-C ₆ H ₁₂ +HCOOH]- The following compounds were prepared by the same general method:

*[M-H-C6H12+HCOOH]- Preparation 27: (1-Methylsulfonyl-4-piperidyl)methanol

(1-Methylsulfonyl-4-piperidyl)methanol (P27-1)

To a solution of ethyl 1-methylsulfonylpiperidine-4-carboxylate (937 mg, 3.99 mmol) in freshly distilled tetrahydrofuran (9.5 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran, 4.6 mL, 4.6 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous sodium carbonate (500 µL) at 0 °C. The mixture was diluted with ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (10 mL), dried over magnesium sulfate, filtered and evaporated to afford the title compound (531 mg, 2.75 mmol, 69%) as a white solid.

TLC: one spot, n-heptane:EtOAc = 1:1 (visualized by PMA) Preparation 28: tert-Butyl 4-(2-bromoethyl)piperidine-1-carboxylate

tert-Butyl 4-(2-bromoethyl)piperidine-1-carboxylate (P28-1)

A solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (2.23 g, 9.72 mmol), carbon tetrabromide (5.21 g, 15.69 mmol) and triphenylphosphine (2.06 g, 13.08 mmol) in dichloromethane (36 mL) was stirred at room temperature for 72 h. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (2.72 g, 9.31 mmol, 96%) as a colorless oil.

1H NMR (500 MHz, DMSO-d ₆ ) d 3.96– 3.80 (m, 2H), 3.54 (t, J = 7.0 Hz, 2H), 2.77– 2.55 (m, 2H), 1.76– 1.66 (m, 2H), 1.64– 1.58 (m, 2H), 1.58– 1.52 (m, 1H), 1.36 (s, 9H), 1.02– 0.90 (m, 2H). Preparation 29: tert-Butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate

Step 1

O1-tert-Butyl O4-ethyl 4-methylpiperidine-1,4-dicarboxylate (P29-1a)

To a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 66 mL, 33 mmol) in freshly distilled tetrahydrofuran (17 mL) was added a solution of O1-tert-butyl O4-ethyl piperidine-1,4-dicarboxylate (5.0 g, 19.43 mmol) in freshly distilled tetrahydrofuran (5 mL) dropwise at -78 °C under argon. The mixture was warmed to -40 °C. To the reaction mixture was added a solution of iodomethane (1.2 mL, 19.43 mmol) in freshly distilled tetrahydrofuran (3 mL) dropwise at -40 °C. The reaction mixture was allowed to warm to room temperature and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice water (100 mL) and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 90:10) to afford the title compound (3.72 g, 13.7 mmol, 70%) as a colorless oil.

LCMS Method B: 96%, t _R =2.357 min, m/z = 172.2 [M+H-Boc] ⁺

1H NMR (500 MHz, Chloroform-d) d 4.18 (q, J = 7.1 Hz, 2H), 3.83– 3.72 (m, 2H), 3.06– 2.96 (m, 2H), 2.11– 2.02 (m, 2H), 1.46 (s, 9H), 1.40– 1.33 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 1.21 (s, 3H). Step 2

tert-Butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (P29-1)

To a solution of O1-tert-butyl O4-ethyl 4-methylpiperidine-1,4-dicarboxylate (5.0 g, 18.5 mmol) in freshly distilled tetrahydrofuran (50 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran, 21.2 mL, 21.2 mmol) dropwise at 0 °C under argon. The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched by careful addition of saturated aqueous sodium carbonate (10 mL), maintaining the temperature between 5 - 10 °C. The mixture was diluted with ethyl acetate (100 mL) and filtered through a pad of Celite. The filtrate was washed with brine (30 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (3.95 g, 17.2 mmol, 93%) as a colorless oil.

1H NMR (500 MHz, Chloroform-d) d 3.69 (s, 2H), 3.40 (d, J = 5.5 Hz, 2H), 3.15 (ddd, J = 13.7, 10.3, 3.5 Hz, 2H), 1.47 (s, 11H), 1.42 (t, J = 5.8 Hz, 1H), 1.33– 1.26 (m, 3H), 1.00 (s, 3H).

The following compounds were prepared by the same general method:

Preparation 30: t Butyl 1-((acetylthio)methyl)piperidine-4-carboxylate

Step 1

tert-Butyl 1-(((methylsulfonyl)oxy)methyl)piperidine-4-carboxylate (P30-1a) To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.00 g, 4.65 mmol) and triethylamine (1.9 mL, 14.0 mmol) in anhydrous dichloromethane (25 mL) was added a solution of methanesulfonyl chloride (430 mL, 5.58 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The mixture was washed with saturated aqueous sodium bicarbonate (2 x 10 mL), dried over magnesium sulfate, filtered and evaporated to afford the title compound (1.44 g, 4.91 mmol, crude) as a pale yellow semi-solid, which was used without further purification.

TLC: Rf=0.43, heptane:EtOAc = 1:1 (visualized by PMA) Step 2

tert-Butyl 1-((acetylthio)methyl)piperidine-4-carboxylate (P30-1)

To a solution of crude tert-butyl 1-(((methylsulfonyl)oxy)methyl)piperidine-4-carboxylate (814 mg) in dry N,N-dimethylformamide (11 mL) was added potassium thioacetate (555 mg, 4.86 mmol) and the reaction mixture was stirred at 65 °C for 5 h. The reaction mixture was poured into water (110 mL) and the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to afford the title compound (711 mg, 2.604 mmol, 94%) as a brown oil.

LCMS Method F: 97%, t _R =2.339 min, m/z = 174.2 [M+H-Boc] ⁺

Preparation 31: tert-Butyl 4-(hydroxymethyl)-2,6-dimethylpiperidine-1-carboxylate

Step 1

Methyl 2,6-dimethylpyridine-4-carboxylate (P31-1a)

To a suspension of 2,6-dimethylisonicotinic acid (1.0 g, 6.62 mmol) in methanol (25 mL) was added thionyl chloride (1.4 mL, 19.85 mmol) dropwise at 0 °C over 10 min. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated and the residue was taken up in methanol (25 mL). To the mixture was added thionyl chloride (1.4 mL, 19.85 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated. The residue was diluted with diethyl ether (10 mL) and evaporated. This was repeated twice to remove thionyl chloride to give the title compound (1.28 g, crude) as a yellow solid.

LCMS Method F: 100%, tR=1.567 min, m/z=166.0 [M+H] ⁺

Step 2

Methyl 2,6-dimethylpiperidine-4-carboxylate (P31-1b)

A mixture of crude methyl 2,6-dimethylpyridine-4-carboxylate (1.25 g), trifluoroacetic acid (1.7 mL, 22.72 mmol) and 10% palladium on carbon (625 mg) in methanol (150 mL) was stirred in a sealed vessel under hydrogen (10 bar) for 5 h at 50 °C. The reaction mixture was filtered through a pad of Celite and the Celite was washed with methanol (50 mL). The filtrate was evaporated to afford the title compound (1.1 g, crude) as a brown oil.

LCMS Method F: low UV absorption, tR=0.200 min, m/z = 172.1 [M+H] ⁺

Step 3

O1-tert-Butyl O4-methyl 2,6-dimethylpiperidine-1,4-dicarboxylate (P31-1c)

A suspension of crude methyl 2,6-dimethylpiperidine-4-carboxylate (1.1 g) and sodium bicarbonate (6.4 g, 75.76 mmol) in 1,4-dioxane (28 mL) was stirred at room temperature for 30 min. To the mixture was added di-tert-butyl dicarbonate (5.0 g, 22.7 mmol) and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 80:20) to afford the title compound (988 mg, 3.65 mmol, 55% over three steps) as a colorless oil.

LCMS Method F: 90%, tR=2.279 min, m/z = 172.1 [M+H-Boc] ⁺

1H NMR (300 MHz, DMSO-d ₆ ) d 4.18– 4.02 (m, 2H), 3.61 (s, 3H), 2.46– 2.36 (m, 1H), 2.20– 2.05 (m, 2H), 1.53 (ddd, J = 13.7, 11.0, 6.7 Hz, 2H), 1.40 (s, 9H), 1.16 (d, J = 6.8 Hz, 6H).

Step 4

tert-Butyl 4-(hydroxymethyl)-2,6-dimethylpiperidine-1-carboxylate (P31-1)

To a solution of O1-tert-butyl O4-methyl 2,6-dimethylpiperidine-1,4-dicarboxylate (988 mg, 3.65 mmol) in distilled tetrahydrofuran (10 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran, 4.19 mL, 4.19 mmol) dropwise at 0 °C under argon. The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched by careful addition of saturated aqueous sodium carbonate (1.5 mL), maintaining the temperature between 0 - 5 °C. The mixture was diluted with ethyl acetate (15 mL) and filtered. The filtrate was washed with brine (10 mL) and the organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (804 mg, 3.31 mmol, 91%) as a colorless oil.

LCMS Method F: 91%, t _R =1.909 min, m/z = 174.1 [M+H-tBu] ⁺ The following compounds were prepared by the same general method:

Example 1: 4-[4-[(1-Acetyl-4-methyl-4-piperidyl)methoxy]-1H-pyrrolo[2,3 -b]pyridin-3- yl]benzonitrile

Step 1

4-[4-[(1-Acetyl-4-methyl-4-piperidyl)methoxy]-1-(2-trimet hylsilylethoxymethyl)pyrrolo[2,3- b]pyridin-3-yl]benzonitrile (1-1a)

A mixture of 1-[4-[[3-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b ]pyridin-4- yl]oxymethyl]-4-methyl-1-piperidyl]ethanone (120 mg, 0.242 mmol), 4-cyanophenylboronic acid (53 mg, 0.361 mmol), RuPhos palladacycle G3 (20 mg, 0.024 mmol) and tribasic potassium phosphate (153 mg, 0.721 mmol) in a mixture of toluene (2.4 mL) and ethanol (600 µL) was stirred at 80 °C for 16 h under argon. The reaction mixture was evaporated. The residue was purified by silica gel column chromatography eluting with chloroform. The crude product was purified by preparative HPLC to give the title compound (76 mg, 0.146 mmol, 61%) as a yellow oil.

LCMS Method B: 93%, t _R =2.632 min, m/z = 519.2 [M+H] ⁺

Step 2

4-[4-[(1-Acetyl-4-methyl-4-piperidyl)methoxy]-1H-pyrrolo[ 2,3-b]pyridin-3-yl]benzonitrile (1-1) A solution of 4-[4-[(1-acetyl-4-methyl-4-piperidyl)methoxy]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-3-yl]benzon itrile (70 mg, 0.135 mmol) and hydrogen chloride (4.2 M in 1,4-dioxane, 7 mL, 29.4 mmol) was stirred at room temperature for 5 h. The reaction mixture was evaporated. The residue was taken up in a mixture of dichloromethane and methanol (1:1, 4 mL). To the solution was added 1,2-ethylenediamine (18 µL, 0.270 mmol) and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was evaporated. The residue was partitioned between dichloromethane (10 mL) and water (10 mL). The aqueous layer was extracted with dichloromethane (1 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel flash chromatography eluting with chloroform:methanol (100:0 ^ 100:5) to give the title compound (28 mg, 0.072 mmol, 53%) as a white powder.

LCMS Method D: 96%, t _R =1.681 min, m/z = 389.2 [M+H] ⁺

1H NMR (500 MHz, DMSO-d6) d 12.03 (br. s, 1H), 8.15 (d, J = 5.5 Hz, 1H), 7.81– 7.78 (m, 2H), 7.78 – 7.75 (m, 2H), 7.64 (d, J = 2.5 Hz, 1H), 6.79 (d, J = 5.6 Hz, 1H), 3.95 (d, J = 9.4 Hz, 1H), 3.91 (d, J = 9.3 Hz, 1H), 3.83 (dt, J = 13.4, 5.0 Hz, 1H), 3.51 (dt, J = 13.7, 5.0 Hz, 1H), 3.25 (ddd, J = 13.6, 10.2, 3.3 Hz, 1H), 3.05 (ddd, J = 13.6, 10.2, 3.5 Hz, 1H), 1.98 (s, 3H), 1.48 (ddd, J = 13.7, 10.0, 4.1 Hz, 1H), 1.41 (ddd, J = 14.0, 10.1, 4.3 Hz, 1H), 1.31– 1.19 (m, 2H), 0.94 (s, 3H).

The following compounds were prepared by the same general method:

Example 2: 4-[4-[(1-Acetyl-4-piperidyl)methoxy]-1H-pyrrolo[2,3-b]pyridi n-3-yl]-N- methylsulfonylbenzamide ammonium salt

Step1

4-[4-[(1-Acetyl-4-piperidyl)methoxy]-1-(2-trimethylsilyle thoxymethyl)pyrrolo[2,3-b]pyridin-3- yl]-N-methylsulfonylbenzamide (2-1a)

To a solution of 1-[4-(hydroxymethyl)-1-piperidyl]ethanone (275 mg, 1.75 mmol) in dry dimethyl sulfoxide (2.5 mL) was added sodium hydride (60% dispersion in mineral oil, 70 mg, 1.75 mmol) and the reaction mixture was stirred at room temperature for 15 min. To the mixture was added a solution of 4-[4-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]py ridin-3-yl]-N- methylsulfonylbenzamide (164 mg, 0.354 mmol) in dry dimethyl sulfoxide (1.5 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (25 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with chloroform:methanol (100:0 ^ 100:5) to give the title compound (98 mg, 0.163 mmol, 46%) as a yellow oil.

LCMS Method E: 92%, t _R =2.147 min, m/z = 601.3 [M+H] ⁺

Step 2

4-[4-[(1-Acetyl-4-piperidyl)methoxy]-1H-pyrrolo[2,3-b]pyr idin-3-yl]-N-methylsulfonylbenzamide ammonium salt (2-1)

A solution of 4-[4-[(1-acetyl-4-piperidyl)methoxy]-1-(2-trimethylsilyletho xymethyl)pyrrolo[2,3- b]pyridin-3-yl]-N-methylsulfonylbenzamide (98 mg, 0.163 mmol) and hydrogen chloride (4.2 M in 1,4-dioxane, 2 mL, 8.40 mmol) was stirred at room temperature for 3 h. The reaction mixture was evaporated. The residue was dissolved in water (10 mL) and the mixture was made basic to pH 12 by addition of 5 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated and the residue was purified by preparative HPLC to give the title compound (24 mg, 0.051 mmol, 31%) as a white powder. LCMS Method B: 96%, t _R =1.430 min, m/z = 471.2 [M+H] ⁺ .

1H NMR (500 MHz, DMSO-d6) d 11.82– 11.79 (m, 1H), 8.11 (d, J = 5.4 Hz, 1H), 7.96– 7.86 (m, 2H), 7.64– 7.58 (m, 2H), 7.51 (d, J = 2.2 Hz, 1H), 7.37– 6.85 (m, 4H), 6.68 (d, J = 5.5 Hz, 1H), 4.38– 4.31 (m, 1H), 4.04– 3.94 (m, 2H), 3.82– 3.70 (m, 1H), 3.03– 2.96 (m, 1H), 2.95 (s, 3H), 2.54– 2.51 (m, 1H), 2.04– 1.98 (m, 1H), 1.97 (s, 3H), 1.69– 1.60 (m, 2H), 1.22– 1.10 (m, 1H), 1.07– 0.97 (m, 1H).

The following compounds were prepared by the same general method:

Example 3: 4-[(1,4-Dimethyl-4-piperidyl)methoxy]-3-phenyl-1H-pyrrolo[2, 3-b]pyridine 2-[[4-[(1,4-Dimethyl-4-piperidyl)methoxy]-3-phenylpyrrolo[2, 3-b]pyridin-1- yl]methoxy]ethyltrimethylsilane (3-1a)

To a solution of (1,4-dimethyl-4-piperidyl)methanol (100 mg, 0.698 mmol) in dry dimethyl sulfoxide (900 µL) was added sodium hydride (60% dispersion in mineral oil, 31 mg, 0.775 mmol) and the reaction mixture was stirred at room temperature for 15 min. To the mixture was added a solution of 2-[(4-fluoro-3-phenylpyrrolo[2,3-b]pyridin-1-yl)methoxy]ethy ltrimethylsilane (120 mg, 0.350 mmol) in dry dimethyl sulfoxide (500 µL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice water (10 mL). The mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with chloroform:methanol (100:0 ^ 100:5). The residue was purified by preparative HPLC to give the title compound (55 mg, 0.118 mmol, 33%) as a yellow oil.

LCMS Method D: 93%, tR=2.598 min, m/z = 466.2 [M+H] ⁺

Step 2

4-[(1,4-Dimethyl-4-piperidyl)methoxy]-3-phenyl-1H-pyrrolo [2,3-b]pyridine (3-1)

A solution of 2-[[4-[(1,4-dimethyl-4-piperidyl)methoxy]-3-phenylpyrrolo[2, 3-b]pyridin-1- yl]methoxy]ethyltrimethylsilane (55 mg, 0.118 mmol) and hydrogen chloride (4.2 M in 1,4- dioxane, 1 mL, 4.2 mmol) was stirred at room temperature for 21 h. The reaction mixture was evaporated. The residue was taken up in a mixture of dichloromethane and methanol (1:1, 3 mL). To the solution was added 1,2-ethylenediamine (16 µL, 0.236 mmol) and the reaction mixture was stirred at 50 °C for 2 h. The reaction mixture was evaporated. The residue was partitioned between dichloromethane (5 mL) and water (5 mL). The aqueous layer was extracted with dichloromethane (1 x 5 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (21 mg, 0.063 mmol, 50%) as a white powder.

LCMS Method B: 95%, tR=1.968 min, m/z = 336.2 [M+H] ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) d 11.74 (s, 1H), 8.10 (d, J = 5.5 Hz, 1H), 7.59– 7.53 (m, 2H), 7.38 (d, J = 2.4 Hz, 1H), 7.35– 7.29 (m, 2H), 7.26– 7.19 (m, 1H), 6.70 (d, J = 5.5 Hz, 1H), 3.84 (s, 2H), 2.41 – 2.31 (m, 2H), 2.19– 2.10 (m, 2H), 2.15 (s, 3H), 1.45 (ddd, J = 13.3, 9.4, 3.9 Hz, 2H), 1.31– 1.21 (m, 2H), 0.83 (s, 3H).

The following compounds were prepared by the same general method:

Example 4: 4-[(4-Methyl-4-piperidyl)methoxy]-3-phenyl-1H-pyrrolo[2,3-b] pyridine hydrochloride

4-[(4-Methyl-4-piperidyl)methoxy]-3-phenyl-1H-pyrrolo[2,3 -b]pyridine hydrochloride (4-1) A solution of 1-[4-methyl-4-[(3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxyme thyl]-1- piperidyl]ethanone (19 mg, 0.052 mmol) in hydrochloric acid (6 M, 800 ^L) was stirred at 80 °C for 48 h. The mixture was lyophilized to give the title compound (17 mg, 0.047 mmol, 91%) as a pale yellow solid.

LCMS Method B: 97%, tR=1.738 min, m/z = 322.2 [M+H] ⁺

1H NMR (500 MHz, DMSO-d6) d 12.76 (s, 1H), 8.87 (s, 2H), 8.42 (d, J = 6.5 Hz, 1H), 7.58– 7.56 (m, 1H), 7.55– 7.51 (m, 2H), 7.42– 7.38 (m, 2H), 7.35– 7.30 (m, 1H), 7.15 (d, J = 6.6 Hz, 1H), 4.14 (s, 2H), 3.10– 3.01 (m, 2H), 3.00– 2.84 (m, 3H), 1.63– 1.51 (m, 2H), 1.47– 1.36 (m, 2H), 0.82 (s, 3H). The following compounds were prepared by the same general method:

Example 5: N-[[4-[4-[(4-Methyl-4-piperidyl)methoxy]-1H-pyrrolo[2,3-b]py ridin-3- yl]phenyl]methyl] methanesulfonamide

Step 1 tert-Butyl 4-[[3-[4-(methanesulfonamidomethyl)phenyl]-1-(2-trimethylsil ylethoxymethyl) pyrrolo[2,3-b]pyridin-4-yl]oxymethyl]-4-methylpiperidine-1-c arboxylate (5-1a)

To a solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (637 mg, 2.78 mmol) in dry dimethyl sulfoxide (4 mL) was added sodium hydride (60% dispersion in mineral oil, 111 mg, 2.78 mmol). The reaction mixture was stirred at room temperature for 10 min. To the mixture was added a solution of N-[[4-[4-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridin-3-yl]phenyl]methyl]methanesulfonamide (250 mg, 0.556 mmol) in dry dimethyl sulfoxide (3 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (50 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography eluting with heptanes:1,4-dioxane (9:1 ^ 3:2) to give the title compound (360 mg, 0.546 mmol, 99%) as a colorless oil.

LCMS Method A: 100%, tR=2.035 min, m/z = 659.3 [M+H] ⁺

Step 2

N-[[4-[4-[(4-Methyl-4-piperidyl)methoxy]-1H-pyrrolo[2,3-b ]pyridin-3-yl]phenyl]methyl] methanesulfonamide (5-1)

To a solution of tert-butyl 4-[[3-[4-(methanesulfonamidomethyl)phenyl]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]-4-methylpiperidine-1- carboxylate (360 mg, 0.546 mmol) in 1,4-dioxane (3 mL) was added hydrochloric acid (6 M, 3 mL) and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was evaporated. The residue was taken up in water (15 mL) and made basic to pH 12 by addition of 5 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature for 30 min. The mixture was extracted with a mixture of chloroform:isopropyl alcohol (3:1, 3 x 15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was triturated with ethanol (6 mL). The crude product was purified by preparative HPLC twice to give the title compound (27 mg, 0.063 mmol, 11%) as a white powder.

LCMS Method C: 98%, t _R =1.638 min, m/z = 429.2 [M+H] ⁺

1H NMR (300 MHz, DMSO-d ₆ ) d 11.76 (br. s, 1H), 8.10 (d, J = 5.5 Hz, 1H), 7.57 (d, J = 7.8 Hz, 2H), 7.40 (s, 1H), 7.31 (d, J = 7.8 Hz, 2H), 7.18– 6.82 (m, 1H), 6.72 (d, J = 5.6 Hz, 1H), 4.22– 4.09 (m, 2H), 3.85, 3.70– 4.49 (m, 1H), (s, 2H), 2.83 (s, 3H), 2.76– 2.58 (m, 4H), 1.50– 1.29 (m, 2H), 1.28 – 1.15 (m, 2H), 0.89 (s, 3H). The following compounds were prepared by the same general method:

Example 6: N-[[4-[4-[(4-Fluoro-1-methyl-4-piperidyl)methoxy]-1H-pyrrolo [2,3-b]pyridin-3- yl]phenyl]methyl]methanesulfonamide

Step 1

tert-Butyl 4-fluoro-4-[[3-[4-(methanesulfonamidomethyl)phenyl]-1-(2-tri methylsilylethoxy- methyl)pyrrolo[2,3-b]pyridin-4-yl]oxymethyl]piperidine-1-car boxylate (6-1a)

To a solution of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (519 mg, 2.22 mmol) in dry dimethyl sulfoxide (4 mL) was added sodium hydride (60% dispersion in mineral oil, 90 mg, 2.22 mmol) and the reaction mixture was stirred at room temperature for 20 min. To the mixture was added a solution of N-[[4-[4-fluoro-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridin-3-yl]phenyl]methyl]methanesulfonamide (200 mg, 0.445 mmol) in dry dimethyl sulfoxide (2 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water (40 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was triturated with diethyl ether (10 mL) to give the title compound (183 mg, 0.276 mmol, 62%) as a white powder.

LCMS Method B: 97%, t _R =2.792 min, m/z = 663.2 [M+H] ⁺

Step 2

N-[[4-[4-[(4-Fluoro-1-methyl-4-piperidyl)methoxy]-1-(2-tr imethylsilylethoxymethyl)pyrrolo[2,3- b]pyridin-3-yl]phenyl]methyl]methanesulfonamide (6-1b)

To a solution of tert-butyl 4-fluoro-4-[[3-[4-(methanesulfonamidomethyl)phenyl]-1-(2- trimethylsilylethoxy-methyl)pyrrolo[2,3-b]pyridin-4-yl]oxyme thyl]piperidine-1-carboxylate (100 mg, 0.151 mmol) in freshly distilled tetrahydrofuran (2 mL) was added lithium aluminum hydride (1 M in tetrahydrofuran, 300 µL, 0.300 mmol) dropwise while maintaining the temperature between 0-5 °C under argon. The reaction mixture was allowed to warm to room temperature. The reaction mixture was heated to 50 °C for 2 h. The reaction was quenched with 10% aqueous sodium carbonate (200 µL). The mixture was evaporated and the residue was purified by silica gel column chromatography eluting with chloroform:methanol (100:2 ^100:10) to give the title compound (64 mg, 0.111 mmol, 73%) as an off-white powder.

LCMS Method B: 98%, t _R =2.440 min, m/z = 577.2 [M+H] ⁺

Step 3

N-[[4-[4-[(4-Fluoro-1-methyl-4-piperidyl)methoxy]-1H-pyrr olo[2,3-b]pyridin-3- yl]phenyl]methyl]methanesulfonamide (6-1)

A mixture of N-[[4-[4-[(4-fluoro-1-methyl-4-piperidyl)methoxy]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-3-yl]phenyl ]methyl]methanesulfonamide (64 mg, 0.111 mmol) in trifluoroacetic acid (650 µL) was stirred at room temperature for 1 h. The reaction mixture was evaporated. The residue was dissolved in water (10 mL) and the mixture was made basic to pH 12 by addition of 5 M aqueous sodium hydroxide. The reaction mixture was stirred at room temperature for 30 min. The mixture was evaporated. The residue was purified by preparative HPLC to give the title compound (35 mg, 0.078 mmol, 70%) as a white powder. LCMS Method B: 100%, t _R =1.702 min, m/z = 447.1 [M+H] ⁺

1H NMR (300 MHz, DMSO-d ₆ ) d 11.81 (br. s, 1H), 8.12 (d, J = 5.5 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.58– 7.50 (m, 1H), 7.47 (s, 1H), 7.29 (d, J = 7.9 Hz, 2H), 6.71 (d, J = 5.6 Hz, 1H), 4.21 (d, J = 21.0 Hz, 2H), 4.16– 4.12 (s, 2H), 2.83 (s, 3H), 2.59– 2.54 (m, 2H), 2.18 (s, 3H), 2.16– 2.05 (m, 2H), 1.81 – 1.73 (m, 2H), 1.73– 1.68 (m, 1H), 1.68– 1.52 (m, 1H).

The following compounds were prepared by the same general method:

Example 7: 3-(3-Fluorophenyl)-4-[(4-methyl-4-piperidyl)methoxy]-1H-pyrr olo[2,3-b]pyridine Step 1

tert-Butyl 4-[[3-(3-fluorophenyl)-1-(2-trimethylsilylethoxymethyl)pyrro lo[2,3-b]pyridin-4- yl]oxymethyl]-4-methylpiperidine-1-carboxylate (7-1a)

A mixture of tert-butyl 4-(((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo [2,3- b]pyridin-4-yl)oxy)methyl)-4-methylpiperidine-1-carboxylate (300 mg, 0.54 mmol), (3- fluorophenyl)boronic acid (228 mg, 1.63 mmol), RuPhos palladacycle G3 (45 mg, 0.054 mmol) and aqueous tribasic potassium phosphate (2 M, 820 µL, 1.64 mmol) in a mixture of toluene (6 mL) and ethanol (1.5 mL) was stirred at 80 °C for 16 h under argon. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 60:40) to afford the title compound (276 mg, 0.485 mmol, 89%) as a colorless oil.

LCMS Method H: 96%, t _R =3.088 min, m/z = 570.5 [M+H] ⁺

Step 2

3-(3-Fluorophenyl)-4-[(4-methyl-4-piperidyl)methoxy]-1H-p yrrolo[2,3-b]pyridine (7-1)

To tert-butyl 4-(((3-(3-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl) -1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)methyl)-4-methylpiperidine-1-carboxylate (276 mg, 0.49 mmol) was added hydrogen chloride (4.7 M in 1,4-dioxane, 4.9 mL, 23.03 mmol) at room temperature and the mixture was stirred for 8 h. The mixture was evaporated and the residue was taken up in a mixture of dichloromethane (7 mL), methanol (7 mL) and 1,2-ethylenediamine (65 µL, 0.97 mmol). The reaction mixture was stirred at 50 °C for 2 h and then evaporated. The crude product was purified by preparative HPLC to afford the title compound (53 mg, 0.156 mmol, 32%) as a white powder.

LCMS Method F: 99%, tR=1.717 min, m/z = 340.2 [M+H] ⁺

1H NMR (500 MHz, DMSO-d ₆ ) d 11.87 (s, 1H), 8.12 (d, J = 5.5 Hz, 1H), 7.50 (s, 1H), 7.44– 7.33 (m, 3H), 7.07– 7.02 (m, 1H), 6.74 (d, J = 5.6 Hz, 1H), 3.86 (s, 2H), 3.41– 3.34 (m, 1H), 2.72– 2.55 (m, 4H), 1.44– 1.30 (m, 2H), 1.26– 1.14 (m, 2H), 0.89 (s, 3H).

The following compounds were prepared by the same general method: 7- 7- 7- 7- 7- 7- 7- 7- 7- 7- 7- 7- 7- 7- 7- 7- Example 8: 2-[2-Fluoro-4-[4-[(4-methyl-4-piperidyl)methoxy]-1H-pyrrolo[ 2,3-b]pyridin-3- yl]phenyl]acetonitrile

Step 1

tert-Butyl 4-[[3-[4-(cyanomethyl)-3-fluorophenyl]-1-(2-trimethylsilylet hoxymethyl)pyrrolo[2,3- b]pyridin-4-yl]oxymethyl]-4-methylpiperidine-1-carboxylate (8-1a)

A mixture of tert-butyl 4-(((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo [2,3- b]pyridin-4-yl)oxy)methyl)-4-methylpiperidine-1-carboxylate (300 mg, 0.54 mmol), 2-(2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonit rile (704 mg, 2.70 mmol), RuPhos palladacycle G3 (45 mg, 0.054 mmol) and aqueous tribasic potassium phosphate (2 M, 820 µL, 1.64 mmol) in toluene (6 mL) and ethanol (1.5 mL) was stirred at 80 °C for 18 h under argon. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (179 mg, 0.294 mmol, 54%) as a pale-yellow oil.

LCMS Method F: 83%, t _R =2.646 min, m/z = 609.4 [M+H] ⁺

Step 2

2-[2-Fluoro-4-[4-[(4-methyl-4-piperidyl)methoxy]-1H-pyrro lo[2,3-b]pyridin-3- yl]phenyl]acetonitrile (8-1)

To a solution of tert-butyl 4-(((3-(4-(cyanomethyl)-3-fluorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )oxy)methyl)-4-methylpiperidine-1- carboxylate (106 mg, 0.174 mmol) in 1,4-dioxane (1 mL) was added trifluoroacetic acid (1 mL, 13 mmol) and the mixture was stirred at room temperature for 4 d. The reaction mixture was evaporated and the residue was taken up in a mixture of dichloromethane (2 mL), methanol (2 mL) and 1,2-ethylenediamine (23 µL, 0.35 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC to afford the title compound (9 mg, 0.015 mmol, 9%) as a pale orange powder.

LCMS Method F: 99%, tR=1.582 min, m/z = 379.2 [M+H] ⁺

1H NMR (500 MHz, DMSO-d6) d 11.86 (s, 1H), 8.09 (d, J = 5.5 Hz, 1H), 7.50 (s, 1H), 7.46– 7.41 (m, 2H), 7.40– 7.34 (m, 1H), 6.72 (d, J = 5.6 Hz, 1H), 4.02 (s, 2H), 3.83 (s, 2H), 3.38– 3.25 (m, 1H), 2.68– 2.54 (m, 4H), 1.39– 1.24 (m, 2H), 1.23– 1.11 (m, 2H), 0.86 (s, 3H).

The following compounds were prepared by the same general method:

Example 9: 4-[(4-Methyl-4-piperidyl)methoxy]-3-(6-methyl-2-pyridyl)-1H- pyrrolo[2,3-b]pyridine

Step 1

tert-Butyl 4-methyl-4-[[3-(6-methyl-2-pyridyl)-1-(2-trimethylsilylethox ymethyl)pyrrolo[2,3- b]pyridin-4-yl]oxymethyl]piperidine-1-carboxylate (9-1a)

A mixture of tert-butyl 4-(((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo [2,3- b]pyridin-4-yl)oxy)methyl)-4-methylpiperidine-1-carboxylate (250 mg, 0.452 mmol), 2-methyl-6- (tributylstannyl)pyridine (230 µL, 0.682 mmol), tetrakis(triphenylphosphine)palladium (52 mg, 0.045 mmol) and lithium chloride (23 mg, 0.54 mmol) in 1,4-dioxane (11 mL) was heated to 120 °C for 45 min under argon under microwave irradiation. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with chloroform:methanol (100:0 to 95:5) to afford the title compound (44 mg, 0.078 mmol, 17% yield) as a yellow oil.

LCMS Method F: 98%, tR=2.427 min, m/z = 567.4 [M+H] ⁺

Step 2

4-[(4-Methyl-4-piperidyl)methoxy]-3-(6-methyl-2-pyridyl)- 1H-pyrrolo[2,3-b]pyridine (9-1)

To tert-butyl 4-methyl-4-(((3-(6-methylpyridin-2-yl)-1-((2-(trimethylsilyl )ethoxy)methyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)methyl)piperidine-1-carbox ylate (44 mg, 0.078 mmol) was added hydrogen chloride (4.7 M in 1,4-dioxane, 780 µL, 3.67 mmol) and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was evaporated and the residue was taken up in a mixture of dichloromethane (1.1 mL), methanol (1.1 mL) and 1,2-ethylenediamine (10 µL, 0.16 mmol). The reaction mixture was stirred at 50 °C for 2 h and then evaporated. The crude product was purified by preparative HPLC to afford the title compound (5 mg, 0.015 mmol 19%) as a colorless oil.

LCMS Method F: 99%, t _R =1.491 min, m/z = 337.2 [M+H] ⁺

1H NMR (500 MHz, DMSO-d ₆ ) d 11.87 (s, 1H), 8.11 (d, J = 5.5 Hz, 1H), 7.73– 7.68 (m, 1H), 7.64 (s, 1H), 7.63– 7.58 (m, 1H), 7.08– 7.01 (m, 1H), 6.76 (d, J = 5.5 Hz, 1H), 3.89 (s, 2H), 3.37– 3.30 (m, 1H), 2.71– 2.58 (m, 4H), 2.48 (s, 3H), 1.46– 1.34 (m, 2H), 1.27– 1.13 (m, 2H), 0.94 (s, 3H). The following compounds were prepared by the same general method:

Example 10: N-Methyl-4-[4-[(4-methyl-4-piperidyl)methoxy]-1H-pyrazolo[3, 4-b]pyridin-3- yl]benzenesulfonamide

Step 1

4-[4-Chloro-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4- b]pyridin-3-yl]-N- methylbenzenesulfonamide (10-1a)

To a solution of 4-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyra zolo[3,4- b]pyridine (300 mg, 0.733 mmol) and (4-(N-methylsulfamoyl)phenyl)boronic acid (205 mg, 0.953 mmol) in 1,2-dimethoxyethane (7.5 mL) was added saturated aqueous sodium bicarbonate (3 mL) and tetrakis(triphenylphosphine)palladium (42 mg, 0.037 mmol) and the reaction mixture was stirred at 100 °C for 18 h. The reaction mixture was evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (263 mg, 0.581 mmol, 79%) as a colorless oil.

LCMS Method F: 96%, tR=2.280 min, m/z = 453.0 [M+H] ⁺

Step 2

tert-Butyl 4-methyl-4-[[3-[4-(methylsulfamoyl)phenyl]-1-(2- trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]oxyme thyl]piperidine-1-carboxylate (10- 1b)

To a solution of 4-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo [3,4- b]pyridin-3-yl)-N-methylbenzenesulfonamide (263 mg, 0.582 mmol) in dry dimethyl sulfoxide (4 mL) was added sodium hydride (60% dispersion in mineral oil, 70 mg, 1.75 mmol) at room temperature and the suspension was stirred at room temperature for 30 min. To the mixture was added a solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (267 mg, 1.16 mmol) in dry dimethyl sulfoxide (4 mL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water (80 mL) and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 70:30) to afford the title compound (351 mg, crude) as a pale yellow oil, which was used without further purification. LCMS Method H: 68%, tR=2.533 min, m/z = 646.2 [M+H] ⁺

Step 3

N-Methyl-4-[4-[(4-methyl-4-piperidyl)methoxy]-1H-pyrazolo [3,4-b]pyridin-3- yl]benzenesulfonamide (10-1)

To crude tert-butyl 4-methyl-4-(((3-(4-(N-methylsulfamoyl)phenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-4-y l)oxy)methyl)piperidine-1- carboxylate (351 mg) was added hydrogen chloride (4.7 M in 1,4-dioxane, 5.6 mL, 26.3 mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated and the residue was taken up in a mixture of dichloromethane (5 mL), methanol (5 mL) and 1,2-ethylenediamine (1.1 mL, 16.45 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC to afford the title compound (27 mg, 0.065 mmol, 11% over two steps) as a white powder.

LCMS method F: 99%, t _R =1.449 min, m/z = 416.0 [M+H] ^{+ 1} H NMR (500 MHz, DMSO-d ₆ ) d 8.40 (d, J = 5.4 Hz, 1H), 8.15– 8.07 (m, 2H), 7.87– 7.81 (m, 2H), 7.50 (br. s, 1H), 6.85 (d, J = 5.5 Hz, 1H), 3.97 (s, 2H), 3.32– 3.22 (m, 1H), 2.74– 2.58 (m, 4H), 2.44 (s, 3H), 1.48– 1.34 (m, 2H), 1.26– 1.18 (m, 2H), 0.95 (s, 3H).

The following compounds were prepared by the same general method:

Example 11: 4-[(4-Methyl-4-piperidyl)methoxy]-3-tetrahydropyran-4-yl-1H- pyrrolo[2,3- b]pyridine

Step 1 2-[(4-Fluoro-3-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-1- yl)methoxy]ethyltrimethylsilane (11-1a)

A mixture of nickel(II) chloride ethylene glycol dimethyl ether complex (25 mg, 0.12 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (31 mg, 0.12 mmol) in anhydrous ethylene glycol dimethyl ether (10 mL) was stirred at room temperature for 10 min under argon atmosphere.

To a mixture of 3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyr rolo[2,3- b]pyridine (400 mg, 1.16 mmol), 4-bromotetrahydro-2H-pyran (261 µL, 1.74 mmol), Ir[dF(CF ₃ )ppy] ₂ (dtbbpy)PF ₆ (13 mg, 0.01 mmol) and lithium hydroxide (7.6 mg, 2.3 mmol) in anhydrous ethylene glycol dimethyl ether (10 mL) was added the solution of nickel(II) chloride ethylene glycol dimethyl ether and 4,4'-di-tert-butyl-2,2'-bipyridine in anhydrous ethylene glycol dimethyl ether. To the mixture was added tris(trimethylsilyl)silane (360 µL, 1.16 mmol) and the reaction mixture was stirred at room temperature for 16 h irradiated by blue LED light (Optonica ST4825 blue LED strip, 35W). The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 80:20) to afford a first crop of the title compound (50 mg, 0.143 mmol, 12%) as a colorless oil. LCMS Method F: 83%, tR=2.371 min, m/z = 351.3 [M+H] ⁺

Additional column fractions were collected to afford a second crop of the title compound (120 mg, 0.343 mmol, 30%) as a colorless oil.

LCMS Method F: 95%, tR=2.360 min, m/z = 351.2 [M+H] ⁺

Step 2

tert-Butyl 4-methyl-4-[[3-tetrahydropyran-4-yl-1-(2-trimethylsilylethox ymethyl)pyrrolo[2,3- b]pyridin-4-yl]oxymethyl]piperidine-1-carboxylate (11-1b)

To a solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (222 mg, 0.971 mmol) in anhydrous dimethyl sulfoxide (1.9 mL) was added sodium hydride (60% dispersion in mineral oil, 58 mg, 1.45 mmol) and the reaction mixture was stirred for 30 min at room temperature. To the reaction mixture was added a solution of 2-[(4-fluoro-3- tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-1-yl)methoxy]ethy ltrimethylsilane (170 mg, 0.486 mmol) in anhydrous dimethyl sulfoxide (2.3 mL) and the reaction mixture was stirred for 4.5 h at room temperature. The reaction was quenched with water (42 mL) and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (120 mg, 0.215 mmol, 44%) as a colorless oil.

LCMS Method H: 94%, tR=2.755 min, m/z = 560.4 [M+H] ⁺

Step 3

4-[(4-Methyl-4-piperidyl)methoxy]-3-tetrahydropyran-4-yl- 1H-pyrrolo[2,3-b]pyridine (11-1) To tert-butyl 4-methyl-4-[[3-tetrahydropyran-4-yl-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]piperidine-1-carboxylate (120 mg, 0.215 mmol) was added hydrogen chloride (4.7 M in 1,4-dioxane, 2.1 mL, 9.87 mmol) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was evaporated and the residue was dissolved in a mixture of dichloromethane (3 mL), methanol (3 mL) and 1,2-ethylenediamine (29 µL, 0.43 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC to afford the title compound (30 mg, 0.091 mmol, 42%).

LCMS Method F: 98%, t _R =1.419 min, m/z = 330.2 [M+H] ⁺

1H NMR (500 MHz, DMSO-d ₆ ) d 11.18 (s, 1H), 7.99 (d, J = 5.4 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 5.5 Hz, 1H), 3.97– 3.89 (m, 2H), 3.84 (s, 2H), 3.46– 3.34 (m, 2H), 3.22– 3.14 (m, 2H), 2.79 – 2.63 (m, 4H), 1.93– 1.84 (m, 2H), 1.61 (ddd, J = 12.3, 4.3 Hz, 2H), 1.56– 1.50 (m, 2H), 1.36– 1.30 (m, 2H), 1.08 (s, 3H).

The following compounds were prepared by the same general method:

Compound 11-5 was prepared by the same general method from the product of Step 1 that formed by reaction between P1-1 and the reaction solvent of ethylene glycol dimethyl ether. Example 12: N-[[2-Fluoro-4-[4-[(4-methyl-4-piperidyl)methoxy]-1H-pyrrolo [2,3-b]pyridin-3- yl]phenyl]methyl]methanesulfonamide

Step 1

tert-Butyl 4-[[3-[3-fluoro-4-(methanesulfonamidomethyl)phenyl]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]-4-methylpiperidine-1- carboxylate (12-1a)

To a solution of N-(2-fluoro-4-(4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl) -1H- pyrrolo[2,3-b]pyridin-3-yl)benzyl)methanesulfonamide (50 mg, 0.11 mmol) in dry dimethyl sulfoxide (400 µL) was added sodium hydride (60% dispersion in mineral oil, 13 mg, 0.32 mmol) at room temperature and the suspension was stirred at room temperature for 30 min. To the mixture was added a solution of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (49 mg, 0.22 mmol) in dry dimethyl sulfoxide (500 µL) and the reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water (9 mL) and the mixture was extracted with ethyl acetate (3 x 3 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (29 mg, 0.043 mmol, 40%) as a colorless oil.

TLC: one spot, heptanes:EtOAc = 1:1 (visualized by UV at 254 nm)

Step 2

N-[[2-Fluoro-4-[4-[(4-methyl-4-piperidyl)methoxy]-1H-pyrr olo[2,3-b]pyridin-3- yl]phenyl]methyl]methanesulfonamide (12-1)

To tert-butyl 4-(((3-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )oxy)methyl)-4-methylpiperidine-1- carboxylate (58 mg, 0.086 mmol) was added hydrogen chloride (4.7 M in 1,4-dioxane, 860 µL, 4.04 mmol) and the reaction mixture was stirred at room temperature for 3 h. The mixture was evaporated and the residue was taken up in a mixture of dichloromethane (1.5 mL), methanol (1.5 mL) and 1,2-ethylenediamine (12 µL, 0.17 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC to afford the title compound (4 mg, 0.009 mmol 10%) as a pale yellow glass.

LCMS Method F: 94%, tR=1.598 min, m/z = 447.2 [M+H] ⁺

1H NMR (300 MHz, Methanol-d ₄ ) d 8.13 (d, J = 5.6 Hz, 1H), 7.51– 7.28 (m, 4H), 6.77 (d, J = 5.8 Hz, 1H), 4.35 (s, 2H), 3.94 (s, 2H), 2.93 (s, 3H), 2.88– 2.71 (m, 4H), 1.58– 1.43 (m, 2H), 1.43– 1.28 (m, 2H), 1.00 (s, 3H).

The following compounds were prepared by the same general method:

Example 13: 4-[(1,4-Dimethyl-4-piperidyl)methoxy]-3-[4-(methoxymethyl)ph enyl]-1H- pyrrolo[2,3-b]pyridine

Step 1

[4-[4-[(1,4-Dimethyl-4-piperidyl)methoxy]-1-(2-trimethyls ilylethoxymethyl)pyrrolo[2,3- b]pyridin-3-yl]phenyl]methanol (13-1a)

To a mixture of 2-[[3-bromo-4-[(1,4-dimethyl-4-piperidyl)methoxy]pyrrolo[2,3 -b]pyridin- 1-yl]methoxy]ethyltrimethylsilane (130 mg, 0.278 mmol) and [4-(hydroxymethyl)phenyl]boronic acid (54 mg, 0.355 mmol) was added RuPhos palladacycle G3 (11 mg, 0.013 mmol), toluene (6 mL), ethanol (1.5 mL) and aqueous potassium phosphate (1 M, 0.8 mL, 0.80 mmol) under argon. The reaction mixture was stirred for 5 h at 80 °C under argon. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (20 mL) and filtered through a pad of Celite. The Celite was washed with ethyl acetate (2 x 20 mL). The combined filtrates were washed with water (2 x 20 mL) and brine (1 x 20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in acetonitrile (2 x 2 mL) and evaporated to give the title compound (140 mg, crude) as a brown gum which was used in the next step without purification.

LCMS Method A: 65%, tR=1.270 min, m/z = 496.3 [M+H] ⁺

Step 2

4-[(1,4-Dimethyl-4-piperidyl)methoxy]-3-[4-(methoxymethyl )phenyl]-1H-pyrrolo[2,3-b]pyridine (13-1)

To a solution of [4-[4-[(1,4-dimethyl-4-piperidyl)methoxy]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-3-yl]phenyl ]methanol (138 mg, crude) in 1,4- dioxane (10 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 1.4 mL, 5.60 mmol) and the reaction mixture was stirred for 5.5 h at 80 °C. The reaction mixture was evaporated. The residue was taken up in a mixture of dichloromethane (6 mL) and methanol (6 mL). To the solution was added 1,2-ethylenediamine (50 µL, 0.748 mmol) and the reaction mixture was stirred for 17 h at 50 °C. The reaction mixture was evaporated. The residue was taken up in dichloromethane (40 mL) and the organic layer was washed with water (2 x 10 mL). The combined aqueous layers were extracted with dichloromethane (1 x 40 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over sodium sulfate, filtered and evaporated. To the residue was added acetonitrile (2 mL) and the mixture was evaporated. To the residue was added ethanol (2 mL) and the mixture was evaporated. The residue was taken up in 1,4-dioxane (8 mL) and to the solution was added hydrogen chloride (4 M in 1,4-dioxane, 1.0 mL, 4.0 mmol). The reaction mixture was stirred for 11 h at 50 °C. The reaction mixture was evaporated. The residue was taken up in a mixture of dichloromethane (6 mL) and methanol (6 mL). To the solution was added 1,2-ethylenediamine (40 µL, 0.598 mmol) and the reaction mixture was stirred for 5.5 h at 50 °C. The reaction mixture was evaporated. The residue was taken up in dichloromethane (40 mL) and the organic layer was washed with water (3 x 10 mL). The combined aqueous layers were extracted with dichloromethane (1 x 40 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over sodium sulfate, filtered and evaporated. To the residue was added acetonitrile (2 mL) and the mixture was evaporated. The residue was purified by preparative HPLC to afford the title compound (11.0 mg, 0.0290 mmol, 10% over 2 steps) as an off-white powder.

LCMS Method F: 99%, tR=1.665 min, m/z = 380.3 [M+H] ^{+ 1} H NMR (500 MHz, DMSO-d ₆ ) d 11.73 (s, 1H), 8.10 (d, J = 5.4 Hz, 1H), 7.58– 7.52 (m, 2H), 7.39 (s, 1H), 7.31– 7.23 (m, 2H), 6.70 (d, J = 5.6 Hz, 1H), 4.42 (s, 2H), 3.83 (s, 2H), 3.26 (s, 3H), 2.38– 2.30 (m, 2H), 2.13 (s, 3H), 2.13– 2.05 (m, 2H), 1.50– 1.41 (m, 2H), 1.29– 1.20 (m, 2H), 0.84 (s, 3H). Example 14: 4-[(4-Methyl-4-piperidyl)methoxy]-1H-pyrrolo[2,3-b]pyridine- 3-carbonitrile

Step1

tert-Butyl 4-[[3-cyano-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]py ridin-4-yl]oxymethyl]-4- methylpiperidine-1-carboxylate (14-1a)

To a solution of tert-butyl 4-(((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-4-yl)oxy)methyl)-4-methylpiperidine-1- carboxylate (300 mg, 0.542 mmol) and zinc cyanide (96 mg, 0.81 mmol) in anhydrous, degassed N,N-dimethylformamide (3 mL) was added tetrakis(triphenylphosphine)palladium (125 mg, 0.108 mmol) and the reaction mixture was stirred at 110 °C for 18 h. To the reaction mixture was added zinc cyanide (192 mg, 1.62 mmol) and tetrakis(triphenylphosphine)palladium (250 mg, 0.216 mmol) and the reaction mixture was stirred at 150 °C for 4 h. The reaction was quenched with saturated aqueous sodium bicarbonate (9 mL) and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (105 mg, 0.210 mmol, 39%) as a colorless oil.

LCMS Method H: 96%, tR=2.596 min, m/z = 501.2 [M+H] ⁺

Step 2

4-[(4-Methyl-4-piperidyl)methoxy]-1H-pyrrolo[2,3-b]pyridi ne-3-carbonitrile (14-1)

A mixture of tert-butyl 4-(((3-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo [2,3- b]pyridin-4-yl)oxy)methyl)-4-methylpiperidine-1-carboxylate (95 mg, 0.19 mmol) and hydrogen chloride (4.7 M in 1,4-dioxane, 1.9 mL, 8.93 mmol) was stirred at room temperature for 6 h. The reaction mixture was evaporated and the residue was taken up in a mixture of dichloromethane (2.4 mL), methanol (2.4 mL) and 1,2-ethylenediamine (25 µL, 0.38 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC to afford the title compound (19 mg, 0.070 mmol, 37%).

LCMS Method F: 100%, tR=1.339 min, m/z = 271.1 [M+H] ⁺

1H NMR (500 MHz, DMSO-d6) d 8.19 (d, J = 5.5 Hz, 1H), 8.18 (s, 1H), 6.82 (d, J = 5.6 Hz, 1H), 3.91 (s, 2H), 3.60– 3.30 (m, 1H), 2.75– 2.63 (m, 4H), 1.56– 1.47 (m, 2H), 1.42– 1.32 (m, 2H), 1.11 (s, 3H). Example 15: 3-(2-Fluorophenyl)-6-methyl-4-(piperidin-4-ylmethoxy)-1H-pyr rolo[2,3-b]pyridine hydrochloride

Step 1

tert-Butyl 4-(((6-chloro-3-(2-fluorophenyl)-1-((2-(trimethylsilyl)ethox y)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)methyl)piperidine-1-carboxylate (15-1a) A mixture of tert-butyl 4-(((6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H - pyrrolo[2,3-b]pyridin-4-yl)oxy)methyl)piperidine-1-carboxyla te (300 mg, 0.483 mmol), 2- fluorophenylboronic acid (68 mg, 0.48 mmol), RuPhos palladacycle G3 (40 mg, 0.048 mmol) and aqueous tribasic potassium phosphate (2 M, 0.725 mL, 1.45 mmol) in toluene (6 mL) and ethanol (1.5 mL) was stirred at room temperature for 28 h under argon. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 60:40) to afford the title compound (302 mg, crude) as a brown oil, which was used without further purification.

LCMS Method H: 97%, tR=3.385 min, m/z = 590.1 [M+H]+

Step 2

tert-Butyl 4-(((3-(2-fluorophenyl)-6-methyl-1-((2-(trimethylsilyl)ethox y)methyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)oxy)methyl)piperidine-1-carboxylate (15-1b)

A mixture of crude tert-butyl 4-(((6-chloro-3-(2-fluorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )oxy)methyl)piperidine-1- carboxylate (282 mg), trimethylboroxine (201 µL, 1.44 mmol), RuPhos palladacycle G3 (40 mg, 0.048 mmol) and aqueous tribasic potassium phosphate (2 M, 0.761 mL, 1.52 mmol) in toluene (5.6 mL) and ethanol (1.4 mL) was stirred at 80 °C for 18 h under argon. To the reaction mixture was added trimethylboroxine (201 µL, 1.44 mmol) and RuPhos palladacycle G3 (40 mg, 0.048 mmol) and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 60:40) to afford the title compound (140 mg, 0.250 mmol, 52% over two steps) as a colorless oil.

LCMS Method H: 94%, tR =3.080 min, m/z = 570.2 [M+H]+

Step 3

3-(2-Fluorophenyl)-6-methyl-4-(piperidin-4-ylmethoxy)-1H- pyrrolo[2,3-b]pyridine hydrochloride (15-1)

A mixture of tert-butyl 4-(((3-(2-fluorophenyl)-6-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )oxy)methyl)piperidine-1- carboxylate (140 mg, 0.246 mmol) and hydrogen chloride (4.7 M in 1,4-dioxane, 7.5 mL, 35.25 mmol) was stirred for 72 h at room temperature. The reaction mixture was evaporated and the residue was dissolved in a mixture of dichloromethane (3.5 mL), methanol (3.5 mL) and 1,2- ethylenediamine (33 µL, 0.49 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC. The residue was suspended in hydrogen chloride (3.8 M in diethyl ether, 5 mL, 19.0 mmol) and evaporated to afford the title compound (32 mg, 0.094 mmol, 38%) as a white solid.

LCMS Method F: 100%, t _R =1.573 min, m/z = 340.1 [M+H] ⁺

1H NMR (300 MHz, DMSO-d ₆ ) d 12.73 (s, 1H), 9.21– 9.03 (m, 1H), 8.88– 8.65 (m, 1H), 7.55– 7.52 (m, 1H), 7.52– 7.38 (m, 2H), 7.35– 7.22 (m, 2H), 7.04 (s, 1H), 4.09 (d, J = 7.1 Hz, 2H), 3.27– 3.11 (m, 2H), 2.85– 2.71 (m, 2H), 2.70 (s, 3H), 1.90 (s, 1H), 1.62– 1.50 (m, 2H), 1.40– 1.19 (m, 2H). Example 16: 3-(3,5-Difluorophenyl)-4-(4-piperidylmethylsulfanyl)-1H-pyrr olo[2,3-b]pyridine hydrochloride

tert-Butyl 4-[[3-(3,5-difluorophenyl)-1-(2-trimethylsilylethoxymethyl)p yrrolo[2,3-b]pyridin-4- yl]sulfanylmethyl]piperidine-1-carboxylate (16-1a)

To a solution of tert-butyl 4-((acetylthio)methyl)piperidine-1-carboxylate (711 mg, 2.60 mmol) in anhydrous dimethyl sulfoxide (6.5 mL) was added sodium hydride (60% dispersion in mineral oil, 347 mg, 8.68 mmol) and the reaction mixture was stirred for 30 min at room temperature. To the reaction mixture was added a solution of 3-(3,5-difluorophenyl)-4-fluoro-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (820 mg, 2.17 mmol) in anhydrous dimethyl sulfoxide (8.2 mL) and the reaction mixture was stirred for 20 h at room temperature. The reaction mixture was poured into water (150 mL) and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over magnesium sulfate, filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (173 mg, 0.294 mmol, 14%) as a colorless oil.

LCMS Method H: 96%, t _R =3.108 min, m/z = 590.1 [M+H] ⁺

Step 2

3-(3,5-Difluorophenyl)-4-(4-piperidylmethylsulfanyl)-1H-p yrrolo[2,3-b]pyridine hydrochloride (16-1)

A mixture of tert-butyl 4-(((3-(3,5-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)met hyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)thio)methyl)piperidine-1-carbo xylate (173 mg, 0.29 mmol) and hydrogen chloride (4.7 M in 1,4-dioxane, 2.94 mL, 13.82 mmol) was stirred for 2 h at room temperature. The reaction mixture was evaporated and the residue was dissolved in a mixture of dichloromethane (5 mL), methanol (5 mL) and 1,2-ethylenediamine (39 µL, 0.59 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC. The residue was suspended in hydrogen chloride (3.8 M in diethyl ether, 5 mL, 19 mmol) and the mixture was evaporated to afford the title compound (33 mg, 0.077 mmol, 26%) as a pale yellow crystalline solid.

LCMS Method A: 100%, t _R =1.028 min, m/z = 360.1 [M+H] ⁺

1H NMR (500 MHz, DMSO-d ₆ ) d 12.57 (s, 1H), 9.16– 8.90 (m, 1H), 8.83– 8.65 (m, 1H), 8.24 (d, J = 5.7 Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.26– 7.16 (m, 4H), 3.25– 3.17 (m, 2H), 3.10 (d, J = 6.7 Hz, 2H), 2.84– 2.74 (m, 2H), 1.93– 1.87 (m, 2H), 1.87– 1.77 (m, 1H), 1.47– 1.34 (m, 2H). Example 17: 3-(3,5-Difluorophenyl)-4-((piperidin-4-ylmethyl)sulfonyl)-1H -pyrrolo[2,3-b]pyridine hydrochloride

Step 1

tert-Butyl 4-(((3-(3,5-Difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)met hyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)sulfonyl)methyl)piperidine-1-carboxylate (17-1a)

A solution of tert-butyl 4-(((3-(3,5-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)met hyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)thio)methyl)piperidine-1-carbo xylate (160 mg, 0.271 mmol) and 3- chloroperbenzoic acid (77%, 94 mg, 0.42 mmol) in dichloromethane (4 mL) was stirred for 4 h at room temperature. To the reaction mixture was added 3-chloroperbenzoic acid (77%, 94 mg, 0.42 mmol) and the reaction mixture was stirred for 18 h at room temperature. To the reaction mixture was added 3-chloroperbenzoic acid (977%, 4 mg, 0.42 mmol) and the reaction mixture was stirred for 3 d at room temperature. The reaction mixture was filtered and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 50:50) to afford the title compound (46 mg, crude), which was used without further purification.

LCMS Method F: 57%, tR=2.729 min, m/z = 566.1 [M+H-tBu] ⁺

Step 2

3-(3,5-Difluorophenyl)-4-((piperidin-4-ylmethyl)sulfonyl) -1H-pyrrolo[2,3-b]pyridine

hydrochloride (17-1)

A mixture of crude tert-butyl 4-(((3-(3,5-difluorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl )sulfonyl)methyl)piperidine-1- carboxylate (46 mg) and hydrogen chloride (4.7 M in 1,4-dioxane, 740 µL, 3.48 mmol) was stirred for 48 h at room temperature. The reaction mixture was evaporated and the residue was dissolved in a mixture of dichloromethane (1.15 mL), methanol (1.15 mL) and 1,2- ethylenediamine (10 µL, 0.15 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC. The residue was suspended in hydrogen chloride (3.8 M in diethyl ether, 1 mL, 3.8 mmol) and the mixture was evaporated to afford the title compound (3 mg, 0.006 mmol, 2% over two steps) as a yellow oil.

LCMS Method F: 100%, tR=1.584 min, m/z = 392.0 [M+H] ⁺

1H NMR (500 MHz, Methanol-d4) d 8.58 (d, J = 5.0 Hz, 1H), 7.81 (d, J = 5.0 Hz, 1H), 7.75 (s, 1H), 7.19– 7.12 (m, 2H), 7.09– 6.99 (m, 1H), 3.34– 3.28 (m, 2H), 3.04 (d, J = 6.5 Hz, 2H), 2.99– 2.89 (m, 2H), 2.11– 1.99 (m, 1H), 1.99– 1.89 (m, 2H), 1.48– 1.37 (m, 2H). Example 18: 3-(3,5-Difluorophenyl)-N-(piperidin-4-ylmethyl)-1H-pyrrolo[2 ,3-b]pyridin-4-amine dihydrochloride

Step 1

tert-Butyl 4-(((3-(3,5-Difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)met hyl)-1H-pyrrolo[2,3- b]pyridin-4-yl)amino)methyl)piperidine-1-carboxylate (18-1a)

A mixture of 3-(3,5-difluorophenyl)-4-fluoro-1-((2-(trimethylsilyl)ethoxy )methyl)-1H- pyrrolo[2,3-b]pyridine (200 mg, 0.529 mmol) and tert-butyl 4-(aminomethyl)piperidine-1- carboxylate (1.10 g, 5.29 mmol) was stirred for 18 h at 120 °C. The reaction mixture was purified directly by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 60:40) to afford the title compound (220 mg, 0.384 mmol, 73%) as a colorless oil. LCMS Method H: 100%, t _R =2.819 min, m/z = 573.1 [M+H] ⁺

Step 2 3-(3,5-Difluorophenyl)-N-(piperidin-4-ylmethyl)-1H-pyrrolo[2 ,3-b]pyridin-4-amine

dihydrochloride (18-1)

A mixture of tert-butyl 4-(((3-(3,5-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)met hyl)- 1H-pyrrolo[2,3-b]pyridin-4-yl)amino)methyl)piperidine-1-carb oxylate (220 mg, 0.384 mmol) and hydrogen chloride (4.7 M in 1,4-dioxane, 3.8 mL, 17.9 mmol) was stirred for 27 h at room temperature. The reaction mixture was evaporated and the residue was dissolved in a mixture of dichloromethane (5.5 mL), methanol (5.5 mL) and 1,2-ethylenediamine (51 µL, 0.77 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC. The residue was suspended in hydrogen chloride (3.8 M in diethyl ether, 5 mL, 19 mmol) and evaporated to afford the title compound (54 mg, 0.12 mmol, 31%) as a white powder.

LCMS Method F: 100%, t _R =1.592 min, m/z = 343.1 [M+H]+

1H NMR (300 MHz, DMSO-d6) d 14.44– 14.25 (m, 1H), 12.73 (s, 1H), 9.07– 8.96 (m, 1H), 8.95– 8.83 (m, 1H), 8.10 (d, J = 7.0 Hz, 1H), 7.53 (s, 1H), 7.32– 7.24 (m, 1H), 7.24– 7.13 (m, 1H), 6.78 (d, J = 7.1 Hz, 1H), 6.70– 6.62 (m, 1H), 3.35– 3.20 (m, 4H), 2.91– 2.76 (m, 2H), 1.97– 1.83 (m, 3H), 1.56– 1.36 (m, 2H). Example 19: N-Methyl-N-[4-[4-[(4-methyl-4-piperidyl)methoxy]-1H-pyrrolo[ 2,3-b]pyridin-3- yl]phenyl]methanesulfonamide

Step 1

tert-Butyl 4-methyl-4-[[3-[4-(methylamino)phenyl]-1-(2-trimethylsilylet hoxymethyl)pyrrolo[2,3- b]pyridin-4-yl]oxymethyl]piperidine-1-carboxylate (19-1a)

To a mixture of N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anil ine (106 mg, 0.454 mmol) and RuPhos palladacycle G3 (20 mg, 0.024 mmol) in toluene (6 mL) was added a solution of tert-butyl 4-[[3-bromo-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]py ridin-4- yl]oxymethyl]-4-methylpiperidine-1-carboxylate (210 mg, 0.380 mmol) in ethanol (1.6 mL) and aqueous potassium phosphate (1 M, 1.2 mL, 1.2 mmol) under argon. The reaction mixture was stirred at 80 °C for 4.5 h under argon. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (20 mL) and filtered through a pad of Celite. The Celite was washed with ethyl acetate (3 x 20 mL). The combined filtrates were washed with water (3 x 10 mL) and brine (1 x 20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound (280 mg, crude) as an orange oil which was used in the next step without purification.

LCMS Method A: 46%, tR=1.872 min, m/z = 581.4 [M+H] ⁺

Step 2

tert-Butyl 4-methyl-4-[[3-[4-[methyl(methylsulfonyl)amino]phenyl]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]piperidine-1-carboxylate (19- 1b)

To a solution of crude tert-butyl 4-methyl-4-[[3-[4-(methylamino)phenyl]-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]piperidine-1-carboxylate (240 mg) in dichloromethane (12 mL) was added methanesulfonyl chloride (65 µL, 0.83 mmol) and triethylamine (115 µL, 0.824 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 21 h. To the reaction mixture was added was added methanesulfonyl chloride (65 µL, 0.83 mmol) and triethylamine (115 µL, 0.824 mmol) and the reaction mixture was stirred for 5 h at room temperature. The reaction was quenched with water (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with saturated sodium bicarbonate (1 x 10 mL), water (1 x 10 mL) and brine (1 x 10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound (290 mg, crude) as an orange oil which was used in the next step without purification.

LCMS Method A: 49%, tR=2.003 min, m/z = 659.3 [M+H] ⁺

Step 3

N-Methyl-N-[4-[4-[(4-methyl-4-piperidyl)methoxy]-1H-pyrro lo[2,3-b]pyridin-3- yl]phenyl]methanesulfonamide (19-1)

To a solution of crude tert-butyl 4-methyl-4-[[3-[4- [methyl(methylsulfonyl)amino]phenyl]-1-(2-trimethylsilyletho xymethyl)pyrrolo[2,3-b]pyridin-4- yl]oxymethyl]piperidine-1-carboxylate (290 mg) in 1,4-dioxane (10 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 1.9 mL, 7.6 mmol) and the reaction mixture was stirred for 17.5 h at 50 °C. The reaction mixture was evaporated. The residue was taken up in a mixture of dichloromethane (8 mL) and methanol (8 mL). To the solution was added 1,2-ethylenediamine (70 µL, 1.1 mmol) and the reaction mixture was stirred for 5 h at 50 °C. The reaction mixture was evaporated. The residue was partitioned between dichloromethane (10 mL) and water (10 mL). The aqueous layer was extracted with dichloromethane (2 x 40 mL). The combined organic layers were washed with water (1 x 20 mL) and brine (1 x 20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative HPLC to afford the title compound (5.3 mg, 0.0124 mmol, 3% over 3 steps) as an off-white foam.

LCMS Method F: 100%, tR=1.571 min, m/z = 429.1 [M+H] ⁺

1H NMR (500 MHz, Methanol-d ₄ ) d 8.19– 8.09 (m, 1H), 7.62– 7.54 (m, 2H), 7.47– 7.39 (m, 2H), 7.28 (s, 1H), 6.76 (d, J = 5.6 Hz, 1H), 3.97 (s, 2H), 3.35 (s, 3H), 3.22– 3.08 (m, 4H), 2.96 (s, 3H), 1.69– 1.53 (m, 4H), 1.02 (s, 3H). Example 20: N-Benzyl-3-(3,5-difluorophenyl)-4-(4-piperidylmethoxy)-1H-py rrolo[2,3-b]pyridin-6- amine dihydrochloride

Step 1

tert-Butyl 4-[[6-chloro-3-(3,5-difluorophenyl)-1-(2-trimethylsilylethox ymethyl)pyrrolo[2,3- b]pyridin-4-yl]oxymethyl]piperidine-1-carboxylate (20-1a)

A mixture of tert-butyl 4-(((6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H - pyrrolo[2,3-b]pyridin-4-yl)oxy)methyl)piperidine-1-carboxyla te (727 mg, 1.17 mmol), (3,5- difluorophenyl)boronic acid (555 mg, 3.51 mmol), RuPhos palladacycle G3 (98 mg, 0.12 mmol) and aqueous tribasic potassium phosphate (2 M, 1.75 mL, 3.512 mmol) in a mixture of toluene (13 mL) and ethanol (3 mL) was stirred at 80 °C for 16 h under argon. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 75:25) to afford the title compound (200 mg, 0.329 mmol, 28%) as a colorless oil.

LCMS Method H: 100%, tR=3.797 min, m/z = 608.2 [M+H] ⁺

Step 2

tert-Butyl 4-[[6-(benzylamino)-3-(3,5-difluorophenyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]piperidine-1-carboxylate (20- 1b)

To a solution of tert-butyl 4-[[6-chloro-3-(3,5-difluorophenyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]piperidine-1-carboxylate (200 mg, 0.329 mmol), benzylamine (72 µL, 0.66 mmol), [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride (12 mg, 0.016 mmol) and dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphe nyl]-2-yl)phosphine (BrettPhos, 18 mg, 0.033 mmol) in anhydrous 1,4-dioxane (5 mL) was added potassium tert-butoxide (74 mg, 0.659 mmol) and the reaction mixture was stirred at 120 °C for 16 h under argon. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 80:20) to afford the title compound (100 mg, 0.147 mmol, 45%) as an off-white powder.

LCMS Method H: 100%, tR=4.109 min, m/z = 679.3 [M+H] ⁺

Step 3

N-Benzyl-3-(3,5-difluorophenyl)-4-(4-piperidylmethoxy)-1H -pyrrolo[2,3-b]pyridin-6-amine dihydrochloride (20-1)

To tert-butyl 4-[[6-(benzylamino)-3-(3,5-difluorophenyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]piperidine-1-carboxylate (100 mg, 0.147 mmol) was added hydrogen chloride (4.7 M in 1,4-dioxane, 1.5 mL, 7.05 mmol) and the reaction mixture was stirred for 72 h at room temperature. The reaction mixture was evaporated and the residue was dissolved in a mixture of dichloromethane (2.5 mL), methanol (2.5 mL) and 1,2-ethylenediamine (20 µL, 0.294 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC. The residue was suspended in hydrogen chloride (3.8 M in diethyl ether, 5 mL, 19 mmol) and the mixture was evaporated to afford the title compound (15 mg, 0.029 mmol, 20%) as a pale yellow crystalline solid.

LCMS Method F: 99%, t _R =1.897 min, m/z = 449.1 [M+H] ⁺

1H NMR (300 MHz, DMSO-d ₆ ) d 11.81 (s, 1H), 9.06– 8.83 (m, 1H), 8.76– 8.55 (m, 1H), 7.44– 7.35 (m, 4H), 7.35– 7.25 (m, 5H), 7.16– 7.01 (m, 1H), 6.17 (s, 1H), 4.64 (s, 2H), 4.01 (d, J = 6.9 Hz, 2H), 3.34– 3.21 (m, 2H), 2.90– 2.76 (m, 2H), 2.12– 1.96 (m, 1H), 1.89– 1.71 (m, 2H), 1.53– 1.33 (m, 2H). Example 21: 3-(3,5-Difluorophenyl)-N,N-dimethyl-4-(4-piperidylmethoxy)-1 H-pyrrolo[2,3- b]pyridine-5-carboxamide dihydrochloride

Step 1

Methyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]-3-(3,5-difluo rophenyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxyl ate (21-1a)

A mixture of methyl 3-bromo-4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-c arboxylate (370 mg, 0.620 mmol), (3,5-difluorophenyl)boronic acid (292 mg, 1.86 mmol), RuPhos palladacycle G3 (52 mg, 0.062 mmol) and aqueous tribasic potassium phosphate (2 M, 930 µL, 1.86 mmol) in a mixture of toluene (6 mL) and ethanol (1.5 mL) was stirred at 80 °C for 16 h under argon. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:0 to 80:20) to afford the title compound (330 mg, crude) as a pale yellow oil, which was used without further purification LCMS Method A: 65%, t _R =2.200 min, m/z = 632.3 [M+H] ⁺

Step 2

4-[(1-tert-Butoxycarbonyl-4-piperidyl)methoxy]-3-(3,5-dif luorophenyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carboxyl ic acid (21-1b)

To a solution of crude methyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]-3-(3,5- difluorophenyl)-1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3- b]pyridine-5-carboxylate (310 mg) in a mixture of tetrahydrofuran (10 mL) and water (2 mL) was added lithium hydroxide (62 mg, 1.47 mmol) and the reaction mixture was stirred at 40 °C for 43 h. The reaction mixture was concentrated to remove tetrahydrofuran and the residue was diluted with water (5 mL). The mixture was neutralized by addition of 0.6 M hydrochloric acid (5 mL). The mixture was evaporated to afford the title compound (586 mg, crude) as a pale yellow oil, which was used without purification.

LCMS Method A: 62%, tR=2.037 min, m/z = 618.3 [M+H] ⁺

Step 3

tert-Butyl 4-[[3-(3,5-difluorophenyl)-5-(dimethylcarbamoyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]piperidine-1-carboxylate (21- 1c)

To a solution of 4-[(1-tert-butoxycarbonyl-4-piperidyl)methoxy]-3-(3,5-difluo rophenyl)-1- (2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-carbo xylic acid (200 mg, 0.324 mmol) in anhydrous N,N-dimethylacetamide (5 mL) was added dimethylamine hydrochloride (53 mg, 0.648 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (185 mg, 0.486 mmol) and N,N-diisopropylethylamine (224 µL, 1.30 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (50 mL) and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over magnesium sulfate and evaporated. The residue was purified by gradient silica gel column chromatography eluting with n-heptane:ethyl acetate (100:00 to 70:30) to afford the title compound (137 mg, 0.213 mmol, 66%) as a pale yellow oil.

LCMS Method A: 100%, tR=2.053 min, m/z = 645.3 [M+H] ⁺

Step 4

3-(3,5-Difluorophenyl)-N,N-dimethyl-4-(4-piperidylmethoxy )-1H-pyrrolo[2,3-b]pyridine-5- carboxamide dihydrochloride (21-1) To tert-butyl 4-[[3-(3,5-difluorophenyl)-5-(dimethylcarbamoyl)-1-(2- trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-4-yl]oxymet hyl]piperidine-1-carboxylate (137 mg, 0.213 mmol) was added hydrogen chloride (4.7 M in 1,4-dioxane, 2.13 mL, 10.0 mmol) and the reaction mixture was stirred for 5 h at room temperature. The reaction mixture was evaporated and the residue was dissolved in a mixture of dichloromethane (2 mL), methanol (2 mL) and 1,2-ethylenediamine (28 µL, 0.426 mmol). The reaction mixture was stirred at 50 °C for 1 h and then evaporated. The crude product was purified by preparative HPLC. The residue was suspended in hydrogen chloride (3.8 M in diethyl ether, 5 mL, 19 mmol) and the mixture was evaporated to afford the title compound (43 mg, 0.088 mmol, 42%) as an off-white crystalline solid.

LCMS Method A: 100%, t _R =1.011 min, m/z = 415.3 [M+H] ⁺

1H NMR (300 MHz, DMSO-d ₆ ) d 12.41 (d, J = 2.8 Hz, 1H), 9.03– 8.89 (m, 1H), 8.72– 8.54 (m, 1H), 8.12 (s, 1H), 7.86 (d, J = 2.7 Hz, 1H), 7.38– 7.27 (m, 2H), 7.21– 7.03 (m, 1H), 3.59 (d, J = 6.1 Hz, 2H), 3.26– 3.12 (m, 2H), 3.05 (s, 3H), 2.93 (s, 3H), 2.82– 2.63 (m, 2H), 1.83– 1.64 (m, 1H), 1.65– 1.51 (m, 2H), 1.38– 1.22 (m, 2H).

The following compounds were prepared by the same general method:

Biological assays

The ability of the compounds of the invention to inhibit serum and glucocorticoid- regulated kinase 1 (SGK1) was assessed in an enzymatic activity assay by determining their effect on the ability of the isolated SGK enzyme to catalyze the transfer of phosphate from ATP to serine/threonine residues in a substrate peptide, and in cellular assays by determining their effect on cellular function. In one of the cellular assays, the SGK1 dependent phosphorylation of N-myc downstream regulated 1 (NDRG1) protein in MDA-MD-231 cells was measured. In another, functional proliferation assay, SGK1 dependent inhibition of cellular proliferation of human MDA-MB-231 cells was measured.

Kinase activity assay A

The compounds were tested for SGK1 inhibitory activity in a substrate phosphorylation assay designed to measure the ability of the isolated enzyme to catalyze the transfer of phosphate from ATP to serine/threonine residues in a peptide (CKRPRAASFAE) based on the N- terminus of GSK3. Compounds were screened with an ADP-Glo Kinase assay (Promega V9102/3), using activated SGK1 (Thermo Fisher #PR7358A). The enzyme reaction was carried out in assay buffer containing 40 mM Tris-HCl (pH 7.5), 20 mM MgCl2, 0.1 mg/mL BSA and 50 µM DTT. To determine compound dose response, a 50 mM DMSO stock solution was diluted and tested in an eleven-point, three-fold dilution series run in duplicate beginning at 1 mM final concentration. Compound solution (0.5 µL) in 100% DMSO was added to a 96-well plate (Black, ½ area, NBS, Corning #3993). A master mix was made to consist of (final assay concentrations): assay buffer, 40 µg/mL Akt peptide (SignalChem A05-58), 50 µM ATP (provides a maximal kinase signal, but is low enough to allow detection of weak inhibitors). The master mix (22 µL) was added to each well containing compound and the reaction was started by the addition of 14 nM SGK1 (2.5 µL). The reaction was incubated in the dark for 45 min at room temperature. To each well was added an equal volume (25 µL) of ADP-Glo reagent (Promega #V912A) and the plate was incubated in the dark for an additional 40 min at room temperature. To each well was added 50 µL of Kinase Detection Substrate (Promega # V914B) and the plate was incubated in the dark for an additional 30 min at room temperature. The plate was then read on a luminescence plate reader (BMG Clariostar). Data were analyzed using a four- parameter curve fit with a fixed minimum and a maximum experimentally defined as the average of positive and negative controls on each plate using GraphPad Prism 5.0.

Kinase activity assay B Compounds were screened with an Omnia Kinase Assay (ThermoFisher) using activated SGK1 (Thermo Fisher #PR7358A) and AQT0076 Sox labeled peptide substrate (Thermo Fisher # KNZ1041). The enzyme reaction was carried out in assay buffer containing (final assay concentrations): 50 mM HEPES (pH 7.4), 10 mM MgCl ₂ , 1 mM DTT, 0.01% Brij-35, 0.5 mM EGTA, 10 µM peptide substrate and 50 µM ATP. To determine compound dose response, a 50 mM DMSO stock solution was serially diluted and tested in a dilution series run in duplicate beginning at 100 µM final concentration. Compound solution (1 µL) in 20% DMSO was added to a 384-well plate (Black, Corning #4514). The assay buffer (17 µL) was added to each well containing compound and the plate was incubated at 27 °C for 5 min. The reaction was started by the addition of 5 nM SGK1 (2 µL). The plate was then read on a luminescence plate reader (BMG Clariostar). Data were analyzed using a four- parameter curve fit with a fixed minimum and a maximum experimentally defined as the average of positive and negative controls on each plate using GraphPad Prism 5.0.

Kinase activity assay C

Compounds were screened with an Omnia Kinase Assay (Assay Quant Technologies) using activated SGK1 (Thermo Fisher #PR7358A) and AQT0080 Sox labeled peptide substrate (Assay Quant Technologies). The enzyme reaction was carried out in assay buffer containing (final assay concentrations): 50 mM HEPES (pH 7.4), 10 mM MgCl2, 1 mM DTT, 0.01% Brij-35, 0.5 mM EGTA, 5 µM peptide substrate and 100 µM ATP. To determine compound dose response, a 50 mM DMSO stock solution was serially diluted and tested in a dilution series run in duplicate beginning at 100 µM final concentration. Compound solution (1 µL) in 20% DMSO was added to a 384-well plate (Black, Corning #4514). The assay buffer (17 µL) was added to each well containing compound and the plate was incubated at 27 °C for 5 min. The reaction was started by the addition of 2 nM SGK1 (2 µL). The plate was then read on a luminescence plate reader (BMG Clariostar). Data were analyzed using a four- parameter curve fit with a fixed minimum and a maximum experimentally defined as the average of positive and negative controls on each plate using GraphPad Prism 5.0.

Cell Biology

Anti-proliferative activity of compounds was determined in a TNBC cell line. MDA-MB-231 cells were cultured in 96-well plates in triplicate with RPMI media supplemented with 10% fetal bovine serum, 2 mM glutamine and 100 units/mL penicillin/streptomycin (“complete media”), and were allowed to attach overnight. For analysis of growth inhibition, compounds were added over an 11 point dose range with a final DMSO concentration of 0.1%. Cell proliferation was determined at 48 h post-compound addition by measurement of BrdU incorporation (BioVision) according to the manufacturer’s instructions. Incorporation of BrdU was plotted with a best-fit sigmoidal variable slope dose–response curve using GraphPad Prism 5.0.

Anti-proliferative activity of compounds was determined in thyroid cancer cell lines. T683 or M957 cells were cultured in 96-well plates in triplicate with Dulbecco’s Modified Eagle Media (DMEM) and were allowed to attach overnight. For analysis of growth inhibition, compounds were added over a 10 point dose range with a final DMSO concentration of 0.1%. Cell proliferation was determined at 48 h post-compound addition by replacement of the medium with fresh DMEM and addition of Alamar blue. Cells were incubated for an additional 2-4 h and fluorescence was read according to the manufacturer’s instructions. Relative fluorescence was plotted with a best-fit sigmoidal variable slope dose–response curve using GraphPad Prism 5.0. Measurement of inhibition of NDRG1 phosphorylation (SGK1 biomarker) in cells

The protein N-myc downstream regulated 1 (NDRG1) is an established biomarker for SGK1 cellular activity that has been used to monitor the activity of several SGK1 inhibitors (Ackermann, et al., Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol.2011, 28, 137–146; Heikamp, et al., Nat. Immunol. 2014, 15, 457–464; Mansley, et al., Br. J. Pharmacol. 2010, 161, 571–588). NDRG1 Ser346 is specifically phosphorylated by SGK1 and not by other kinases (McCaig, et al., Biochem. Biophys. Res. Commun., 2011, 411, 227–234; Murray, et al., Biochem. J., 2004, 384, 477–488). This residue is not phosphorylated in sgk1 -/- animal tissues54. Thus, NDRG1 phosphorylation is a biomarker to assess SGK1 activity in cells and tissues.

After overnight plating of cancer cells in 12-well plates in triplicate, compounds were added over an 8-point dose range (DMSO £0.1%). After 1 h of compound incubation, the cells were fixed with 4% formaldehyde, permeabilized with ice cold methanol, and incubated with phospho-NDRG1 (Thr346) (D98G11) XP® Rabbit mAb (Alexa Fluor® 647 Conjugate Cell Signaling). NDRG1 phosphorylation was detected by flow cytometric analysis on a Miltenyi MACS Quant Analyzer 10 flow cytometer. GraphPad Prism 5.0 was used to plot growth inhibition with a best- fit sigmoidal variable slope dose-response curve.

Caco-2 permeability

Caco-2 cell plates were obtained commercially and were maintained for 21 d at 37 ºC with 5% CO2. Cells were washed with Hank’s Balanced Salt Solution (HBSS) 30 min before starting the experiment. Test compound solutions were prepared by diluting from DMSO stock into HBSS buffer.

Prior to the experiment, cell monolayer integrity was verified by transendothelial electrical resistance (TEER). The transport experiment was initiated by adding test compounds to the apical (75 mL) or basal (250 mL) side. Transport plates were incubated at 37 ºC in a humidified incubator with 5% CO2. Samples were taken from the donor and acceptor compartments after 1 hour and analyzed by liquid chromatography with tandem mass spectrometry (LC/MS/MS).

Apparent permeability (Papp) values were calculated using the following equation:

Papp = (dQ/dt)/A/C0

where dQ/dt is the initial rate of amount of test compound transported across cell monolayer, A is the surface area of the filter membrane, and C0 is the initial concentration of the test compound.

Net flux ratio between the two directional transports was calculated by the following equation:

Ratio = Papp, B-A/Papp, A-B

where Papp, B-A and Papp, A-B represent the apparent permeability of test compound from the basal to apical and apical to basal side of the cellular monolayer, respectively. Table of biological data

IC50 values reported in the table above were determined using one or both kinase activity assay methods. For assays A and B, potency ranges are reported as A, IC50< 1 µM; B, IC501-10 µM; C, IC ₅₀ >10 µM. For assay C, potency ranges are reported as A, IC ₅₀ < 100 nM; B, IC ₅₀ 100 nM-1 µM; C, IC50 >1 µM.

Cell EC50 values reported in the table above were determined using the cell biology method. Potency ranges are reported as A, EC ₅₀ < 3 µM; B, EC ₅₀ 3-10 µM; C, EC ₅₀ >10 µM.

Caco-2 Papp values reported in the table above were determined using the Caco-2 permeability method. Apparent permeability is reported as the ratio of B-A/A-B.

Abbreviations:

ADME: Absorption, distribution, metabolism, and excretion; ATP:Adenosine 5'- TriPhosphate; BL1:Basal-like 1; BL2:Basal-like 2; BrdU:5-Bromo-2-Deoxyuridine; Ca ²⁺ : Calcium; Caco-2: Human colonic ADENOCARCINOMA cells; ClogP: calculated partition coefficient; cLogP: Calculated Log P; CYP: cytochrome P450 enzymes; DMEM: Dulbecco’s Modified Eagle Media; DMSO: dimethyl sulfoxide; ER: Estrogen receptor; FBS: fetal bovine serum; GR: Glucocorticoid receptor; HLE: high ligand efficiency; HTS: High Throughput Screening; i.v.: IntraVenous; IC ₅₀ : concentration giving half-maximal inhibition; kDa or Da: kilodalton, Dalton; KO: knockout; LE: Ligand efficiency; Lead-like: Compounds that are smaller (MW about 400 Da) and more polar (cLogP approximately 4) than drugs; MEM: Modified Eagle's medium; MLM: mouse liver microsomes; MSL: Mesenchymal Stem cell-Like; MW: molecular weight; PBMC: peripheral blood mononuclear cells; PD: Pharmacodynamics; PK: Pharmacokinetics; PMA: Phosphomolybdic acid; PR: Progesterone receptor; SGK1: Serum and glucocorticoid-regulated kinase 1; TNBC: Triple- negative breast cancer; tPSA: topological polar surface area, a metric of drugs ability to permeate cells; UNC: Unclassified; vScreen: Virtual Screening. Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and etc. used in herein are to be understood as being modified in all instances by the term“about.” Each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters may be modified according to the desired properties sought to be achieved, and should, therefore, be considered as part of the disclosure. At the very least, the examples shown herein are for illustration only, not as an attempt to limit the scope of the disclosure.

The terms“a,”“an,”“the” and similar referents used in the context of describing embodiments of the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illustrate embodiments of the present disclosure and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non- claimed element essential to the practice of the embodiments of the present disclosure.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the embodiments of the present disclosure to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context. In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and describe.