BACKGROUND

Field

The present disclosure relates to compounds and/or pharmaceutical compositions for use as inhibitors of a receptor tyrosine kinase as well as methods of synthesis and use of the same. More particularly, the compounds can be used for inhibiting a discoidin domain receptor, such as DDR1, or others.

Description of Related Art

A biologically active receptor known as the discoidin domain receptor family, member 1 (hereinafter “DDR1”) is involved in various biological processes, such as being a receptor tyrosine kinase that facilitates communication of cells. DDR1 is a cell surface receptor for fibrillar collagen, and regulates cell attachment to the extracellular matrix, and remodeling the extracellular matrix. DDR1 is involved in regulation of cell growth, differentiation, cell migration, proliferation, and metabolism, and can be found in epithelial cells, such as the kidney, lung, gastrointestinal tract, and brain. DDR1 collagen binding triggers a signaling pathway that involves SRC (non-receptor tyrosine kinase) and leads to the activation of MAP kinases. DDR1 also regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. It is thought that DDR1 may be required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Also, normal DDR1 production has been linked to normal ear morphology and normal hearing (by similarity). DDR1 also promotes smooth muscle cell migration, and thereby contributes to arterial wound healing.

However, DDR1 is significantly over-expressed in some human tumors, such as breast, ovarian, esophageal, and pediatric brain, and may play a role in tumor cell invasion. As a result, DDR1 inhibitors are desirable in order to inhibit the adverse activity of DDR1, and may be useful in cancer therapy.

Accordingly, it would be advantageous to have a DDR1 inhibitor that can inhibit DDR1 activity. It would also be advantageous to have a specific DDR1 inhibitor that selectively inhibits DDR1. Additionally, it would be advantageous to have a broad spectrum kinase inhibitor that inhibits a broad spectrum of kinases.

SUMMARY

In some embodiments, a compound that is a kinase inhibitor can have a structure of Formula A, derivative thereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof, or solvate thereof, or having any chirality at any chiral center,


wherein: ring A is a ring structure; ring B is a ring structure; the X1, X2, X3, X4, and X5are each independently a carbon or a hetero atom with or without a substituent; the Y is a linker; and each R1, R2, R3, R5, and R6is independently at least one R group substituent, wherein R5and/or R6is optionally nothing, and each n is an integer and defines the number of R group substituents.

In some embodiments, ring A is a cycloaliphatic, hetero cycloaliphatic, aryl, hetero aryl, polyaryl, poly hetero aryl, or combinations thereof; ring B is a cycloaliphatic, hetero cycloaliphatic, aryl, hetero aryl, polyaryl, poly hetero aryl, or combinations thereof; X′ is CH2, NH, O, or S; X2, X3, X4, and X5are each independently CH or N; Y is selected from O, S, C, N, straight aliphatics, branched aliphatics, cyclic aliphatics, substituted aliphatics, unsubstituted aliphatics, saturated aliphatics, unsaturated aliphatics, aromatics, polyaromatics, substituted aromatics, hetero-aromatics, amines, primary amines, secondary amines, tertiary amines, aliphatic amines, carbonyls, carboxyls, amides, esters, amino acids, derivatives thereof, any substituted or unsubstituted, or combinations thereof; and R1, R2, R3, R5, and R6are each at least one substituent that are each independently hydrogen, halogens, hydroxyls, alkoxys, straight aliphatics, branched aliphatics, cyclic aliphatics, substituted aliphatics, unsubstituted aliphatics, saturated aliphatics, unsaturated aliphatics, aromatics, polyaromatics, substituted aromatics, hetero-aromatics, amines, primary amines, secondary amines, tertiary amines, aliphatic amines, carbonyls, carboxyls, amides, esters, amino acids, derivatives thereof, any substituted or unsubstituted, or combinations thereof, wherein R5and/or R6is optionally nothing.

In some embodiments, ring A is a cycloaliphatic with 5-24 ring atoms, hetero cycloaliphatic with 5-24 ring atoms, aryl with 5-24 ring atoms, hetero aryl with 5-24 ring atoms, polyaryl with 5-24 ring atoms, poly hetero aryl with 5-24 ring atoms, or combinations thereof; ring B is a cycloaliphatic with 5-24 ring atoms, hetero cycloaliphatic with 5-24 ring atoms, aryl with 5-24 ring atoms, hetero aryl with 5-24 ring atoms, polyaryl with 5-24 ring atoms, poly hetero aryl with 5-24 ring atoms, or combinations thereof; X1is O; X2X3, X4, and X5are each independently CH or N; Y is selected from O, S, C, N, straight aliphatics with 1-24 chain atoms, branched aliphatics with 1-24 chain atoms, cyclic aliphatics with 5-20 ring atoms, substituted aliphatics with 1-24 chain atoms and/or 5-20 ring atoms, unsubstituted aliphatics with 1-24 chain atoms and/or 5-20 ring atoms, saturated aliphatics with 1-24 chain atoms and/or 5-20 ring atoms, unsaturated aliphatics with 1-24 chain atoms and/or 5-20 ring atoms, aromatics with 5-20 ring atoms, polyaromatics with 5-20 ring atoms, substituted aromatics with 5-20 ring atoms, hetero-aromatics with 5-20 ring atoms, substituted hetero-aromatics with 5-20 ring atoms, amines, primary amines, secondary amines, tertiary amines, aliphatic amines with 1-24 chain atoms and/or 5-20 ring atoms, carbonyls, carboxyls, amides, esters, amino acids, derivatives thereof, any substituted or unsubstituted, or combinations thereof; and each substituent of each R1, R2, R3, R5, and R6are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, halo, hydroxyl, sulfhydryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, acyl, alkylcarbonyl, arylcarbonyl, acyloxy, alkoxycarbonyl, aryloxycarbonyl, halocarbonyl, alkylcarbonato, arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(alkyl)-substituted carbamoyl, di-(alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(alkyl)-substituted amino, mono- and di-(aryl)-substituted amino, alkylamido, arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, alkyl sulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, any with or without hetero atoms, any being substituted, derivatives thereof, and combinations thereof, wherein R5and/or R6is optionally nothing.

In some embodiments, ring A is a cycloaliphatic with 5-12 ring atoms, hetero cycloaliphatic with 5-12 ring atoms, aryl with 5-12 ring atoms, hetero aryl with 5-12 ring atoms, polyaryl with 5-12 ring atoms, poly hetero aryl with 5-12 ring atoms, or combinations thereof; ring B is a cycloaliphatic with 5-12 ring atoms, hetero cycloaliphatic with 5-12 ring atoms, aryl with 5-12 ring atoms, hetero aryl with 5-12 ring atoms, polyaryl with 5-12 ring atoms, poly hetero aryl with 5-12 ring atoms, or combinations thereof; X1is O; X2X3, X4, and X5are each independently CH or N; Y is selected from O, S, C, N, straight aliphatics with 1-12 chain atoms, branched aliphatics with 1-12 chain atoms, cyclic aliphatics with 5-12 ring atoms, substituted aliphatics with 1-12 chain atoms and/or 5-12 ring atoms, unsubstituted aliphatics with 1-12 chain atoms and/or 5-12 ring atoms, saturated aliphatics with 1-12 chain atoms and/or 5-12 ring atoms, unsaturated aliphatics with 1-12 chain atoms and/or 5-12 ring atoms, aromatics with 5-12 ring atoms, hetero aromatics with 5-12 ring atoms, polyaromatics with 5-12 ring atoms, substituted aromatics with 5-12 ring atoms, hetero-aromatics with 5-12 ring atoms, amines, primary amines, secondary amines, tertiary amines, aliphatic amines with 1-12 chain atoms and/or 5-12 ring atoms, carbonyls, carboxyls, amides, esters, amino acids, derivatives thereof, substituted or unsubstituted, or combinations thereof; and the one or more substituents of each of R1, R2, R3, R5, and R6are each independently any one or more of the substituents selected from the group of hydrogen, C1-C24alkyl, C2-C24alkenyl, C2-C24alkynyl, C5-C20aryl, C6-C24alkaryl, C6-C24aralkyl, halo, hydroxyl, sulfhydryl, C1-C24alkoxy, C2-C24alkenyloxy, C2-C24alkynyloxy, C5-C20aryloxy, acyl, acyloxy, C2-C24alkoxycarbonyl, C6-C20aryloxycarbonyl, halocarbonyl, C2-C24alkylcarbonato, C6-C20arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C1-C24alkyl)-substituted carbamoyl, di-(C1-C24alkyl)-substituted carbamoyl, mono-substituted arylcarbamoyl, di-substituted arylcarbamoyl, thiocarbamoyl, mono-(C1-C24alkyl)-substituted thiocarbamoyl, di-(C1-C24alkyl)-substituted thiocarbamoyl, mono-substituted arylthiocarbamoyl, di-substituted arylthiocarbamoyl, carbamido, mono-(C1-C24alkyl)-substituted carbamido, di-(C1-C24alkyl)-substituted carbamido, mono-substituted aryl carbamido, di-substituted aryl carbamido, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C1-C24alkyl)-substituted amino, mono- and di-(C5-C20aryl)-substituted amino, C2-C24alkylamido, C6-C20arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfonic acid, sulfonate, C1-C24alkylsulfanyl, C5-C20arylsulfanyl, C1-C24alkylsulfinyl, C5-C20arylsulfinyl, C1-C24alkylsulfonyl, C5-C20arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, any with or without hetero atoms, any substituted or unsubstituted, derivatives thereof, and combinations thereof, wherein R5and/or R6is optionally nothing. Accordingly, each shown R group substituent can be one or more substituents, and the number of substituents is defined by the available atoms of the structure for having a substituent.

In some embodiments, a pharmaceutical composition can include: the compound of one of the embodiments; and a pharmaceutically acceptable carrier having the compound.

In some embodiments, a method of inhibiting a kinase can include: providing the compound of one of the embodiments described herein to the kinase such that the kinase is inhibited. In some aspects, a method of inhibiting a kinase in a subject, such as DDR1, can include: administering the compound of one of the embodiments to a subject. In some aspects, the administering includes a therapeutically effective amount of the compound sufficient to treat cancer by: inhibiting cancer cell growth; inhibiting cancer cell migration; inhibiting cancer cell proliferation; or inhibiting cancer cell migration.

In some embodiments, a method of inhibiting cellular communication can include providing the compound of one of the embodiments to a cell so as to inhibit communication of the cell with a surrounding environment of the cell.

In some embodiments, a method of inhibiting a cell attachment to an extracellular matrix can include: providing the compound of one of the embodiments to a DDR1 receptor of the cell to inhibit the DDR1 receptor from interacting with fibrillar collagen.

In some embodiments, a method of inhibiting cell activity can include: providing the compound of one of the embodiments to a cell so as to inhibit at least one biological function of the cell.

In some embodiments, a method of promoting remodeling of an extracellular matrix can include: providing the compound of one of the embodiments to a DDR1 receptor so as to cause upregulation of a matrix metalloproteinase.

In some embodiments, a method of inhibiting blastocyte implantation during pregnancy can include: providing the compound of one of the embodiments to a DDR1 receptor of an undifferentiated cell in a blastula stage of an embryo.

In some embodiments, a method of inhibiting mammary gland differentiation can include: providing the compound of one of the embodiments to a DDR1 receptor of a mammary gland so as to inhibit differentiation of cells of the mammary gland.

In some embodiments, a method of inhibiting activity of a cancer cell can include: administering the compound of one of the embodiments to the cancer cell so as to inhibit a biological activity of the cancer cell.

In some embodiments, a method of treating cancer in a subject can include:

administering the compound of one of the embodiments to a subject that has cancer.

In some embodiments, a method of synthesizing the compound of Formula A can include performing at least one synthesis step with at least two reactants that react to form the compound having a structure of Formula A, derivative thereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof, or solvate thereof, or having any chirality at any chiral center. In some aspects, the method can include: obtaining a reactant A that includes the ring A; and obtaining a reactant B that includes the ring B. In some aspects, the method can include: obtaining a first reactant having a ring structure; and reacting a second reactant with the first reactant to form a polycylic structure, the polycyclic structure having variables X1, X2, X3, X4, and X5.

The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the drawings and the following detailed description.

