Selective G Protein-Coupled Receptor Kinase 5 Inhibitors, Compositions, and Methods of Use - Patent application

Abstract

A highly selective and potent inhibitor of G protein-coupled receptor kinase 5 (GRK5), a pharmaceutical composition containing the same, and a method for using the same in the treatment of heart disease or cancer, etc.

Description

[Technical field]

[0001] Statement of Government Support This invention was made with Government support under HL071818 awarded by the National Institutes of Health. The Government has certain rights in this invention.

[0002] The present disclosure relates to G protein-coupled receptor kinase 5 (GRK5) inhibitors, compositions comprising same, and methods of use, such as in the treatment of cardiovascular disease and cancer. [Background technology]

[0003] There is a need for effective treatments for cardiac disease (e.g., hypertrophic cardiomyopathy and heart failure) and cancer. Selective and potent inhibitors of G protein-coupled receptor kinase 5 (GRK5) could address this need. Summary of the Invention [Problem to be solved by the invention]

[0004] In view of the above, it is an object of the present disclosure to provide highly selective and potent GRK5 inhibitors. This and other objects and advantages, as well as features of the invention, will become apparent from the description provided herein. [Means for solving the problem]

[0005] formula:

[0006] [ka]

[0007] (In the formula, R 1 is R 5 , -alkyl-R 5 , -C(O)R 5 ,

[0008] [ka]

[0009] where R 5 is alkyl, hydroxy, alkoxy, amido, cyano, alkenyl, haloalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 5 and R 7 can form a cycloalkyl group; R 1A is H or alkyl, or R 1A and R 9 can form a heterocyclyl group; X 1 is O or NR 6A where R 6A is H or alkyl, or R 6A and R 5 can form a heterocyclyl group; p, d, and q each independently represent an integer of 0 to 5; R 2 and R 3 are each independently alkyl; R 6 is H or alkyl; R 7 is H, alkyl or aryl; R 8 is H or alkyl; R 9 is H or alkyl; and R 4 is aryl, arylalkyl, or heteroarylalkyl or a pharma- ceutically acceptable salt thereof.

[0010] Such compounds are apparently selective and potent inhibitors of G protein-coupled receptor kinase 5 (GRK5). For example, the compounds are selective for GRK5 over GRK2. For example, the compounds have an IC 50 IC >10 μM for GRK550 can be 1 to 999 nM (e.g., 1 to 100 nM).

[0011] The present disclosure also relates to a method for treating a subject in need of inhibition of G protein-coupled receptor kinase 5 (GRK5), comprising administering to a subject in need thereof an effective amount of the compound described above, whereby the subject in need of inhibition of GRK5 is treated. The subject may be suffering from a heart disease and / or cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Reference will now be made in detail to particular embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0013] Formula (I), (II) or (III):

[0014] [ka]

[0015] (In the formula, R 1 is R 5 , -alkyl-R 5 , -C(O)R 5 ,

[0016] [ka]

[0017] where R 5 is alkyl, hydroxy, alkoxy, amido, cyano, alkenyl, haloalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 5 and R 7 can form a cycloalkyl group; R 1A is H or alkyl, or R 1A and R 9 can form a heterocyclyl group; X 1 is O or NR 6A where R 6A is H or alkyl, or R 6A and R 5 can form a heterocyclyl group; p, d, and q each independently represent an integer of 0 to 5; R 2 and R 3 are each independently alkyl; R 6 is H or alkyl; R 7 is H, alkyl or aryl; R 8 is H or alkyl; R 9 is H or alkyl; and R 4 is aryl, arylalkyl, or heteroarylalkyl or a pharma- ceutically acceptable salt thereof.

[0018] Examples of compounds of formulae (I), (II), and (III) include compounds of formulae (Ia), (IIa), and (IIIa):

[0019] [ka]

[0020] The compounds include: In any of the compounds (e.g., compounds of formula (I), (Ia), (II), (IIa), (III), and (IIIa)), R 2 and R 3 are each independently 1 ~C 3 -alkyl, e.g., methyl. Additionally or alternatively, in the compound, R4 is an arylalkyl, e.g., (C 1 ~C 6 ) alkylaryl and (C 1 ~C 6 )Alkyl(C 6 ~C 10 ) aryl. Alternatively, R 4 is represented by formula (II):

[0021] [ka]

[0022] where R 10 is H, halo, alkyl, haloalkyl, amido or alkoxy; and X 1 is absent or is an alkyl (e.g., (C 1 ~C 6 ) alkylaryl and (C 1 ~C 6 )Alkyl(C 6 ~C 10 ) aryl). R 10 can be halo (e.g. fluoro). Examples of groups of formula (II) include groups of the formula:

[0023] [ka]

[0024] In particular, R 11 is alkyl, which may be substituted by a heterocyclyl, e.g. pyranyl group. Examples of groups of formula (II) include groups of the formula:

[0025] [ka]

[0026] Also included are the groups: Formula (I):

[0027] [ka]

[0028] (In the formula, R 2 , R 3 , and R 4 is defined herein, and R 1 is R 5 , -alkyl-R 5 , -C(O)R 5 or

[0029] [ka]

[0030] where R 5 is alkyl, cycloalkyl, aryl or heteroaryl. In the compound of formula (I), R 5 can be furanyl, indolyl, imidazolyl, benzimidazolyl or imidazo[1,2-a]pyridinyl; q is 0, p is 0, and d is 0; and / or R 1 is -alkyl-R 5 , for example -(C 1 ~C 3 ) Alkyl-R 5 It is.

[0031] Formula (II):

[0032] [ka]

[0033] (In the formula, R 1 is R 5 , -alkyl-R 5 or

[0034] [ka]

[0035] where R 5 is alkyl, hydroxy, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl. In the compound of formula (II), R 5 can be tetrahydrofuranyl, pyranyl, furanyl, tetrahydro-2H-thiopyran-1,1-dioxide or benzimidazolyl; q can be 0, d can be 0; and / or R 1 is -alkyl-R 5 , for example -(C 1 ~C 3 ) Alkyl-R 5 For example, in the compound of formula (II), R 1 teeth,

[0036] [ka]

[0037] where R 5 and R 7 is a cycloalkyl group (e.g., (C 3 ~C 6 ) a cycloalkyl group). Alternatively, in the compound of formula (II), R 1 is R 5 or -alkyl-R 5 R 5 can be hydroxy or alkoxy.

[0038] Examples of compounds of formula (I), (Ia), (II), (IIa), (III), and (IIIa) include compounds of the formula:

[0039] [ka]

[0040] [ka]

[0041] [ka]

[0042] [ka]

[0043] and compounds of the formula:

[0044] [ka]

[0045] [ka]

[0046] [ka]

[0047] [ka]

[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] [ka]

[0052]

change

[0053]

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[0054]

change

[0055]

change

[0056]

change

[0057]

change

[0058]

change

[0059]

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[0060]

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[0061]

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[0062]

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[0063] [ka]

[0064] [ka]

[0065] [ka]

[0066] [ka]

[0067] [ka]

[0068] [ka]

[0069] The compounds include: The above compounds are known in the art and can be synthesized according to methods exemplified herein, see, e.g., Example 1.

[0070] The compound may be a pharmaceutically acceptable salt. Examples of acceptable salts include, but are not limited to, alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts; however, generally any salt that is non-toxic and effective when administered to the subject being treated is acceptable. Similarly, "pharmaceutically acceptable salt" refers to a salt with a counterion that can be used in pharmaceuticals. Such salts may include, but are not limited to, (1) acid addition salts obtainable by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, and the like, or organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, malonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like. Pharmaceutically acceptable salts are well known to those skilled in the art, and any such pharma-ceutically acceptable salt is contemplated.

[0071] Acceptable salts can be obtained using standard procedures known in the art, including, but not limited to, reacting a sufficiently acidic compound with an appropriate base that provides a physiologically acceptable anion. Suitable acid addition salts are formed from acids that form non-toxic salts. Illustrative, but non-limiting examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate. Suitable base salts of compounds can be formed from bases which form non-toxic salts. Illustrative, but non-limiting, examples include arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemi-salts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts.

[0072] Those skilled in the art will further recognize that the compounds may be "deuterated," meaning that one or more hydrogen atoms may be replaced by deuterium. Since deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be effected.

[0073] The compounds, in some embodiments, contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomers defined in terms of absolute stereochemistry as (R) or (S). Unless otherwise specified, all stereoisomers of the compounds are intended to be contemplated. When the conjugate contains an alkene double bond, and unless otherwise specified, both E and Z geometric isomers (e.g., cis or trans) are intended to be included. Similarly, all possible isomers and their racemic and optically pure forms, as well as all tautomers, are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, e.g., ortho, meta, and para isomers around a benzene ring.

[0074] Further provided is a pharmaceutical composition comprising the compound and a pharma- ceutically acceptable carrier or excipient. The term "composition" generally refers to any product containing two or more components, including the compound. It should be understood that the composition may be prepared from an isolated compound, or from salts, solutions, hydrates, solvates, and other forms of the compound. It is recognized that certain functional groups, such as hydroxyl groups, amino groups, and the like, may form complexes with water and / or various solvents in various physical forms of the compound. It should also be understood that the composition may be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and / or other morphological forms of the compound, and that the composition may be prepared from various hydrates and / or solvates of the compound. Thus, such pharmaceutical compositions may include each of the various morphological forms and / or solvates or hydrate forms of the compound, or any combination or individual forms.

[0075] Any pharma- ceutically acceptable carrier and excipient known in the art can be used. Pharmaceutically acceptable carriers can include physiologically compatible solvents, dispersion media, coatings, antibacterial and / or antifungal agents, isotonic and / or absorption delaying agents, and the like, and combinations thereof. Carriers are suitable for parenteral administration and can be, for example, sterile aqueous solutions or dispersions, or sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.

[0076] Examples of various components include, but are not limited to, color additives, preservatives, and stabilizers.More specific examples include crystalline cellulose, carmellose calcium, carmellose sodium, hydropropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, and magnesium stearate.Such compositions can be prepared according to the methods of the art, for example, the methods described in Remington's "The Science and Practice of Pharmacy", 22nd edition.Auxiliary active compounds can also be incorporated into the composition.

[0077] The oral dosage unit may be, for example, a tablet or a capsule. Other compositions for oral administration include elixirs, syrups, and the like. Solutions of the active compositions may be aqueous, optionally mixed with non-toxic surfactants, and / or contain carriers or excipients such as salts, carbohydrates, and buffers (preferably pH 3-9), although in some applications they may be more appropriately formulated as sterile non-aqueous solutions or as dry forms used with an appropriate vehicle such as sterile pyrogen-free water or phosphate-buffered saline. For example, dispersions may be prepared in glycerol, liquid PEG, triacetin, and mixtures thereof, as well as in oils. Under normal conditions of storage and use, these preparations may further contain a preservative to prevent the growth of microorganisms.

[0078] The excipients may include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, which may be naturally occurring phosphatides, such as lecithin; condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethyleneoxcycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ascorbic acid, ethyl, n-propyl, or p-hydroxybenzoate; or one or more coloring agents.

[0079] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional excipients, such as coloring agents, can also be present.

[0080] Suitable emulsifiers can be naturally occurring gums, such as gum acacia or gum tragacanth; naturally occurring phosphatides, such as soybean lecithin; and esters, including partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.Isotonic agents, such as sugars, polyhydric alcohols, such as mannitol or sorbitol, or sodium chloride, can be included in the composition.Prolonged absorption of the injectable composition can be achieved by including in the composition an agent that delays absorption, such as monostearate salts and gelatin.

[0081] Liquid formulations can include suspensions and solutions. Such formulations can include a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by the reconstitution of a solid.

[0082] Still further, a method of treating a subject in need of inhibition of G protein-coupled receptor kinase 5 (GRK5) is provided. The method comprises administering to a subject in need thereof an effective amount of the compound or a pharmaceutical composition comprising the compound and a pharma-ceutically acceptable carrier or excipient. In one embodiment, the subject may suffer from a cardiac disease (e.g., hypertrophic cardiomyopathy or heart failure). In another embodiment, the subject may suffer from cancer.

[0083] Also contemplated herein is one or more compounds described herein for use as a medicament for treating a patient in need of inhibition of G protein-coupled receptor kinase 5 (GRK5). The subject may be suffering from cardiac disease (e.g., hypertrophic cardiomyopathy or heart failure) and / or cancer.

[0084] The compounds can be formulated as pharmaceutical compositions and administered to subjects, such as mammals, for example humans, in a variety of forms adapted to the selected route of administration, as described above. For example, the compositions can be administered as oral dosage units, injectable compositions (i.e., for subcutaneous or intravenous injection), or infusions. See, for example, Remington, supra.

[0085] The effective amount of the compound or pharmaceutical composition comprising the compound can be determined according to methods known in the art (e.g., animal models, human data, and human data of compounds used in similar methods). The amount can be determined by taking into account various factors such as the potency of the conjugate, body weight, mode of administration, type and location of the fracture, and its causal relationship. The effective amount can range from about 0.1 μg / kg / day, e.g., 0.5 μg / kg / day, 0.7 μg / kg / day, or 0.01 mg / kg / day, to about 1,000 mg / kg / day. Intravenous doses can be several orders of magnitude lower. The compound / composition can be administered more than once, e.g., daily (1-3 or more times per day), weekly (including 1-3 or more times on specific days), biweekly (including 1-3 or more times on specific days), monthly (including 1-3 or more times on specific days), or bimonthly (including 1-3 or more times on specific days).

[0086] The terms "substituted," "substituent," and "functional group" refer to a group that can be or is substituted on a molecule or another group (e.g., an aryl or alkyl group). Examples of substituents include halogens (e.g., F, Cl, Br, and I), OR, OC(O)N(R). 2 , CN, NO, NO 2 , O.N.O. 2 , Azide, CF 3 , OCF 3 , R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , S.O. 3 R, -(CH 2 ) 0~2 P(O)(OR) 2 , C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R) 2 , O.C.(O)N(R) 2 , C(S)N(R) 2 , (CH 2 )0~2 N(R)C(O)R, (CH 2 ) 0~2 N(R)C(O)OR, (CH 2 ) 0~2 N(R)N(R) 2 , N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R) 2 , N(R)SO 2 R, N(R)SO 2 N(R) 2 , N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R) 2 , N(R)C(S)N(R) 2 , N(COR)COR, N(OR)R, C(=NH)N(R) 2 , C(O)N(OR)R, or C(═NOR)R, where each R can independently be hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, where any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, or two R groups attached to a nitrogen atom or adjacent nitrogen atoms can be taken together with the nitrogen atom to form a heterocyclyl, which can be mono- or independently multiply-substituted.

[0087] As used herein, the term "alkyl" refers to an alkyl group having 1 to 40 carbon atoms (C 1 ~C 40 ), 1 to about 20 carbon atoms (C 1 ~C 20 ), 1 to 12 carbons (C 1 ~C 12 ), 1 to 8 carbon atoms (C 1 ~C 8 ), or in some embodiments, 1 to 6 carbon atoms (C 1 ~C 6) refers to substituted or unsubstituted straight-chain and branched monovalent or divalent alkyl and cycloalkyl groups. Examples of straight-chain alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted one or more times with any of the groups described herein, such as amine, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0088] As used herein, the term “alkenyl” refers to an alkyl group having at least one double bond and having 1 to 40 carbon atoms (C 1 ~C 40 ), 1 to about 20 carbon atoms (C 1 ~C 20 ), 1 to 12 carbons (C 1 ~C 12 ), 1 to 8 carbon atoms (C 1 ~C 8 ), or in some embodiments, 1 to 6 carbon atoms (C 1 ~C 6 ) refers to substituted or unsubstituted linear and branched monovalent or divalent alkenyl and cycloalkenyl groups. Examples of linear alkenyl groups include those having 1 to 8 carbon atoms, such as -CH=CH-, -CH=CHCH 3 , and -CH 2 CH=CHCH 2 - groups, where the double bond can have an E or Z configuration. And, when multiple bonds are present, each double bond can independently have an E or Z configuration. Examples of branched alkenyl groups include -CH=C(CH 3 )- and CH 2 C=CH(CH3 Representative substituted alkenyl groups include, but are not limited to, substituted alkenyl groups, which may be substituted one or more times with any of the groups described herein, such as amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0089] The term "cycloalkyl" as used herein refers to substituted or unsubstituted cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups can have from 3 to about 8-12 ring members, while in other embodiments the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Cycloalkyl groups can have any number of carbon atoms, for example, from 3 to 8 carbon atoms (C 3 ~C 8 ), 3 to 6 carbon atoms (C 3 ~C 6 ), and 4 to 8 carbon atoms (C 4 ~C 8 Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings, such as, but not limited to, decalinyl.

[0090] The term "cycloalkylalkyl" as used herein refers to a substituted or unsubstituted alkyl group, as defined herein, in which a hydrogen or carbon bond of an alkyl group, as defined herein, is replaced with a bond to a cycloalkyl group, as defined herein. Representative cycloalkylalkyl groups include, but are not limited to, cyclopentylalkyl.

[0091] The term "alkylcycloalkyl" as used herein refers to a substituted or unsubstituted cycloalkyl group, as defined herein, in which a hydrogen of the cycloalkyl group, as defined herein, is replaced by a bond to an alkyl group, as defined herein. Representative alkylcycloalkyl groups include, but are not limited to, alkylcyclopropyl.

[0092] The term "acyl" as used herein refers to a group containing a carbonyl moiety, which is bonded through the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which may be part of a substituted or unsubstituted alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group, and the like. In the special case where the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, which is an acyl group as defined herein. An acyl group can contain 0 to about 12-40, 6-10, 1-5, or 2-5 additional carbon atoms bonded to the carbonyl group. An acryloyl group is an example of an acyl group. An acyl group can also contain heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups. When the group containing the carbon atom bonded to the carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl" group. One example is the trifluoroacetyl group.

[0093] The term "heterocyclylcarbonyl" is an example of an acyl group attached to a substituted or unsubstituted heterocyclyl group, as the term "heterocyclyl" is defined herein. An example of a heterocyclylcarbonyl group is a prolyl group, which can be a D- or L-prolyl group.

[0094] The term "aryl" as used herein refers to a substituted or unsubstituted cyclic aromatic hydrocarbon that does not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups have from about 6 to about 14 carbons (C 6 ~C 14 ) or 6 to 10 carbon atoms (C 6 ~C 10 ). Aryl groups can be unsubstituted or substituted as defined herein. The terms "aryl" and "aryl group" include fused ring species, including those containing fused aromatic and non-aromatic groups. Thus, the terms "aryl" and "aryl group" include groups of the formula:

[0095] [ka]

[0096] each of which may be substituted or unsubstituted, for example, hydroxy substituted. Representative substituted aryl groups may be mono-substituted or substituted more than once, such as, but not limited to, di-, tri-, tetra-, penta- or hexa-substituted phenyl or di- to octa-substituted naphthyl groups, which may be substituted with carbon or non-carbon groups as described herein.

[0097] The terms "aralkyl" and "arylalkyl" refer to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group, as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups, as well as fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group, as defined herein.

[0098] The term "heterocyclyl" or "heterocyclo" refers to substituted or unsubstituted aromatic and non-aromatic ring compounds containing three or more ring members, one or more (e.g., 1, 2, or 3) of which are heteroatoms, such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl or heteroaryl, or any combination thereof if polycyclic. In some embodiments, heterocyclyl groups contain from 3 to about 20 ring members, while other such groups have from 3 to about 15 ring members. In some embodiments, heterocyclyl groups contain from 3 to 8 carbon atoms (C 3 ~C 8 ), 3 to 6 carbon atoms (C 3 ~C 6 ), 3 to 5 carbon atoms (C 3 ~C 5 ) or 6 to 8 carbon atoms (C 6 ~C 8 C 2 A heterocyclyl group designated as -heterocyclyl can be a 5-membered ring having 2 carbon atoms and 3 heteroatoms, a 6-membered ring having 2 carbon atoms and 4 heteroatoms, etc. 4 -Heterocyclyl can be a 5-membered ring having one heteroatom, a 6-membered ring having two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring has the formula:

[0099] [ka]

[0100] They may also contain one or more double bonds, such as the groups 3,6-dihydro-2H-pyran and 3,4-dihydro-2H-pyran, each of which may be optionally substituted, having the following formula:

[0101] A heteroaryl ring is one embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species, including those containing fused aromatic and non-aromatic groups. Representative heterocyclyl groups include those of the formula:

[0102] [ka]

[0103] optionally substituted tetrahydro-2H-thiopyran-1,1-dioxides having the formula:

[0104] [ka]

[0105] and optionally substituted 4a,5,6,7-tetrahydro-4H-pyrrolo[1,2-d][1,3,4]oxadiazinyl, pyrrolidinyl, pyrrolidinone (e.g., pyrrolidin-2-one), azetidinyl, piperidinyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, having the formula:

[0106] [ka]

[0107] Examples of indolinyl groups include, but are not limited to, optionally substituted imidazo[1,2-a]pyridinyl, triazyolyl, tetrazolyl, benzoxazolinyl, thiazolyl, benzthiazolinyl, and benzimidazolinyl groups having the general formula:

[0108] [ka]

[0109] where R is as defined herein. Examples of isoindolinyl groups include those of the general formula:

[0110] [ka]

[0111] where R is as defined herein. Examples of benzoxazolinyl groups include those of the general formula:

[0112] [ka]

[0113] where R is as defined herein. Examples of benzthiazolinyl groups include those of the general formula:

[0114] [ka]

[0115] where R is as defined herein. In some embodiments, the group R in the benzoxazolinyl and benzthiazolinyl groups is N(R) 2In some embodiments, each R is a hydrogen or alkyl group, where the alkyl group is substituted or unsubstituted. In some embodiments, the alkyl group is substituted with a heterocyclyl group (e.g., a pyrrolidinyl group).

[0116] The term "heterocyclylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylmethyl, and indol-2-ylpropyl.

[0117] The term "heterocyclylalkoxy" refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group, as defined herein, is replaced with a bond to a heterocyclyl group, as defined herein, and the alkyl group is bonded to an oxygen. Representative heterocyclylalkoxy groups include -O-(CH 2 ) q Heterocyclyl, including, but not limited to, where q is an integer from 1 to 5. In some embodiments, heterocyclylalkoxy groups include -O-(CH 2 ) q Morpholinyl, e.g. -O-CH 2 CH 2 -Contains morpholine.

[0118] The term "heteroarylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group, as defined herein.

[0119] The term "alkoxy" refers to an oxygen atom bonded to an alkyl group, including cycloalkyl groups, as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can contain 1 to about 12-20 or about 12-40 carbon atoms bonded to an oxygen atom, and can further contain double or triple bonds and can contain heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in the context in which two adjacent atoms of the structure are replaced therewith.

[0120] The terms "amine", "amine group", "amino" and "amino group" refer to -NH 2 , -NHR, -NR 2 , or -NR 3 + where each R is defined herein, and -NR 3 + (which cannot be protonated). Thus, any compound substituted with an amino group can be considered an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.

[0121] "Alkylamino" groups include monoalkylamino, dialkylamino, and trialkylamino groups. Examples of "alkylamino" are -NH-alkyl and -N(alkyl) 2 It is.

[0122] Examples of "cycloalkylamino" groups are -NH-cycloalkyl and -N(cycloalkyl) 2 It is. An example of a "cycloalkylheterocycloamino" group is -NH-(heterocyclocycloalkyl) where the heterocyclo group is attached to the nitrogen and the cycloalkyl group is attached to the heterocyclo group.

[0123] An example of a "heterocyclocycloamino" group is -NH-(cycloalkylheterocycle) where the cycloalkyl group is attached to the nitrogen and the heterocyclo group is attached to the cycloalkyl group.

[0124] The term "amide" refers to an amide having the formula -C(O)NR 2 where R is defined herein. The terms "halo," "halogen," and "halide" group, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0125] The term "haloalkyl" group includes monohaloalkyl groups, polyhaloalkyl groups (where all halo atoms can be the same or different), and perhaloalkyl groups (where all hydrogen atoms are replaced by halogen atoms, such as fluoro). Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, -CF(CH 3 ) 2 etc.

[0126] As used herein, the terms "salt" and "pharmaceutical acceptable salt" refer to derivatives of the disclosed compounds, where the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutical acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups, such as amines; and alkali or organic salts of acidic groups, such as carboxylic acids. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; as well as the salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

[0127] Pharmaceutically acceptable salts can be synthesized from parent compounds that contain a basic or acidic moiety by conventional chemical methods. In some cases, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts can be found in "Remington's Pharmaceutical Sciences", 17th Edition, Mack Publishing Company, Easton, Pa., 1985, the disclosure of which is incorporated herein by reference for its teachings.

[0128] The term "solvate" means a compound or a salt thereof that further contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0129] The term "prodrug" refers to derivatives of compounds that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide active compounds, particularly the compounds of the present invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds that contain biohydrolyzable moieties, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Particular prodrugs of compounds with carboxyl functional groups are lower alkyl esters of the carboxylic acid. Carboxylic acid esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described in "Burger's Medicinal Chemistry and Drug Discovery", 6th Edition (ed. Donald J. Abraham, 2001, Wiley) and "Design and Application of Prodrugs" (ed. H. Bundgaard, 1985, Harwood Academic Publishers GmbH).

[0130] Those skilled in the art will recognize that many modifications to the embodiments described herein are possible without departing from the spirit and scope of the present disclosure. Thus, the present description is not intended to be, and should not be construed as, limited to the examples given, and the full scope of protection provided by the appended claims and their equivalents should be accorded. In addition, some of the features of the present disclosure can be used without the corresponding use of other features. Thus, the above described or illustrative embodiments are provided for the purpose of illustrating the principles of the present disclosure, and are not intended to be limiting thereof, and may include modifications thereto and permutations thereof.

[0131] Values ​​expressed in range format should be interpreted in a flexible manner to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were expressly recited. For example, the range "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not only about 0.1% to about 5%, but also the individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the range recited. The description "about X to Y" has the same meaning as "about X to about Y" unless otherwise indicated. Similarly, the description "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z" unless otherwise indicated.

[0132] In this document, the terms "a," "an," or "the" are used to include one or more, unless the context clearly dictates otherwise. The term "or" is used to refer to a non-exclusive "or," unless otherwise stated. In addition, any words or terms used herein and not otherwise defined should be understood to be for descriptive purposes only and not for limiting purposes. Any use of section headings is intended to aid in the interpretation of this document and should not be construed as limiting. Additionally, information associated with a section heading may appear within or outside that particular section. Additionally, all publications, patents, and patent documents referenced in this document are incorporated herein by reference in their entirety as if individually incorporated by reference. In the event of a conflict in usage between this document and any document so incorporated by reference, the usage in the incorporated reference should be considered as supplementary to the usage in this document, and in the event of any inconsistent conflict, the usage in this document shall control.

[0133] In the methods described herein, steps may be performed in any order without departing from the principles of the invention, unless a chronological or operational order is explicitly recited. Moreover, certain steps may be performed simultaneously, unless express claim language recites that they be performed separately. For example, a claimed step of performing X and a claimed step of performing Y may be performed simultaneously in a single operation, and the resulting process would fall within the literal scope of the claimed process.

[0134] As used herein, the term "about" may allow for a degree of variation in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or the limits of a stated range. As used herein, the term "substantially" refers to a majority or majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999%, or more.

[0135] As used herein, the term "substantially free" refers to less than about 30%, 25%, 20%, 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.001%, or less than about 0.0005%, or less than about 0%, or 0%.

[0136] Those skilled in the art will recognize that many modifications to the embodiments described herein are possible without departing from the spirit and scope of the present disclosure. Thus, the present description is not intended to be, and should not be construed as, limited to the examples given, and the full scope of protection provided by the appended claims and their equivalents should be accorded. In addition, some of the features of the present disclosure can be used without the corresponding use of other features. Thus, the above described or illustrative embodiments are provided for the purpose of illustrating the principles of the present disclosure, and are not intended to be limiting thereof, and may include modifications thereto and permutations thereof. EXAMPLES

[0137] The present disclosure may be better understood by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the examples given herein. Example 1 Preparation of Compound 1

[0138] [ka]

[0139] The synthesis of compound 2 was carried out using literature reports (Rowlands, RA; Chen, Q.; Bouley, RA; Avramova, LV; Tesmer, JJG; White, AD, J. Med. Chem., 2021, 64, 566-585). Compound 3 was obtained from a commercial source.

[0140] To a solution of 2 (60 mg, 0.14 mmol, 1 equiv) in dry DMF (2.5 mL) was added (S)-mandelic acid 3 (26 mg, 0.17 mmol, 1.1 equiv), HATU (63 mg, 0.17 mmol, 1.2 equiv) and DIPEA (37 mg, 0.29 mmol, 2 equiv) at 0° C. The reaction was stirred at room temperature for 12 h. Upon completion, the reaction mixture was extracted with ethyl acetate and brine and purified using flash column chromatography (DCM:MeOH) (94:6) to give compound 1 (24 mg) as a red solid. Yield: 49%; 1 H NMR(400MHz,DMSO):δ 11.03(s,1H),9.28(s,1H),8.58(d,J=8.0Hz,1H),8.17(d,J=1.2Hz,1H),7.65(dd,J=8.1,1. 6Hz,1H),7.60(s,1H),7.57-7.47(m,2H),7.42(dd,J=8.6,5.6Hz,2H),7.36(dd,J=8.0,6.7Hz ,2H),7.29(d,J=7.3Hz,1H),7.13(t,J=8.9Hz,2H),6.90(d,J=8.1Hz,1H),6.28(d,J=4.7Hz,1 Chemical formula of compound 1: C 32 H 29FN 4 O 4 ESI-MASS calculated: 522.22 found [M+H]+.

[0141] Preparation of Compounds 2 and 3:

[0142] [ka]

[0143] Synthesis of compound 6 To a stirred solution of compound 5-carboxyindoline 4 (438 mg, 2.47 mmol, 1.2 equiv.) in dry DMF (4 mL), (R)-1-phenylethan-1-amine 5 (0.26 mL, 2.06 mmol, 1 equiv.), HATU (904 mg, 2.47 mmol, 1.2 equiv.) and DIPEA (0.46 mL, 2.7 mmol, 1.3 equiv.) were added under Ar atmosphere at 0° C. and the mixture was stirred at 23° C. for 12 h. Upon completion of the reaction (monitored by TLC), the mixture was diluted with saturated Na 2 CO 3 (10 mL) and the mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (2x50 mL) and then with NaSO 4 The mixture was dried over 100 ml and concentrated under reduced pressure. The crude mixture was purified by column chromatography (0-15% MeOH in DCM) to give compound 6 as a pale pink solid in 89% yield.

[0144] Synthesis of compound 7 To a stirred solution of compound 6 (100 mg, 0.41 mmol, 1 equiv) in absolute ethanol (2 mL) was added 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (151 mg, 0.48 mmol, 1.1 equiv). To this solution was added piperidine (0.04 mL, 0.497 mmol, 1.2 equiv) and the resulting mixture was heated to reflux (90° C.) for 4 h. Upon completion, the reaction was allowed to cool to room temperature, the product was filtered, and the collected orange solid compound 7 was washed with cold ether and dried under vacuum. Yield 78%. This compound was used in the next reaction without further purification.

[0145] Synthesis of compound 2 To a stirred solution of compound 7 (30 mg, 0.06 mmol) in dry DMF (1 mL), (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol 8 (8.4 mg, 0.06 mmol), HATU (22.7 mg, 0.06 mmol) and DIPEA (12 μL, 0.07 mmol) were added under argon atmosphere at 0 °C and the mixture was stirred at 23 °C for 12-14 h. Once the reaction was complete (monitored by TLC), the solvent was evaporated under reduced pressure and the crude mixture was diluted with water and extracted with DCM (3x10 mL). The combined organic layers were washed with NaSO 4 The mixture was dried over 100 ml and concentrated under reduced pressure. The resulting crude mixture was purified by column chromatography (0-5% MeOH in DCM) to give compound 2 as an orange solid in 61% yield (18 mg). 1 H NMR(400MHz,DMSO-d6)δ 11.14(s,1H),8.62(d,J=7.9Hz,1H),8.26(s,1H),8.02(d,J=8.6Hz,1H),7.71(d,J=4.8Hz,2H) ,7.42(d,J=7.5Hz,2H),7.34(t,J=7.6Hz,2H),7.27-7.17(m,5H),6.95(d,J=8.1Hz,1H),5.35(d ,J=5.8Hz,1H),5.28(t,J=7.7Hz,1H),5.23-5.15(m,1H),4.42-4.34(m,1H),3.17(dd,J=15.5, 7.3Hz,1H),2.75(dd,J=15.3,7.7Hz,1H),2.56-2.42(m,6H),1.52(d,J=7.0Hz,3H).Chemical formula of compound 2:C 34 H 32 N 4 O 4 ;ESI-MASS calculated value: 560.65 Found value [M+H] + .

[0146] Synthesis of compound 3 To a stirred solution of compound 7 (30 mg, 0.06 mmol) in dry DMF (1 mL), (tetrahydrofuran-2-yl)methanamine 9 (6.3 mg, 0.06 mmol), HATU (22.7 mg, 0.06 mmol) and DIPEA (12 μL, 0.07 mmol) were added under argon atmosphere at 0 °C and the mixture was stirred at 23 °C for 12-14 h. Once the reaction was complete (monitored by TLC), the solvent was evaporated under reduced pressure and the crude mixture was diluted with water and extracted with DCM (3x10 mL). The combined organic layers were washed with NaSO 4 The mixture was dried over 100 ml and concentrated under reduced pressure. The resulting crude mixture was purified by column chromatography (0-3% MeOH in DCM) to give compound 3 as an orange solid in 64% yield (19 mg). 1 H NMR(400MHz,DMSO-d6)δ 11.11(s,1H),8.58(d,J=8.0Hz,1H),8.22(s,1H),7.73-7.63(m,3H),7.39(d,J=7.3Hz,2H),7 .31(t,J=7.6Hz,2H),7.20(t,J=7.3Hz,1H),6.91(d,J=8.1Hz,1H),5.21-5.13(m,1H),3.96-3. 91(m,1H),3.79-3.74(m,1H),3.62(d,J=6.8Hz,1H),3.26(d,J=5.0Hz,2H),2.41(d,J=6.6Hz,6 H),1.87(ddd,J=23.4,13.6,7.2Hz,3H),1.63-1.56(m,1H),1.48(d,J=7.1Hz,3H).Chemical formula of compound 3:C 30 H 32 N 4 O 4 ESI-MASS calculated value: 512.61 Found value [M+H] + .

[0147] Other compounds described herein can be synthesized in a similar manner to the compounds described in this Example. Example 2 GRK2 and GRK5 Inhibition Assay: All newly synthesized compounds were assayed for IC40 of human GRK5 and bovine GRK2 using the radiometric assay described by the inventors in the literature (Rowlands et al. (2021) supra). 50 The values ​​were determined using the published procedure: 20 mM HEPES (pH 7.0), 2 mM MgCl 2 GRK (50 nM) was incubated with 500 nM porcine brain tubulin (PurSolutions) and 0.01–50 μM de novo synthetic inhibitors in 0.025% dodecylmaltoside (DDM) and 1% DMSO for 3–5 min, after which radioactive [γ- 32 The reaction was initiated with the addition of 5 μM [P]-ATP (PerkinElmer Life Sciences). The reaction was quenched at 8 min by adding 5 μL of 4X SDS gel loading dye to 10 μL of the reaction. Samples (12 μL) were resolved on 4-15% Criterion TGX precast gels (Bio-Rad). Low nanomolar IC 50 For potent inhibitors with IC values, the inhibitor concentration should be adjusted to approximately 0–50 × [IC] estimated from the first run for a more accurate measurement. 50 [Inhibitor] was adjusted to 0.05%. Gels were dried, exposed overnight to a storage phosphor screen, and scanned using a Personal Molecular Imager (Bio-Rad). Bands corresponding to phosphorylated tubulin were quantified using ImageQuant, plotted as a function of log[inhibitor], and fitted to a four-parameter log(inhibitor) vs. response model in GraphPad Prism 7.03 to determine IC 50 , mean, and standard deviation values ​​were determined. Outliers were automatically removed at a Q value of 1%. Experiments were performed at least three times.

[0148] PKA inhibition assays were performed using the ADP-Glo ​​system (Promega Corporation) according to the manufacturer's instructions. 2 PKA (500 nM) was incubated with 1 μg of CREBtide (KRREILSRRPSYR) (Genscript Corporation) substrate, 50 μM ATP, and inhibitors in 0.025% dodecylmaltoside (DDM), and 4% DMSO for 30 min. The concentration range of each inhibitor varied depending on its solubility in 4% DMSO, with the highest concentration being 100–500 μM. After the first reaction, ADP-Glo ​​reagent was added to the reaction and incubated for another 40 min. Finally, kinase detection reagent was added and incubated for 30 min, and luminescence was measured using a FlexStation 3 Multi-mode Microplate Reader (Molecular Devices). All data were analyzed in the same way as the GRK inhibition assay. Experiments were performed three times in duplicate.

[0149] A standard control compound is run during each assay to assess consistency across time, experimenters, and minor changes in assay conditions that may be required to preserve compound dissolution and dispersion (e.g., by addition of DDM or 3% DMSO). Paroxetine was used as a control for GRK2 ("Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility" by Thal, DM; Homan, KT; Chen, J.; Wu, EK; Hinkle, PM; Huang, ZM; Chuprun, JK; Song, J.; Gao, E.; Cheung, JY; Sklar, LA; Koch, WJ; Tesmer, JJG, ACS Chemical Biology. Chem. Biol. 2012, 7, 1830-1839), and PKA and CCG215022 were used as controls for GRK5 ("Crystal Structure of G Protein-coupled Receptor Kinase 5 in Complex with a Rationally Designed Inhibitor," Homan, KT; Waldschmidt, HV; Glukhova, A.; Cannavo, A.; Song, J.; Cheung, JY; Koch, WJ; Larsen, SD; Tesmer, JJ, J. Biol. Chem. 2015, 290, 20649-20659).

[0150] List of compounds, structures, and in vitro inhibition data coverage of GRK2 and GRK5

[0151] [Table 1-1]

[0152] [Table 1-2]

[0153] [Table 1-3]

[0154] [Table 1-4]

[0155] [Table 1-5]

[0156] [Table 1-6]

[0157] [Table 1-7]

[0158] [Table 1-8]

[0159] [Table 1-9]

[0160] [Table 1-10]

Claims

1. formula: 【Chemistry 1】 (In the formula, R １ is R ５ , -alkyl-R ５ , -C(O)R ５ , 【Chemistry 2】 where R ５ is alkyl, hydroxy, alkoxy, amido, cyano, alkenyl, haloalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, or R ５ and R ７ can form a cycloalkyl group; R １Ａ is H or alkyl, or R １Ａ and R ９ can form a heterocyclyl group; X １ is O or NR ６Ａ where R ６Ａ is H or alkyl, or R ６Ａ and R ５ can form a heterocyclyl group; p, d, and q are each independently an integer from 0 to 5; R ２ and R ３ are each independently alkyl; R ６ is H or alkyl; R ７ is H, alkyl or aryl; R ８ is H or alkyl; R ９ is H or alkyl; and R ４ is aryl, arylalkyl, or heteroarylalkyl; or a pharma- ceutically acceptable salt thereof.

2. The compound has the formula: 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof.

3. R ２ and R ３ are each independently １ ~C ３ 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein: -alkyl.

4. R ２ and R ３ and R are each methyl; or a pharma- ceutically acceptable salt thereof.

5. R ４ 3. The compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, wherein:

6. R ４ is the formula: 【Chemistry 4】 where R １０ is H, halo, alkyl, haloalkyl, amido or alkoxy; and X １ is absent or alkyl; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

7. R １０ or a pharma- ceutically acceptable salt thereof.

8. R ４ is the formula: 【Chemistry 5】 where R １１ is alkyl, 7. The compound of claim 6 or a pharma- ceutically acceptable salt thereof.

9. R ４ is the formula: 【Chemistry 6】 2. The compound of claim 1, which is a group represented by the formula:

10. The compound has the formula: 【Chemistry 7】 is a compound of the formula: R １ is R ５ , -alkyl-R ５ , -C(O)R ５ or 【Chemistry 8】 where R ５ is alkyl, cycloalkyl, aryl or heteroaryl, or a pharma- ceutically acceptable salt thereof.

11. R ５ is furanyl, indolyl, imidazolyl, benzimidazolyl or imidazo[1,2-a]pyridinyl; q is 0, p is 0 and d is 0; and / or R １ is -alkyl-R ５ , for example -(C １ ~C ３ ) alkyl-R ５ 11. The compound of claim 10, which is: or a pharma- ceutically acceptable salt thereof.

12. The compound has the formula: 【Chemistry 9】 is a compound of the formula: R １ is R ５ , -alkyl-R ５ or 【Chemistry 10】 where R ５ is alkyl, hydroxy, alkoxy, cycloalkyl, aryl, heterocyclyl or heteroaryl, or R ５ and R ７ The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is a cycloalkyl group;

13. R ５ is tetrahydrofuranyl, pyranyl, furanyl, tetrahydro-2H-thiopyran-1,1-dioxide or benzimidazolyl; q is 0 and d is 0; and / or R １ is -alkyl-R ５ , for example -(C １ ~C ３ ) alkyl-R ５ 13. The compound of claim 12, wherein:

14. R １ teeth, 【Chemistry 11】 where R ５ and R ７ The compound of claim 12, or a pharma- ceutically acceptable salt thereof, wherein:

15. R １ is R ５ or -alkyl-R ５ and R ５ is hydroxy or alkoxy, or a pharma- ceutically acceptable salt thereof.

16. The compound has the formula: 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 【Chemistry 12-4】 or a pharma- ceutically acceptable salt thereof.

17. The compound has the formula: 【Chemistry 13-1】 【Chemistry 13-2】 【Chemistry 13-3】 【Chemistry 13-4】 【Chemistry 13-5】 【Chemistry 13-6】 【Chemistry 13-7】 【Chemistry 13-8】 【Chemistry 13-9】 【Chemistry 13-10】 【Chemistry 13-11】 【Chemistry 13-12】 【Chemistry 13-13】 【Chemistry 13-14】 【Chemistry 13-15】 【Chemistry 13-16】 【Chemistry 13-17】 【Chemistry 13-18】 【Chemistry 13-19】 【Chemistry 13-20】 【Chemistry 13-21】 【Chemistry 13-22】 【Chemistry 13-23】 【Chemistry 13-24】 【Chemistry 13-25】 or a pharma- ceutically acceptable salt thereof.

18. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable carrier or excipient.

19. 20. A method for treating a subject in need of inhibition of G protein-coupled receptor kinase 5 (GRK5), comprising administering to the subject in need thereof an effective amount of a compound of claim 1 or a pharmaceutical composition of claim 18, whereby the subject in need of inhibition of GRK5 is treated.

20. 20. The method of claim 19, wherein the subject is suffering from cardiovascular disease.

21. 21. The method of claim 20, wherein the cardiac disease is hypertrophic cardiomyopathy or heart failure.

22. 20. The method of claim 19, wherein the subject is suffering from cancer.