WO2024036305A2 - Process for the preparation of 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1h-pyrazol-4-yl)-1h-pyrrolo[2,3-s]pyridine - Google Patents

Abstract

Provided herein is a synthetic process for preparing a compound of Formula I, or a salt thereof: (I) The disclosure further provides useful intermediates, pharmaceutically acceptable compositions, and salts of the compound of Formula I. These compounds are useful for the treatment of various diseases, including cancer.

Description

Attorney Docket No. GFB0002-401-PC PROCESS FOR THE PREPARATION OF 3-(3,5-DIFLUORO-2- METHOXYPHENYL)-5-(1-(1-(METHYLSULFONYL)PIPERIDIN-4-YL)-1H- PYRAZOL-4-YL)-1H-PYRROLO[2,3-B]PYRIDINE [001] This application claims the benefit of priority of United States provisional application no.63/371,260, filed August 12, 2022, the contents of which are incorporated by reference as if written herein in their entirety. [002] Ovarian cancer is a leading cause of gynecological cancer death. Each year, 230,000 women will be diagnosed with ovarian cancer and 150,000 will die from the disease worldwide. High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and long-term survival has not changed significantly for several decades. Most patients are treated with cytoreductive surgery and combination chemotherapy using carboplatin and paclitaxel. Seventy percent of patients with primary disease experience a clinical response, but <20% of patients can be cured with advanced stage disease. [003] Owing to a need for new therapeutic targets, there has been a search for kinases that regulate the response of ovarian cancer cells to chemotherapeutic drugs, e.g., paclitaxel and carboplatin, and whose inhibition might improve outcomes for women with ovarian cancer. One of the most promising targets to date are salt-induced kinases (SIKs), which are overexpressed in a significant percentage of ovarian cancers. In particular, the overexpression of salt-induced kinase 2 (SIK2) and salt-induced kinase 3 (SIK3) have been linked to ovarian cancer cell proliferation and metastasis. SIK inhibitors sensitize ovarian cancer cell lines and xenografts to chemotherapeutic drugs, and previous studies have discovered that combinations of SIK inhibitors and conventional chemotherapeutic drugs, such as cisplatin, carboplatin, and/or paclitaxel, or combinations of these drugs with other chemotherapeutic drugs known in the art, provide an increased or enhanced anticancer response and increased killing of cancer cells in ovarian and triple-negative breast cancer cell lines and xenografts. [004] Novel potent inhibitors of SIK2 and SIK3 have been described, for example, in US 9,260,426, the contents of which are hereby incorporated by reference in their entirety. The compound 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)- 1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine and related compounds have been described in US 17/584,116, the contents of which are hereby incorporated by reference in their entirety, as inhibitors of SIK2 and SIK3 with promising potential. Attorney Docket No. GFB0002-401-PC [005] There exists a need for new and improved methods for the production of 3- (3,5-difluoro-2-methoxyphenyl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)- 1H-pyrrolo[2,3-b]pyridine and related compounds which are amenable to large-scale, high- purity synthesis. [006] Citation of any reference throughout this application is not to be construed as an admission that such reference is prior art to the present application. SUMMARY [007] Provided herein is a process for preparing a compound of structural Formula I: (I) or a salt thereof,

to a compound of

In some embodiments, PG¹ is chosen from a tosylate group, an acetyl group, a trifluoroacetyl group, a benzoyl group, and a 9-fluorenylmethyloxycarbonyl (Fmoc) group. [008] Also provided herein is a composition comprising a compound of Formula I: (I) or a salt thereof, and

[009] Also provided herein is a composition comprising a compound of Formula I: Attorney Docket No. GFB0002-401-PC (I) or a salt thereof, and less solvent. [010] Also

of structural Formula I: I. a patient in need

thereof, comprising administering to the patient therapeutically effective amounts of a compound of Formula I or a composition of Formula I and at least one additional chemotherapeutic drug. [012] Also provided herein is a compound of structural formula: or a salt thereof.

[013] Also provided is a method for inhibiting activity of salt-induced kinase 2 (SIK2) or salt-induced kinase 3 (SIK3), or a mutant thereof, in a biological sample, comprising the step of contacting the biological sample with a compound as recited herein, or a composition as recited herein. [014] Also provided is a method for inhibiting activity of salt-induced kinase 2 (SIK2) or salt-induced kinase 3 (SIK3), or a mutant thereof, in a patient, comprising the step of administering to the patient a compound as recited herein, or a composition as recited herein. Attorney Docket No. GFB0002-401-PC [015] Also provided is a method for treating a SIK2-mediated disorder in a subject in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound as recited herein, or a composition as recited herein. [016] Also provided is a method for treating a SIK3-mediated disorder in a subject in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound as recited herein, or a composition as recited herein. [017] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds. BRIEF DESCRIPTION OF THE DRAWINGS [018] FIG.1 shows the XRD diffractogram of a compound of structural Formula I. [019] FIG.2 shows the chemical structure and a three-dimensional cartoon model of a compound of structural Formula I. DETAILED DESCRIPTION [020] Provided herein is a process for preparing a compound of structural Formula I: (I) or a salt thereof,

to a compound of

[021] In some embodiments, PG¹ is chosen from a tosylate group, an acetyl group, a trifluoroacetyl group, a benzoyl group, and a 9-fluorenylmethyloxycarbonyl (Fmoc) group. [022] In some embodiments, the conversion comprises reacting the compound of Formula II with a base in a protic solvent. Attorney Docket No. GFB0002-401-PC [023] In some embodiments, the base is chosen from potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, and sodium tert-butoxide. [024] In some embodiments, the base is used in a molar excess of about 4:1 to 6:1 relative to the compound of Formula II. [025] In some embodiments, the protic solvent is chosen from tert-butanol, n- butanol, ethanol, isopropanol, methanol, and water. [026] In some embodiments, the protic solvent is tert-butanol. [027] In some embodiments, the conversion is carried out at a temperature of about 55°C to about 70°C. [028] In some embodiments, the process further comprises isolating the compound of Formula I, or a salt thereof, wherein after said isolating the compound of Formula I, or a salt thereof, has a purity of about 99.5% or greater as determined by HPLC. [029] In some embodiments, the compound of Formula II is prepared by contacting a

with mesyl chloride in the

a compound of Formula II. [030] In some embodiments, the mesyl chloride is used in a molar excess of about 1.5:1 to 2.5:1 relative to the compound of Formula III. [031] In some embodiments, the non-nucleophilic base is chosen from N,N- diisopropylethylamine (DIPEA), triethylamine (TEA), 8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 2,6-di-tert-butylpyridine, tert-butyl-lithium, tert- butyl-phosphazene, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide, potassium bis(trimethylsilyl)amide (KHMDS), lithium Attorney Docket No. GFB0002-401-PC tetramethylpiperidide (LiTMP), sodium hydride, potassium hydride, sodium tert-butoxide, and potassium tert-butoxide. [032] In some embodiments, the non-nucleophilic base is triethylamine (TEA). [033] In some embodiments, the base is used in a molar excess of about 4:1 to 6:1 relative to the compound of Formula III. [034] In some embodiments, the contacting is carried out in an aprotic solvent, such as dichloromethane, chloroform, tetrahydrofuran, acetonitrile, or dichloroethane. In some embodiments, the solvent is dichloromethane or chloroform. [035] In some embodiments, the contacting is carried out at a temperature of about 10°C to about 20°C. [036] In some embodiments, the process further comprises isolating the compound of Formula II, wherein after said isolating the compound of Formula II has a purity of about 98.0% or greater as determined by HPLC. [037] In some embodiments, the compound of Formula III is prepared by contacting a

with a strong acid to form

is a protecting group. [038] In some embodiments, the strong acid is chosen from hydrochloric acid, trifluoroacetic acid (TFA), sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, and perchloric acid. [039] In some embodiments, the strong acid is TFA. [040] In some embodiments, the strong acid is used in a molar ratio of about 1:1 to 2:1 relative to the compound of Formula IV. Attorney Docket No. GFB0002-401-PC [041] In some embodiments, the contacting is carried out in an aprotic solvent, such as dichloromethane, tetrahydrofuran, acetonitrile, or dichloroethane. In some embodiments, the solvent is dichloromethane. [042] In some embodiments, the contacting of Formula IV with strong acid is carried out at a temperature of about 10°C to about 20°C. [043] In some embodiments, PG² is chosen from tert-butyoxycarbonyl (Boc), trityl, benzylidene, and carbobenzyloxy (Cbz). [044] In some embodiments, the compound of Formula IV

is prepared by contacting the compound of Formula V with a compound of Formula VI: in the presence of

wherein X is chosen from bromo, chloro, fluoro, and iodo. [045] In some embodiments, the transition metal catalyst is chosen from palladium, nickel, iron, copper, and ruthenium. [046] In some embodiments, the transition metal catalyst is palladium. [047] In some embodiments, the transition metal catalyst is Pd(dppf)Cl2. [048] Also provided herein is a compound of Formula I: (I) or a salt thereof, prepared by

Attorney Docket No. GFB0002-401-PC [049] In some embodiments, the process further comprises formulating the compound of Formula I, or a salt thereof, into a pharmaceutical composition. [050] Also provided herein is a composition comprising a compound of Formula I: (I) or a salt thereof, and less

[051] Also a a of Formula I: (I) or a salt thereof, and less solvent.

[052] Also provided herein is crystalline form of a compound of structural Formula I: I.

of structural Formula I: I is substantially free of

[054] In some embodiments, the compound is characterized by having an X-ray diffraction (XRD) pattern with peaks at about 11.6, 17.9, 18.9, 20.2, and 22.6 ± 0.3 degrees two theta, wherein the XRD is measured using an incident beam of Mo radiation. Attorney Docket No. GFB0002-401-PC [055] In some embodiments, the compound is characterized by having an X-ray diffraction (XRD) pattern with peaks at about 6.7, 11.6, 13.4, 17.9, 18.9, 20.2, and 22.6 ± 0.3 degrees two theta, wherein the XRD is measured using an incident beam of Mo radiation. [056] In some embodiments, the compound is characterized by having an X-ray diffraction (XRD) pattern with peaks at about 6.7, 11.6, 13.4, 17.5, 17.9, 18.9, 19.6, 20.2, 22.6, and 27.5 ± 0.3 degrees two theta, wherein the XRD is measured using an incident beam of Mo radiation. [057] In some embodiments, the compound is characterized by having an X-ray diffraction (XRD) pattern with peaks at about 7.6, 4.9, 4.7, 4.4, and 3.9 Å in d-spacing, wherein the XRD is measured using an incident beam of Mo radiation. [058] In some embodiments, the compound is characterized by having an X-ray diffraction (XRD) pattern with peaks at about.2, 7.6, 6.6, 5.0, 4.7, 4.4, and 3.9 Å in d-spacing, wherein the XRD is measured using an incident beam of Mo radiation. [059] In some embodiments, the compound is characterized by having an X-ray diffraction (XRD) pattern with peaks at about 13.2, 7.6, 6.6, 5.1, 5.0, 4.7, 4.5, 4.4, 3.9, and 3.2 Å in d-spacing, wherein the XRD is measured using an incident beam of Mo radiation. [060] In some embodiments, the compound is characterized by having an X-ray diffraction (XRD) pattern substantially as shown in FIG.1. [061] Also provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient therapeutically effective amounts of a compound of Formula I, or a salt thereof, as described herein, or a composition as described herein, and at least one additional chemotherapeutic drug. [062] Also provided herein is a compound of structural formula: or a salt thereof.

[063] In some embodiments, the compound of Formula I is 3-(3,5-difluoro-2- methoxyphenyl)-5-(1-(1-(methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3- b]pyridine. [064] In some embodiments, the compound of Formula III is: Attorney Docket No. GFB0002-401-PC [065] In some IV is:

[066] In some is:

[067] In some

Formula VI is: [068] Also

of salt-induced kinase 2 (SIK2) or salt-induced kinase 3 (SIK3), or a mutant thereof, in a biological sample, comprising the step of contacting the biological sample with a compound as recited herein, or a composition as recited herein. [069] Also provided is a method for inhibiting activity of salt-induced kinase 2 (SIK2) or salt-induced kinase 3 (SIK3), or a mutant thereof, in a patient, comprising the step of administering to the patient a compound as recited herein, or a composition as recited herein. [070] Also provided is a method for treating a SIK2-mediated disorder in a subject in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound as recited herein, or a composition as recited herein. [071] In some embodiments, the subject is a human. Attorney Docket No. GFB0002-401-PC [072] In some embodiments, the SIK2-mediated disorder is chosen from cancer, autophagy function, stroke, obesity, and type II diabetes. [073] In some embodiments, the SIK2-mediated disorder is cancer. [074] Also provided is a method for treating a SIK3-mediated disorder in a subject in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound as recited herein, or a composition as recited herein. [075] In some embodiments, the SIK3-mediated disorder is chosen from cancer, autophagy function, stroke, obesity, and type II diabetes. [076] In some embodiments, the SIK3-mediated disorder is cancer. [077] In some embodiments, the cancer is chosen from ovarian, breast, prostate, diffuse large B-cell lymphoma, lung, NSCL and melanoma. [078] In some embodiments, the cancer is ovarian cancer. Definitions [079] As used herein, the terms below have the meanings indicated. [080] When ranges of values are disclosed, and the notation “from n₁ … to n₂” or “between n1 … and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 µM (micromolar),” which is intended to include 1 µM, 3 µM, and everything in between to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.). [081] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a range. When no particular range, such as a margin of error or a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean the greater of the range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures, and the range which would encompass the recited value plus or minus 20%. [082] The term “protecting group,” as used herein, refers to a chemical moiety that is temporarily attached to a functional group to prevent said group from reacting under one or more synthetic conditions. Attorney Docket No. GFB0002-401-PC [083] When a group is defined to be “null,” what is meant is that said group is absent. [084] The term “disease” as used herein means any disease or other deleterious condition in which a SIK2 and/or SIK3 is known to play a role. The term “disease” also means those diseases or conditions that are alleviated by treatment with SIK2 and/or SIK3 modulators. Such conditions include, without limitation, cancer and other hyperproliferative disorders as well as inflammation. In certain embodiments, the cancer is a cancer of colon, breast, stomach, prostate, pancreas, or ovarian tissue. [085] The term “SIK2-mediated disorder” or “disease”, as used herein, means any disease or other deleterious condition in which SIK2 activity is known to play a role. The term “SIK3-mediated disorder” or “disease”, as used herein, means any disease or other deleterious condition in which SIK3 activity is known to play a role. [086] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. [087] As used herein, a “SIK2/SIK3 inhibitor” refers to a compound, molecule, drug, etc., that inhibits the activity of salt-inducible kinase 2 (SIK2) and/or salt-induced kinase 3 (SIK3), which plays a role in several types of cancer, including ovarian cancer as described herein. As would be known to one of skill in the art, some compounds, molecules, or drugs described herein may inhibit one of SIK2 or SIK3 or may inhibit both SIK2 and SIK3. In some embodiments, a SIK2/SIK3 inhibitor useful for the present disclosure in combination with at least a first chemotherapeutic drug may inhibit only SIK2, referred to as a SIK2 inhibitor, or may inhibit only SIK3, referred to herein as a SIK3 inhibitor. [088] The phrase “therapeutically effective amount” refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of: (1) reducing the size of the tumor; (2) inhibiting tumor metastasis; (3) inhibiting tumor growth; and/or (4) relieving one or more symptoms associated with the cancer. Attorney Docket No. GFB0002-401-PC [089] The term “therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. [090] As used herein the term “treat,” “treating”, or “treatment” means the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example, “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term “treating” in reference to a disorder means a reduction in severity of one or more symptoms associated with that particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder. [091] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human. [092] The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002). [093] The term “therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during Attorney Docket No. GFB0002-401-PC the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like. [094] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine. [095] A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid. Attorney Docket No. GFB0002-401-PC Pharmaceutical Compositions [096] While it may be possible for the compounds described herein to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. [097] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. [098] Formulations of the compounds, or salts thereof, disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Attorney Docket No. GFB0002-401-PC [099] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0100] The compounds, or salts thereof, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit- dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0101] Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the Attorney Docket No. GFB0002-401-PC intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [0102] In addition to the formulations described previously, the compounds, or salts thereof, may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [0103] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth. [0104] The compounds, or salts thereof, may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides. [0105] Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration. [0106] Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less Attorney Docket No. GFB0002-401-PC than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation. [0107] For administration by inhalation, compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds, or salts thereof, according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. [0108] Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient. [0109] It should be understood that in addition to the ingredients particularly mentioned above, the formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. [0110] Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. [0111] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. [0112] The compounds, or salts thereof, can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the Attorney Docket No. GFB0002-401-PC severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity. Indications and Methods of Treatment [0113] Also provided herein are methods for treating SIK2-mediated disorders or SIK3-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of SIK2-mediated disorders or SIK3-mediated disorders. [0114] Specific diseases to be treated by the compounds, compositions, and methods disclosed herein include cancer (ovarian, breast, prostate, diffuse large B-cell lymphoma, lung, NSCL and melanoma), autophagy function, stroke, obesity, and type II diabetes. [0115] Besides being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. EXAMPLES General Synthetic Methods for Preparing Compounds [0116] The following invention is further illustrated by the following Examples. All IUPAC names were generated using CambridgeSoft’s ChemDraw 20.0. [0117] In the Examples below and throughout the disclosure, the following abbreviations may be used: MeCN = acetonitrile; DCM = dichloromethane; DMAP = 4- dimethylaminopyridine; EtOAc = ethyl acetate; DMF = dimethylformamide; EtOH = ethanol; H2O = water; IPA = isopropanol = propan-2-ol; IPAc = iso-propyl acetate; KHMDS = potassium bis(trimethylsilyl)amide; MeOH = methanol; MTBE = methyl tert-butyl ether = TBME = tert-butyl methyl ether; NaBH4 = sodium borohydride; NMP = N-methyl-2- pyrrolidone; PdO(Ac)₂ = palladium diacetate; STAB = sodium triacetoxyborohydride; THF = tetrahydrofuran; ¹H-NMR = Proton Nuclear magnetic Resonance; HPLC = High Performance Liquid Chromatography; UPLC = Ultra Performance Liquid Chromatography; TLC = Thin Attorney Docket No. GFB0002-401-PC Layer Chromatography. Other abbreviations may be used and will be familiar in context to those of skill in the art. Example 1: Synthesis of 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1- (methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine [0118] Formula 1 can be synthesized using the following general synthetic procedure set forth in Scheme 1. Scheme 1

[0119] To a stirred solution of Compound 101 (1.0 eq) and Compound 102 (1.3 eq) in dioxane/water, degassed and purged with nitrogen for 10 minutes, was added potassium Attorney Docket No. GFB0002-401-PC carbonate (6.0 eq) and Pd(dppf)Cl₂ (0.06 eq). The reaction mixture was stirred for 2-3 hours at 25±5°C. Upon completion of the reaction as indicated by TLC, the reaction mixture was diluted with chloroform and filtered through a celite bed. The organic layer was completely distilled to yield the crude product, which was passed through 100-200 mesh silica gel with ethyl acetate in hexanes to afford Compound 103, with a purity of 92.3% and an isolated yield of 75%. Step 2

in acetonitrile/water, degassed and purged with nitrogen for 10 minutes, was added cesium carbonate (2.0 eq) and Pd(dppf)Cl2 (0.06 eq). The reaction mixture was heated to 85±5°C and stirred for 2-3 hours. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature, diluted with chloroform, and filtered through a celite bed. The organic layer was completely distilled to yield the crude product, which was passed through 100-200 mesh silica gel with ethyl acetate in hexanes to afford Compound 105, with a purity of 98.8% and an isolated yield of 85%. Step 3

[0121] A mixture of Compound 105 (100 g, 1.0 eq) in dichloromethane (1000 ml, 10 volumes with respect to compound 105) was stirred for 10-15 minutes at 25±5°C. The reaction mixture was cooled to a temperature between 10-20°C and trifluoroacetic acid (1.7 eq) was added. Following the addition, the reaction vessel was stirred for 8-10 hours at 25±5°C. Upon completion of the reaction as indicated by TLC, the reaction mixture was cooled to a temperature between 0-10°C. The pH was adjusted to >8 with aqueous ammonia (~4 volumes). The reaction mixture was heated to 25±5°C, stirred for an additional 45-60 Attorney Docket No. GFB0002-401-PC minutes, and then filtered. The layers were separated and the aqueous layer was washed with additional dichloromethane. The combined organic layers were washed with water (30 volumes) and NaCl (10%) (10 volumes), then dried with sodium sulfate and concentrated. The residue was charged with dichloromethane (1 volume) and methyl tert-butyl ether (5 volumes) and stirred at 20±5°C for 16-20 hours. The resulting solid was filtered, washed with methyl tert-butyl ether, and dried under vacuum to afford Compound 106, with a purity of 99.32% and an isolated yield of 70%. Step 4 F F F

was stirred for 10-15 minutes at 25±5°C. The reaction mixture was cooled to a temperature between 10-20°C and triethylamine (5.0 eq) was added. Following the addition, the reaction vessel was stirred for 10-15 minutes. Mesyl chloride (1.5 eq) was added and the reaction mixture was heated to 25±5°C and stirred for 2-3 hours. The reaction mixture was then cooled to 10-20°C and a second allotment of mesyl chloride (0.5 eq) was added. Following this second addition, the reaction mixture was stirred at 25±5°C for 16-20 hours. Upon completion of the reaction as indicated by TLC, methyl tert-butyl ether (20 volumes) was added and the reaction mass was stirred for 1-2 hours. The resulting solid was filtered and washed with methyl tert-butyl ether, then charged in a mixture of acetone (8 volumes) and dichloromethane (10 volumes). The reaction mass was stirred for 10-15 minutes at 25±5°C, heated to at 70±5°C for 45-60 minutes, then cooled to 25±5°C and stirred for an additional 16-20 hours. The resulting solid was filtered, washed with acetone, and dried under vacuum to afford Compound 107, with a purity of 99.22% and an isolated yield of 80%. Step 5 Attorney Docket No. GFB0002-401-PC [0123] A mixture of Compound 107 (100 g, 1.0 eq) in tert-butanol (10 volumes) was stirred for 10-15 minutes at 25±5°C, then charged with potassium tert-butoxide (5.0 eq). The reaction mixture was stirred for 10-15 minutes, then heated to 60±5°C and stirred for 1-2 hours. Upon completion of the reaction as indicated by TLC, methyl tert-butyl ether (10 volumes) was added and the reaction mass was stirred for 30-60 minutes at 25±5°C. The resulting solid was filtered and washed with methyl tert-butyl ether, then charged with water (10 volumes), stirred for 30-45 minutes, and filtered again. The solid was charged with acetone (10 volumes), stirred for 10-15 minutes, then filtered, washed with acetone and methyl tert-butyl ether, and dried under vacuum to afford the compound of Formula I, with a purity of >99.6% and an isolated yield of 60%. Example 2: Single Crystal of 3-(3,5-difluoro-2-methoxyphenyl)-5-(1-(1- (methylsulfonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine [0124] Crystal data was collected on a Bruker D8 Quest diffractometer. The crystals were collected at room temperature. The instrument was equipped with a graphite monochromatized Mo Kα X-ray source (λ = 0.71073 Å). The X-ray generator was operated at 50 kV and 1 mA. The X-ray data acquisition was monitored by the APEX3 program suite. Data were corrected for Lorentz–polarization and absorption effects using the SAINT and SADABS programs, which are an integral part of the APEX3 package. The structures were solved by direct methods and refined by full-matrix least squares, based on F², using SHELXL. Crystal structures were refined using Olex2-1.0 software. Anisotropic refinement was performed for all non-H atoms. All hydrogen atoms were refined isotropically. The structures were examined using the ADSYM subroutine of PLATON to ensure that no additional symmetry could be applied to the models. Mercury software was used to prepare packing diagrams and molecular interactions. Crystal data, data collection, and structure refinement details are summarized in Table 1. Table 1. Crystal data, data collection, and structure refinement details Crystal data

Attorney Docket No. GFB0002-401-PC β = 99.143 (1)° T = 298 K V = 2257.50 (15) Å3 Needle, colourless Z 4 2 1

[0125] The single crystal structure of the sample agrees with the given molecular structure of the compound of Formula I. Per single crystal X-ray diffraction (XRD) data, the positions of all heteroatoms, heterocyclic rings, along with the position of fluoro and methoxy groups, is clearly distinguished and identified. The structure is free from any solvate or hydrate form. See FIGS.1 and 2 and Table 2. Table 2. XRD peak data Peak number 2-Theta d-spacing Intensity (I) I/Imax

Attorney Docket No. GFB0002-401-PC Peak number 2-Theta d-spacing Intensity (I) I/Imax 12 17.5024 5.06295 744· 28.5

[0126] All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls. [0127] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

Attorney Docket No. GFB0002-401-PC CLAIMS We claim: 1. A process for preparing a compound of Formula I: I or a salt of Formula II:

II to a

wherein PG¹ is a protecting group. 2. The process of claim 1, wherein PG¹ is chosen from a tosylate group, an acetyl group, a trifluoroacetyl group, a benzoyl group, and a 9-fluorenylmethyloxycarbonyl (Fmoc) group. 3. The process of claim 1 or 2, wherein the conversion comprises reacting the compound of Formula II with a base in a protic solvent. 4. The process of claim 3, wherein the base is chosen from potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, and sodium tert-butoxide. 5. The process of claim 4, wherein the base is used in a molar excess of about 4:1 to 6:1 relative to the compound of Formula II. 6. The process of any one of claims 3-5, wherein the protic solvent is chosen from tert- butanol, n-butanol, ethanol, isopropanol, methanol, and water. 7. The process of claim 6, wherein the protic solvent is tert-butanol. 8. The process of any one of claims 3-7, wherein the conversion is carried out at a temperature of about 55°C to about 70°C. 9. The process of any one of the preceding claims, further comprising isolating the compound of Formula I, or a salt thereof, wherein after said isolating the compound Attorney Docket No. GFB0002-401-PC of Formula I, or a salt thereof, has a purity of about 99.5% or greater as determined by HPLC. 10. The process of any one of the preceding claims, wherein the compound of Formula II II is prepared

with mesyl

base to produce a compound of Formula II. 11. The process of claim 10, wherein the mesyl chloride is used in a molar excess of about 1.5:1 to 2.5:1 relative to the compound of Formula III. 12. The process of claim 10, wherein the non-nucleophilic base is chosen from N,N- diisopropylethylamine (DIPEA), triethylamine (TEA), 8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 2,6-di-tert-butylpyridine, tert-butyl- lithium, tert-butyl-phosphazene, lithium diisopropylamide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium tert-butoxide, potassium bis(trimethylsilyl)amide (KHMDS), lithium tetramethylpiperidide (LiTMP), sodium hydride, potassium hydride, sodium tert-butoxide, and potassium tert-butoxide. 13. The process of claim 12, wherein the non-nucleophilic base is triethylamine (TEA). 14. The process of any one of claims 12-13, wherein the base is used in a molar excess of about 4:1 to 6:1 relative to the compound of Formula III. 15. The process of claim 10, wherein the contacting is carried out at a temperature of about 10°C to about 20°C. 16. The process of any one of claims 10-15, further comprising isolating the compound of Formula II, wherein after said isolating the compound of Formula II has a purity of about 98.0% or greater as determined by HPLC. Attorney Docket No. GFB0002-401-PC 17. The process of any one of claims 10-16, wherein the compound of Formula III IV wherein PG² is a

protecting group. 18. The process of claim 17, wherein the strong acid is chosen from hydrochloric acid, trifluoroacetic acid (TFA), sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, and perchloric acid. 19. The process of claim 18, wherein the strong acid is TFA. 20. The process of either claim 18 or 19, wherein the strong acid is used in a molar ratio of about 1:1 to 2:1 relative to the compound of Formula IV. 21. The process of any one of claims 18-20, wherein the contacting is carried out at a temperature of about 10°C to about 20°C. 22. The process of any one of claims 17 to 21, wherein PG² is chosen from tert- butyoxycarbonyl (Boc), trityl, benzylidene, and carbobenzyloxy (Cbz). 23. The process of any one of claims 17 to 22, wherein the compound of Formula IV

is prepared by contacting the compound of Formula V with a compound of Formula VI: Attorney Docket No. GFB0002-401-PC VI in of Formula

IV, 24. The process of claim 23, wherein the transition metal catalyst is chosen from palladium, nickel, iron, copper, and ruthenium. 25. The process of claim 24, wherein the transition metal catalyst is palladium. 26. The process of claim 25, wherein the transition metal catalyst is Pd(dppf)Cl₂. 27. The process of any one of the preceding claims, further comprising formulating the compound of Formula I into a pharmaceutical composition. 28. A compound of Formula I I prepared by

claims. 29. A composition comprising a compound of Formula I: I or a salt

of impurities. 30. A composition comprising a compound of Formula I: I Attorney Docket No. GFB0002-401-PC or a salt thereof, and less than about 0.5% by weight of residual organic solvent. 31. A crystalline form of a compound of structural Formula I: I. 32. The compound as form is substantially

free of solvent. 33. The compound as recited in claim 33, having an X-ray diffraction (XRD) pattern with peaks at about 11.6, 17.9, 18.9, 20.2, and 22.6 ± 0.3 degrees two theta, wherein the XRD is measured using an incident beam of Mo radiation. 34. The compound as recited in claim 33, having an X-ray diffraction (XRD) pattern with peaks at about 6.7, 11.6, 13.4, 17.9, 18.9, 20.2, and 22.6 ± 0.3 degrees two theta, wherein the XRD is measured using an incident beam of Mo radiation. 35. The compound as recited in claim 33, having an X-ray diffraction (XRD) pattern with peaks at about 6.7, 11.6, 13.4, 17.5, 17.9, 18.9, 19.6, 20.2, 22.6, and 27.5 ± 0.3 degrees two theta, wherein the XRD is measured using an incident beam of Mo radiation. 36. The compound as recited in claim 33, having an X-ray diffraction (XRD) pattern with peaks at about 7.6, 4.9, 4.7, 4.4, and 3.9 Å in d-spacing, wherein the XRD is measured using an incident beam of Mo radiation. 37. The compound as recited in claim 33, having an X-ray diffraction (XRD) pattern with peaks at about 13.2, 7.6, 6.6, 5.0, 4.7, 4.4, and 3.9 Å in d-spacing, wherein the XRD is measured using an incident beam of Mo radiation. 38. The compound as recited in claim 33, having an X-ray diffraction (XRD) pattern with peaks at about 13.2, 7.6, 6.6, 5.1, 5.0, 4.7, 4.5, 4.4, 3.9, and 3.2 Å in d-spacing, wherein the XRD is measured using an incident beam of Mo radiation. 39. The compound as recited in claim 33, having an X-ray diffraction (XRD) pattern substantially as shown in FIG.1. 40. A pharmaceutical composition comprising a compound as recited in any one of claims 31–39, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Attorney Docket No. GFB0002-401-PC 41. A method for inhibiting activity of salt-induced kinase 2 (SIK2) or salt-induced kinase 3 (SIK3), or a mutant thereof, in a biological sample, comprising the step of contacting the biological sample with a compound as recited in any one of claims 28 or 31–39, or a composition of any one of claims 29, 30, or 40. 42. A method for inhibiting activity of salt-induced kinase 2 (SIK2) or salt-induced kinase 3 (SIK3), or a mutant thereof, in a patient, comprising the step of administering to the patient a compound as recited in any one of claims 28 or 31–39, or a composition of any one of claims 29, 30, or 40. 43. A method for treating a SIK2-mediated disorder in a subject in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound as recited in any one of claims 28 or 31–39, or a composition of any one of claims 29, 30, or 40. 44. The method of claim 43, wherein the subject is a human. 45. The method of claim 43, wherein the SIK2-mediated disorder is chosen from cancer, autophagy function, stroke, obesity, and type II diabetes. 46. The method of claim 45, wherein the SIK2-mediated disorder is cancer. 47. The method of claim 46, wherein the cancer is chosen from ovarian, breast, prostate, diffuse large B-cell lymphoma, lung, NSCL and melanoma. 48. The method of claim 47, wherein the cancer is ovarian cancer. 49. A method for treating a SIK3-mediated disorder in a subject in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound as recited in any one of claims 28 or 31–39, or a composition of any one of claims 29, 30, or 40. 50. The method of claim 49, wherein the subject is a human. 51. The method of claim 49, wherein the SIK3-mediated disorder is chosen from cancer, autophagy function, stroke, obesity, and type II diabetes. 52. The method of claim 51, wherein the SIK3-mediated disorder is cancer. 53. The method of claim 52, wherein the cancer is chosen from ovarian, breast, prostate, diffuse large B-cell lymphoma, lung, NSCL and melanoma. 54. The method of claim 53, wherein the cancer is ovarian cancer. 55. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound as recited in any one of claims 28 or 31–39, or a composition of any one of claims 29, 30, or 40, and at least one additional chemotherapeutic drug. Attorney Docket No. GFB0002-401-PC 56. A compound of structural formula: