Selective inhibitors of g protein-coupled receptor kinase 5, compositions, and methods of use

Abstract

A compound having the structure of formula I or la; a pharmaceutical composition comprising the compound of formula I or la and a pharmaceutically acceptable carrier or excipient; and a method of inhibiting G protein-coupled receptor kinase 5 in a subject.

Description

SELECTIVE INHIBITORS OF G PROTEIN-COUPLED RECEPTOR KINASE 5, COMPOSITIONS, AND METHODS OF USECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority from U.S. Appl. No. 63 / 665,662, filed June 28, 2024, which is incorporated by reference as if fully set forth herein.STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under contract HL071818 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present disclosure relates to selective inhibitors of G protein-coupled receptor kinase (GRK) 5, compositions comprising same, and methods of administering the compounds or compositions to a subject in need of GRK5 inhibition.BACKGROUND

[0004] G protein-coupled receptors (GPCRs) modulate cellular events in response to extracellular signals. GPCR-related kinases (GRK) selectively recognize and phosphorylate activated GPCRs, leading to their desensitization and internalization, a process critical for maintaining cellular homeostasis. The seven known GRKs (GRK1-7) are classified by structural and sequence similarities into three subfamilies - GRK1 (GRK1 and 7), GRK2 (GRK2 and 3), and GRK4, (GRK4, 5 and 6) (Pitcher et al., Ann Rev Biochem 67(1): 653-692 (1998)). GRK1 and 7 are expressed primarily in the retina, whereas GRK4 is primarily expressed in the testes and GRK2, 3, 5 and 6 are more ubiquitously expressed (Ferguson, Pharmacol Rev 53(1): 1-24 (2001)). Of these kinases, GRK2 and GRK5 are the two isoforms found in the highest concentration in cardiovascular tissue. The GRK5 subfamily is part of a larger superfamily that includes the catalytic domains of serine / threonine kinases protein tyrosine kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphatidylinositide 3-kinases.

[0005] GRK2 and GRK5 are considered therapeutic targets for various disease states, such as cancer, inflammation, Parkinson’s disease, Alzheimer’s disease, heart failure and hypertrophic cardiomyopathy (Jiang et al., Cell Death Dis 9(3): 295 (2018); Belmonte et al., Circ Res 111(8): 957-958 (2012); Brinks et al., Today Dis Meeh 7(2): e129-e134 (2010); Lymperopoulos et al., Nat Med 13(3): 315-323(2007); and Nogues et al., Semin Cancer Biol 48: 78-90 (2018)). GRK5 is unique among the GRKs because it undergoes a Ca2+-calmodulin-dependent nuclear localization event. Once translocated to the nucleus, GRK5 can phosphorylate histone deacetylase 5 (HDAC5), which is responsible for increasing transcription of genes associated with hypertrophic cardiomyopathy. In studies where GRK5 was knocked down, cardiomyocytes were protected from hypertrophic cardiomyopathy (Huang et al., Front Biosci Landmark Ed 16: 3047-3060 (2011)). The influence of GRK5 in progressive heart failure and hypertrophic cardiomyopathy remains unclear, in part because GRK2 can also mediate hypertrophic responses (Schlegel et al., PLoS One 12(7): e0182110 (2017); Lieu et al., Exp Opin Ther Targets 23(3): 201-214 (2019)), and there are no available GRK5-selective and GRK5 subfamily-selective compounds to test mechanisms of action.

[0006] GRK5 is also involved in the progression of several human cancers. Malignant cells can hijack the normal physiological functions of GPCRs to proliferate autonomously and evade immune detection (Dorsam et al., Nat Rev Cancer 7: 79-94 (2007)). In vivo experiments have validated the therapeutic benefit of eliminating GRK5 in suppressing multiple types of cancer growth (Chakraborty et al., Cancer Res 74: 3489-3500 (2014); Jiang et al. (2018), supra).

[0007] Accordingly, GRK5- and GRK5-subfamily- (e.g., GRK4, GRK5 and GRK6) selective compounds are needed. In view of the foregoing, it is an object of the present disclosure to provide compounds that selectively inhibit G protein- coupled receptor kinase (GRK) 5. Such compounds can be administered to subjects, such as subjects with heart disease or cancer, in need of such inhibition. This and other objects and advantages, as well as inventive features, will be apparent from the detailed description provided herein.SUMMARY

[0008] A compound having the structure of formula I:(Formula I) is provided, wherein:Ri is H, C1-C3 alkyl, -O-Ci-Ce alkyl, or halo;R2 is -N(H)-pyrazole, which is optionally substituted with a Ci-Ce alkyl;R3 is H or Ci-Ce alkyl;R4 is at least one but not more than two, which can be the same or different, of halo, -O-C1-C6 alkyl, -O-C2-C6 alkenyl, NH2, or CH2NH; wherein, when Rds -O- C1-C6 alkyl or -O-C2-C6 alkenyl, R4 can form a ring structure with a carbon atom in the pyrazole ring of R2;Rs is H, C1-C3 alkyl, -O-Ci-Ce alkyl, -N-Ci-Ce alkyl, or halo; and n = 0 or 1 ; or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0009] In embodiments of the compound of formula I, Ci-Ce alkyl can be methyl or ethyl. In embodiments of the compound of formula I, halo can be F or Cl. In embodiments of the compound of formula I, C2-C6 alkenyl can be pentenyl.

[0010] A compound of formula la:wherein:A1is aryl or heterocyclyl;A2is cycloalkyl, aryl or heterocyclyl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, alkyl-O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl; or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof. In embodiments of the compound of formula la, L3is present.

[0011] In an embodiment of the compound of formula I and la, the compound has the structure:

[0012] In an embodiment of the compound of formula I and la, the compound has the structure:

[0013] In an embodiment of the compound of formula I and la, the compound has the structure:

[0014] In an embodiment of the compound of formula I and la, the compound has the structure:la, the compound has the structure:

[0015] In an embodiment of the compound of formula I and la, the compound has the structure:

[0016] In an embodiment of the compound of formula I and la, the compound has the structure:

[0017] In an embodiment of the compound of formula I and la, the compound has the structure:

[0018] In an embodiment of the compound of formula I and la, the compound has the structure:

[0019] In an embodiment of the compound of formula I and la, the compound has the structure:

[0020] In an embodiment of the compound of formula I and la, the compound has the structure:59

[0021] In an embodiment of the compound of formula I and la, the compound has the structure:

[0022] Also provided are compounds having a structure selected from:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0023] Also provided are compounds having a structure selected from:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0026] Also provided are compounds having a structure selected from:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0027] In view of the above, also provided is a pharmaceutical composition. The pharmaceutical composition comprises an above-described compound and a pharmaceutically acceptable carrier or excipient.

[0028] A method of inhibiting a G protein-coupled receptor kinase (GRK) 5 in a subject is also provided. The method comprises administering an abovedescribed compound or an above-described pharmaceutical composition in an amount effective to inhibit GRK5. In embodiments of the method, the subject has cancer, such as multiple myeloma. In other embodiments of the method, the subject has heart disease, such as heart failure or cardiac hypertrophy.DESCRIPTION

[0029] Reference will now be made in detail to certain 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 exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

[0030] The present disclosure is based on the discovery of G protein-coupled receptor kinase (GRK) 5 inhibitors. Thus, provided is a compound having the structure of formula I:(Formula I) wherein:R1 is H, C1-C3 alkyl, -O-Ci-Ce alkyl, or halo;R2 is -N(H)-pyrazole, which is optionally substituted with a Ci-Ce alkyl;R3 is H or Ci-Ce alkyl;R4 is at least one but not more than two, which can be the same or different, of halo, -O-Ci-Ce alkyl, -O-C2-C6 alkenyl, NH2, or CH2NH; wherein, when Rds -O- C1-C6 alkyl or -O-C2-C6 alkenyl, R4 can form a ring structure with a carbon atom in the pyrazole ring of R2;Rs is H, C1-C3 alkyl, -O-Ci-Ce alkyl, -N-Ci-Ce alkyl, or halo; and n = 0 or 1 ; or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0031] In embodiments of the compound of formula I, Ci-Ce alkyl can be methyl or ethyl. In embodiments of the compound of formula I, halo can be F or Cl. In embodiments of the compound of formula I, C2-C6 alkenyl can be pentenyl.

[0032] Also provided is a compound having the structure of formula la:(Formula la) wherein:A1is aryl or heterocyclyl (e.g., a monocyclic aryl or heterocyclyl);A2is cycloalkyl, aryl or heterocyclyl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl; or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0033] In embodiments, L3is present.

[0034] In an embodiment, the compound of formula (la) is a compound wherein: A1is aryl (e.g., phenyl or naphthyl);A2is cycloalkyl (e.g., cyclopentyl optionally fused with aryl, such as phenyl), aryl (e.g., phenyl or naphthyl) or heterocyclyl (e.g., furanyl, tetrahydrofuranyl, pyrazolyl, benzpyrazolyl, and indolyl);G1and G2are each, independently, heterocyclyl (e.g., where G1is pyrimidinyl and G2is pyrazolyl);L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl. In one embodiment L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; and L2is NR6; and L3is absent, *-alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.

[0035] In an embodiment, the compound of formula (la) is a compound wherein: A1is aryl (e.g., phenyl or naphthyl);A2is cycloalkyl (e.g., cyclopentyl optionally fused with aryl, such as phenyl);G1and G2are each, independently, heterocyclyl (e.g., where G1is pyrimidinyl and G2is pyrazolyl);L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl. In one embodiment L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; L2is NR6; and L3is absent, *-alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.

[0036] In an embodiment, the compound of formula (la) is a compound wherein: A1is aryl (e.g., phenyl or naphthyl);A2is aryl (e.g., phenyl or naphthyl);G1and G2are each, independently, heterocyclyl (e.g., where G1is pyrimidinyl and G2is pyrazolyl);L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl. In one embodiment L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; L2is NR6; and L3is absent, *-alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.

[0037] In an embodiment, the compound of formula (la) is a compound wherein: A1is aryl (e.g., phenyl or naphthyl);A2is heterocyclyl (e.g., furanyl, tetrahydrofuranyl, pyrazolyl, benzpyrazolyl, and indolyl);G1and G2are each, independently, heterocyclyl (e.g., where G1is pyrimidinyl and G2is pyrazolyl);L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl. In one embodiment L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; L2is NR6; and L3is absent, *-alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.

[0038] In an embodiment, A1is Ce-Cw aryl, such as phenyl or naphthyl. Alternatively, A1is C2-C5 heterocyclyl, such as furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl. In one embodiment, A1is an optionally substituted phenyl group:

[0039] Alternatively, or in addition to the variables for A1, A2is C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which can be fused with Ce-Cw aryl. In one embodiment, A2is C3-C7 cycloalkyl fused with Ce-Cw aryl, such as:wherein * denotes the point of attachment of A2to L1and ** denotes the point of attachment of A2to L3, when L3is present. Alternatively, A2is C2-C7 heterocyclyl, such as furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, benzpyrazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl. Alternatively, A2is Ce-C aryl, such as phenyl or naphthyl. In one embodiment, A2is an optionally substituted phenyl group (e.g., optionally substituted with one or more alkyl; haloalkyl, such as CF3; alkenyl; alkoxy; alkenyloxy; amino; aminoalkyl; or halo, such as F or Cl). In another embodiment, A2is optionally substituted furanyl, tetraydrofuranyl, pyrrolyl, indolyl, pyrazolyl or benzpyrazolyl:In an embodiment, A2is furanyl, tetrahydrofuranyl, pyrazolyl or benzpyrazolyl.

[0040] Alternatively, or in addition to the variables for A1and / or A2, G1is C2-C5 heterocyclyl, such as furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl. In an embodiment, G1is optionally substituted pyrimidinyl:

[0041] Alternatively, or in addition to the variables for A1, A2, and / or G1, G2is C2- C5 heterocyclyl, such as furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl. In an embodiment, G2is optionally substituted pyrazolyl (e.g., optionally substituted with one or more alkoxy, alkyl or alkenyl):wherein * denotes the point of attachment of G2to L2and ** denotes the point of attachment of G2to L3, when L3is present.

[0042] In embodiments, the group:represents optionally substituted C6-C9 heterocyclyl, such as optionally substituted:wherein * represents the point of attachment of G1to L2and ** represents the point of attachment of G1to L1.

[0043] In embodiments, the group:is an optionally substituted group of formula: h as optionally substituted: nts, the group:is an optionally substituted group of formula:wherein A2is an optionally substituted group of formula:s the point of attachment of A2to L3, when L3is present. In embodiments, L3is absent.

[0045] Alternatively, or in addition to the variables for A1, A2, G1, G2, and / or the group:A1( G1L1is optionally substituted -NR6-Ci-Ce alkyl-, -Ci-Ce alkyl-NR6-, -O-Ci-Ce alkyl-, -Ci-Ce alkyl-O- or combinations thereof, wherein each R6is H or alkyl. In one embodiment, L1is optionally substituted -NR6-Ci-Ce alkyl-. In another embodiment, L1is optionally substituted -NR6-CI-C3 alkyl-. In another embodiment, L1is optionally substituted -NR6-Ci alkyl- or -NR6-C2 alkyl-. In one embodiment, L1is -NR6-Ci alkyl-. In another embodiment, L1is NR6, such as NH. In yet another embodiment, L1is NR6(C)O, such as NHC(O).

[0046] Alternatively, or in addition to the variables for A1, A2, G1, G2, the group:and / or L1, L2is optionally substituted -NR6-Ci-Ce alkyl-, -Ci-Ce alkyl-NR6-, -O-C1- Ce alkyl-, -Ci-Ce alkyl-O- or combinations thereof, wherein each R6is H or alkyl. In one embodiment, L2is optionally substituted -NR6-Ci-Ce alkyl-. In another embodiment, L2is optionally substituted -NR6-CI-C3 alkyl-. In another embodiment, L2is optionally substituted -NR6-Ci alkyl- or -NR6-C2 alkyl- (e.g., unsubstituted or optionally substituted with one or more alkyl or alkenyl). In one embodiment, L2is optionally substituted -NR6-Ci alkyl-. In another embodiment, L2is NR6, such as NH.

[0047] Alternatively, or in addition to the variables for A1, A2, G1, G2, the group:L1and / or L2, L3is absent, -O-C3-C10 alkyl-, -C3-C10 alkyl-O-, -O-C3-C10 alkenyl- or -C3-C10 alkenyl-O-. In one embodiment, L3is -O-C5-C10 alkyl-, -C5-C10 alkyl-O-, - O-C5-C10 alkenyl- or -C5-C10 alkenyl-O-. In another embodiment, L3is -O-Ce-Cs alkyl-, -Ce-Cs alkyl-O-, -O-Ce-Cs alkenyl- or -Ce-Cs alkenyl-O-.

[0048] In an embodiment of the compound of formula I and la, the compound has the structure:

[0049] In an embodiment of the compound of formula I and la, the compound has the structure:

[0050] In an embodiment of the compound of formula I and la, the compound has the structure:

[0051] In an embodiment of the compound of formula I and la, the compound has the structure:la, the compound has the structure:

[0052] In an embodiment of the compound of formula I and la, the compound has the structure:

[0053] In an embodiment of the compound of formula I and la, the compound has the structure:

[0054] In an embodiment of the compound of formula I and la, the compound has the structure:

[0055] In an embodiment of the compound of formula I and la, the compound has the structure:

[0056] In an embodiment of the compound of formula I and la, the compound has the structure:

[0057] In an embodiment of the compound of formula I and la, the compound has the structure:59

[0058] In an embodiment of the compound of formula I and la, the compound has the structure:

[0059] Also provided are compounds having a structure selected from:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0060] Also provided are compounds having a structure selected from:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0063] Also provided are compounds having a structure selected from:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

[0064] The above compounds can be synthesized in accordance with methods known in the art and exemplified herein. See, e.g., the Examples section provided herein.

[0065] The terms “substituted,” “substituent,” and “functional group” refer to a group that can be or is substituted onto a molecule or onto another group (e.g., on an aryl or an alkyl group). Examples of substituents include, but are not limited to, a halogen (e.g., F, Cl, Br, and I), OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, -(CH2)0.2P(O)(OR)2, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)O-2N (R)C(0) R, (CH2)O-2N (R)C(0)OR, (CH2)O-2N(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)SO2R, N(R)SO2N(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 wherein each R can be, independently, hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl or two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl, which can be mono- or independently multi-substituted.

[0066] The term “alkyl” as used herein refers to substituted or unsubstituted straight chain and branched mono- or divalent alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms (C1-C40), 1 to about 20 carbon atoms (C1-C20), 1 to 12 carbons (C1-C12), 1 to 8 carbon atoms (Ci-Cs), or, in some embodiments, from 1 to 6 carbon atoms (Ci-Ce). Examples of straight chain alkyl groups include those with from 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, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and ante-isoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0067] The term “alkenyl” as used herein refers to substituted or unsubstituted straight chain and branched mono- or divalent alkenyl groups and cycloalkenyl groups having at least one double bond and having from 1 to 40 carbon atoms (C1-C40), 1 to about 20 carbon atoms (C1-C20), 1 to 12 carbons (C1-C12), 1 to 8 carbon atoms (Ci-Cs), or, in some embodiments, from 1 to 6 carbon atoms (C1- Ce) or 2 to 6 carbon atoms (C2-C6). Examples of straight chain alkenyl groups include those with from 1 to 8 carbon atoms such as -CH=CH-, -CH=CHCH3, and -CH2CH=CHCH2- groups, wherein the double bonds can have an E- or Z- configuration. And when there are multiple bonds, each double bond can, independently, have an E- or a Z-configuration. Examples of branched alkenyl groups include, but are not limited to, -CH=C(CH3)- and CH2C=CH(CH3) groups. Representative substituted alkenyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

[0068] 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, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups can have any number of carbon atoms, e.g., 3 to 8 carbon atoms (Ca-Cs), 3 to 6 carbon atoms (Ca-Ce), and 4 to 8 carbon atoms (C4-C8). 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, and the like.

[0069] The term “cycloalkylalkyl” as used herein refers to substituted or unsubstituted alkyl groups 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.

[0070] The term “alkylcycloalkyl” as used herein refers to substituted or unsubstituted cycloalkyl groups as defined herein in which a hydrogen of a cycloalkyl group as defined herein is replaced with a bond to an alkyl group as defined herein. Representative alkylcycloalkyl groups include, but are not limited to, alkylcyclopropyl.

[0071] The term “acyl” as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a “formyl” group, an acyl group as the term is defined herein. An acyl group can include 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 include heteroatoms within the meaning here. 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 and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a “haloacyl” group. An example is a trifluoroacetyl group.

[0072] The term “heterocyclylcarbonyl” is an example of an acyl group that is bonded to a substituted or unsubstituted heterocyclyl group, as the term “heterocyclyl” is defined herein. An example of a heterocyclylcarbonyl group is a prolyl group, wherein the prolyl group can be a D- or an L-prolyl group.

[0073] The term “aryl” as used herein refers to substituted or unsubstituted cyclic aromatic hydrocarbons that do 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 contain about 6 to about 14 carbons (C6-C14) or from 6 to 10 carbon atoms (Ce-C ) in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. “Aryl” and the phrase “arylgroup” includes fused ring species including those that include fused aromatic and non-aromatic groups. Accordingly, “aryl” and the phrase “aryl group” include groups of the formula:, each of which can be substituted or unsubstituted, such as hydroxy substituted.

[0074] Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6- substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed herein.

[0075] The terms “aralkyl” and “arylalkyl” refer to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.

[0076] The term “heterocyclyl” or “heterocyclo” refers to substituted or unsubstituted aromatic and non-aromatic ring compounds containing 3 or more ring members, of which one or more (e.g., 1 , 2 or 3) is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl or a heteroaryl or, if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. In some embodiments, heterocyclyl groups include heterocyclyl groups that include 3 to 8 carbon atoms (Ca-Cs), 3 to 6 carbon atoms (Ca-Ce), 3 to 5 carbon atoms (C3-C5) or 6 to 8 carbon atoms (Ce- Cs). A heterocyclyl group designated as a Ca-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4- heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds, such as in the group 3,6-dihydro-2H-pyran and 3,4-dihydro-2H-pyran, having the formula:Hrespectively, each of which can be substituted.

[0077] A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. Representative heterocyclyl groups include, but are not limited to tetrahydro-2H-thiopyran-1 ,1-dioxide, having the formula: O, which can be substituted, 4a,5,6,7-tetrahydro-4H-pyrrolo[1 ,2- d][1 ,3,4]oxadiazinyl, having the formula:, which can be substituted, pyrrolidinyl, pyrrolidinone (e.g., pyrrolidin-2-one), azetidinyl, piperidynyl, piperazinyl, morpholinyl, chromanyl, indolinonyl, isoindolinonyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, imidazo[1,2- a]pyridinyl, having the formula:, which can be substituted, triazyolyl, tetrazolyl, benzoxazolinyl, thiazolyl, benzthiazolinyl, and benzimidazolinyl groups. Examples of indolinonyl groups include groups having the general formula:, wherein R is as defined herein.

[0078] Examples of isoindolinonyl groups include groups having the general formula:wherein R is as defined herein.

[0079] Examples of benzoxazolinyl groups include groups having the general formula:, wherein R is as defined herein.

[0080] Examples of benzthiazolinyl groups include groups having the general formula:wherein R is as defined herein.

[0081] In some embodiments, the group R in benzoxazolinyl and benzthiazolinyl groups is an N(R)2 group. In some embodiments, each R is hydrogen or alkyl, wherein the alkyl group is substituted or unsubstituted. In some embodiments, the alkyl group is substituted with a heterocyclyl group (e.g., with a pyrrolidinyl group).

[0082] The term “heterocyclylalkyl” refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an 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-yl methyl, furan-3- yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl methyl, and indol-2-yl propyl.

[0083] The term “heterocyclylalkoxy” refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein and the alkyl group is attached to an oxygen. Representative heterocyclylalkoxy groups include, but are not limited to, -O-(CH2)qheterocyclyl, wherein q is an integer from 1 to 5. In some embodiments, heterocyclylalkoxy groups include -O-(CH2)qmorpholinyl such as - O-CH2CH2-morpholine.

[0084] The term “heteroarylalkyl” refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein.

[0085] The term “alkoxy” refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are 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 include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, can further include double or triple bonds, and can also include 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 a context where two adjacent atoms of a structure are substituted therewith.

[0086] The terms “amine,” “amine group,” “amino,” and “amino group” refer to a substituent of the form -NH2, -NHR, -NR2, or -NRa+, wherein each R is defined herein, and protonated forms of each, except for -NRa+, which cannot be protonated. Accordingly, any compound substituted with an amino group can beviewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.

[0087] An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group. An example of a “alkylamino” is -NH-alkyl and -N(alkyl)2.

[0088] An example of a “cycloalkylamino” group is -NH-cycloalkyl and -N(cycloalkyl)2.

[0089] An example of a “cycloalkyl heterocycloamino” group is -NH-(heterocyclo cycloalkyl), wherein the heterocyclo group is attached to the nitrogen and the cycloalkyl group is attached to the heterocyclo group.

[0090] An example of a “heterocyclo cycloamino” group is -NH-(cycloalkyl heterocycle), wherein the cycloalkyl group is attached to the nitrogen and the heterocyclo group is attached to the cycloalkyl group.

[0091] The term “amido” refers to a group of the formula -C(O)NR2, wherein R is defined herein.

[0092] 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. In embodiments, of the compound, halo can be fluorine (F) or chlorine (Cl).

[0093] The term “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkyl groups, wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein 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(CH3)2 and the like.

[0094] The compound can be a pharmaceutically acceptable salt. Examples of acceptable salts include, without limitation, alkali metal (for example, sodium, potassium or lithium) or alkaline earth metals (for example, calcium) salts; however, any salt that is generally non-toxic and effective when administered to the subject being treated is acceptable. Similarly, “pharmaceutically acceptable salt” refers to those salts with counter ions, which may be used in pharmaceuticals. Such salts may include, without limitation, (1) acid addition salts, which can be obtained 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 with organic acids, such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or (2) salts formedwhen an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinates 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 pharmaceutically acceptable salts are contemplated.

[0095] Acceptable salts can be obtained using standard procedures known in the art, including (without limitation) reacting a sufficiently acidic compound with a suitable base affording a physiologically acceptable anion. Suitable acid addition salts are formed from acids that form non-toxic salts. Illustrative, albeit nonlimiting, examples include the acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. Suitable base salts of the compounds can be formed from bases that form nontoxic salts. Illustrative, albeit nonlimiting, examples include the arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemi-salts of acids and bases, such as hemi-sulphate and hemi-calcium salts, also can be formed.

[0096] The solvate can be any pharmaceutically acceptable solvate. When the solvent is water, the solvate is a hydrate.

[0097] One of ordinary skill in the art will further appreciate that the above compounds can be “deuterated,” meaning one or more hydrogen atoms can be replaced with deuterium. As deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be made.

[0098] The compounds, in some embodiments, can contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R) or (S). Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds are contemplated. When the conjugates contain alkene double bonds, and unless specified otherwise, it is intended that both E and Z geometricisomers (e.g., cis or trans) are included. Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and paraisomers around a benzene ring.

[0099] Accordingly, use of the term “compound” is intended to encompass, for example, stereoisomers, geometric isomers, and tautomers. In addition, the “compound” can contain one or more asymmetric centers, thereby giving rise to enantiomers, diastereomers, and other stereoisomeric forms (e.g., R and S). When double bonds are present, E and Z (e.g., cis and trans) geometric isomers are possible. All isomers, including racemic, tautomeric, and optically pure forms are encompassed. Also encompassed are positional isomers, such as ortho, meta and para structural isomers.

[0100] Further provided is a pharmaceutical composition comprising an above-described compound and a pharmaceutically acceptable carrier or excipient. In some embodiments of the pharmaceutical composition, the composition may further comprise one or more additional pharmaceutically active agents. The term "composition" generally refers to any product comprising more than one ingredient, including the compound. It is to be understood that the compositions can be prepared from isolated compounds or from salts, solutions, hydrates, solvates, and other forms of the compounds. It is appreciated that certain functional groups, such as the hydroxy, amino, and like groups can form complexes with water and / or various solvents, in the various physical forms of the compound. It is also to be understood that the compositions can be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and / or other morphological forms of the compounds, and the compositions can be prepared from various hydrates and / or solvates of the compounds. Accordingly, such pharmaceutical compositions can include each of, or any combination of, or individual forms of, the various morphological forms and / or solvate or hydrate forms of the compounds.

[0101] Any pharmaceutically acceptable carriers and excipients as known in the art can be used. A pharmaceutically acceptable carrier can include a solvent, dispersion medium, a coating, an antibacterial and / or antifungal agent(s), an isotonic and / or absorption delaying agent(s), and the like, and combinations thereof, that are physiologically compatible. The carrier can be suitable for parenteral administration, e.g., a sterile aqueous solution or dispersion or a sterilepowder for the extemporaneous preparation of a sterile injectable solution or dispersion.

[0102] Examples of various ingredients include, but are not limited to, a color additive, a preservative, and a stabilizer. More specific examples include crystal cellulose, calcium carmellose, sodium carmellose, hydropropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, and magnesium stearate. Such compositions can be manufactured in accordance with methods in the art and described, for example, in Remington, The Science and Practice of Pharmacy, 22nd edition. Supplementary active compounds can also be incorporated into the compositions.

[0103] Oral dosage units can be tablets or capsules, for example. Other compositions for oral administration include elixirs, syrups, and the like.

[0104] Solutions of the active composition can be aqueous, optionally mixed with a nontoxic surfactant and / or can contain carriers or excipients, such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but, for some applications, they can be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle, such as sterile, pyrogen-free water or phosphate-buffered saline. For example, dispersions can be prepared in glycerol, liquid PEGs, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can further contain a preservative to prevent the growth of microorganisms.

[0105] Excipients can include suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, which can be a naturally occurring phosphatide, for example, lecithin; a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxcycetanol; a condensation product of ethylene oxide with a partial ester derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate; or a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ascorbic acid, ethyl, n-propyl, or p-hydroxybenzoate; or one or more coloring agents.

[0106] 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, for example, coloring agents, can also be present.

[0107] Suitable emulsifying agents can be naturally occurring gums, for example, gum acacia or gum tragacanth; naturally occurring phosphatides, for example, soybean lecithin; and esters including partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Isotonic agents, for example, sugars, polyalcohols, such as mannitol or sorbitol, or sodium chloride can be included in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, such as monostearate salts and gelatin.

[0108] Liquid formulations can include suspensions and solutions. Such formulations can comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by the reconstitution of a solid.

[0109] The compound can be formulated as a pharmaceutical composition and administered to a subject, such as a mammal, e.g., a human, in a variety of forms adapted to the chosen route of administration as discussed above. For example, the composition can be administered as an oral dosage unit, an injectable composition (i.e. , for subcutaneous or intravenous injection), or an infusion. See, e.g., Remington, supra.

[0110] An effective amount of the compound, or the pharmaceutical composition comprising the compound, can be determined in accordance with methods known in the art (e.g., animal models, human data, and human data for compounds that are used in a similar manner). The amount can be determined by taking into consideration various factors, such as the potency of the conjugate, body weight, mode of administration, the type and location of fracture, and its causation. The effective amount can range from about 0.1 pg / kg / day, such as 0.5 pg / kg / day, 0.7 pg / kg / day, or 0.01 mg / kg / day up 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, such as daily (1-3 or more times per day), weekly (including 1-3 or more times on a given day), bi-weekly (including 1-3 or more times on a given day), monthly (including 1-3 or more times on a given day), or bimonthly (including 1-3 or more times on a given day).

[0111] Prodrugs of the compounds described in the disclosure are also contemplated. The term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Specific prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate 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 by Burger’s Medicinal Chemistry and Drug Discovery, 6th ed. (Donald J. Abraham ed., 2001 , Wiley), and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0112] A method of inhibiting a G protein-coupled receptor kinase(GRK) 5 in a subject is also provided. The method comprises administering an above-described compound or an above-described pharmaceutical composition in an amount effective to inhibit GRK5. In embodiments of the method, the subject has cancer, such as multiple myeloma. In other embodiments of the method, the subject has heart disease, such as heart failure or cardiac hypertrophy.

[0113] “Administering” includes all means of introducing the conjugate or the pharmaceutical composition comprising same. Useful dosages of the compounds can be determined by comparing their in vitro activity with their in vivo activity in animal models. Methods of extrapolating effective dosages in mice and other animals to human subjects are known in the art. Indeed, the dosage of the compounds can vary significantly depending on the condition of the subject, the age of the subject, the type of disease the subject is experiencing or at risk of experiencing, the particular compounds used, how advanced the pathology is, the route of administration of the compounds and the possibility of co-usage of other therapeutic treatments or additional drugs in combination therapies. The amount of the composition required to inhibit GRK5 will vary not only with the particular application, but also with the salt selected (if applicable) and the characteristics of the subject (such as, for example, age, condition, sex, thesubject’s body surface area and / or mass, tolerance to drugs) and will ultimately be at the discretion of the attendant physician, clinician, or otherwise.

[0114] The disclosure also relates to the following numbered Embodiments, which are listed in no particular order of importance:1. A compound having the structure of formula I :wherein:Ri is H, C1-C3 alkyl, -O-Ci-Ce alkyl, or halo;R2 is -N(H)-pyrazole, which is optionally substituted with a Ci-Ce alkyl;R3 is H or Ci-Ce alkyl;R4 is at least one but not more than two, which can be the same or different, of halo, -O-Ci-Ce alkyl, -O-C2-C6 alkenyl, NH2, or CH2NH; wherein, when R4 is -O- C1-C6 alkyl or -O-C2-C6 alkenyl, R4 can form a ring structure with a carbon atom in the pyrazole ring of R2;Rs is H, C1-C3 alkyl, -O-Ci-Ce alkyl, -N-Ci-Ce alkyl, or halo; and n = 0 or 1 ; or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.2. The compound of Embodiment 1 , wherein Ci-Ce alkyl can be methyl or ethyl.3. The compound of Embodiment 1 or 2, wherein halo can be F or Cl.4. The compound of any one of Embodiments 1-3, wherein C2-C6 alkenyl can be pentenyl.5. Also provided is a compound having the structure of formula la:wherein:A1is aryl or heterocyclyl;A2is cycloalkyl, aryl or heterocyclyl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, alkyl-O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl; or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.6. The compound of Embodiment 5, wherein A1is a monocyclic aryl or heterocyclyl.7. The compound of Embodiment 5, wherein L3is present.8. The compound of Embodiment 5, wherein:A1is aryl;A2is cycloalkyl, aryl or heterocyclyl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl- O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl.9. The compound of Embodiment 8, wherein:L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; L2is NR6; and L3is absent, *- alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.10. The compound of Embodiment 5, wherein:A1is aryl;A2is cycloalkyl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O- or combinations thereof, wherein each R6is H or alkyl; and L3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl.11. The compound of Embodiment 10, wherein:L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; andL2is NR6; and L3is absent, *-alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.12. The compound of Embodiment 5, wherein:A1is aryl;A2is aryl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O- or combinations thereof, wherein each R6is H or alkyl; and L3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl.13. The compound of Embodiment 12, wherein:L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; L2is NR6; and L3is absent, *- alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.14. The compound of Embodiment 5, wherein:A1is aryl;A2is heterocyclyl;G1and G2are each, independently, heterocycly;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl- O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6- alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl.15. The compound of Embodiment 14, wherein:L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; L2is NR6; and L3is absent, *- alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.16. The compound of any one of Embodiments 5-15, wherein:A1is Ce-C aryl.17. The compound of Embodiment 16, wherein A1is phenyl or naphthyl.18. The compound of any one of Embodiments 5-17, wherein A1is an optionally substituted phenyl group of the formula:19. The compound of Embodiment 5, wherein A1is C2-C5 heterocyclyl.20. The compound of Embodiment 19, wherein A1is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl.21. The compound of any one of Embodiments 5-10, wherein A2is C3-C7 cycloalkyl.22. The compound of Embodiment 21 , wherein A2is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which can be fused with Ce-Cw aryl.23. The compound of Embodiment 22, wherein A2is C3-C7 cycloalkyl fused with Ce-Cw aryl.24. The compound of Embodiment 22 or 23, wherein A2is of formula:wherein * denotes the point of attachment of A2to L1and ** denotes the point of attachment of A2to L3, when L3is present.25. The compound of Embodiment 5, 8, 9 or 14, wherein A2is C2-C7 heterocyclyl.26. The compound of Embodiment 25, wherein A2is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, benzpyrazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl.27. The compounf of Embodiment 25, wherein A2is furanyl, tetrahydrofuranyl, pyrazolyl or benzpyrazolyl.28. The compound of Embodiment 5, 8, 9 or 13, wherein A2is Ce-Cw aryl.29. The compound of Embodiment 28, wherein A2is an optionally substituted phenyl group.30. The compound of Embodiment 28, wherein the A2is substituted with one or more alkyl; haloalkyl; alkenyl; alkoxy; alkenyloxy; amino; aminoalkyl; or halo.31. The compound of any of Embodiments 5-30, wherein G1is C2-C5 heterocyclyl.32. The compound of Embodiment 31 , wherein G1is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl.33. The compound of Embodiment 31 , wherein G1is optionally substituted pyrimidinyl.34. The compound of any of Embodiments 5-33, wherein G2is C2-C5 heterocyclyl.35. The compound of Embodiment 34, wherein G2is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl.36. The compound of Embodiment 34, wherein G2is optionally substituted pyrazolyl.37. The compound of Embodiment 36, wherein G2is substituted with one or more alkoxy, alkyl or alkenyl.38. The compound of any of Embodiments 5-37, wherein:represents optionally substituted C6-C9 heterocyclyl.39. The compound of Embodiment 38, wherein:represents optionally substituted:wherein * represents the point of attachment of G1to L2and ** represents the point of attachment of G1to L1.40. The compound of any of Embodiments 5-29, wherein L1is optionally substituted -NR6-Ci-Ce alkyl-, -Ci-Ce alkyl-NR6-, -O-Ci-Ce alkyl-, -Ci-Ce alkyl-O- or combinations thereof, wherein each R6is H or alkyl.41 . The compound of Embodiment 40, wherein L1is optionally substituted - NR6-CI-C6alkyl-.42. The compound of Embodiment 40, wherein, L1is optionally substituted - NR6-CI-C3alkyl-.43. The compound of Embodiment 40, wherein L1is optionally substituted - NR6-Ci alkyl- or -NR6-C2 alkyl-.44. The compound of Embodiment 40, wherein L1is -NR6-Ci alkyl-.45. The compound of any of Embodiments 5-29, wherein L1is NR6wherein R6is H or alkyl.46. The compound of Embodiment 45, wherein L1is NH.47. The compound of any of Embodiments 5-29, wherein L1is NR6(C)O.48. The compound of Embodiment 47, wherein L1is NHC(O).49. The compound of any of Embodiments 5-48, wherein L2is optionally substituted -NR6-Ci-Ce alkyl-, -Ci-Ce alkyl-NR6-, -O-Ci-Ce alkyl-, -Ci-Ce alkyl-O- or combinations thereof, wherein each R6is H or alkyl.50. The compound of Embodiment 49, wherein L2is optionally substituted - NR6-CI-C6alkyl-.51 . The compound of Embodiment 49, wherein L2is optionally substituted - NR6-CI-C3alkyl-.52. The compound of Embodiment 49, wherein L2is optionally substituted - NR6-Ci alkyl- or -NR6-C2 alkyl-.53. The compound of Embodiment 49, wherein L2is optionally substituted - NR6-Ci alkyl-.54. The compound of any of Embodiments 49-53 wherein L2is unsubstituted or optionally substituted with one or more alkyl or alkenyl.55. The compound of any of Embodiments 5-48, wherein L2is NR6, wherein R6is H or alkyl.56. The compound of Embodiment 55, wherein L2is NH.57. The compound of any of Embodiments 5-56, wherein L3is absent, -O- C3-C10 alkyl-, -C3-C10 alkyl-O-, -O-C3-C10 alkenyl- or - C3-C10 alkenyl-O-.58. The compound of Embodiment 57, wherein L3is -O-C5-C10 alkyl-, -C5- C10 alkyl-O-, -O-C5-C10 alkenyl- or -Cs-C alkenyl-O-.59. The compound of Embodiment 57, wherein L3is -O-Ce-Cs alkyl-, -Ce-Cs alkyl-O-, -O-Ce-Cs alkenyl- or -Ce-Cs alkenyl-O-.60. The compound of Embodiment 1 or 2, which has the structure:61. The compound of Embodiment 1 or 2, which has the structure:59 The compound of Embodiment 1 or 2, which has the structure:The compound of Embodiment 1 or 2, which has the structure:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.73. The compound of Embodiment 1 or 2, which has the structure:pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.74. The compound of Embodiment 1 or 2, which has the structure:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.75. A pharmaceutical composition comprising a compound of any one of Embodiments 1-74 and a pharmaceutically acceptable carrier or excipient.76. A method of inhibiting a G protein-coupled receptor kinase (GRK) 5 in a subject, which method comprises administering a compound of any one of Embodiments 1-74 or a pharmaceutical composition of Embodiment 75 in an amount effective to inhibit GRK5, whereupon GRK5 in the subject is inhibited.77. The method of Embodiment 76, wherein the subject has cancer.78. The method of Embodiment 77, wherein the cancer is multiple myeloma.79. The method of Embodiment 76, wherein the subject has heart disease.80. The method of Embodiment 79, wherein the heart disease is heart failure or cardiac hypertrophy.Examples

[0115] The disclosure can be better understood by reference to the following examples which are offered by way of illustration. The disclosure is not limited to the examples given herein.I. Preparation of Inhibitor 23:Step-(A) Synthesis of 1-(methoxymethyl)-3-nitro-1H-pyrazole 3:

[0116] To a stirred solution of 2(1 g, 8.84 mmol, 1.0 equiv) in THF (10 mL) was added NaH 60% (0.53 g, 13.27 mmol, 1.5 equiv) at 0 °C slowly and after 5-10 min added methoxy methyl chloride (0.87 mL, 11.50 mmol, 1.3 equiv) at 0 °C then reaction continued for 12h at room temperature. After completion of the starting material (monitored the reaction using TLC), the reaction was quenched with saturated NH4CI, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (EtOAc / hexanes) to afford 3 (1.3 g, 94%) as light brown color oil.Step-(B) Synthesis of 5-allyl-1-(methoxymethyl)-3-nitro-1H-pyrazole 4:

[0117] To a solution of diisopropylamine (2.23 mL, 12.42 mmol, 1.5 equiv) in THF (10 mL) was added "BuLi (8.87 mL, 12.42 mmol, 1.5 equiv) at 0 °C the reaction mixture was stirred at 0 °C for 30 min. After that compound 3 (1.3 g, 8.28 mmol, 1.0 equiv) in THF (10 mL) was cannulated to the reaction mixture at at -78 °C. After stirring for 1 h, CuBr(l) (0.23 g, 1.65 mmol, 1.5 equiv) was added and stirring was continued for 1 h at -78 °C. Allyl bromide (0.86 mL, 9.93 mmol, 1.2 equiv) was added and the reaction stirred at room temperature for 1 h. After completion of the starting material (monitored by TLC), the reaction was quenched with saturated NH4CI, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (EtOAc / Hexane) to provide 4 (0.4 g, 32%) as yellow color oil.

[0118] Step-(C) Synthesis of 5-allyl-1-(methoxymethyl)-1 H-pyrazol-3- amine 6:

[0119] To a stirred solution of compound 4 (0.4 g, 2.03 mmol, 1.0 equiv) in EtOH:H2O (12 mL) was added Fe (1.36 g, 24.36 mmol, 12.0 equiv) and NH4CI (0.43 g, 8.12 mmol, 4.0 equiv) at room temperature, the reaction mixture was stirred at 82 °C for 2 h. After completion of the starting material (monitored by TLC), solvent was filtered through celite and filterate was evaporated under reduced pressure. The crude product was purified by using silica gel column chromatography (EtOAc / hexanes) to give the 6 (0.3 g, 88%) as light orange color oil.Step-(D) Synthesis of N-(5-allyl-1-(methoxymethyl)-1 H-pyrazol-3-yl)-2- chloroquinazolin-4-amine 7:

[0120] To a solution of 2,4-dichloroquinazoline (100 mg, 0.50 mmol, 1.0 equiv) and 3 (92 mg, 0.55 mmol, 1.1 equiv) in dimethyl sulfoxide (1.6mL) was added / V, / V-diisopropylethylamine (0.1 mL, 0.60 mmol, 1.2 equiv) the reaction mixture was stirred at 60 °C for 2 h. After completion of the starting material, add water to the reaction mixture collect the resulting precipitate by filtration, wash the filtrate successfully with ice cold water, the resulting precipitate dried under vaccum to afford compound 7 (100 mg, 60%) as off-white color solid.Step-(E) N-(5-allyl-1-(methoxymethyl)-1 H-pyrazol-3-yl)-2-((2-(but-3-en-1- yloxy)benzyl)-l2-azaneyl)quinazolin-4-amine 9:

[0121] In a seal tube a stirred solution of compound 7 (100 mg, 0.30 mmol, 1.0 equiv) and (2-(but-3-en-1-yloxy)phenyl)methanamine 8 (107 mg, 0.60 mmol, 2.0 equiv) in 1 ,4-dioxane and dimethyl sulfoxide (2 mL) was added N,N- diisopropylethylamine (0.26 mL, 1.51 mmol, 5.0 equiv) the reaction mixture was stirred at 130 °C for 18 h. After completion of the starting material, solvent was evaporated under reduced pressure and the reaction was quenched with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by using silica gel column chromatography (MeOH / CH2CI2) to give the compound 9 (80 mg, 56%) as orange color solid.Step-(F) Synthesis of compound 10:

[0122] An oven dried two neck round bottom flask was loaded with compound 9 (80 mg, 0.17 mmol, 1.0 equiv) in 1 ,2-dichloroethane (59 mL) was added Grubbs second-generation catalyst (21 mg, 0.02 mmol, 0.15 equiv) thereaction mixture was allowed to heat at 83 °C under N2 atmosphere for 20 h. After completion of the starting material, solvent was evaporated under reduced pressure and the residue was purified via silica gel column chromatography (MeOH / CH2Cl2) to afford 10 (52 mg, 69%) as ash color solid.Step-(G) Synthesis of inhibitor 23:

[0123] In a seal tube a mixture of 10 (10 mg, 0.02 mmol, 1.0 equiv) and three drops of cone. HCI in methanol, the reaction mixture was stirred at 100 °C for 18 h. After completion of the starting material, solvent was evaporated under reduced pressure and the reaction was quenched with NaHCOs and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by using silica gel column chromatography (MeOH / CF^Ch) to afford the desired target inhibitor 23 (6 mg, 66%) of 2.5:1 mixture of (EZZ) as a ash color solid; Rf= 0.5 (10% MeOH:CH2CI2);1H NMR (400 MHz, DMSO) 5 11.52 (s, 1 H), 8.88 - 8.54 (m, 2H), 7.90 (d, J = 60.2 Hz, 2H), 7.71 - 6.77 (m, 7H), 6.60 (s, 1 H), 5.64 (d, J = 29.0 Hz, 2H), 4.69 (d, J = 45.0 Hz, 2H), 4.12 (d, J = 33.2 Hz, 2H), 2.83 (s, 1 H), 2.47 (s, 3H); MS [ESI]m / z (M+H)+= 399.

[0124] Synthesis of inhibitor 3: In seal tube a solution of 2-chloro-N-(5- ethyl-1 H-pyrazol-3-yl)-5-methoxyquinazolin-4-amine (10 mg, 0.03 mmol, 1.0 equiv) and (R)-1-(4-fluorophenyl)ethan-1-amine (9.1 mg, 0.06 mmol, 2.0 equiv) in 1 ,4-dioxane and dimethyl sulfoxide was added / V, / V-diisopropylethylamine (28 pmL, 0.16 mmol, 5.0 equiv), the reaction mixture was stirred at 100 °C for 12 h. After completion of the starting material (monitored by TLC), solvent was evaporated under reduced pressure and the reaction was quenched with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by using silica gel column chromatography (MeOH / C^Ch) to afford the desired target inhibitor 3 (6 mg, 45%) as off white color solid; Rf= 0.3 (10% MeOH:CH2CI2);1H NMR (400 MHz, CDCI3) 6 7.55 (s, 1 H), 7.43 - 7.38 (m, 4H), 7.15 - 6.98 (m, 4H), 6.70 (d, J = 8.1 Hz, 1 H), 6.28 (s, 1 H), 5.25 (t, J = 7.0 Hz,1 H), 4.07 (s, 3H), 2.70 (q, J = 7.6 Hz, 2H), 1.63 (d, J = 6.9 Hz, 3H), 1.31 (t, J = 7.6 Hz, 3H); MS [ESI]m / z (M+H)+= 407.Compound StructuresGRK5 Protein Expression and Purification

[0125] Human GRK5 (1-590) WT and D311 N mutants were expressed in E. coli and purified through a series of chromatography from nickel-nitrilotriacetic acid affinity, HiTrap Q HP anion exchange chromatography column followed by HiTrap SP HP cation exchange chromatography column, and Superdex 200 Increase size-exclusion chromatography as described previously (Beyett et al., Protein Expr Purif 168: 105547 (2020)). Bovine GRK5-C474S was purified from baculovirus infected insect cells as previously described (Rowlands et al., J Med Chem 64: 566-585 (2021)).

[0126] GRK5 Kinase Inhibition Assays

[0127] GRK inhibition assays were performed in reaction buffer 20 mM HEPES pH 7.0, 2 mM MgC , 0.025% n-dodecyl-p-D-maltoside with 50 nM human GRK5 wild-type. GRK5 was incubated with 500 nM porcine brain tubulin (PurSolutions) and inhibitors. Reactions were started by the addition of 5 pM ATP supplemented with radioactive [y-32P]-ATP (PerkinElmer Life Sciences) for 5-min reactions at room temperature. Reactions were quenched with 4X SDS loading buffer, separated in SDS-PAGE, dried, and exposed with a phosphor-imaging screen, then quantified via a Personal Molecular Imager and Quantity One 1-D Analysis Software. Data were analyzed via GraphPad Prism, and three- parameter dose-dependent curves (Hill coefficient = 1) plotting phosphate transferred against inhibitor concentration were used for the calculation of IC50. At least three replications were obtained to calculate IC50 values. Activity data are shown in Table I.Table

[0128] Those skilled in the art will appreciate that many modifications to the embodiments described herein are possible without departing from the spirit and scope of the present disclosure. Thus, the description is not intended and should not be construed to be limited to the examples given but should be grantedthe full breadth of protection afforded by the appended claims and equivalents thereto. In addition, it is possible to use some of the features of the present disclosure without the corresponding use of other features. Accordingly, the foregoing description of or illustrative embodiments is provided for the purpose of illustrating the principles of the present disclosure and not in limitation thereof and can include modification thereto and permutations thereof.

[0129] Values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or subranges encompassed within that range as if each numerical value and sub-range were explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1 % to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

[0130] In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading can occur within or outside of that particular section. Furthermore, all publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0131] In the methods described herein, the steps can be carried out in any order without departing from the principles of the invention, except when a temporal or operational sequence is explicitly recited. Furthermore, specified steps can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed step of doing X and a claimed step of doing Y can be conducted simultaneously within a singleoperation, and the resulting process will fall within the literal scope of the claimed process.

[0132] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those in the art to which the disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0133] The invention illustratively described herein may be suitably practiced in the absence of any element(s) or limitation(s), which is / are not specifically disclosed herein. Thus, for example, each instance herein of any of the terms “comprising,” “consisting essentially of,” and “consisting of” may be replaced with either of the other two terms. Likewise, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, references to “the method” includes one or more methods and / or steps of the type, which are described herein and / or which will become apparent to those ordinarily skilled in the art upon reading the disclosure. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated.

[0134] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. The following terms and phrases shall have the meaning indicated.

[0135] The term “about,” when referring to a number or a numerical value or range (including, for example, whole numbers, fractions, and percentages), means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error) and thus the numerical value or range can vary between 1% and 15% of the stated number or numerical range (e.g., + / - 5 % to 15% of the recited value, such as within 10%, within 5%, or within 1% of a stated value or stated limit of a range) provided that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). The term “substantially” can allow for a degree of variability in a value or range, for example, within 90%, within 95%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more of a stated value or of a stated limit of a range.

[0136] In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting. Further, information that is relevant to a section heading may occur within or outside of that particular section.

Claims

What is claimed is:

1. A compound having the structure of formula I :(Formula I) wherein:R1 is H, C1-C3 alkyl, -O-Ci-Ce alkyl, or halo;R2 is -N(H)-pyrazole, which is optionally substituted with a Ci-Ce alkyl;R3 is H or Ci-Ce alkyl;R4 is at least one but not more than two, which can be the same or different, of halo, -O-Ci-Ce alkyl, -O-C2-C6 alkenyl, NH2, or CH2NH; wherein, when R4is -O-Ci-Ce alkyl or -O-C2-C6 alkenyl, R4can form a ring structure with a carbon atom in the pyrazole ring of R2;Rs is H, C1-C3 alkyl, -O-Ci-Ce alkyl, -N-Ci-Ce alkyl, or halo; and n = 0 or 1 ; or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

2. The compound of claim 1 , wherein Ci-Ce alkyl can be methyl or ethyl.

3. The compound of claim 1 or 2, wherein halo can be F or Cl.

4. The compound of claim 1 , wherein C2-C6 alkenyl can be pentenyl.

5. A compound having the structure of formula la:(Formula la) wherein:A1is aryl or heterocyclyl;A2is cycloalkyl, aryl or heterocyclyl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, alkyl-O- or combinations thereof, wherein each R6is H or alkyl; andL3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6-alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl; or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

6. The compound of claim 5, wherein A1is a monocyclic aryl or heterocyclyl.

7. The compound of claim 5, wherein L3is present.

8. The compound of claim 5, wherein:A1is aryl;A2is cycloalkyl, aryl or heterocyclyl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, - alkyl-O- or combinations thereof, wherein each R6is H or alkyl; and L3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6-alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl.

9. The compound of claim 8, wherein:L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; L2is NR6; and L3is absent, *-alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.

10. The compound of claim 5, wherein:A1is aryl;A2is cycloalkyl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O- or combinations thereof, wherein each R6is H or alkyl; and L3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6-alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl.

11. The compound of claim 10, wherein:L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; and L2is NR6; and L3is absent, *-alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.

12. The compound of claim 5, wherein:A1is aryl;A2is aryl;G1and G2are each, independently, heterocyclyl;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O- or combinations thereof, wherein each R6is H or alkyl; and L3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6-alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl.

13. The compound of claim 12, wherein:L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; L2is NR6; and L3is absent, *-alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.

14. The compound of claim 5, wherein:A1is aryl;A2is heterocyclyl;G1and G2are each, independently, heterocycly;L1and L2are each NR6, NR6C(O), O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, - alkyl-O- or combinations thereof, wherein each R6is H or alkyl; and L3is absent, a bond, NR6, O, -NR6-alkyl-, -alkyl-NR6-, -O-alkyl-, -alkyl-O-, -NR6-alkenyl-, -alkenyl-NR6-, -O-alkenyl-, -alkenyl-O- or combinations thereof, wherein each R6is H or alkyl.

15. The compound of claim 14, wherein:L1is *-NR6-alkyl-**, wherein * represents the point of attachment of L1to G1and ** represents the point of attachment of L1to A2; L2is NR6; and L3is absent, *-alkyl-O-** or *-alkenyl-O-**, wherein * represents the point of attachment of L3to G2and ** represents the point of attachment of L3to A2.

16. The compound of claim 5, wherein:A1is Ce-Cio aryl.

17. The compound of claim 16, wherein A1is phenyl or naphthyl.

18. The compound of claim 5, wherein A1is an optionally substituted phenyl group of the formula:

19. The compound of claim 5, wherein A1is C2-C5 heterocyclyl.

20. The compound of claim 19, wherein A1is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl.

21. The compound of claim 5, wherein A2is C3-C7 cycloalkyl.

22. The compound of claim 21 , wherein A2is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which can be fused with Ce-Cio aryl.

23. The compound of claim 22, wherein A2is C3-C7 cycloalkyl fused with Ce- Cio aryl.

24. The compound of claim 22 or 23, wherein A2is of formula:wherein * denotes the point of attachment of A2to L1and ** denotes the point of attachment of A2to L3, when L3is present.

25. The compound of claim 5, 8, 9 or 14, wherein A2is C2-C7 heterocyclyl.

26. The compound of claim 25, wherein A2is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, benzpyrazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl.

27. The compounf of claim 25, wherein A2is furanyl, tetrahydrofuranyl, pyrazolyl or benzpyrazolyl.

28. The compound of claim 5, 8, 9 or 13, wherein A2is Ce-C aryl.

29. The compound of claim 28, wherein A2is an optionally substituted phenyl group.

30. The compound of claim 28, wherein the A2is substituted with one or more alkyl; haloalkyl; alkenyl; alkoxy; alkenyloxy; amino; aminoalkyl; or halo.

31. The compound of claim 5, wherein G1is C2-C5 heterocyclyl.

32. The compound of claim 31 , wherein G1is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl.

33. The compound of claim 31 , wherein G1is optionally substituted pyrimidinyl.

34. The compound of claim 5, wherein G2is C2-C5 heterocyclyl.

35. The compound of claim 34, wherein G2is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl or pyrazinyl.

36. The compound of claim 34, wherein G2is optionally substituted pyrazolyl.

37. The compound of claim 36, wherein G2is substituted with one or more alkoxy, alkyl or alkenyl.

38. The compound of claim 5, wherein:represents optionally substituted Ce-Cg heterocyclyl.

39. The compound of claim 38, wherein:represents optionally substituted:wherein * represents the point of attachment of G1to L2and ** represents the point of attachment of G1to L1.

40. The compound of claim 5, wherein L1is optionally substituted -NR6-Ci- Ce alkyl-, -Ci-C6alkyl-NR6-, -O-Ci-Ce alkyl-, -Ci-Ce alkyl-O- or combinations thereof, wherein each R6is H or alkyl.

41. The compound of claim 40, wherein L1is optionally substituted -NR6-Ci- Ce alkyl-.

42. The compound of claim 40, wherein, L1is optionally substituted -NR6-Ci- C3 alkyl-.

43. The compound of claim 40, wherein L1is optionally substituted -NR6-Ci alkyl- or -NR6-C2 alkyl-.

44. The compound of claim 40, wherein L1is -NR6-Ci alkyl-.

45. The compound of claim 5, wherein L1is NR6wherein R6is H or alkyl.

46. The compound of claim 45, wherein L1is NH.

47. The compound of claim 5, wherein L1is NR6(C)O.

48. The compound of claim 47, wherein L1is NHC(O).

49. The compound of claim 5, wherein L2is optionally substituted -NR6-Ci- C6alkyl-, -Ci-Ce alkyl-NR6-, -O-Ci-Ce alkyl-, -Ci-Ce alkyl-O- or combinations thereof, wherein each R6is H or alkyl.

50. The compound of claim 49, wherein L2is optionally substituted -NR6-Ci- Ce alkyl-.

51. The compound of claim 49, wherein L2is optionally substituted -NR6-Ci- C3 alkyl-.

52. The compound of claim 49, wherein L2is optionally substituted -NR6-Ci alkyl- or -NR6-C2 alkyl-.

53. The compound of claim 49, wherein L2is optionally substituted -NR6-Ci alkyl-.

54. The compound of claim 49 wherein L2is unsubstituted or optionally substituted with one or more alkyl or alkenyl.

55. The compound of claim 5, wherein L2is NR6, wherein R6is H or alkyl.

56. The compound of claim 55, wherein L2is NH.

57. The compound of claim 5, wherein L3is absent, -O-C3-C10 alkyl-, -C3-C10 alkyl-O-, -O-C3-C10 alkenyl- or - C3-C10 alkenyl-O-.

58. The compound of claim 57, wherein L3is -O-C5-C10 alkyl-, -C5-C10 alkyl- O-, -O-C5-C10 alkenyl- or -Cs-C alkenyl-O-.

59. The compound of claim 57, wherein L3is -O-Ce-Cs alkyl-, -Ce-Cs alkyl- O-, -O-Ce-Cs alkenyl- or -Ce-Cs alkenyl-O-.

60. The compound of claim 1 or 2, which has the structure:61 . The compound of claim 1 or 2, which has the structure:

62. The compound of claim 1 or 2, which has the structure:

63. The compound of claim 1 or 2, which has the structure:

64. The compound of claim 1 or 2, which has the structure:

65. The compound of claim 1 or 2, which has the structure:

67. The compound of claim 1 or 2, which has the structure:

68. The compound of claim 1 or 2, which has the structure:

69. The compound of claim 1 or 2, which has the structure:

70. The compound of claim 1 or 2, which has the structure:

71. The compound of claim 1 or 2, which has the structure:

72. The compound of claim 1 or 2, which has the structure:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

73. The compound of claim 1 or 2, which has the structure:pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

74. The compound of claim 1 or 2, which has the structure:or a pharmaceutically acceptable salt, hydrate, tautomer, or optical isomer thereof.

75. A pharmaceutical composition comprising a compound of claim 1or 2 and a pharmaceutically acceptable carrier or excipient.

76. A method of inhibiting a G protein-coupled receptor kinase (GRK) 5 in a subject, which method comprises administering a compound of claim 1 or 2 or a pharmaceutical composition of claim 75 in an amount effective to inhibit GRK5, whereupon GRK5 in the subject is inhibited.

77. The method of claim 76, wherein the subject has cancer.

78. The method of claim 77, wherein the cancer is multiple myeloma.

79. The method of claim 76, wherein the subject has heart disease.

80. The method of claim 79, wherein the heart disease is heart failure or cardiac hypertrophy.

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