SRPK1 inhibitors and methods of use

Abstract

Provided herein are compounds having the structure of Formula (I) and pharmaceutically acceptable salts thereof, which are useful as modulators of serine / arginine rich splicing factor protein kinase-1 (SRPK1). Further disclosed herein are methods for treating cancer and vascular diseases and disorders.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to compounds useful as modulators of serine / arginine-rich splicing factor-protein kinase-1 (SRPK1), pharmaceutical formulations thereof, and methods of using the compounds to treat cancer and vascular disorders and diseases. BACKGROUND

[0002] Serine / arginine-rich splicing factor-protein kinase-1 (SRPK1) is a kinase that plays an important role in constitutive and alternative splicing processes by regulating the intracellular localization of splicing factors. Most nuclear messenger RNA precursors (pre-mRNAs) in higher eukaryotes contain multiple introns that are precisely excised via RNA splicing. Alternative splicing can allow more than one distinct protein to be produced from a single pre-mRNA. Recently, increasing evidence has demonstrated the important role of SRPK1 in various human disorders and diseases, including various cancers, vascular diseases, and macular degeneration, making it a potential target for various diseases.

[0003] SRPK1 has been reported to be overexpressed in a variety of cancers, including prostate cancer, breast cancer, lung cancer, and glioma (Oncotarget. 2017, 37, 61944). In breast cancer, overexpression of SRPK1 was found to be associated with the development and progression of breast cancer and possible resistance to taxanes (Oncotarget, 2017, 8, 103327). Several studies further established that inhibition / downregulation of SRPK1 causes tumor suppressive effects, such as reduced angiogenesis and reduced cancer cell migration. Therefore, modulators of SRPK1 can be useful as potential new anticancer agents.

[0004] It is also known that SRPK1 plays a role in regulating the expression of vascular endothelial growth factor (VEGF), a key factor in angiogenesis and vascular leakage. VEGF is upregulated during the progression of macular degeneration. In addition, knockdown of SRPK1 effectively reduced VEGF-mediated angiogenesis in tumors in vivo, and inhibition of SRPK1 reduced angiogenesis in vivo. Therefore, SRPK1 is an important target for potential treatment of macular degeneration.

[0005] Accordingly, there is a need for compounds that modulate the SRPK1 pathway that can be used to treat various disorders and diseases, including cancers and vascular diseases. SUMMARY

[0006] Provided herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt thereof:

[0007] wherein: ring A is a 5- to 10-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; Cy is a 4- to 10-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1 to 4 R A ; each R A is independently halo, OH, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 0-6 alkylene-N(R N )2, C 0-6 alkylene-C(O)N(R N )2, C 0-6 alkylene-OC(O)C 1-6 alkyl, C 0-6 alkylene-C(O)C 1-6 alkyl, C 0-6 alkylene-CO2R N , or a C 0-3 alkylene-4- to 8-membered heterocycle having 1, 2, 3, or 3 ring heteroatoms independently selected from N, O, and S; R 1 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl; R 2 is halo, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 haloalkyl, CO2H, or Het; Het is a 5- to 8-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and optionally substituted with 1 or 2 R B ; each R B is independently halo, OH, oxo (=O), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 0-6 alkylene-N(R N )2, C 0-6 alkylene-4- to 8-membered heterocycle having 1, 2, 3, or 3 ring heteroatoms independently selected from N, O, and S; R 3 is H, halo, or C 1-6 alkyl; and each R N is independently H or C1-3 alkyl.

[0008] Also provided herein are pharmaceutical compositions comprising a compound as disclosed herein. Also provided are methods of treating or preventing a disease or disorder associated with aberrant serine / arginine-rich splicing factor kinase-1 (SRPK1) activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein.

[0009] Other aspects and advantages will become apparent to those of ordinary skill in the art upon reading the following detailed description in conjunction with the drawings. While the compounds and methods disclosed herein are susceptible to various modifications and alternative forms, specific implementations are described below, which should not be interpreted as limiting the disclosure to the specific implementations described. DETAILED DESCRIPTION

[0010] There is a need for new SRPK1 inhibitors to provide new and effective treatments for diseases and disorders, such as cancer, as well as vascular diseases and disorders. Provided herein are compounds that can be used as SRPK1 modulators, such as compounds of Formula (I) and pharmaceutically acceptable salts thereof: wherein ring A, Cy, R 1 , R 2 , and R 3 are as described herein.

[0011] Compounds of the disclosure

[0012] Disclosed herein are compounds having the structure of Formula (I) and pharmaceutically acceptable salts thereof:

[0013] wherein:

[0014] ring A is a 5- to 10-membered heterocyclic ring having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S;

[0015] Cy is a 4- to 10-membered heterocyclic ring having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and optionally substituted with 1 to 4 R A ;

[0016] each R A is independently halo, OH, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 0-6 alkylene-N(R N )2, C 0-6 alkylene-C(O)N(R N )2, C 0-6 alkylene-OC(O)C 1-6 alkyl, C0-6 Alkylene-C(O)C 1-6 Alkyl, C 0-6 Alkylene-CO2R N Or C having 1, 2, 3 or 3 independent cyclic heteroatoms selected from N, O and S. 0-3 Alkylene-4 to 8-membered heterocycles;

[0017] R 1 H, halogenated, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0018] R 2 Halogenated, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups, CO2H, or Het;

[0019] Het is a 5- to 8-membered heterocycle having 1, 2, or 3 independent cyclic heteroatoms selected from N, O, and S, and optionally substituted with 1 or 2 R atoms. B ;

[0020] Each R B Independently halogenated, OH, oxo-substituted (=O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 0-6 Alkylene-N(R) N )2 or C having 1, 2, 3 or 3 independent cyclic heteroatoms selected from N, O and S. 0-6 Alkylene-4 to 8-membered heterocycles;

[0021] R 3 H, halogenated or C 1-6 Alkyl; and

[0022] Each R N Independently H or C 1-3 alkyl.

[0023] In compounds of Formula (I), ring A can be a 5- to 10-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. In instances, ring A is aromatic, and is optionally a 5- or 6-membered aromatic ring. In instances, ring A is furan, oxazole, isoxazole, thiophene, thiazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine. In instances, ring A is furan. In some instances, ring A is 2-furan. In some instances, ring A is pyridine. In some instances, ring A is pyrazole.

[0024] In instances, the compound has the structure of Formula (II):

[0025]

[0026] In instances, the compound has the structure of Formula (III):

[0027]

[0028] As disclosed herein, Cy can be a 4- to 10-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. In instances, Cy can be optionally substituted with 1 to 4 R A In many instances, Cy is unsubstituted (i.e., R A groups) are absent. In some instances, Cy is substituted with 1 R A In some instances, Cy is substituted with 2 R A In instances, Cy is azetidine, pyrrolidine, piperidine, piperazine, azepane, morpholine, thiomorpholine, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 2,4,6,7- tetrahydro-pyrazolo[4,3-c]pyridine, 2-oxa-7-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, or 1,8-diazaspiro[4.5]decane. In some instances, Cy is

[0029]

[0030] As disclosed herein, each R A may independently be halo, OH, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 0-6 alkylene-N(R N )2, C 0-6 alkylene-C(O)N(R N )2, C 0-6alkylene-OC(O)C 1-6 alkyl, C 0-6 alkylene-C(O)C 1-6 alkyl, C 0-6 alkylene-CO2R N or C 0-3 alkylene-4- to 8-membered heterocycle. In many instances, at least one R A is OH, F, CH3, C(O)N(R N )2, CH2OH, oxo, CF3, OC(O)CH3, CO2CH3, CO2H, CH2-pyridine, C(O)CH3, or CH2N(R N )2.

[0031] As disclosed herein, R 1 may be H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl. In many instances, R 1 is halo. In some instances, R 1 is CF3. In some instances, R 1 is cyclopropyl.

[0032] As disclosed herein, R 2 may be halo, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CO2H, or Het. In some instances, R 2 is halo, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 1-6 haloalkyl, CO2H, or Het. In many instances, R 2 is halo, C 1-3 alkoxy, or C 1-3 haloalkyl. In some instances, R 2 is Het.

[0033] As disclosed herein, Het can be a 5- to 8-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S. In many instances, Het can be optionally substituted with 1 to 4 R BIn some cases, Het is unsubstituted (no R B In some cases, Het is substituted with 1 R B In some cases, Het is substituted with 2 R B In various cases, Het is pyridine, pyrazole, tetrahydropyran, pyrazine, pyrimidine, pyridazine, or piperidine. In some cases, Het is

[0034] As disclosed herein, each R B may be independently halo, OH, oxo (=0), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 0-6 alkylene-N(R N )2, or C 0-6 alkylene-4- to 8-membered heterocycle having 1, 2, 3, or 3 ring heteroatoms independently selected from N, O, and S. In various cases, at least one R B is NH2, OH, CH3, or F.

[0035] As disclosed herein, R 3 may be H, halo, or C 1-6 alkyl. In various cases, R 3 is H.

[0036] As disclosed herein, each R N may be independently H or C 1-3 alkyl. In various cases, each R N is H or methyl.

[0037] The compounds disclosed herein include those provided in Table A, or a pharmaceutically acceptable salt thereof. For the avoidance of doubt, all stereocenters shown in the compounds of Table A are relative, not absolute stereochemistry.

[0038] Table A

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure unless explicitly described otherwise. For example, unless specifically noted, R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in the present disclosure. Thus, single stereochemical isomers, as well as enantiomeric, diastereomeric, cis / trans, conformational, and rotational mixtures are within the scope of the present disclosure. In some instances, the compounds disclosed herein are stereoisomers. “Stereoisomers” refers to compounds which have a chiral center and which are not identical to each other in three-dimensional structure. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein can exist as single stereoisomers or as mixtures of stereoisomers. Unless otherwise discussed, stereochemistry shown herein represents relative stereochemistry, not absolute stereochemistry. As shown herein, single stereoisomers, diastereomers, or enantiomers refer to compounds that are at least more than 50% of the indicated stereoisomer, diastereomer, or enantiomer, and in some instances, at least 90% or 95% of the indicated stereoisomer, diastereomer, or enantiomer.

[0054] In some instances, the compounds of the disclosure are optically pure. As used herein, “optically pure” refers to a compound that predominantly exists as one enantiomer (e.g., at least a 99% enantiomeric excess) if multiple stereochemical configurations can exist.

[0055] Unless otherwise indicated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0056] The compounds of the present disclosure are defined herein by their chemical structure and / or chemical name. When a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.

[0057] As used herein, the term "alkyl" refers to straight and branched chain saturated hydrocarbon groups containing 1 to 30 carbon atoms, for example, 1 to 20 carbon atoms or 1 to 10 carbon atoms. The term C n means that the alkyl group has "n" number of carbon atoms. For example, C6alkyl refers to an alkyl group having 6 carbon atoms. C 1-7 Alkyl refers to alkyl groups having a number of carbon atoms encompassing the entire range as well as all subsets, i.e., 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl (2-methylpropyl), and t-butyl (1,1-dimethylethyl). Unless otherwise specified, alkyl groups can be unsubstituted alkyl groups or substituted alkyl groups.

[0058] As used herein, the term "alkylene" refers to a divalent saturated aliphatic group. The term C n means that the alkylene group has "n" number of carbon atoms, for example, C1alkylene is CH2. For example, C 1-6 Alkylene refers to alkylene groups having a number of carbon atoms encompassing the entire range as well as all subsets, as previously described for "alkyl" groups.

[0059] As used herein, the term "cycloalkyl" specifically refers to non-aromatic rings in which each atom of the ring is carbon (i.e., carbocyclic), i.e., carbocyclic, and can be monocyclic, bicyclic, bridged cyclic, fused cyclic, or spirocyclic. The term C n means that the cycloalkyl group has "n" number of ring carbon atoms. For example, C5cycloalkyl refers to a cycloalkyl group having 5 ring carbon atoms in the ring. C 3-8 Cycloalkyl refers to cycloalkyl groups having a number of ring carbon atoms encompassing the entire range, i.e., 3 to 8 carbon atoms, as well as all subsets, for example, 4 to 8, 3 to 7, 4 to 7, 3 to 6, 4 to 6, 3 to 5, 4 to 5, 3, 4, 5, 6, 7, and 8 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0060] As used herein, the term "heterocycle" refers to a ring containing one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, and can be aromatic or non-aromatic (e.g., fully saturated or partially unsaturated). Additionally, a heterocycle of the present disclosure can be monocyclic, bicyclic, bridged, fused, or spirocyclic. Non-limiting examples of heterocyclic groups include piperidine, piperazine, tetrahydrofuran, furan, tetrahydropyran, pyran, dihydrofuran, morpholine, oxazepane, oxazole, isoxazole, thiazole, pyrrole, and pyridine. Additional non-limiting examples of heterocyclic groups include benzothiazolyl, quinolinyl, indole, isoquinolinyl, or quinazolinyl, among others.

[0061] As used herein, the term "alkoxy" refers to a "-O-alkyl" group.

[0062] As used herein, the term "halo" refers to a fluorine (F), chlorine (CI), bromine (Br), or iodine (I) group.

[0063] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen. In some cases, the haloalkyl is perhalogenated (i.e., all hydrogen atoms are replaced by halogen atoms). Haloalkyl groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2-fluoroethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl.

[0064] As used herein, the term "haloalkoxy" refers to an alkoxy or "-O-alkyl" group in which one or more hydrogen atoms are replaced by a halogen group. Such groups include, but are not limited to, fluoromethoxy, chloromethoxy, bromomethoxy, fluoroethoxy, iodoethoxy, and the like.

[0065] As used herein, the term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl (OH) group. Such groups include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.

[0066] As used herein, a "substituted" functional group is a functional group having at least one hydrogen group replaced by a non-hydrogen group (i.e., a substituent). Examples of non-hydrogen groups (or substituents) include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkyl, alkynyl, ether, aryl, heteroaryl, heterocycle, hydroxyl, oxo (or oxo), alkoxy, ester, thioester, acyl, carboxyl, cyano, nitro, amino, thiol, and halo. When a substituted alkyl group contains more than one non-hydrogen group, the substituents can be bonded to the same carbon or different carbon atoms.

[0067] Pharmaceutically acceptable salts

[0068] As used herein, the term "pharmaceutically acceptable salt" means a salt of a compound that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio, e.g., as used herein.

[0069] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

[0070] Where a compound described herein contains a basic moiety or a bioisostere that is sufficiently basic, acid addition salts can be prepared by 1) reacting the purified compound in its free base form with a suitable organic or inorganic acid, and 2) isolating the salt thus formed. In practice, acid addition salts can be more convenient to use than the free base form and, for example, the use of such salts is equivalent to the use of the free base form.

[0071] Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate and the like.

[0072] In cases where the compounds described herein contain a carboxyl or a bioisostere acidic enough, base addition salts can be prepared by 1) reacting the purified compound in its acid form with the appropriate organic or inorganic base and 2) isolating the salt thus formed. In practice, use of the base addition salt form can be more convenient and is inherently equivalent to use of the free acid form. Salts derived from appropriate bases include alkali metal (for example, sodium, potassium, and lithium), alkaline earth metal (for example, magnesium and calcium), ammonium and N + (C 1-4 alkyl)4salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products are obtained by such salt formation.

[0073] Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. Sodium and potassium salts are generally preferred. Additional pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, and the like. Suitable amine base addition salts are prepared from amines commonly used in pharmaceutical chemistry because of their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine, and the like.

[0074] Other acids and bases, while not in themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and the pharmaceutically acceptable acid or base addition salts thereof.

[0075] It is understood that the compounds disclosed herein can exist in mixtures / combinations of different pharmaceutically acceptable salts. Mixtures / combinations of compounds in free form and pharmaceutically acceptable salts are also contemplated.

[0076] Pharmaceutical formulations, dosage, and routes of administration

[0077] Also provided herein are pharmaceutical formulations comprising an effective amount of a compound of the disclosure and one or more pharmaceutically acceptable excipients. As used herein, the term “formulation” can be used interchangeably with “composition.”

[0078] “Effective amount” includes “therapeutically effective amount” and “prophylactically effective amount.” The term “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to treat and / or ameliorate a disease or condition of a subject. The term “prophylactically effective amount” refers to an amount effective, at doses and for periods of time necessary, to prevent and / or substantially reduce the chances of a disease or condition of a subject. As used herein, the terms “patient” and “subject” can be used interchangeably and refer to an animal such as a dog, cat, cow, horse, and sheep (i.e., a non-human animal), as well as a human. A particular patient or subject is a mammal (e.g., a human). The terms “patient” and “subject” include both males and females.

[0079] As used herein, the term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient other than the active pharmaceutical ingredient (API), which is suitably selected with respect to the intended form of administration and consistent with conventional pharmaceutical practice.

[0080] The compounds of the disclosure can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds can be administered in a single dose (e.g., by bolus injection), multiple doses (e.g., by a series of tablets), or delivered substantially uniformly over a period of time (e.g., using transdermal delivery). It is also noted that the dosage of the compounds can vary over time.

[0081] If desired, the compounds disclosed herein and other pharmaceutically active compounds can be administered to a subject or patient by any appropriate route, such as orally, topically, rectally, parenterally (e.g., by subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, and intrathecal injection or infusion techniques), or as an oral, inhalation, or nasal spray. Administration can provide a systemic effect (e.g., enterally or parenterally). All methods available to the skilled artisan for administering a pharmaceutically active agent are contemplated. In some cases, the disclosed formulations can be administered orally or topically.

[0082] The compounds used in the methods of the disclosure can be formulated into unit dosage forms. The term “unit dosage forms” refers to physically discrete units suitable for unitary dosing to a subject undergoing therapy, wherein each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. Unit dosage forms can be used for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage forms of each dose can be the same or different.

[0083] The compounds of the present disclosure can be administered to a subject or patient at dosage levels of ranging from about 0.1 mg to about 3000 mg per day. For a normal human adult having a body mass of about 70 kg, a dosage ranging from about 0.01 mg to about 100 mg per kg of body mass is generally sufficient. The specific dosage and dosage range to be used will potentially depend on many factors including the needs of the subject or patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimum dosages for a particular subject or patient is well within the ordinary skill in the art.

[0084] Methods of treatment

[0085] The compounds disclosed herein, and pharmaceutically acceptable salts thereof, can be used as modulators of SRPK1. Serine / arginine-rich splicing factor-protein kinase-1 (SRPK1) is a kinase that plays an important role in constitutive and alternative splicing processes by regulating the intracellular localization of splicing factors. Several studies have further established that inhibition / down-regulation of SRPK1 causes tumor suppressive effects, such as reduced angiogenesis and reduced cancer cell migration. In addition, knockdown of SRPK1 effectively reduced vascular endothelial growth factor (VEGF)-mediated angiogenesis in tumors in vivo, and inhibition of SRPK1 reduced angiogenesis in vivo.

[0086] Therefore, this disclosure provides a method for modulating serine / arginine-rich splicing factor protein kinase-1 (SRPK1), comprising contacting SRPK1 with a therapeutically effective amount of the disclosed compound or salt or a formulation thereof to effectively modulate the amount of SRPK1. In some cases, contact occurs in vitro. In some cases, contact occurs in vivo. In some cases, contact includes administration to a subject in need. As used herein, the terms “patient” and “subject” are used interchangeably and refer to animals such as dogs, cats, cattle, horses, and sheep (i.e., non-human animals), and humans. A specific patient is a mammal (e.g., a human). In many cases, the subject suffers from a disease or condition associated with abnormal SRPK1 activity. In some cases, the disease or condition is cancer. In some cases, the cancer is colon cancer, breast cancer, prostate cancer, pancreatic cancer, kidney cancer, head and neck cancer, leukemia, lymphoma, liver cancer, brain cancer, ovarian cancer, skin cancer, gastrointestinal cancer, or lung cancer. In many cases, a disease or condition can be a vascular disease (e.g., vasoconstriction and conditions characterized by vasoconstriction, as well as cardiovascular disease), malignant or benign tumor formation (e.g., angiogenesis-dependent cancers, such as neoplastic cancers), tumor metastasis, inflammatory diseases, diabetes, diabetic retinopathy, diabetic neovascularization, diabetic macular edema, trachoma, retrolental hyperplasia, neovascular glaucoma, age-related macular degeneration, wet age-related macular degeneration (wAMD), macular edema, hemangioma, or implanted corneal tissue. Immune rejection, corneal angiogenesis associated with eye injury or infection, Osier-Webber syndrome, myocardial angiogenesis, wound granulation tissue hyperplasia, telangiectasia, hemophilic arthritis, angiofibroma, telangiectasia, psoriasis, scleroderma, pyogenic granuloma, iridochromia, obesity, arthritis (e.g., rheumatoid arthritis), hematopoietic disorders, angiogenesis, gingivitis, atherosclerosis, endometriosis, neoendometrial hyperplasia, psoriasis, hirsutism, or proliferative retinopathy, idiopathic pulmonary fibrosis, or diabetic nephropathy.

[0087] In jurisdictions where patentability is prohibited for methods performed on humans, "administration" of a composition to a human subject or patient should be limited to the prescription of a controlled substance that the human subject or patient will self-administer by any technique (e.g., oral, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation is desired, conforming to the law or regulation defining the patentable subject matter. In jurisdictions where patentability is not prohibited for methods performed on humans, "administration" of a composition includes both methods performed on humans and the aforementioned activities.

[0088] Synthesis of compounds of the disclosure

[0089] The compounds of the disclosure can be synthesized by any method known in the art. For example, the compounds of the disclosure (compounds of Formula (I)) can be synthesized according to Schemes 1, 2, and 3.

[0090] Scheme 1

[0091]

[0092] Coupling of the desired Cy group to the desired pyridyl moiety (a) where X is halo yields intermediate (b), which is reduced with Pd / C and H2gas to yield the aminopyridyl moiety (c), which can be coupled to the desired ring A group to yield a compound of the disclosure (d).

[0093] An alternative synthetic scheme is shown in Scheme 2 below.

[0094] Scheme 2

[0095]

[0096] Coupling of the desired Cy group to the desired pyridyl moiety (a’) where X is halo yields intermediate (b’), which can be reduced with Pd / C and H2gas to yield the aminopyridyl moiety (c’), which can be coupled to the desired halo-substituted ring A group to yield another intermediate (d’), which can be coupled to the desired Het group conjugated with an organoboronic acid to yield a compound of the disclosure (e’). It will be appreciated that coupling of the desired Het group can be performed using other coupling chemistry, including Kumada, Negishi, Stille, or Suzuki coupling conditions.

[0097] In some cases, the ring A moiety can be coupled to the pyridyl moiety, followed by coupling of the Cy group to the pyridyl moiety, as shown in Scheme 3 below.

[0098] Scheme 3

[0099]

[0100] Coupling of the desired ring A group to the desired pyridyl moiety (a”) where X is halo yields intermediate (b”), which can be coupled to the desired Cy group to yield a compound of the disclosure (c”).

[0101] Embodiments of the disclosure

[0102] 1. A compound having the structure of (I):

[0103]

[0104] wherein

[0105] Ring A is a 5- to 10-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S;

[0106] Cy is a 4- to 10-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and optionally substituted with 1 to 4 R A substituted 4- to 10-membered heterocycle;

[0107] each R A is independently halo, OH, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 0-6 alkylene-N(R N )2, C 0-6 alkylene-C(O)N(R N )2, C 0-6 alkylene-OC(O)C 1-6 alkyl, C 0-6 alkylene-C(O)C 1-6 alkyl, C 0-6 alkylene-CO2R N or C 0-3 alkylene-4- to 8-membered heterocycle having 1, 2, 3, or 3 ring heteroatoms independently selected from N, O, and S;

[0108] R 1 is H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl;

[0109] R 2 is halo, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkene, C 2-6 alkyne, C 1-6 haloalkyl, CO2H, or Het;

[0110] Het is a 5- to 8-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and optionally substituted with 1 or 2 R B ;

[0111] each R B is independently halo, OH, oxo (=O), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6alkoxy, C 1-6 haloalkoxy, C 0-6 alkylene-N(R N )2or C 0-6 alkylene-4- to 8-membered heterocycle;

[0112] R 3 is H, halo or C 1-6 alkyl; and

[0113] each R N is independently H or C 1-3 alkyl.

[0114] 2. The compound or salt according to Embodiment 1, wherein ring A is aromatic, optionally a 5- or 6-membered ring.

[0115] 3. The compound or salt according to Embodiment 1, wherein ring A is furan, oxazole, isoxazole, thiophene, thiazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine.

[0116] 4. The compound or salt according to Embodiment 3, wherein ring A is furan.

[0117] 5. The compound or salt according to Embodiment 4, wherein ring A is 2-furan.

[0118] 6. The compound or salt according to Embodiment 5, having the structure of Formula (II):

[0119]

[0120] 7. The compound or salt according to Embodiment 3, wherein ring A is pyridine.

[0121] 8. The compound or salt according to Embodiment 7, having the structure of Formula (III):

[0122]

[0123] 9. The compound or salt according to any one of Embodiments 1 to 8, wherein Cy is azetidine, pyrrolidine, piperidine, piperazine, azepane, morpholine, thiomorpholine, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine, 2-oxa-7-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, or 1,8-diazaspiro[4.5]decane.

[0124] 10. The compound or salt according to any one of embodiments 1 to 9, wherein C is unsubstituted.

[0125] 11. The compound or salt according to any one of embodiments 1 to 9, wherein Cy is substituted with 1 R A .

[0126] 12. The compound or salt according to any one of embodiments 1 to 9, wherein Cy is substituted with 2 R A .

[0127] 13. The compound or salt according to embodiment 11 or 12, wherein at least one R A is OH, F, CH3, C(O)N(R N )2, CH2OH, oxo, CF3, OC(O)CH3, CO2CH3, CO2H, CH2-pyridine, C(O)CH3, or CH2N(R N )2.

[0128] 14. The compound or salt according to any one of embodiments 1 to 8, wherein Cy is

[0129] 15. The compound or salt according to any one of embodiments 1 to 14, wherein R 1 is halogen.

[0130] 16. The compound or salt according to any one of embodiments 1 to 14, wherein R 1 is CF3.

[0131] 17. The compound or salt according to any one of embodiments 1 to 14, wherein R 1 is cyclopropyl.

[0132] 18. The compound or salt according to any one of embodiments 1 to 17, wherein R 2 is halogen, C 1-3 alkoxy, or C 1-3 haloalkyl.

[0133] 19. The compound or salt according to any one of embodiments 1 to 17, wherein R 2 is Het.

[0134] 20. The compound or salt according to embodiment 19, wherein Het is pyridine, pyrazole, tetrahydropyran, pyrazine, pyrimidine, pyridazine, or piperidine.

[0135] 21. The compound or salt according to embodiment 19 or 20, wherein Het is unsubstituted.

[0136] 22. The compound or salt according to either of embodiments 19 or 20, wherein Het is substituted with 1 R B .

[0137] 23. The compound or salt according to either of embodiments 19 or 20, wherein Het is substituted with 2 R B .

[0138] 24. The compound or salt according to either of embodiments 22 or 23, wherein at least one R B is NH2, OH, CH3, or F.

[0139] 25. The compound or salt according to any one of embodiments 1 to 17, wherein Het is

[0140] 26. The compound or salt according to any one of embodiments 1 to 25, wherein R 3 is H.

[0141] 27. A compound listed in Table A, or a pharmaceutically acceptable salt thereof.

[0142] 28. A pharmaceutical composition comprising a compound or salt according to any one of embodiments 1 to 27, and a pharmaceutically acceptable excipient.

[0143] 29. A method of inhibiting SRPK1, comprising contacting SRPK1 with an effective amount of a compound or salt according to any one of embodiments 1 to 27 to inhibit SRPK1.

[0144] 30. Use of a compound or salt according to any one of embodiments 1 to 27 as an inhibitor of SRPK1.

[0145] 31. A compound or salt according to any one of embodiments 1 to 27 for use as a medicament.

[0146] 32. A method of treating a subject having a disease or disorder associated with aberrant SRPK1 activity, comprising administering to the subject a therapeutically effective amount of a compound or salt according to any one of embodiments 1 to 27.

[0147] 33. The method of embodiment 32, wherein the disease or disorder is a vascular disease (e.g., vasoconstriction and disorders characterized by vasoconstriction, and cardiovascular disease), a malignant or benign neoplasia (e.g., an angiogenesis-dependent cancer, e.g., a neoplastic cancer), tumor metastasis, an inflammatory disease, diabetes, diabetic retinopathy, diabetic neovascularization, diabetic macular edema, trachoma, retrolental proliferation, neovascular glaucoma, age-related macular degeneration, wet age-related macular degeneration (wAMD), macular edema, hemangioma, immune rejection of corneal tissue implants, corneal angiogenesis associated with ocular injury or infection, Osier-Webber syndrome, myocardial angiogenesis, wound granulation proliferation, telangiectasia, hemophilic joints, angiofibroma, telangiectasia, psoriasis, scleroderma, pyogenic granuloma, rubeosis, obesity, arthritis (e.g., rheumatoid arthritis), hematopoietic disease, angiogenesis, gingivitis, atherosclerosis, endometriosis, neointimal proliferation, psoriasis, hypertrichosis, proliferative retinopathy, idiopathic pulmonary fibrosis, or diabetic nephropathy.

[0148] 34. The method of embodiment 32, wherein the disease or disorder is a cancer.

[0149] 35. The method of embodiment 34, wherein the cancer is colon cancer, breast cancer, prostate cancer, pancreatic cancer, kidney cancer, head and neck cancer, leukemia, lymphoma, liver cancer, brain cancer, ovarian cancer, skin cancer, gastrointestinal cancer, or lung cancer.

[0150] Examples

[0151] The following examples are provided for illustration and are not intended to limit the scope of the present application.

[0152] Synthesis of compounds

[0153] LCMS Method 1 was performed with the following materials and parameters: Waters SunFire C18 50*4.6mm 5μm 2.000 mL / minute 2.6 minute column temperature: 40°C gradient: 5% B hold 0.2 minute, increase to 95% B in 1.40 minutes, hold at 95% B for 0.9 minutes, then back to 5% B in 0.01 minute. Pump A: 0.03% TFA in H2O; Pump B: 0.03% TFA in ACN. Compounds 001 to 023, 098, and 099 were analyzed using LCMS Method 1.

[0154] LCMS Method 2: Shimadzu Acquity UPLC method; Mass spectrometer: Shimadzu LCMS-2020; Column: Shim-pack Scepter C18-120 (3.0 x 33 mm) 3 pm; Solvent A: 0.05% HCOOH in water; Solvent B: 0.05% HCOOH in acetonitrile; Gradient: 3 min total (Time (min) / %B): 0 / 5, 1.3 / 95, 2.0 / 95, 2.1 / 5, 3 / 5; Flow rate: 1.3 mL / min Wavelength: 254 nm. Compounds 024 to 097 and 100 to 105 were analyzed using LCMS Method 2.

[0155] Example 1 Preparation of N-(2-(4-(pyridin-2-ylmethyl)piperazin-1-yl)-5- (trifluoromethyl)pyridin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 002) Example 2 Preparation of N-(2-(4-hydroxypiperidin-1-yl)-5-(trifluoromethyl)pyridin-3- yl)-5-(pyridin-4-yl)furan-2-carboxamide (Compound 004)

[0156]

[0157] Step 1. To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (2.0 g, 8.8 mmol) and l-(pyridin-2-ylmethyl)piperazine (3.13 g, 17.6 mmol) in DMF (30 mL) was added K2CO3 (2.4 g, 17.6 mmol). The reaction mixture was stirred at 80 °C overnight. LCMS showed the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with EA (3 x 6 mL), brine (6 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo to give the desired product l-methyl-4-(3-nitro-5- (trifluoromethyl)pyridin-2-yl)piperazine. LCMS: 368 [M+l]; Retention time: 1.15 min.

[0158] Step 2. A solution of l-methyl-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine (4 g, 10.9 mmol) and Pd / C (400 mg, 3.63 mmol) in MeOH (50 mL) was stirred at room temperature under 1 atm H2for 4 h. LCMS showed the reaction was complete. The reaction mixture was filtered with celite and the filtrate was concentrated to give the desired product 2-(4-methylpiperazin-l-yl)-5- (trifluoromethyl)pyridin-3-amine. LCMS: 338 [M+l]; Retention time: 1.52 min.

[0159] Step 3. To a solution of 2-(4-methylpiperazin-l-yl)-5-(trifluoromethyl)pyridin-3-amine (100 mg, 0.3 mmol), 5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxylic acid (58 mg, 0.3 mmol) and pyridine (0.13 mL, 0.9 mmol) in DCM (5 mL) cooled to 0 °C was added POCl3(0.1 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was poured into water (5 mL) and extracted with EA (3 x 3 mL), brine (6 mL), dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by prep-HPLC (TFA) to give the desired product N-(2-(4-(pyridin-2-ylmethyl)piperazin-l-yl)-5- (trifluoromethyl)pyridin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide. LCMS Method 1 : 516 [M+l]; Retention time: 1.31 min.

[0160] 1 H NMR (400 MHz, CDC13) δ 8.89 (s, 1H), 8.66 (s, 1H), 8.51 (d, J = 4.3 Hz, 1H), 8.28 (s, 1H), 7.63 (t, J = 7.3 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.14 (d, J = 3.4 Hz, 2H), 6.18 (d, J = 3.2 Hz, 1H), 4.04 (s, 2H), 3.71 (s, 2H), 3.54 (t, J = 10.9 Hz, 2H), 3.19 (s, 4H), 2.95 (d, J = 11.2 Hz, 1H), 2.74 (s, 4H), 1.98 (s, 4H).

[0161] The following compounds were prepared in a similar manner to the above procedure.

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] Example 3: Preparation of N-[2-(4-hydroxy-4-methyl-1-piperidinyl)-5-(trifluoromethyl)- 3-pyridinyl]-5-tetrahydropyran-4-yl-furan-2-carboxamide (Compound 027) Example 4: Preparation of methyl 4-methyl-1-[3-[(5-tetrahydropyran-4-ylfuran-2- carbonyl)amino]-5-(trifluoromethyl)-2-pyridinyl]piperidine-4-carboxylate (Compound 032)

[0168]

[0169] Step 1. To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1 g, 4.4 mmol) and piperidin-4-ol (892 mg, 8.8 mmol) in DMF (10 mL) was added K2CO3 (1.22 g, 8.8 mmol). The reaction mixture was stirred at 80 °C overnight. LCMS showed the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with EA (3 x 6 mL), brine (6 mL), dried over anhydrous Na2SO4, filtered, concentrated under vacuum to give the desired product 1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-ol. LCMS: 292 [M+1]; Retention time: 1.45 min.

[0170] Step 2. To a solution of 1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-ol (1 g, 3.4 mmol) and TEA (1.45 mL, 9 mmol) in DMF (20 mL) was added acetyl chloride (0.4 mL, 3.6 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with EA (3 x 6 mL), brine (6 mL), dried over anhydrous Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by silica gel column chromatography to give the desired compound 1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate. LCMS: 334 [M+1]; Retention time: 1.64 min.

[0171] Step 3. A solution of 1-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate (640 mg, 1.92 mmol) and Pd / C (64 mg, 0.6 mmol) in MeOH (30 mL) was stirred at room temperature under 1 atm H2for 4 h. LCMS showed the reaction was complete. The reaction mixture was filtered with celite and the filtrate was concentrated to give the desired product 1-(3-amino-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate. LCMS: 304 [M+1]; Retention time: 1.98 min.

[0172] Step 4. To a solution of 2-(4-methylpiperazin-l-yl)-5-(trifluoromethyl)pyridin-3-amine (1 g, 3.85 mmol), 5-bromo furan-2-carboxylic acid (735 mg, 3.85 mmol) and pyridine (0.93 mL, 11.54 mmol) in DCM (15 mL) cooled to 0 °C was added POCl3(0.7 mL, 7.7 mmol). The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was poured into water (5 mL) and extracted with EA (3 x 3 mL), brine (6 mL), dried over anhydrous Na2SO4, filtered and evaporated to get the crude product. The crude product was purified by prep-HPLC (TFA) to get the desired product 5-bromo-N-(2-(4-methylpiperazin-l-yl)-5- (trifluoromethyl)pyridin-3-yl)furan-2-carboxamide. LCMS: 435 [M+l]; Retention time: 1.22 min.

[0173] Step 5. A solution of 5-bromo-N-(2-(4-methylpiperazin-l-yl)-5- (trifluoromethyl)pyridin-3-yl)furan-2-carboxamide (60 mg, 0.13 mmol), pyridin-4-ylboronic acid (31 mg, 0.26 mmol), K2CO3(35 mg, 0.26 mmol) and DPPF (7 mg, 0.01 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL). The reaction mixture was stirred at 90 °C for 7 h. LCMS showed the reaction was complete. The reaction mixture was poured into water (8 mL) and extracted with EA (3 x 6 mL), brine (6 mL), dried over anhydrous Na2SO4, filtered and evaporated to get the crude product. The crude product was purified by prep-HPLC (TFA) to get the desired compound l-(3-(5-(pyridin-4-yl)furan-2-carboxamide)-5- (trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate. LCMS: 475 [M+l]; Retention time: 1.36 min.

[0174] Step 6. To a solution of SMl (56 mg, 0.12 mmol) in MeOH (1 mL) and THF (1 mL) was added K2CO3(18 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 4 h. LCMS showed the reaction was complete. The mixture was evaporated to get the crude product. The crude product was purified by prep-HPLC (TFA) to get the desired compound. LCMS: 433 [M+l]; Retention time: 1.26 min.

[0175] 1H NMR (400 MHz, CDC13) δ 9.03 - 8.98 (m, 1H), 8.96 - 8.88 (m, 1H), 8.69 - 8.63 (m, 2H), 8.32 - 8.27 (m, 1H), 7.60 - 7.55 (m, 2H), 7.38 - 7.31 (m, 1H), 7.01 - 6.94 (m, 1H), 5.34 - 5.23 (m, 1H), 4.01 - 3.89 (m, 1H), 3.38 - 3.21 (m, 2H), 3.02 - 2.95 (m, 2H), 2.13 - 2.08 (m, 2H), 1.86 - 1.77 (m, 2H).

[0176] The following compounds were prepared in a similar manner to the above procedure.

[0177]

[0178]

[0179] Example 5: Preparation of 1-(5-cyclopropyl-3-(5-(pyridin-4-yl)furan-2-carboxamide) pyridin-2-yl)piperidin-4-yl acetate (Compound 033) Example 6: Preparation of N-(2-((2R,4S)-4-hydroxy-2-methylpiperidin-1-yl)-5- (trifluoromethyl)pyridin-3-yl)-5-(pyridin-4-yl)furan-2-carboxamide (Compound 079) and N-(2-((2S,4S)-4-hydroxy-2-methylpiperidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-5- (pyridin-4-yl)furan-2-carboxamide (Compound 080)

[0180]

[0181] Step 1. To a solution of 4-methylpiperidin-4-ol (305 mg, 2.65 mmol) and 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (500 mg, 2.21 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (610 mg, 4.41 mmol). The mixture was heated at 80 °C for 2 h. TLC analysis showed the formation of the target product. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (30 mL x 3) and brine (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7: 1) to give 4-methyl-l-[3-nitro-5-(trifluoromethyl)-2-pyridyl]piperidin-4-ol.

[0182] Step 2. To a solution of 4-methyl-l-[3-nitro-5-(trifluoromethyl)-2-pyridyl]piperidin-4-ol (1 g, 3.28 mmol) in methanol (30 mL) was added Pd / C (1 g, wet) under N2. The mixture was degassed with H2three times and the mixture was stirred at 25 °C under H2(15 psi) for 2 h. LCMS analysis showed the formation of the target product. The reaction mixture was filtered and concentrated under reduced pressure to give l-[3-amino-5-(trifluoromethyl)-2-pyridyl]-4-methyl-piperidin-4-ol.

[0183] LCMS (ESI) m / z: [M+H] + 276.0; purity = 95% (254 nm); retention time = 1.24 min.

[0184] Step 3. To a solution of 5-tetrahydropyran-4-ylfuran-2-carboxylic acid (71 mg, 0.36 mmol) and l-[3-amino-5-(trifluoromethyl)-2-pyridyl]-4-methyl-piperidin-4-ol (100 mg, 0.36 mmol) in dichloromethane (5 mL) was added pyridine (575 mg, 7.27 mmol) under nitrogen. The mixture was stirred at 0 °C for 10 min. Then phosphorus oxychloride (1.11 g, 7.27 mmol) was added slowly dropwise at 0 °C under nitrogen. The mixture was stirred at 25 °C for 0.5 h. LCMS analysis showed the formation of the target product. The reaction mixture was quenched by water and diluted with ethyl acetate (50 mL) and washed with water (30 mL x 3) and brine (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give N-[2-(4-hydroxy-4-methyl-l-piperidyl)-5-(trifluoromethyl)-3-pyridyl]-5-tetrahydropyran-4-yl-furan-2-carboxamide.

[0185] 1 HNMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.35 (d, J = 4.0 Hz, 1H), 7.27 (d, J = 4.0 Hz, 1H), 6.42 (d, J = 4.0 Hz, 2H), 4.38 (s, 1H), 3.93-3.89 (m, 2H), 3.47-3.41 (m, 3H), 3.26-3.19 (m, 2H), 3.04-2.98 (m, 1H), 1.92 (d, J = 4.0 Hz, 2H), 1.89-1.57 (m, 6H), 1.17 (s, 3H).

[0186] LCMS (ESI) m / z: [M+H] + 454.1; purity = 94% (254 nm); retention time = 1.51 min.

[0187] Example 7: Preparation of 4-hydroxy-1-[3-[(5-tetrahydropyran-4-ylfuran-2- carbonyl)amino]-5-(trifluoromethyl)-2-pyridinyl]piperidine-4-carboxamide (Compound 096) Example 8: Preparation of N-(2-(4-hydroxypiperidin-1-yl)-5-(trifluoromethyl)pyridin-3- yl)-5-(pyrazin-2-yl)furan-2-carboxamide (Compound 074)

[0188]

[0189] Step 1. To a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (4.2 g, 18.54 mmol) in DMF (30 mL) was added 4-methylpiperidine-4-carboxylic acid (2.92 g, 20.39 mmol, HC1 salt) and K2CO3(7.68 g, 55.62 mmol), the mixture solution was stirred at 80 °C for 1.5 h, the reaction was monitored by LCMS, which showed the starting material was consumed and the product was formed. Added water (20 mL) and adjusted to pH = 5-6 by 2N HC1, extracted with EA (50 mL*3), the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product (4-methyl-1-[3-nitro-5-(trifluoromethyl)-2-pyridyl]piperidine-4-carboxylic acid, without further purification.

[0190] Step 2. To a solution of 4-methyl-1-[3-nitro-5-(trifluoromethyl)-2-pyridyl]piperidine-4- carboxylic acid (500 mg, 1.50 mmol) in MeOH (10 mL) was added thionyl chloride (2 mL) slowly, and the reaction solution was stirred at 80 °C for 2 h. TLC showed the starting material was consumed and the product was formed, the solvent and thionyl chloride were removed under reduced pressure to give a residue. The residue was purified by flash chromatography column, eluted with PE:EA = 9:1 to give 4-methyl-1-[3-nitro-5-(trifluoromethyl)-2-pyridyl]piperidine-4-carboxylic acid methyl ester.

[0191] Step 3. To a solution of 4-methyl-1-[3-nitro-5-(trifluoromethyl)-2-pyridyl]piperidine-4- carboxylic acid methyl ester (489 mg, 1.41 mmol) in MeOH (10 mL) was added Pd / C (wet) (50 mg), and the mixture solution was stirred at 25 °C under hydrogen atmosphere (15 psi) for 4 h, TLC showed the starting material was consumed and the product was formed, the reaction solution was filtered and the filtrate was concentrated to give 1-[3-amino-5-(trifluoromethyl)-2-pyridyl]-4-methyl-piperidine-4-carboxylic acid methyl ester.

[0192] Step 4. To a solution of methyl 5-bromofuran-2-carboxylate (5.85 g, 28.54 mmol) in dioxane (50 mL) and H2O (10 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.19 g, 34.24 mmol), K2CO3 (11.81 g, 85.61 mmol) and Pd(dppf)Cl2 (2.07 g, 2.85 mmol), the mixture solution was stirred at 90 °C under nitrogen atmosphere for 4 h, TLC showed the starting material was consumed completely and the product was formed, then the dioxane was removed to give a residue, water (50 mL) was added and extracted with EA (50 mL*3), the combined organic layers were dried over anhydrous Na2SO4, filtered to give a residue. The residue was purified by flash column chromatography eluting with PE:EA (5:1) to give methyl 5-(3,6-dihydro-2H-pyran-4-yl)furan-2-carboxylate.

[0193] Step 5. To a solution of methyl 5-(3,6-dihydro-2H-pyran-4-yl)furan-2-carboxylate (4.04 g, 19.40 mmol) in MeOH (50 mL) was added Pd / C (wet) (400 mg), and the mixture solution was stirred at 25 °C under hydrogen atmosphere (15 psi) for 2 h, the reaction was monitored by LCMS and TLC, which showed the starting material was consumed, the reaction solution was filtered, the filtrate was concentrated to give methyl 5-tetrahydropyran-4-ylfuran-2-carboxylate as a colorless oil.

[0194] Step 6. To a solution of methyl 5-tetrahydropyran-4-ylfuran-2-carboxylate (5.2 g, 24.74 mmol) in THF (9.17 mL) and H2O (1 mL) was added lithium hydroxide monohydrate (2.08 g, 49.47 mmol, 1.37 mL), and the mixture solution was stirred at 25 °C for 16 h, the reaction was monitored by TLC, which showed the starting material was consumed and the product was formed, the THF was removed under reduced pressure to give a residue, water was added, acidified to pH = 5 by 2N HCl, and extracted with EA (50 mL*3), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 5-tetrahydropyran-4-ylfuran-2-carboxylic acid.

[0195] Step 7. To a solution of 1-[3-amino-5-(trifluoromethyl)-2-pyridyl]-4-methyl- piperidine-4-carboxylic acid methyl ester (50 mg, 0.16 mmol) in DCM (10 mL) was added 5-tetrahydropyran-4-ylfuran-2-carboxylic acid (31 mg, 0.16 mmol) and pyridine (1.2 mL) at 0 °C, the reaction solution was stirred at 0 °C for 5 min, then POCI3 (1 mL) was added, the resulting solution was stirred at 0 °C for 10 min, then the reaction solution was stirred at room temperature for 1.2 h. TLC showed the starting material was consumed and product was formed. The solution was poured into ice water (10 mL) and extracted with EA (20 mL*2), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by prep-TLC (DCM:MeOH=95:5) to give methyl 4-methyl-1-[3-[(5- tetrahydropyran-4-ylfuran-2-carbonyl)amino]-5-(trifluoromethyl)-2-pyridyl]piperidine- 4-carboxylate.

[0196] 1 HNMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.39-8.38 (m, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 3.6 Hz, 1H), 6.4 (dd, J = 3.6, 0.8 Hz, 1H), 3.91-3.86 (m, 2H), 3.62 (s, 3H), 3.45-3.36 (m, 4H), 3.02-2.95 (m, 3H), 2.11-2.07 (m, 2H), 1.90 -1.86 (m, 2H), 1.72-1.54 (m, 4H), 1.17 (s, 3H)

[0197] LCMS (ESI) m / z: [M+H] + 496.1; purity = 95% (254 nm); retention time = 1.77 min.

[0198] The following compounds were prepared in a similar manner to the above procedure.

[0199]

[0200]

[0201] Example 9: Preparation of N-[2-(4-hydroxy-1-piperidinyl)-5-(trifluoromethyl)-3- pyridinyl]-4-(1H-pyrazol-4-yl)pyridine-2-carboxamide (Compound 094) Example 10: Preparation of N-[5-cyclopropyl-2-(4-hydroxy-4-methyl-1-piperidinyl)-3- pyridinyl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide (Compound 095)

[0202]

[0203] Step 1. To a solution of 5-bromo-2-chloro-3-nitropyridine (2.36 g, 20 mmol) in DMF (30 mL) was added 4-piperidinol hydrochloride (4.11 g, 30 mmol) and K2CO3(8.28 g, 60 mmol), then the reaction solution was stirred at 80 °C for 16 h. The reaction was monitored by TLC, which showed the formation of the desired product. The solvent was extracted with ethyl acetate (100 mL) and water (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get a residue, and purified by flash column chromatography eluting with PE:EA = 3:1 to get 1-(5-bromo-3-nitropyridin-2-yl)piperidin-4-ol.

[0204] Step 2. To a solution of 1-(5-bromo-3-nitropyridin-2-yl)piperidin-4-ol (2.5 g, 8.3 mmol) and cyclopropylboronic acid (0.86 g, 10 mmol) in dioxane (50 mL) and water (50 mL) was added cesium carbonate (8 g, 24.9 mmol) and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.59 g, 0.83 mmol). The mixture solution was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction was monitored by TLC, which showed the starting material was consumed and the formation of the desired product, extracted with ethyl acetate (100 mL) and water (150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get a residue, and purified by flash column chromatography eluting with PE:EtOAc = 4:1 to get 1-(5-cyclopropyl-3-nitropyridin-2-yl)piperidin-4-ol.

[0205] Step 3. To a solution of 1-(5-cyclopropyl-3-nitropyridin-2-yl)piperidin-4-ol (1.8 g, 7.8 mmol) in pyridine (30 mL) was added acetyl chloride (1.2 g, 15.6 mmol). The mixture solution was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by TLC, which showed the starting material was consumed and the formation of the desired product, extracted with ethyl acetate (60 mL) and water (80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to get a residue, and purified by flash column chromatography eluting with PE:EtOAc = 5:1 to get 1-(5-cyclopropyl-3-nitropyridin-2-yl)piperidin-4-yl acetate.

[0206] Step 4. To a solution of l-(5-cyclopropyl-3-nitropyridin-2-yl)piperidin-4-yl acetate (1.3 g, 4.3 mmol) in EtOH (50 mL) and water (10 mL) was added Fe (2.4 g, 43 mmol) and ammonium chloride (1.2 g, 21.5 mmol). The mixture solution was stirred at 75 °C for 4 h under nitrogen atmosphere. The reaction was monitored by TLC, which showed the starting material was consumed and the desired product was formed, the iron was filtered off to give a residue, which was extracted with ethyl acetate (50 mL) and water (70 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by flash column chromatography eluting with PE:EtOAc = 1:5 to give l-(3-amino-5-cyclopropylpyridin-2-yl)piperidin-4-yl acetate.

[0207] Step 5. To a solution of l-(3-amino-5-cyclopropylpyridin-2-yl)piperidin-4-yl acetate (200 mg, 0.73 mmol) and 5-(pyridin-4-yl)furan-2-carboxylic acid (138 mg, 0.73 mmol) in DMA (20 mL) and pyridine (20 mL) was added POCl3(335 mg, 2.19 mmol) at 0 °C under nitrogen atmosphere, then the mixture was stirred at 25 °C for 0.5 h, TLC showed the starting material was consumed and the desired product was formed, water (80 mL) was added to quench the reaction, and extracted with EA (40 mL), the combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash column chromatography eluting with PE:EtOAc = 1:5 to give l-(5-cyclopropyl-3-(5-(pyridin-4-yl)furan-2- carboxamide)pyridin-2-yl)piperidin-4-yl acetate.

[0208] 1 HNMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.66 (dd, J = 4.4, 1.6 Hz, 2H), 7.93 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 4.4, 1.6 Hz, 2H), 7.48 (d, J = 3.6 Hz, 1H), 7.43 (d, J = 3.6 Hz, 1H), 4.95 - 4.73 (m, 1H), 3.26 - 3.19 (m, 2H), 2.96 - 2.86 (m, 2H), 2.00 - 1.87 (m, 6H), 1.82 - 1.67 (m, 2H), 0.93 - 0.91 (m, 2H), 0.67 - 0.60 (m, 2H).

[0209] LCMS (ESI) m / z: [M+H]+ 447.1; Purity = 95% (254nm); Retention time = 1.35 minutes.

[0210] Example 11: Preparation of N-[2-(4-hydroxy-1-piperidinyl)-5-(trifluoromethyl)-3- pyridinyl]-5-(1H-pyrazol-4-yl)pyridine-2-carboxamide (Compound 097) Example 12: Preparation of N-(2-(2-oxo-7-azaspiro[3.5]non-7-yl)-5- (trifluoromethyl)pyridin-3-yl)-5-(pyridin-4-yl)furan-2-carboxamide (Compound 098) ​

[0211]

[0212] Step 1. Add pyridine (2.49 g, 31.52 mmol, 2.54 mL) to a solution of 5-(4-pyridyl)furan-2-carboxylic acid (119.23 mg, 0.6 mmol) and [1-[3-amino-5-(trifluoromethyl)-2-pyridyl]-2-methyl-4-piperidinyl]acetate (200 mg, 0.6 mmol) in N,N-dimethylacetamide (1 mL). Stir the mixture at 0 °C for 10 min. Then add phosphorus oxychloride (1.93 g, 12.61 mmol, 1.18 mL) at 0 °C. Stir the mixture at 25 °C for 30 min. Dilute the reaction mixture with ethyl acetate (50 mL) and wash with water (30 mL × 3) and brine (30 mL × 3). Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to obtain (2S,4S)-2-methyl-1-(3-(5-(pyridin-4-yl)furan-2-carboxamide)-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate and (2R,4S)-2-methyl-1-(3-(5-(pyridin-4-yl)furan-2-carboxamide)-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate.

[0213] Step 2. Potassium carbonate (33.95 mg, 0.24 mmol) was added to a solution of (2S,4S)-2-methyl-1-(3-(5-(pyridin-4-yl)furan-2-carboxamide)-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate (40 mg, 0.08 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL). The mixture was stirred at 25 °C for 6 hours. LCMS analysis showed the formation of the target product. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (30 mL × 3) and brine (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain N-(2-((2S,4S)-4-hydroxy-2-methylpiperidin-1-yl)-5-(trifluoromethyl)pyridin-3-yl)-5-(pyridin-4-yl)furan-2-carboxamide.

[0214] 1HNMR (400 MHz, DMSO -d6 ) δ 9.97 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.58 (s, 1H), 7.89 (d, J = 4.4 Hz, 2H), 7.58 (d, J = 4.0 Hz, 1H), 7.53 (d, J = 3.6 Hz, 2H), 4.94 (d, J = 3.6 Hz, 1H), 3.79-3.70 (m, 1H), 3.48-3.41 (m, 1H), 3.13-3.08 (m, 1H), 2.87-2.80 (m, 1H), 2.08-2.05 (m, 1H), 1.98-1.94 (m, 1H), 1.70-1.61 (m, 1H), 1.54-1.46 (m, 1H), 0.94 (d, J = 3.6 Hz, 3H).

[0215] LCMS (ESI) m / z: [M+H] + 447.19; Purity = 97.25% (254 nm); Retention time = 2.421 min.

[0216] Step 3. To a solution of (2R,4S)-2-methyl-l-(3-(5-(pyridin-4-yl)furan-2- carboxamide)-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate (15 mg, 0.03 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added potassium carbonate (12.73 mg, 0.09 mmol). The mixture was stirred at 25 °C for 6 hours. LCMS analysis showed the formation of the target product. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (30 mL x 3) and brine (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20: 1) to afford N-(2-((2R,4S)-4-hydroxy-2-methylpiperidin-l-yl)-5- (trifluoromethyl)pyridin-3-yl)-5-(pyridin-4-yl)furan-2-carboxamide.

[0217] 1 HNMR (400 MHz, DMSO -d6) δ 9.98 (s, 1H), 8.70 (d, J = 6.0 Hz, 2H), 8.48 (d, J = 1.6 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 6.0 Hz, 2H), 7.52 (d, J = 3.6 Hz, 1H), 7.48 (d, J = 4.0 Hz, 1H), 4.63 (d, J = 4.4 Hz, 1H), 4.22-4.18 (m, 1H), 3.93-3.86 (m, 1H), 369-3.64 (m, 1H), 3.13-3.06 (m, 1H), 1.85-1.81 (m, 1H), 1.74-1.69 (m, 1H), 1.60-1.50 (m, 2H), 1.11 (d, J = 6.8 Hz, 3H)

[0218] LCMS (ESI) m / z: [M+H] + 447.19; Purity = 99.62% (254 nm); Ret Time = 2.316 min.

[0219] The following compounds were prepared in a similar manner as the above procedure.

[0220]

[0221] ​ ​

[0222]

[0223] Step 1. To a mixture of 1-benzylpiperidin-4-one (4.00 g, 21.14 mmol) in N- methyl-2-pyrrolidinone (40 mL) was added trimethylsilyl cyanide (4.19 g, 42.27 mmol) dropwise at 25 °C. The mixture was stirred at 25 °C for 4 h. TLC (petroleum ether: ethyl acetate = 10: 1, Rf= 0.35) showed 1-benzylpiperidin-4-one was consumed and a new spot appeared. Water (20 mL) was added to the mixture and extracted with ethyl acetate (20 mL x 3). The organic layer was dried over sodium sulfate (25 g), filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1 to 20: 1) to give the title compound 1-benzyl-4-hydroxy-piperidine-4-carbonitrile.

[0224] Step 2. To a solution of l-benzyl-4-hydroxy-piperidine-4-carbonitrile (2.00 g, 9.25 mmol) at 0 °C was added sulfuric acid: water (8 mL, v / v = 9: 1). The reaction mixture was stirred at 25 °C for 16 h. LCMS showed the formation of the desired product. The mixture was poured into water (10 mL). The pH value was then adjusted to 6.0 with aqueous sodium bicarbonate solution (150 mL) and concentrated in vacuum. The solid was washed with dichloromethane:methanol (5: 1) and concentrated in vacuum to give l-benzyl-4-hydroxy-piperidine-4-carboxamide.

[0225] Step 3. To a solution of l-benzyl-4-hydroxy-piperidine-4-carboxamide (950 mg, 4.05 mmol) in methanol (10 mL) was added palladium (431 mg, 4.05 mmol, 10% Pd, wet). The reaction mixture was stirred under hydrogen at 25 °C for 16 h. TLC showed the material was completely consumed. The mixture was filtered through a 6 cm sintered glass funnel and concentrated in vacuum to give the target product 4-hydroxypiperidine-4-carboxamide.

[0226] Step 4. A solution of N-[2-chloro-5-(trifluoromethyl)-3-pyridyl]-5-tetrahydropyran-4- yl-furan-2-carboxamide (100 mg, 0.27 mmol), 4-hydroxypiperidine-4-carboxamide (77 mg, 0.53 mmol) and potassium carbonate (111 mg, 0.80 mmol) in N,N-dimethylacetamide (4 mL) was stirred at 25 °C for 2 h. LCMS showed the formation of the desired product. The mixture was filtered through a 6 cm sintered glass funnel, water (30 mL) was added to the filtrate. The combined aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combined organic layer was washed with water (3 x 10 mL), dried over sodium sulfate (10 g) and concentrated in vacuum. The crude product was purified by preparative TLC (dichloromethane / methanol = 20: 1) to give the target compound 4-hydroxy-l-[3-[(5-tetrahydropyran-4-ylfuran-2- carbonyl)amino]-5-(trifluoromethyl)-2-pyridyl]piperidine-4-carboxamide.

[0227] 1 HNMR (400 MHz, DMSO -d6) δ 9.36 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 1.2 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.42 (d, J = 4.8 Hz, 1H), 5.39 (s, 1H), 3.93-3.90 (m, 2H), 3.55-3.44 (m, 4H), 3.18-3.15 (m, 2H), 3.12-3.03 (m, 1H), 2.16-2.09 (m, 2H), 1.96-1.92 (m, 2H), 1.67-1.55 (m, 4H)

[0228] LCMS (ESI) m / z: [M+H] + 483.27; purity = 99% (254 nm); retention time = 2.37 min.

[0229] The following compounds were prepared in a similar manner to the above procedure.

[0230]

[0231]

[0232]

[0233] ​ ​

[0234]

[0235] Step 1. To a solution of [l-[3-[(5-bromo furan-2-carbonyl)amino]-5- (trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate (50 mg, 0.10 mmol) in 1,4- dioxane (3 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (40 mg, 0.16 mmol), potassium acetate (31 mg, 0.31 mmol) and l,l'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (8 mg, 0.01 mmol). After deoxygenating the flask with three alternating vacuum and purge cycles, the reaction mixture was stirred at 105 °C for 2 h. LCMS analysis showed the mass of the original boronic acid. The mixture was filtered through a 6 cm fritted glass funnel and concentrated in vacuo to give the target compound [l-[3-[[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) furan-2- carbonyl]amino]-5-(trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate.

[0236] Step 2. To a solution of [l-[3-[[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)furan-2-carbonyl]amino]-5-(trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate (20 mg, 0.04 mmol) and 2-bromopyrazine (6 mg, 0.04 mmol) in 1,4-dioxane (3 mL) was added potassium carbonate (16 mg, 0.12 mmol), [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (3 mg, 0.04 mmol) and water (0.3 mL). After deoxygenating the flask with three alternating vacuum and purge cycles, the reaction mixture was stirred at 105 °C for 16 h. LCMS analysis showed the formation of the target product. The mixture was filtered through a 6 cm fritted glass funnel and water (50 mL) was added to the filtrate. The combined aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the combined organic layer was washed with water (3 x 50 mL), dried over brine (2 x 50 mL), sodium sulfate (10 g) and concentrated in vacuo. The crude material obtained as a residue was purified by prep-TLC (dichloromethane / methanol = 17: 1) to give the target compound [l-[3-[(5-pyrazin-2-yl furan-2-carbonyl)amino]-5- (trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate.

[0237] Step 3. To a solution of [l-[3-[(5-pyrazin-2-ylfuran-2-carbonyl)amino]-5- (trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate (10 mg, 0.02 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) was added potassium carbonate (9 mg, 0.06 mmol) and the reaction mixture was stirred at 25 °C for 2 hours. LCMS analysis indicated the formation of the target product. The mixture was filtered through a 6 cm sintered glass funnel and water (20 mL) was added to the filtrate. The combined aqueous layer was extracted with ethyl acetate (3 x 15 mL) and the combined organic layer was washed with water (3 x 20 mL), brine (2 x 20 mL), dried over sodium sulfate (10 g) and concentrated in vacuo. The crude material obtained as a residue was purified by preparative TLC (dichloromethane / methanol = 17:1) to give the target compound N-[2-(4-hydroxy-l-piperidyl)-5-(trifluoromethyl)-3-pyridyl]-5-pyrazin-2-yl-furan-2- carboxamide.

[0238] 1 HNMR (400 MHz, DMSO- d6 ) δ 10.09 (s, 1H), 9.34 (s, 1H), 8.73 (dd, J = 2.4, 1.6 Hz, 1H), 8.65 (d, J = 4.0 Hz, 1H), 8.47 - 8.41 (m, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H), 7.46 (d, J = 4.0 Hz, 1H), 4.73 (d, J = 4.0 Hz, 1H), 3.77 - 3.64 (m, 3H), 3.13 - 3.01 (m, 2H), 1.88 - 1.78 (m, 2H), 1.60 - 1.47 (m, 2H).

[0239] LCMS (ESI) m / z: [M+H] + 476.20; purity = 100.00% (254 nm); retention time = 2.63 minutes.

[0240] ​ ​

[0241]

[0242] Step 1. To a solution of 1-(3-(4-chloropyridinecarboxamide)-5- (trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate (90 mg, 0.2 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (120 mg, 0.4 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was added cesium carbonate (198 mg, 0.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.88 mg, 0.004 mmol). The mixture solution was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction was monitored by TLC, which showed the starting material was consumed and the desired product was formed, extracted with ethyl acetate (100 mL) and water (150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by flash chromatography column eluting with PE:EtOAc = 1:1 to give 1-(3-(4-(1H-pyrazol-4-yl)pyridinecarboxamide)-5- (trifluoromethyl)pyridin-2-yl)piperidin-4-yl acetate.

[0243] Step 2. A solution of [1-[3-[[4-(1H-pyrazol-4-yl)pyridine-2-carbonyl]amino]-5- (trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate (40 mg, 0.084 mmol) and potassium carbonate (35 mg, 0.25 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was stirred at 25 °C for 2 h. LCMS analysis showed the formation of the target product. The mixture was quenched with water (25 mL). The combined aqueous layers were extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were dried over brine (2 x 25 mL), sodium sulfate (10 g) and concentrated in vacuum. The crude product was purified by prep-HPLC to give the target compound N-[2-(4-hydroxy-1-piperidyl)-5- (trifluoromethyl)-3-pyridyl]-4-(1H-pyrazol-4-yl)pyridine-2-carboxamide.

[0244] 1 HNMR (400 MHz, DMSO- d6 ) δ 13.29 (s, 1H), 10.52 (s, 1H), 8.87 (d, J = 2.4 Hz, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.45-8.38 (m, 4H), 7.96-7.94 (m, 1H), 4.78 (s, 1H), 3.76-3.71 (m, 1H), 3.46-3.41 (m, 2H), 3.00-2.94 (m, 2H), 1.97-1.93 (m, 2H), 1.74-1.68 (m, 2H).

[0245] LCMS (ESI) m / z: [M+H] + 433.26; purity = 100% (254 nm); retention time = 2.40 min.

[0246] The following compounds were prepared in a similar manner to the procedure described above.

[0247]

[0248] ​ ​

[0249]

[0250] Step 1. To a solution of 5-bromo-2-chloro-3-nitro-pyridine (5 g, 21.09 mmol) and 4-methylpiperidin-4-ol (2.43 g, 21.09 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (8.73 g, 63.27 mmol) and the reaction mixture was stirred at 25 °C for 2 h. TLC analysis indicated complete consumption of starting material. The mixture was filtered through a 6 cm sintered glass funnel and water (150 mL) was added to the filtrate. The combined aqueous layers were extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with water (3 x 100 mL), brine (2 x 100 mL), dried over sodium sulfate (150 g) and concentrated in vacuo. The crude material obtained as a residue was purified by column chromatography using a column containing 80 g of silica gel, eluting the column with a mixture of petroleum ether and ethyl acetate (10:1) to give the target compound 1-(5-bromo-3-nitro-2-pyridyl)piperidin-4-ol.

[0251] Step 2. A solution of l-(5-bromo-3-nitro-2-pyridyl)-4-methyl-piperidin-4-ol (5.87 g, 18.57 mmol), sodium carbonate (5.90 g, 55.70 mmol, 2.33 mL), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1.36 g, 1.86 mmol) and cyclopropylboronic acid (1.91 g, 22.28 mmol) in 1,4-dioxane (60 mL) and water (10 mL). After deoxygenating the flask with three alternating vacuum and purge cycles, the reaction mixture was stirred at 100 °C for 16 h. LCMS analysis showed complete consumption of l-(5-bromo-3-nitro-2-pyridyl)-4-methyl-piperidin-4-ol with formation of the target product. The mixture was filtered through a 6 cm sintered glass funnel and water (150 mL) was added to the filtrate. The combined aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined organic layer was washed with water (3 x 100 mL), dried over brine (2 x 100 mL), sodium sulfate (150 g) and concentrated in vacuo. The crude material obtained as a residue was purified by column chromatography using a column containing 45 g of silica gel, eluting the column with a mixture of petroleum ether and ethyl acetate (4: 1) to give the target compound l-(5-cyclopropyl-3-nitro-2-pyridyl)-4-methyl-piperidin-4-ol.

[0252] Step 3. To a solution of l-(5-cyclopropyl-3-nitro-2-pyridyl)-4-methyl-piperidin-4-ol (600 mg, 2.16 mmol) in MeOH (20 mL) was added palladium under H2. The mixture was stirred at 25 °C for 2 h. TLC analysis showed formation of the target product. The reaction mixture was filtered and concentrated under reduced pressure to give l-(3-amino-5-cyclopropyl-2-pyridyl)-4-methyl-piperidin-4-ol.

[0253] Step 4. To a solution of l-(3-amino-5-cyclopropyl-2-pyridyl)-4-methyl-piperidin-4-ol (250 mg, 1.01 mmol) and 5-bromo-furan-2-carboxylic acid (193.04 mg, 1.01 mmol) in dichloromethane (5 mL) was added pyridine (1.28 g, 16.14 mmol, 1.3 mL) and phosphorous oxychloride (154.98 mg, 1.01 mmol, 94.22 μί) at 0 °C. The reaction mixture was stirred at 25 °C for 30 min, LCMS analysis showed the formation of the desired product. Water (15 mL) was added, the combined aqueous layer was extracted with ethyl acetate (3 x 15 mL) and the combined organic layer was dried over sodium sulfate (150 g) and concentrated in vacuum. The crude material obtained as residue was purified by column chromatography using a column containing 10 g of silica gel, the column was eluted with a mixture of petroleum ether and ethyl acetate (10: 1) to get the desired compound 5-bromo-N-[5-cyclopropyl-2-(4-hydroxy-4-methyl-l-piperidinyl)-3-pyridyl] furan-2-carboxamide.

[0254] Step 5. A solution of 5-bromo-N-[5-cyclopropyl-2-(4-hydroxy-4-methyl-l- piperidinyl)-3-pyridyl] furan-2-carboxamide (50 mg, 118.96 μmol), sodium carbonate (63.04 mg, 594.81 μmol, 24.90 μΐ), [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) (8.70 mg, 11.90 μmol) and lH-pyrazol-4-ylboronic acid (13.31 mg, 118.96 μmol) in 1,4-dioxane (4 mL) and water (1 mL). After deoxygenating the flask with three alternating vacuum and purge cycles, the reaction mixture was stirred at 100 °C for 16 h. LCMS analysis showed complete consumption of 5-bromo-N-[5-cyclopropyl-2-(4-hydroxy-4-methyl-l- piperidinyl)-3-pyridyl] furan-2-carboxamide, formation of the desired product. The mixture was filtered through a 6 cm sintered glass funnel, water (10 mL) was added to the filtrate. The combined aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combined organic layer was washed with water (3 x 10 mL), dried over brine (2 x 10 mL), sodium sulfate (150 g) and concentrated in vacuum. The crude material obtained as residue was purified by column chromatography using a column containing 5 g of silica gel, the column was eluted with a mixture of petroleum ether and ethyl acetate (1 : 1) to get the desired compound N-[5-cyclopropyl-2-(4-hydroxy-4-methyl-l-piperidinyl)-3-pyridyl]-5-(lH-pyrazol-4-yl) furan-2-carboxamide.

[0255] 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.08 (d, J = 2.2 Hz, 3H), 7.92 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 3.6 Hz, 1H), 6.77 (d, J = 3.6 Hz, 1H), 4.32 (s, 1H), 3.10 (t, J = 12.7 Hz, 2H), 2.94 - 2.89 (m, 2H), 1.94 (d, J = 13.6 Hz, 1H), 1.76 - 1.62 (m, 4H), 1.19 (s, 3H), 0.97 (q, J = 6.3 Hz, 2H), 0.68 - 0.64 (m, 2H).

[0256] LCMS (ESI) m / z: [M+H] + 408.33; purity = 100% (254 nm); retention time = 2.29 min.

[0257] ​ ​

[0258]

[0259] [1-[3-[(6-chloropyridine-2-carbonyl)amino]-5-(trifluoromethyl)-2-pyridyl]-4- piperidyl] acetate (100 mg, 0.23 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (131 mg, 0.68 mmol), sodium carbonate (120 mg, 1.13 mmol) and [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (17 mg, 0.023 mmol) in 1,4-dioxane (2 atm. LCMS analysis showed formation of the desired product). The mixture was quenched with water (30 mL). The combined aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the combined organic layer was dried over brine (2 x 20 mL), sodium sulfate (10 g) and concentrated in vacuum. The crude product was purified by prep-HPLC to get the target compound N-[2-(4-hydroxy-1 -piperidyl)-5-(trifluoromethyl)-3-pyridyl]-5-(1 H-pyrazol-4- yl)pyridine-2-carboxamide.

[0260] 1 H NMR (400 MHz, DMSO -d6δ 13.24 (s, 1H), 10.29 (s, 1H), 9.06 (d, J = 1.2 Hz, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.45 (d, J = 3.2 Hz, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 4.4 Hz, 2H), 8.18-8.16 (m, 2H), 4.81 (d, J = 2.8 Hz, 1H), 3.79-3.73 (m, 1H), 3.46-3.41 (m, 2H), 3.01-2.95 (m, 2H), 1.99-1.94 (m, 2H), 1.75-1.67 (m, 2H).

[0261] LCMS (ESI) m / z: [M+H] + 433.61; purity = 100% (254 nm); retention time = 2.87 minutes.

[0262] ​ Preparation of (tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 065)

[0263]

[0264] Step 1. A solution of N-[2-(2-hydroxy-7-azaspiro[3.5]non-7-yl)-5-(trifluoromethyl)- 3-pyridyl]-5-tetrahydropyran-4-yl-furan-2-carboxamide (12 mg, 0.03 mmol) in dichloromethane (3 mL). To this solution was added 1,1-diacetoxy-3-oxo-1,2- benzoiodoxol-1-yl) acetate (21 mg, 0.05 mmol) and the reaction mixture was stirred at 25 °C for 16 h. TLC analysis indicated complete consumption of starting material. The mixture was filtered through a 6 cm sintered glass funnel and water (15 mL) was added to the filtrate. The combined aqueous layers were extracted with ethyl acetate (3 x 15 mL) and the combined organic layers were washed with water (3 x 10 mL), brine (2 x 50 mL), dried over sodium sulfate (15 g) and concentrated in vacuo. The crude material obtained as a residue was purified by prep-TLC (dichloromethane / methanol = 15:1) to give the target compound N-[2-(2-oxo-7-azaspiro[3.5]non-7-yl)-5-(trifluoromethyl)-3-pyridyl]-5-tetrahydropyran-4-yl-furan-2-carboxamide.

[0265] LCMS (ESI) m / z: [M+H] + 478.27; purity = 100.00% (254 nm); retention time = 3.10 minutes.

[0266] 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.47-8.42 (m, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 4.0 Hz, 1H), 6.42 (d, J = 4.0 Hz, 1H), 3.96-3.86 (m, 2H), 3.48-3.41 (m, 2H), 3.27-3.24 (m, 4H), 3.09-2.97 (m, 1H), 2.87 (s, 4H), 1.94-1.62 (m, 8H).

[0267] Example 13: Preparation of N-[2-(4-hydroxy-l-piperidinyl)-5-(trifluoromethyl)-3- pyridinyl]-5-(l-methyl-4-piperidinyl)furan-2-carboxamide (Compound 066) Example 14: Preparation of N-(2-(l-methylpiperidin-4-yl)-5-(trifluoromethyl)pyridin- 3-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 071)

[0268]

[0269] Step 1. To a solution of [l-[3-[[5-(4-piperidyl)furan-2-carbonyl]amino]-5- (trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate (40 mg, 0.083 mmol) in MeOH (8 mL) was added paraformaldehyde (22 mg, 0.25 mmol) and one drop of acetic acid, the reaction solution was stirred at 25 °C for 1 h, then sodium cyanoborohydride (26 mg, 0.42 mmol) was added, the mixture solution was stirred at 25 °C for 4 h, TLC showed the starting material was consumed and product was formed, water was added to quench the reaction and extracted with EA, the combined organic layers were dried over anhydrous Na2S04, filtered and concentrated to give a residue. The residue was purified by prep-TLC (DCM:MeOH = 9: 1) to give [l-[3-[[5-(l-methyl-4-piperidyl)furan-2-carbonyl]amino]-5- (trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate.

[0270] Step 2. To a solution of [l-[3-[[5-(l-methyl-4-piperidyl)furan-2-carbonyl]amino]-5- (trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate (20 mg, 0.04 mmol) in THF (3 mL) was added K2C03(17 mg, 0.012 mmol) and MeOH (3 mL), and the mixture solution was stirred at 25 °C for 4 h. Then the mixture solution was filtered and the filtrate was concentrated to give a residue, which was purified by prep-TLC (DCM:MeOH = 9: 1) as N-[2-(4-hydroxy-l-piperidyl)-5-(trifluoromethyl)-3-pyridyl]-5-(l-methyl-4- piperidyl)furan-2-carboxamide.

[0271] 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.42 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 3.6 Hz, 1H), 6.40 (d, J = 4.0 Hz, 1H), 4.76 (s, 1H), 3.73-3.66 (m, 1H), 3.61-3.56 (m, 2H), 3.04-2.98 (m, 2H), 2.83-2.81 (m, 2H), 2.73-2.65 (m, 1H), 2.19 (s, 3H), 2.04-1.92 (m, 4H), 1.88-1.84 (m, 2H), 1.73-1.63 (m, 2H), 1.59-1.50 (m, 2H).

[0272] LCMS (ESI) m / z: [M+H + 453.3; purity = 100% (254 nm); retention time = 2.46 min.

[0273] Example 15: Preparation of N-[2-(4-hydroxy-l-piperidinyl)-5-(trifluoromethyl)-3- pyridinyl]pyridine-4-carboxamide (Compound 046) Example 16. Preparation of 5-(3-amino-lH-pyrazol-4-yl)-N-[2-(4-hydroxy-l- piperidinyl)-5-(trifluoromethyl)-3-pyridinyl]furan-2-carboxamide (Compound 106)

[0274]

[0275] Step 1. To a solution of N-(2-(piperidin-4-yl)-5-(trifluoromethyl)pyridin-3-yl)-5- (tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (20 mg, 0.05 mmol), paraformaldehyde (40 mg) in MeOH (5 mL) was added sodium cyanoborohydride (10 mg, 0.15 mmol) and stirred at room temperature for 4 h. LCMS analysis showed the formation of the desired product. The mixture was quenched with water (25 mL). The combined aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the combined organic layer was dried over sodium sulfate (25 g) and concentrated in vacuum. The crude product was purified by prep-TLC (dichloromethane / methanol = 15:1) to get the desired compound N-(2-(1-methylpiperidin-4-yl)-5- (trifluoromethyl)pyridin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide.

[0276] LCMS (ESI) m / z: [M+H] + 438.25; purity = 100% (254 nm); retention time = 2.11 min.

[0277] 1HNMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.82 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.27 (d, J = 3.2 Hz, 1H), 6.41 (d, J = 3.2 Hz, 1H), 3.98-3.89 (m, 2H), 3.53-3.41 (m, 2H), 3.10-2.98 (m, 2H), 2.92-2.81 (m, 2H), 2.17 (s, 3H), 1.99-1.77 (m, 6H), 1.76-1.62 (m, 4H).

[0278] Example 17: Preparation of 5-bromo-N-[2-[(2R,4S)-4-hydroxy-2-methyl-l- piperidinyl]-5-(trifluoromethyl)-3-pyridinyl]furan-2-carboxamide (Compound 107) Example 18: Preparation of N-(5-cyclopropyl-2-(4-hydroxy-4-methylpiperidin-l- yl)pyridin-3-yl)-5-(pyridin-4-yl)furan-2-carboxamide (Compound 136)

[0279]

[0280] Step 1. A solution of 2-chloro-5-(trifluoromethyl)pyridin-3-amine (100 mg, 5.09 mmol), isonicotinic acid (63 mg, 5.09 mmol) and pyridine (1.18 g, 14.90 mmol, 1.2 mL) in dichloromethane (3 mL) was stirred at 0 °C under nitrogen atmosphere for 5 min. Then, POCl3(987 mg, 6.44 mmol, 0.6 mL) was added at 0 °C and the reaction mixture was stirred at 25 °C for 30 min. LCMS analysis showed the formation of the desired product and the mixture was quenched with water (25 mL). The combined aqueous layer was extracted with ethyl acetate (3 x 20 mL), dried over brine (2 x 25 mL) and sodium sulfate (25 g) and concentrated in vacuum. The crude product was purified by prep-TLC (petroleum ether / ethyl acetate = 1:1) to get the desired compound N-[2-chloro-5-(trifluoromethyl)-3-pyridyl]pyridine-4-carboxamide.

[0281] Step 2. A solution of N-[2-chloro-5-(trifluoromethyl)-3-pyridyl]pyridine-4-carboxamide (74 mg, 2.45 mmol), piperidin-4-ol (25 mg, 2.45 mmol) and cesium carbonate (240 mg, 7.36 mmol) in DMA (3 mL) was stirred at 100 °C for 18 h. TLC analysis indicated complete consumption of the starting material. The mixture was filtered through a 6 cm sintered glass funnel and water (10 mL) was added to the filtrate. The combined aqueous layer was extracted with ethyl acetate (3 x 10 mL) and washed with water (3 x 10 mL), dried over brine (2 x 20 mL), sodium sulfate (10 g) and concentrated in vacuum. The crude product was purified by prep-TLC (petroleum ether / ethyl acetate = 1:1) to get the desired compound N-[2-(4-hydroxy-1-piperidinyl)-5-(trifluoromethyl)-3-pyridyl]pyridine-4-carboxamide.

[0282] LCMS (ESI) m / z: [M+H] + 367.0; purity = 97% (254 nm); retention time = 1.19 min

[0283] 1 HNMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.81 (d, J = 8.0 Hz, 2H), 8.44 (s, 1H), 8.06 (s, 1H), 7.87 (d, J = 4.0 Hz, 2H), 4.71 (d, J = 4.0 Hz, 1H), 3.77-3.63 (m, 3H), 3.09-3.04 (m, 2H), 1.80-1.75 (m, 2H), 1.49-1.40 (m, 2H).

[0284] Example 19: Preparation of N-(5-cyclopropyl-2-(4-hydroxy-4-methylpiperidin-l- yl)pyridin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide (Compound 137) ​

[0285]

[0286] Experimental procedure

[0287]

[0288] Step 1. To a solution of [l-[2-[[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)furan-2-carbonyl]amino]-4-(trifluoromethyl)phenyl]-4-piperidyl] acetate (100 mg, 191.45 μmol) and 4-bromo-lH-pyrazol-3-amine (31.01 mg, 191.45 μmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added [2-(2-aminoethyl)phenyl]-chloro-palladium; dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine (12.88 mg, 19.15 μmol). The reaction mixture was stirred at 100 °C for 3 h. LCMS showed the formation of the desired product. The reaction mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic layer was washed with water (100 mL), dried over brine (100 mL), dried over sodium sulfate (50 g) and concentrated in vacuum. The residue was purified by prep-HPLC to get the target compound [l-[3-[[5-(3-amino-lH-pyrazol-4-yl)furan-2-carbonyl]amino]-5-(trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate.

[0289]

[0290] A solution of [1-[3-[[5-(3-amino-1H-pyrazol-4-yl)furan-2-carbonyl]amino]-5- (trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate (5 mg, 10.45 pmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was then added potassium carbonate (4.33 mg, 31.35 pmol). The reaction mixture was stirred at 25 °C for 2 hours. LCMS analysis indicated the formation of the target consumption. The mixture was purified by prep-HPLC to give the target product 5-(3-amino-1H-pyrazol-4-yl)-N-[2-(4-hydroxy-1-piperidyl)-5- (trifluoromethyl)-3-pyridyl]furan-2-carboxamide.

[0291] 1H NMR (400 MHz, DMSO -d6 ) δ 8.41 (m, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.33 (d, J = 4 Hz, 1H), 6.61 (d, J = 4.0 Hz, 1H), 5.36-5.29 (m, 1H), 3.69-3.63 (m, 3H), 3.08-3.01 (m, 2H), 2.05-1.93 (m, 2H), 1.88-1.76 (m, 2H).

[0292] LCMS (ESI) m / z: [M+H] + 437.13; Purity = 97.65% (254 nm); Retention time = 1.36 min.

[0293] The following compounds were prepared in a similar manner to the above procedure.

[0294]

[0295]

[0296]

[0297] ​ ​

[0298]

[0299] Procedure:

[0300]

[0301] Step 1. To a solution of (2R,4S)-2-methylpiperidin-4-ol (508.40 mg, 4.41 mmol) and 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1 g, 4.41 mmol) in N,N-dimethylacetamide (15 mL) was added potassium carbonate (1.83 g, 13.24 mmol). The mixture was heated at 25 °C for 18 h. LCMS analysis showed the formation of the target product. After cooling, the reaction mixture was extracted with ethyl acetate (100 mL x 3) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give (2R,4S)-2-methyl-l-[3-nitro-5-(trifluoromethyl)-2-pyridyl]piperidin-4-ol.

[0302]

[0303] Step 2. To a solution of (2R,4S)-2-methyl-l-[3-nitro-5-(trifluoromethyl)-2- pyridyl]piperidin-4-ol (1.5 g, 4.91 mmol) in dichloromethane (40 mL) was added pyridine (3.89 g, 49.14 mmol, 3.96 mL) under nitrogen atmosphere. The mixture was stirred at 25 °C for 10 min. Then acetyl chloride (3.86 g, 49.14 mmol, 2.98 mL) was added slowly dropwise at 0 °C under nitrogen. The mixture was stirred at 25 °C for 4 h. The reaction mixture was quenched by ice water and extracted with ethyl acetate (150 mL x 3) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel. Chromatography column (petroleum ether: ethyl acetate = 5: 1) to give [(2R,4S)-2-methyl-l-[3-nitro-5-(trifluoromethyl)-2-pyridyl]-4-piperidyl] acetate.

[0304]

[0305] Step 3. To a solution of [(2R,4S)-2-methyl-l-[3-nitro-5-(trifluoromethyl)-2- pyridyl]-4-piperidyl] acetate (200 mg, 0.6 mmol) in ethanol (5 mL) was added stannous chloride dihydrate (649.74 mg, 2.88 mmol). The mixture was heated at 50 °C for 1 h. LCMS analysis showed the formation of the target product. After cooling, the reaction mixture was acidified with saturated aqueous sodium bicarbonate solution to pH = 7, filtered, and diluted with ethyl acetate (100 mL x 3) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give [(2R,4S)-l-[3-amino-5-(trifluoromethyl)-2-pyridyl]-2-methyl-4- piperidyl] acetate.

[0306]

[0307] Step 4. To a solution of 5-bromo furan-2-carboxylic acid (148.66 mg, 0.8 mmol) in dichloromethane (3 mL) was added pyridine (947.28 mg, 11.98 mmol, 1.00 mL) under nitrogen. The mixture was stirred at 25 °C for 10 min. Then phosphorus oxychloride (1.84 g, 11.98 mmol, 1.12 mL) was added slowly dropwise at 0 °C under nitrogen. The mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by water and extracted with ethyl acetate (80 mL x 3) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give [(2R,4S)-l-[3-[(5-bromo furan-2-carbonyl)amino]-5-(trifluoromethyl)-2-pyridyl]-2-methyl-4- piperidyl] acetate.

[0308]

[0309] To a solution of [(2R,4S)-1-[3-[(5-bromo furan-2-carbonyl)amino]-5- (trifluoromethyl)-2-pyridyl]-2-methyl-4-piperidyl] acetate (30 mg, 0.06 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added potassium carbonate (25.37 mg, 0.1 mmol). The mixture was stirred at 25 °C for 3 hours. LCMS analysis showed the formation of the target product. After cooling, the reaction mixture was extracted with ethyl acetate (50 mL x 3) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 5-bromo-N-[2-[(2R,4S)-4-hydroxy-2-methyl-1-piperidyl]-5- (trifluoromethyl)-3-pyridyl] furan-2-carboxamide.

[0310] 1 HNMR (400 MHz, DMSO -d6 ) δ 9.71 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.88 (d, J = 3.6 Hz, 1H), 4.63 (d, J = 4.0 Hz, 1H), 4.17-4.13 (m, 1H), 3.93-3.86 (m, 1H), 3.60-3.55 (m, 1H), 3.09-3.03 (m, 1H), 1.84-1.81 (m, 1H), 1.71-1.67 (m, 1H), 1.58-1.50 (m, 2H), 1.08 (d, J = 6.8 Hz, 3H).

[0311] LCMS (ESI) m / z: [M+H] + 448.1; purity = 100% (254 nm); retention time = 2.199 minutes.

[0312] The following compounds were prepared in a similar manner to the above procedure.

[0313]

[0314] ​ ​

[0315]

[0316] To a solution of 2,5-dichloro-3-nitropyridine (3.00 g, 15.55 mmol) and 4- methylpiperidin-4-ol (1.97 g, 17.10 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (4.30 g, 31.09 mmol) and the reaction mixture was stirred at 80 °C for 2 hours. The mixture was filtered, water (50 mL) was added and the combined aqueous layers were extracted with ethyl acetate (3 x 50 mL), washed with water (3 x 50 mL), dried over brine (2 x 50 mL), sodium sulfate (50 g), and concentrated in vacuo. The crude material was purified by column chromatography to give the target compound 1-(5-chloro-3-nitropyridin-2-yl)-4-methylpiperidin-4-ol. LCMS (ESI) m / z: [M+H] + 271.9; purity = 98% (254 nm); retention time = 1.41 min.

[0317] A solution of 1-(5-chloro-3-nitropyridin-2-yl)-4-methylpiperidin-4-ol (500 mg, 1.84 mmol) and stannous chloride dihydrate (1.74 g, 9.20 mmol) in ethanol (40 mL) was stirred at 80 °C for 1 hour. The pH was then adjusted to 7.0 with 100% aqueous sodium bicarbonate solution and the mixture was filtered, washed with water (20 mL), extracted with ethyl acetate (3 x 20 mL), washed with water (3 x 20 mL), dried over brine (2 x 20 mL), sodium sulfate (25 g), and concentrated in vacuo to give the target compound 1-(3-amino-5-chloro-2-pyridyl)-4-methyl-piperidin-4-ol. LCMS (ESI) m / z: [M+H] + 242.0; purity = 96% (254 nm); retention time = 1.12 min.

[0318] To a solution of 1-(3-amino-5-chloropyridin-2-yl)-4-methylpiperidin-4-ol (2.5 g, 10.34 mmol) and cyclopropylboronic acid (1.33 g, 15.51 mmol) in toluene (30 mL) and water (3 mL) was added potassium phosphate tribasic (5.49 g, 25.86 mmol), palladium (II) acetate (232 mg, 1.03 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (425 mg, 1.03 mmol). After deoxygenating the flask, the reaction mixture was stirred at 95 °C for 16 hours. The mixture was filtered, water (100 mL) was added and the layers were extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (3 x 50 mL), dried over brine (2 x 100 mL), sodium sulfate (150 g), dried over brine (2 x 100 mL), sodium sulfate (150 g) and concentrated in vacuo. The crude material obtained as a residue was purified by column chromatography to give the target compound 1-(3-amino-5-cyclopropylpyridin-2-yl)-4-methylpiperidin-4-ol. LCMS (ESI) m / z: [M+H] + 248.1; purity = 91% (254 nm); retention time = 0.92 min.

[0319] A solution of 1-(3-amino-5-cyclopropylpyridin-2-yl)-4-methylpiperidin-4-ol (1.00 g, 4.04 mmol), 5-(pyridin-4-yl)furan-2-carboxylic acid (918 mg, 4.85 mol) and pyridine (3.26 mL, 40, 43 mmol) in N,N-dimethylacetamide (50 mL) was stirred at 0 °C for 10 minutes. Then, phosphorous oxychloride (3.77 mL, 40, 43 mmol) was added. The reaction mixture was stirred at 25 °C for 0.5 hours. The mixture was quenched with water (50 mL). The combined aqueous layers were extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were dried over brine (2 x 50 mL), sodium sulfate (100 g) and concentrated in vacuo. The crude product was purified by column chromatography to give the target compound N-(5-cyclopropyl-2-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-3-yl)-5-(pyridin-4-yl)furan-2-carboxamide. LCMS (ESI) m / z: [M+H] + 419.1; purity = 95.74% (254 nm); retention time = 1.53 min. 1HNMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.68 (dd, J = 4.0, 1.6 Hz, 2H), 7.96 (dd, J = 8.0, 2.0 Hz, 2H), 7.84 (dd, J = 4.0, 1.6 Hz, 2H), 7.51 (d, J = 4.0 Hz, 1H), 7.44 (d, J = 4.0 Hz, 1H), 4.33 (s, 1H), 3.14-3.08 (m, 2H), 3.01-2.93 (m, 2H), 1.93-1.91 (m, 1H), 1.75-1.60 (m, 4H), 1.18 (s, 3H), 0.97-0.96 (m, 2H), 0.68-0.64 (m, 2H).

[0320] ​ ​

[0321]

[0322] To a solution of 1-(3-amino-5-chloropyridin-2-yl)-4-methylpiperidin-4-ol (20 mg, 0.08 mmol) and cyclopropylboronic acid (11 mg, 0.12 mmol) in toluene (3 mL) and water (0.5 mL) was added potassium phosphate tribasic (44 mg, 0.21 mmol), palladium (II) acetate (2 mg, 0.08 mmol) and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (4 mg, 0.08 mmol). After deoxygenating the flask, the reaction mixture was stirred at 95 °C for 16 h. The mixture was filtered, water (15 mL) was added and the layer was extracted with ethyl acetate (3 x 10 mL), washed with water (3 x 10 mL), dried over brine (2 x 10 mL), sodium sulfate (15 g), and concentrated in vacuo. The crude material obtained as a residue was purified by Prep. TLC to give the target compound 1-(3-amino-5-cyclopropylpyridin-2-yl)-4-methylpiperidin-4-ol. LCMS (ESI) m / z: [M+H] + 248.1; purity = 95% (254 nm); retention time = 0.93 min.

[0323] A solution of 1-(3-amino-5-cyclopropylpyridin-2-yl)-4-methylpiperidin-4-ol (10 mg, 0.04 mmol), 5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxylic acid (10 mg, 0.04 mol) in dichloromethane (3 mL) was stirred at 0 °C for 10 min. Then, pyridine (64 mg, 0.80 mmol) and phosphorus oxychloride (124 mg, 0.80 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 0.5 h. The mixture was quenched with water (25 mL). The combined aqueous layer was extracted with ethyl acetate (3 x 20 mL), dried over brine (2 x 25 mL), sodium sulfate (25 g) and concentrated in vacuum. The crude product was purified by prep TLC to get the target compound N-(5-cyclopropyl-2-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-3-yl)-5-(tetrahydro-2H-pyran-4-yl)furan-2-carboxamide. LCMS (ESI) m / z: [M+H] + 426.4; purity = 85% (254 nm); retention time = 1.38 min. 1 HNMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 4.0 Hz, 1H), 6.43 (dd, J = 4.0, 1.2 Hz, 1H), 4.31 (s, 1H), 3.92 (ddd, J = 12.0, 4.0, 1.6 Hz, 2H), 3.44 (td, J = 12.0, 2.4 Hz, 2H), 3.09 - 3.06 (m, 3H), 2.88 - 2.85 (m, 2H), 1.97 - 1.87 (m, 3H), 1.76 - 1.61 (m, 6H), 1.19 (s, 3H), 0.98 - 0.95 (m, 2H), 0.68 - 0.61 (m, 2H).

[0324] Bioassay

[0325] The SPRK1 assay was performed as follows:

[0326] Method 1: Prepare assay buffer. Dilute control compound to 10 mM. Prepare test compound at a concentration of 30 mM. Transfer 15 nL of compound / DMSO to a multiwell plate. Then, add 7.5 μL of enzyme SRPK1 to each well, spin down the plate at 1000 rpm and centrifuge for 30 seconds. Then, add 7.5 μL of substrate human SRSF1 / SF2 to each well, spin down the plate at 1000 rpm and centrifuge for 30 seconds. Then incubate the plate at 25 °C for 90 minutes. After 90 minutes, add 5 μl of ADP-Glo TMReagents were added to each well and the plate was incubated at room temperature for 60 minutes. Then, 10 μΐ of kinase detection reagent was added to each well and the plate was incubated at room temperature for 60 minutes. Luminescence was recorded for each well on Envision. Test compounds were up to 30 μΜ, 3-fold, in duplicate, and the final concentration of DMSO was 0.1%.

[0327] Method 2: Prepare assay buffer. Dilute control compound to 1 mM in assay buffer. Prepare test compound at a concentration of 100 μΜ, then dilute 3-fold. Transfer 5 nL of compound / DMSO to a 384-well plate. Control compound up to 1000 nM, 3-fold, 10 doses. Test compound up to 100 nM, 3-fold, 10 doses. Add 2.5 μΐ^ of enzyme (SRPK1 final concentration 50 pM) to each well, then spin down the plate at 1000 rpm and centrifuge for 30 seconds. After that, add 2.5 μΐ^ of substrate (human SRSF1 / SF2 final concentration 0.15 μΜ, ATP final concentration 4 μΜ) to the plate, spin down at 1000 rpm and centrifuge for 30 seconds. Then place the plate in an incubator at 25 °C for 3 hours. Then, 5 μΐ^ of ADP-Glo reagent was added to each well and the plate was incubated at room temperature for 40 minutes. Luminescence was recorded for each well on Envision. TM Reagents were added to each well and the plate was incubated at room temperature for 60 minutes. After 60 minutes, 10 μΐ^ of kinase detection reagent was added to each well and the plate was incubated at room temperature for 30 minutes. Luminescence was recorded for each well on Envision.

[0328] The results of the assays for each compound are reported in the table below. All assays were performed using Method 1 except where indicated by an asterisk (*) in the table below (indicating that Method 2 was used). I.A. indicates IC 50 greater than 30 μΜ.

[0329]

[0330]

[0331]

Claims

1. A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof: wherein Ring A is a 5- to 10-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S; Cy is a substituted or unsubstituted 4- to 10-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S and optionally substituted with 1 to 4 R A substituted 4- to 10-membered heterocycle; each R is independently halo, OH, oxo, C A independently halo, OH, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 0-6 alkylene-N(R N )2, C 0-6 alkylene-C(O)N(R N )2, C 0-6 alkylene-OC(O)C 1-6 alkyl, C 0-6 alkylene-C(O)C 1-6 alkyl, C 0-6 alkylene-CO2R N or C 0-3 alkylene-4- to 8-membered heterocycle; R 1 H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl; R 2 halo, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CO2H or Het; Het is a 5- to 8-membered heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O, and S, and is optionally substituted with 1 or 2 R B ; each R is independently halo, OH, oxo (=0), C B independently halo, OH, oxo (=0), C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 0-6 alkylene-N(R N )2or C 0-6 alkylene-4- to 8-membered heterocycle; R 3 R is H, halo or C 1-6 alkyl; and each R is independently H or C N independently H or C 1-3 alkyl.

2. The compound or salt of claim 1, wherein Ring A is aromatic and is optionally a 5- or 6-membered ring.

3. The compound or salt of claim 2, wherein Ring A is furan, oxazole, isoxazole, thiophene, thiazole, imidazole, triazole, pyridine, pyrimidine, pyridazine, or pyrazine.

4. The compound or salt of claim 3, wherein Ring A is furan.

5. The compound or salt of claim 4, wherein Ring A is 2-furan.

6. The compound or salt of claim 5, having the structure of Formula (II):

7. The compound or salt of claim 3, wherein Ring A is pyridine.

8. The compound or salt of claim 7, having the structure of Formula (III):

9. The compound or salt of any one of claims 1 to 8, wherein Cy is azetidine, pyrrolidine, piperidine, piperazine, azepane, morpholine, thiomorpholine, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine, 2-oxa-7-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-oxa-8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, or 1,8-diazaspiro[4.5]decane.

10. The compound or salt of any one of claims 1 to 9, wherein Cy is unsubstituted.

11. The compound or salt of any one of claims 1 to 9, wherein Cy is substituted with 1 R A .

12. The compound or salt of any one of claims 1 to 9, wherein Cy is substituted with 2 R A .

13. The compound or salt of claim 11 or 12, wherein at least one R A is OH, F, CH3, C(O)N(R N )2, CH2OH, oxo, CF3, OC(O)CH3, CO2CH3, CO2H, CH2-pyridine, C(O)CH3, or CH2N(R N )2.

14. The compound or salt of any one of claims 1 to 8, wherein Cy is 15. The compound or salt of any one of claims 1 to 14, wherein R 1 is halogen.

16. The compound or salt of any one of claims 1 to 14, wherein R 1 is CF3.

17. The compound or salt of any one of claims 1 to 14, wherein R 1 is cyclopropyl.

18. The compound or salt according to any one of claims 1 to 17, wherein R 2 is halogen, C 1-3 alkoxy or C 1-3 haloalkyl.

19. The compound or salt of any one of claims 1 to 17, wherein R 2 is Het.

20. The compound or salt of claim 19, wherein Het is pyridine, pyrazole, tetrahydropyran, pyrazine, pyrimidine, pyridazine, or piperidine.

21. The compound or salt of claim 19 or 20, wherein Het is unsubstituted.

22. The compound or salt of claim 19 or 20, wherein Het is substituted with 1 R B .

23. The compound or salt of claim 19 or 20, wherein Het is substituted with 2 R B .

24. The compound or salt of claim 22 or 23, wherein at least one R B is NH2, OH, CH3, or F.

25. The compound or salt of any one of claims 1 to 17, wherein Het is 26. The compound or salt of any one of claims 1 to 25, wherein R 3 is H.

27. A compound listed in Table A or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 27 and a pharmaceutically acceptable excipient.

29. A method of inhibiting SRPK1, comprising contacting SRPK1 with an effective amount of a compound or salt of any one of claims 1 to 27 to inhibit SRPK1.

30. Use of a compound or salt of any one of claims 1 to 27 as an SRPK1 inhibitor.

31. A compound or salt of any one of claims 1 to 27 for use as a medicament.

32. A method of treating a subject having a disease or disorder associated with aberrant SRPK1 activity, comprising administering to the subject a therapeutically effective amount of a compound or salt of any one of claims 1 to 27.

33. The method of claim 32, wherein the disease or disorder is a vascular disease (e.g., vasoconstriction and disorders characterized by vasoconstriction, and cardiovascular disease), a malignant or benign neoplasia (e.g., angiogenesis-dependent cancer, e.g., neoplastic cancer), tumor metastasis, an inflammatory disease, diabetes, diabetic retinopathy, diabetic neovascularization, diabetic macular edema, trachoma, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, wet age-related macular degeneration (wAMD), macular edema, hemangioma, immune rejection of implanted corneal tissue, corneal angiogenesis associated with ocular injury or infection, Osier-Webber syndrome, myocardial angiogenesis, wound granulation proliferation, telangiectasia, hemophilic joints, angiofibroma, telangiectasia, psoriasis, scleroderma, pyogenic granuloma, rubeosis, obesity, arthritis (e.g., rheumatoid arthritis), hematopoietic disease, angiogenesis, gingivitis, atherosclerosis, endometriosis, neointimal proliferation, psoriasis, hypertrichosis, proliferative retinopathy, idiopathic pulmonary fibrosis, or diabetic nephropathy.

34. The method of claim 32, wherein the disease or disorder is a cancer.

35. The method of claim 34, wherein the cancer is colon cancer, breast cancer, prostate cancer, pancreatic cancer, renal cancer, head and neck cancer, leukemia, lymphoma, liver cancer, brain cancer, ovarian cancer, skin cancer, gastrointestinal cancer, or lung cancer.

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