WO2021038419A1

WO2021038419A1 - Kinase inhibitors and methods of synthesis and treatment

Info

Publication number: WO2021038419A1
Application number: PCT/IB2020/057884
Authority: WO
Inventors: Aleksandrs Zavoronkovs; Yan Ivanenkov; Daniil POLYKOVSKIY; Aleksandr ALIPER
Original assignee: Insilico Medicine Ip Limited
Priority date: 2019-08-23
Filing date: 2020-08-22
Publication date: 2021-03-04

Abstract

Compounds that function as kinase inhibitors are provided. The kinase inhibitors can have any structure of the formulae provided herein, such as shown for Compounds 1-4. A pharmaceutical composition can include: the compound of one of the embodiments; and a pharmaceutically acceptable carrier having the compound. 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. The methods can include inhibiting DDR1 and/or DDR2, and thereby providing a modulation or decrease in the activity of DDR1 and/or DDR2. This decrease in DDR1 and/or DDR2 activity can be used as therapy to treat conditions related to DDR1 and/or DDR2 activity, such as fibrosis, cancer, and others.

Description

KINASE INHIBITORS AND METHODS OF SYNTHESIS AND TREATMENT CROSS-REFERENCE [001] This patent application claims priority to U.S. Provisional Application No. 62/891,050 filed August 23, 2019, which provisional is incorporated herein by specific reference in its entirety. BACKGROUND Field: [002] 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 therapeutic 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: [003] 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. [004] 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. [005] 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 [006] In some embodiments, a compound that is a kinase inhibitor is provided. The kinase inhibitor can have any structure of the formulae provided herein, such as shown for Compounds 1-4. [007] In some embodiments, a pharmaceutical composition can include: the compound of one of the embodiments; and a pharmaceutically acceptable carrier having the compound. [008] 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. [009] 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. [010] 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. [011] 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. [012] 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. [013] 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. [014] 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. [015] 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. [016] 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. [017] 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. BRIEF DESCRIPTION OF THE FIGURES [018] The foregoing and following information as well as other features of this disclosure will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings. Understanding that these drawings depict only several embodiments in accordance with the disclosure and are, therefore, not to be considered limiting of its scope, the disclosure will be described with additional specificity and detail through use of the accompanying drawings. [019] Fig.1A includes dose-response curves for Compounds 1-6. [020] Fig.1B includes graphs showing the IC50 of Compounds 2 and 4. [021] Fig. 1C shows the structures of Compounds 1-6 and their IC50 value for DDr1 and DDR2. [022] Fig.2 includes a selectivity profile for Compound 1. [023] Figs. 3A-3I include data that shows the Compound 1 and Compound 2 significantly block DDR1 autophosphorylation in a dose-dependent manner. [024] Figs. 4A-4F include data that show the effects of compounds 1 and 2 on cellular fibrosis markers a-actin and CTGF (normalized to GAPDH) in MRC-5 cells. [025] Fig.5 illustrates the synthesis of INS015_030 (Compound 3) in Scheme 1. [026] Fig.6 illustrates the synthesis of INS015_032 (Compound 4) in Scheme 2. [027] Fig.7 illustrates the synthesis of INS015_036 (Compound 1) in Scheme 3. [028] Fig.8 illustrates the synthesis of INS015_037 (Compound 2) in Scheme 4. [029] Fig.9 illustrates the synthesis of INS015_038 (Compound 5) in Scheme 5. [030] Fig.10 illustrates the synthesis of INS015_039 (Compound 6) in Scheme 6. DETAILED DESCRIPTION [031] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that the aspects of the present disclosure, as generally described herein, and illustrated in the figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein. [032] Generally, the present invention relates to at least one molecule that functions as a kinase inhibitor, such as a DDR1 inhibitor. As such, the molecules described herein can be used in methods related to inhibiting a kinase, such as DDR1, so as to inhibit the kinase (e.g., DDR1) biological activity. As a result, the molecules can be used in therapeutic methods where inhibiting a kinase, such as DDR1, can provide a therapy to a subject that is administered the molecule. Thus, the molecules described herein can each be referred to as a kinase inhibitor, where some are broad spectrum inhibitors of many kinases, and some are specific inhibitors that inhibit a specific kinase, such as DDR1 inhibitor. [033] Accordingly, the kinase (e.g., DDR1) inhibitors can be used to inhibit a receptor tyrosine kinase that facilitates communication of cells so as to inhibit such communication of cells. In some aspects, the DDR1 inhibitor can inhibit binding of the DDR1 receptor a cell surface receptor so as to inhibit binding with fibrillar collagen, and thereby can inhibit biological activity related to regulation of cell attachment to the extracellular matrix, and regulation of remodeling the extracellular matrix. The DDR1 inhibitor can inhibit regulation of cell growth, differentiation, cell migration, proliferation, and metabolism. Accordingly, the inhibitor compounds can be used to treat fibrosis. As such, the inhibitor compounds can be used to inhibit formation of excess fibrous connective tissue in an organ or tissue. The inhibitor compounds can inhibit scarring linked to fibrosis, such as by inhibition of accumulation of extracellular matrix proteins that inhibits thickening (e.g., scarring) of the affected tissue. This also allows for the inhibitor compounds to inhibit exaggerated or excessive wound healing and allow normal organ function. [034] In some embodiments, a method of inhibiting fibrosis can include providing the compound of claim 1 to a DDR1 receptor to inhibit formation of excess fibrous tissue. In some aspects, the DDR1 receptor is associated with a tissue or organ, and thereby inhibition inhibits fibrosis in the tissue or organ. In some aspects, the tissue is associated with a liver or lung, or the organ is the liver or the lung. In some aspects, the DDR1 receptor is associated with pulmonary fibrosis, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), radiation-induced lung injury, bridging fibrosis, cirrhosis, non-alcoholic hepatosteatosis (NASH), non-alcoholic fatty liver disease (NAFLD), atrial fibrosis, endomyocardial fibrosis, myocardial infarction related fibrosis, glial scar, arterial stiffness, arthrofibrosis, crohn’s disease, dupuytren contracture, keloid, mediastinal fibrosis, myelofibrosis, Peyronie’s disease, nephrogenic systemic fibrosis, progressive massive fibrosis, retroperitoneal fibrosis, scleroderma sclerosis, or combinations thereof. Thus, the inhibitor compounds can treat these indications of fibrosis. [035] The DDR1 inhibitor can be applied to cells to be an antagonist or inhibitor of the DDR1 receptor. As such, the DDR1 inhibitor can be applied to epithelial cells, such as the kidney, lung, gastrointestinal tract, and brain so as to inhibit the DDR1 receptor on these cells. The DDR1 inhibitor can inhibit collagen binding to the DDR1 receptor, and thereby inhibit a signaling pathway that involves SRC (non-receptor tyrosine kinase). This can inhibit the activation of MAP kinases. [036] The DDR1 inhibitor can be used to inhibit DDR1 that is over-expressed in some human tumors, such as breast, ovarian, esophageal, and pediatric brain. As such, the DDR1 may be used in cancer therapy. The activity of the DDR1 inhibitor may also inhibit tumor cell invasion. As a result, the DDR1 inhibitor can inhibit the adverse activity of DDR1, and may be useful in cancer therapy. [037] In some embodiments, the invention provides agents (e.g., DDR1 inhibitors) which bind to and/or modulate the activity of DDR1. The DDR1 inhibitors can be included in compositions, such as pharmaceutical compositions for administration. In certain embodiments, the DDR1 inhibitors can specifically bind to DDR1 (e.g., human DDR1). In certain embodiments, the DDR1 inhibitors that specifically bind to and/or modulate the activity of DDR1 may further specifically bind to and/or modulate the activity of the discoidin domain receptor 2 (DDR2) or other kinases. [038] The invention further provides methods of targeting cancer cells with the DDR1 inhibitors. In certain embodiments, the methods comprise reducing the frequency of cancer cells or cancer stem cells in a tumor, reducing the number of cancer cells or cancer stem cells in a tumor, reducing the tumorigenicity of a tumor, and/or reducing the tumorigenicity of a tumor by reducing the number or frequency of cancer cells or cancer stem cells in the tumor. The invention also provides methods of using the DDR1 inhibitors in the treatment of cancer and/or in the inhibition of the growth of tumors. In one aspect, the invention provides a method of inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of one or more DDR1 inhibitors that modulate the activity of DDR1. In certain embodiments of each of the aforementioned aspects, as well as other aspects described elsewhere herein, the tumors which are targeted are breast, colorectal, hepatic, renal, lung, pancreatic, bile duct, ovarian, prostate, or head and neck tumors. The broad spectrum kinase inhibitors may also be used to treat and/or inhibit cancer. [039] The present invention further provides methods of treating cancer in a subject. In some embodiments, the method comprises administering to a subject a therapeutically effective amount of any of the kinase (e.g., DDR1) inhibitors described herein. In some embodiments, the cancer to be treated is breast cancer, colorectal cancer, hepatic cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastrointestinal cancer, melanoma, ovarian cancer, prostate cancer, cervical cancer, bile duct cancer, microsatellite instability-high (MSI-H) cancer, bladder cancer, glioblastoma, and head and neck cancer. In some embodiments, the methods further comprise administering to the subject at least one additional anti-cancer agent along with the kinase (e.g., DDR1) inhibitor. [040] In some embodiments, the invention provides a method of inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of a kinase (e.g., DDR1) inhibitor that modulates the activity of the kinase (e.g., DDR1). In certain embodiments, the kinase (e.g., DDR1) inhibitors reduces tumorigenicity of the tumor by reducing the number or frequency of cancer stem cells in the tumor. In certain embodiments, the kinase (e.g., DDR1) inhibitor is Compound 1 that specifically binds to DDR1. In certain embodiments, the tumor is selected from the group consisting of a breast tumor, colorectal tumor, hepatic tumor, renal tumor, lung tumor, pancreatic tumor, ovarian tumor, prostate tumor, and head and neck tumor. In certain embodiments, the tumor expresses LGR5. In certain embodiments, the tumor expresses LGR5 and the tumor is a colorectal tumor, hepatic tumor, ovarian tumor, or pancreatic tumor. In certain embodiments, the cancer stem cells express LGR5. In certain embodiments, the cancer stem cells express LGR5 and the tumor is a colorectal tumor, hepatic tumor, ovarian tumor, or pancreatic tumor. In certain embodiments, the tumor expresses Hes1. In certain embodiments, the tumor expresses Hes1 and the tumor is a breast tumor, colorectal tumor, renal tumor, lung tumor, pancreatic tumor, or prostate tumor. In certain embodiments, the cancer stem cells express Hes1. In certain embodiments, the cancer stem cells express Hes1 and the tumor is a breast tumor, colorectal tumor, renal tumor, lung tumor, pancreatic tumor, or prostate tumor. In certain embodiments, the subject is a human. The other methods may also include the foregoing by inhibiting DDR1 with the DDR1 inhibitor. [041] In some embodiments, the invention provides a DDR1 inhibitor that modulates the activity of DDR1. In certain embodiments, the DDR1 inhibitors specifically binds to DDR1. In some embodiments, the DDR1 inhibitor binds the extracellular domain of DDR1. In certain embodiments, the DDR1 inhibitor binds the discoidin domain of DDR1. [042] In certain embodiments, the DDR1 inhibitor is an antagonist of DDR1. In some embodiments, the term “antagonist” includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a DDR1 and/or DDR2 protein or fragment thereof. In some embodiments, the term “antagonist” includes any molecule that partially or fully blocks, inhibits, or neutralizes the expression of DDR1, and/or DDR2 protein or fragment thereof. [043] In certain embodiments, the DDR1 inhibitor does not have one or more effector functions. For instance, in some embodiments, the DDR1 inhibitors has minimal or no cellular cytotoxicity activity. In certain embodiments, the DDR1 inhibitor does not bind to an Fc receptor and/or complement factors. In certain embodiments, the DDR1 inhibitor has no effector function. [044] In certain embodiments, the treatment methods further comprise administering at least one additional therapeutic agent appropriate for effecting combination therapy (e.g., a chemotherapeutic agent or other anticancer agent if cancer is to be treated) in addition to the DDR1 inhibitors described herein. In certain embodiments, the additional therapeutic agent is irinotecan or gemcitabine. In certain embodiments, the additional therapeutic agent is irinotecan. In certain embodiments, the additional therapeutic agent is gemcitabine. [045] In certain embodiments, the compounds of the formulae provided herein can be used for cancer therapy and be administered to a subject that has a cancerous growth. The compounds can be used to inhibit tumor growth, or otherwise inhibit any neoplasm. The compounds may also be used to inhibit cancer metastasis. As such, the compounds can be tumorigenic. [046] In some aspects, the compounds can be used to treat cancer that may include a cancer stem cell or solid tumor stem cell. In some aspects, a tumor may be assayed to determine whether or not a cancer stem cell is present prior to the therapy with the compound. For example, stem cell cancer markers may be used to identify the presence of a cancer stem cell. [047] In some instances, a biopsy and diagnostic protocol can be performed to identify a cancer prior to the therapy with the compound. [048] In some embodiments, the compounds can be broad spectrum kinase inhibitors. In some aspects, the compounds can be receptor tyrosine kinase (RTK) inhibitors. Accordingly, the compounds can inhibit kinases from the following RTK families: RTK class I (EGF receptor family) (ErbB family); RTK class II (Insulin receptor family); RTK class III (PDGF receptor family); RTK class IV (VEGF receptors family); RTK class V (FGF receptor family); RTK class VI (CCK receptor family); RTK class VII (NGF receptor family); RTK class VIII (HGF receptor family); RTK class IX (Eph receptor family); RTK class X (AXL receptor family); RTK class XI (TIE receptor family); RTK class XII (RYK receptor family); RTK class XIII (DDR receptor family); RTK class XIV (RET receptor family); RTK class XV (ROS receptor family); RTK class XVI (LTK receptor family); RTK class XVII (ROR receptor family); RTK class XVIII (MuSK receptor family); RTK class XIX (LMR receptor); and/or RTK class XX (Undetermined). [049] In some embodiments, the DDR1 inhibitor has a structure of [050] In some embodiments, the kinase inhibitor is a compound comprising a structure of Formula 1, Formula 2, Formula 3, or Formula 4, or derivative thereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof, or solvate thereof, or having any chirality at any chiral center,

[051] Wherein: the Fluorine Group is a chemical moiety having at least one F; R¹, R², and R³ are each individually a substituent; X¹, X², X³, X⁴, and X⁵ independently include C, N, O, or S; Y¹ is a linker or a bond; Y² is a linker or a bond; n is from 0 to 6; m is from 0 to 5; and o is from 0 to 4. [052] In the formulae, the bonds between chemical structures that are not between atoms illustrates the bonding can be from any atom of the structure. For example, the R1 and Y1 can be on any atom of either ring of the same chemical structure, and the illustrations of the bond to one of the rings is for illustrative purposes to show the chemical structure has the bond. In another example, the R² can be bonded to any atom of either ring of the same structure, such as X¹ or X², if possible. [053] The X atoms can be carbon or hetero atoms such as those listed. These X atoms may include the appropriate number of hydrogen atoms or be without any hydrogen atoms or include a substituent R group or be without any substituent R group in a number that corresponds with the available number of bonds after considering the required bonds. For example, X⁴ of Formula 1 can be O, NH2, and CH3, and so on, which is understood by X⁴ having C, N, O, or S. [054] The n, m, and o identify the number of R substituents on the chemical structure, and each R substituent can be independently selected. For example, R¹ can be a methyl and an hydroxyl when n is 2, or both R¹s can be the same. [055] The Fluorine Group can be a chemical moiety that includes at least one F atom, whether directly bonded to the ring or in a chemical structure that is bonded to the ring. Examples of the Fluorine Group include F, CFH₂, CF₂H, and CF₃, as well as others. [056] In some embodiments, the kinase inhibitor includes a structure of Formula 1A, Formula 2A, Formula 3A, or Formula 4A, or derivative thereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof, or solvate thereof, or having any chirality at any chiral center,

[057] In some embodiments, a kinase inhibitor includes a structure of Formula 1B, Formula 2B, Formula 3B, or Formula 4B, or derivative thereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof, or solvate thereof, or having any chirality at any chiral center,

[058] In some embodiments, R¹, R², and R³ 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, peptides, polypeptides, derivatives thereof, substituted or unsubstituted, or combinations thereof. [059] In some embodiments, R¹, R², and R³ are 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, alkylsulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, any with or without hetero atoms, derivatives thereof, and combinations thereof. [060] In some embodiments, R¹, R², and R³ are each independently hydrogen, C₁ -C₂₄ alkyl, C₂ -C₂₄ alkenyl, C₂ -C₂₄ alkynyl, C5 -C₂0 aryl, C₆ -C₂₄ alkaryl, C₆ -C₂₄ aralkyl, halo, hydroxyl, sulfhydryl, C₁ -C₂₄ alkoxy, C₂ -C₂₄ alkenyloxy, C₂ -C₂₄ alkynyloxy, C₅-C₂₀ aryloxy, acyl, acyloxy, C₂-C₂₄ alkoxycarbonyl, C₆-C₂0 aryloxycarbonyl, halocarbonyl, C₂- C₂₄ alkylcarbonato, C₆-C₂₀ arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C₁ - C₂₄ alkyl)-substituted carbamoyl, di-(C₁ -C₂₄ alkyl)-substituted carbamoyl, mono- substituted arylcarbamoyl, di-substituted arylcarbamoyl, thiocarbamoyl, mono-(C₁ -C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁ -C₂₄ alkyl)-substituted thiocarbamoyl, mono- substituted arylthiocarbamoyl, di-substituted arylthiocarbamoyl, carbamido, mono-(C₁ - C₂₄ alkyl)-substituted carbamido, di-(C₁ -C₂₄ alkyl)-substituted carbamido, mono- substituted aryl carbamido, di-substituted aryl carbamido, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C₁ -C₂₄ alkyl)-substituted amino, mono- and di-(C5 -C₂0 aryl)-substituted amino, C₂ -C₂₄ alkylamido, C₆ -C₂₀ arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfonic acid, sulfonate, C₁ -C₂₄ alkylsulfanyl, C5 -C₂0 arylsulfanyl, C₁ -C₂₄ alkylsulfinyl, C5 -C₂0 arylsulfinyl, C₁ -C₂₄ alkylsulfonyl, C₅ -C₂₀ arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, any with or without hetero atoms, derivatives thereof, and combinations thereof. [061] In some embodiments: X¹ includes N; X² includes N; X³ includes N; X⁴ includes O; and X⁵ includes N. [062] In some embodiments: for Formula 1, R¹ is H, R² is an alkyl (e.g., C₁ -C₂₄ alkyl) with a straight chain or branched, alkoxy, cycloalkyl, alkyl ether, substituted or unsubstituted, and R³ is H; for Formula 2, R¹ is H, R² is H, and R³ is H; for Formula 3, R¹ is H, R² is an alkyl (e.g., C₁ -C₂₄ alkyl) with a straight chain or branched, alkoxy, cycloalkyl, alkyl ether, substituted or unsubstituted, and R³ is H; and for Formula 4, R¹ is H, R² is an alkyl (e.g., C₁ -C₂₄ alkyl) with a straight chain or branched, alkoxy, cycloalkyl, alkyl ether, substituted or unsubstituted, and R³ is dialkyl amine or any alkyl-amine (e.g., C₁ -C₂₄ alkyl) with a straight chain or branched. [063] In some embodiments: for Formula 1, R¹ is H, R² is methyl, and R³ is H; for Formula 2, R¹ is H, R² is H, and R³ is H; for Formula 3, R¹ is H, R² is methyl, and R³ is H; and for Formula 4, R¹ is H, R² is methyl, and R³ is dimethyl amine. [064] In the formulae, the Y¹ or Y² can each independently be a bond or any linker. When Y is one chain atom or more than one chain atom, there may be a R¹ on one or more of the chain atoms. The linker can be O, S, C, N, or a hydrocarbon chain with or without hetero atoms. The linker may include 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, alkyl amides, bis-alkyl amides, esters, amino acids, derivatives thereof, substituted or unsubstituted, or combinations. In some aspects, the liker can include C₁ -C₂₄ alkyl, C₂ -C₂₄ alkenyl, C₂ -C₂₄ alkynyl, C₆ -C₂₀ aryl, C₇ -C₂₄ alkaryl, C7 -C₂₄ aralkyl, amino, mono- and di-(alkyl)-substituted amino, mono- and di- (aryl)-substituted amino, alkylamido, arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, alkylsulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, any with or without hetero atoms, any substituted or unsubstituted, derivatives thereof, and combinations thereof. [065] In some embodiments: for Formula 1, Y¹ includes an alkylene; for Formula 2, Y¹ is a bond; for Formula 3, Y¹ is a bond; and for Formula 4, Y¹ includes an alkylene. [066] In some embodiments: for Formula 1, Y² includes an amino; for Formula 2, Y² includes an amide; for Formula 3, Y² is a bis-alkyl amide; and for Formula 4, Y² includes a bond. [067] In some embodiments: for Formula 1, Y¹ includes an ethylene; for Formula 2, Y¹ is a bond; for Formula 3, Y¹ is a bond; and for Formula 4, Y¹ includes an ethylene. [068] In some embodiments: for Formula 1, Y² includes an amino; for Formula 2, Y² includes an amide, in either direction; for Formula 3, Y² is a bis-methyl amide, in either direction; and for Formula 4, Y² includes a bond. [069] In some embodiments, the kinase inhibitor includes a structure of Compound 1,

(Compound 1). [070] In some embodiments, the kinase inhibitor includes a structure of Compound 2,

(Compound 2). [071] In some embodiments, the kinase inhibitor includes a structure of Compound 3,

(Compound 3). [072] In some embodiments, the kinase inhibitor includes a structure of Compound 4,

(Compound 4). [073] In some embodiments, a pharmaceutical composition can include: the compound of one of the formula or one of Compounds 1-6 or Compounds 1-4; and a pharmaceutically acceptable carrier having the compound. [074] In some embodiments, a method of inhibiting a kinase can include providing the kinase inhibitor to the kinase such that the kinase is inhibited. [075] In some embodiments, a method of inhibiting cellular communication can include providing the kinase inhibitor to a cell so as to inhibit communication of the cell with a surrounding environment of the cell. [076] In some embodiments, a method of inhibiting a cell attachment to an extracellular matrix can include providing the kinase inhibitor to a DDR1 receptor of the cell to inhibit the DDR1 receptor from interacting with fibrillar collagen. [077] In some embodiments, a method of inhibiting cell activity can include providing the kinase inhibitor to a cell so as to inhibit at least one biological function of the cell. [078] In some embodiments, a method of promoting remodeling of an extracellular matrix can include providing the kinase inhibitor to a DDR1 receptor so as to cause upregulation of a matrix metalloproteinase. [079] In some embodiments, a method of inhibiting fibrosis can include providing the kinase inhibitor to a DDR1 receptor to inhibit formation of excess fibrous tissue. [080] In some embodiments, a method of inhibiting mammary gland differentiation can include providing the kinase inhibitor to a DDR1 receptor of a mammary gland so as to inhibit differentiation of cells of the mammary gland. [081] In some embodiments, a method of inhibiting activity of a cancer cell can include administering the kinase inhibitor to the cancer cell so as to inhibit a biological activity of the cancer cell. [082] In some embodiments, a method of treating cancer in a subject can include administering the kinase inhibitor to a subject that has cancer. [083] In some embodiments, a method of inhibiting a DDR1 kinase can include providing the kinase inhibitor to the DDR1 kinase such that the DDR1 kinase is inhibited. [084] In some embodiments, a method of inhibiting a disease related to DDR1 kinase in a subject can include providing the kinase to the DDR1 kinase of the subject such that the DDR1 kinase is inhibited in the subject. [085] In the formulae, the R substituent groups, such as R¹, R², and R³ can be any possible substituent or one substituent or a combination of the substituents recited herein. Each ring atom may have the corresponding R substituent, or only 1, 2, 3, 4, or 5 ring atoms may have the R substituent, which may be adjacent or separate from each other. Depending on the ring atom, there may or may not be an R substituent group. These R substituent groups can be on one or more ring atoms or linker atom (e.g., Y). As such, each atom of a ring or linker atom may include a substituent as shown in Formula A. Each R substituent for a specific atom can be any possible substituent or one substituent or a combination of substituents. [086] Compounds 1-4 are examples of kinase (e.g., DDR1) inhibitors. Also, the Compounds 1-6 may represent other examples where the substituents are on other atoms from or on additional atoms than shown. [087] In some embodiments, the compounds can be devoid of a P, S, or Si atom. [088] The kinase (e.g., DDR1) inhibitors can be formulated for experiments or therapies. The formulations are prepared for storage and use by combining a purified kinase (e.g., DDR1) inhibitor of the present invention with a pharmaceutically acceptable vehicle (e.g., carrier, excipient) (Remington, The Science and Practice of Pharmacy 20th Edition Mack Publishing, 2000). Suitable pharmaceutically acceptable vehicles include, but are not limited to, nontoxic buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight polypeptides (e.g. less than about 10 amino acid residues); proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; carbohydrates such as monosaccharides, disaccharides, glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and non-ionic surfactants such as TWEEN or polyethylene glycol (PEG). [089] The pharmaceutical composition of the present invention can be administered in any number of ways for either local or systemic treatment. Administration can be topical (such as to mucous membranes including vaginal and rectal delivery) such as transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders; pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, intranasal, epidermal and transdermal); oral; or parenteral including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; intratumoral, or intracranial (e.g., intrathecal or intraventricular) administration. [090] The therapeutic formulation can be in unit dosage form. Such formulations include tablets, pills, capsules, powders, granules, solutions or suspensions in water or non-aqueous media, or suppositories for oral, parenteral, or rectal administration or for administration by inhalation. In solid compositions such as tablets the principal active ingredient is mixed with a pharmaceutical carrier. Conventional tableting ingredients include corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other diluents (e.g. water) to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. The solid preformulation composition is then subdivided into unit dosage forms of the type described above. The tablets, pills, etc. of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner composition covered by an outer component. Furthermore, the two components can be separated by an enteric layer that serves to resist disintegration and permits the inner component to pass intact through the stomach or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. [091] Pharmaceutical formulations include kinase (e.g., DDR1) inhibitors of the present invention complexed with liposomes (Epstein, et al., 1985, Proc. Natl. Acad. Sci. USA 82:3688; Hwang, et al., 1980, Proc. Natl. Acad. Sci. USA 77:4030; and U.S. Pat. Nos. 4,485,045 and 4,544,545). Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556. Some liposomes can be generated by the reverse phase evaporation with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. [092] The kinase (e.g., DDR1) inhibitor can also be entrapped in microcapsules. Such microcapsules are prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions as described in Remington, The Science and Practice of Pharmacy 20th Ed. Mack Publishing (2000). [093] In addition sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing the kinase (e.g., DDR1) inhibitor, which matrices are in the form of shaped articles (e.g. films or microcapsules). Examples of sustained-release matrices include polyesters, hydrogels such as poly(2-hydroxyethyl-methacrylate) or poly(vinylalcohol), polylactides (U.S. Pat. No.3,773,919), copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid- glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid. [094] In some embodiments, the treatment involves the combined administration of a DDR1 inhibitor agent of the present invention and a chemotherapeutic agent or cocktail of multiple different chemotherapeutic agents. Combination therapy often uses agents that work by different mechanisms of action. Combination therapy using agents with different mechanisms of action often results in additive or synergetic effects. Combination therapy may allow for lower doses of each agent than is used in monotherapy thereby reducing toxic side effects. Combination therapy may decrease the likelihood that resistant cancer cells will develop. In some embodiments, the combination therapy comprises a kinase (e.g., DDR1) inhibitor that binds to kinase (e.g., DDR1) and a chemotherapeutic agent. [095] Pharmaceutical compositions include, without limitation, lyophilized powders or aqueous or non-aqueous sterile injectable solutions or suspensions, which may further contain antioxidants, buffers, bacteriostats and solutes that render the compositions substantially compatible with the tissues or the blood of an intended recipient. Other components that may be present in such compositions include water, surfactants (e.g., Tween ^® ), alcohols, polyols, glycerin and vegetable oils, for example. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, tablets, or concentrated solutions or suspensions. The composition may be supplied, for example but not by way of limitation, as a lyophilized powder which is reconstituted with sterile water or saline prior to administration to the patient. [096] Suitable pharmaceutically acceptable carriers include essentially chemically inert and nontoxic compositions that do not interfere with the effectiveness of the biological activity of the pharmaceutical composition. Examples of suitable pharmaceutical carriers include, but are not limited to, water, saline solutions, glycerol solutions, ethanol, N-(1 (2,3- dioleyloxy)propyl)N,N,N-trimethylammonium chloride (DOTMA), diolesyl- phosphotidyl-ethanolamine (DOPE), and liposomes. Such compositions should contain a therapeutically effective amount of the compound, together with a suitable amount of carrier so as to provide the form for direct administration to the patient. [097] The compositions described herein can be administered for example, by parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol or oral administration. Common carriers or excipients can be used for preparing pharmaceutical compositions designed for such routes of administration. [098] For the treatment of the disease, the appropriate dosage of a kinase (e.g., DDR1) inhibitor of the present invention depends on the type of disease to be treated, the severity and course of the disease, the responsiveness of the disease, whether the kinase (e.g., DDR1) inhibitor is administered for therapeutic or preventative purposes, previous therapy, patient's clinical history, and so on, all at the discretion of the treating physician. The kinase (e.g., DDR1) inhibitor can be administered one time or over a series of treatments lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved (e.g., reduction in tumor size). Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient and will vary depending on the relative potency of an individual kinase (e.g., DDR1) inhibitor. The administering physician can easily determine optimum dosages, dosing methodologies and repetition rates. In general, dosage is from 0.01 mg to 100 mg per kg of body weight, and can be given once or more daily, weekly, monthly or yearly. The treating physician can estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. [099] The present invention provides kits comprising the kinase (e.g., DDR1) inhibitor described herein and that can be used to perform the methods described herein. In certain embodiments, a kit comprises at least one purified kinase (e.g., DDR1) inhibitor in one or more containers. In some embodiments, the kits contain all of the components necessary and/or sufficient to perform a detection assay, including all controls, directions for performing assays, and any necessary software for analysis and presentation of results. One skilled in the art will readily recognize that the disclosed kinase (e.g., DDR1) inhibitors of the present invention can be readily incorporated into one of the established kit formats which are well known in the art. [0100] In some embodiments, the compounds can have an inhibitory activity against a wild type or mutant (especially a clinically relevant mutant) kinase, especially a Src family kinase such as Src, Yes, Lyn or Lck; a VEGF-R such as VEGF-R1 (Flt-1), VEGF- R2 (kdr), or VEGF-R3; a PDGF-R; an Abl kinase; or DDR1 kinase; or another kinase of interest with an IC50 value of 1 mM or less (as determined using any scientifically acceptable kinase inhibition assay), preferably with an IC50 of 500 nM or better, and optimally with an IC50 value of 250 nM or better. In some aspects, the compounds can have an inhibitory activity against both Src and kdr with a 1 mM or better IC50 value against each. In some aspects, the compounds can have a cytotoxic or growth inhibitory effect on cancer cell lines maintained in vitro, or in animal studies using a scientifically acceptable cancer cell xenograft model, or against live tumors in an individual. [0101] Also provided is a composition comprising at least one compound of the invention or a salt, hydrate or other solvate thereof, and at least one pharmaceutically acceptable excipient or additive. Such compositions can be administered to a subject in need thereof to inhibit the growth, development and/or metastasis of cancers, including solid tumors (e.g., breast, colon, pancreatic, CNS and head and neck cancers, among others) and various forms of leukemia, including leukemias and other cancers which are resistant to other treatment, including those which are resistant to treatment with Gleevec or another kinase inhibitor, and generally for the treatment and prophylaxis of diseases or undesirable conditions mediated by one or more kinases which are inhibited by a compound of this invention. [0102] The cancer treatment method of this invention involves administering (as a monotherapy or in combination with one or more other anti-cancer agents, one or more agents for ameliorating side effects, radiation, etc) a therapeutically effective amount of a compound of the invention to a human or animal in need of it in order to inhibit, slow or reverse the growth, development or spread of cancer, including solid tumors or other forms of cancer such as leukemias, in the recipient. Such administration constitutes a method for the treatment or prophylaxis of diseases mediated by one or more kinases inhibited by one of the disclosed compounds or a pharmaceutically acceptable derivative thereof. “Administration” of a compound of this invention encompasses the delivery to a recipient of a compound of the sort described herein, or a prodrug or other pharmaceutically acceptable derivative thereof, using any suitable formulation or route of administration, as discussed herein. Typically the compound is administered one or more times per month, often one or more times per week, e.g. daily, every other day, 5 days/week, etc. Oral and intravenous administrations are of particular current interest. [0103] One embodiment is a method for treating cancer in a subject in need thereof, which comprises administering to the subject a treatment effective amount of a composition containing a compound of this invention. Various cancers which may be thus treated are noted elsewhere herein and include, among others, cancers which are or have become resistant to another anticancer agent such as Gleevec, Iressa, Tarceva or one of the other agents noted herein. Treatment may be provided in combination with one or more other cancer therapies, include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, etc.), endocrine therapy, biologic response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF) to name a few), hyperthermia, cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and other cancer chemotherapeutic drugs. The other agent(s) may be administered using a formulation, route of administration and dosing schedule the same or different from that used with the compound of this invention. [0104] While the present disclosure uses DDR1 as the target for the kinase inhibitors, the data shows that these kinase inhibitors also inhibits DDR2. Thus, the subject matter of the present application may also include DDR2 inhibitors, or using the kinase inhibitors to inhibit DDR2. In many instances, DDR1 and DDR2 are implicated in the same disease states, such as fibrosis, and thereby the methods of treatment include inhibiting DDR1 and/or DDR2. [0105] In some embodiments, the invention includes the synthesis of one of the compounds of the invention. [0106] The invention also comprises the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment either acutely or chronically of cancer (including leukemias and solid tumors, primary or metastatic, including cancers such as noted elsewhere herein and including cancers which are resistant or refractory to one or more other therapies). The compounds of this invention are useful in the manufacture of an anti-cancer medicament. The compounds of the present invention are also useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of one or more kinases such as Src, kdr, abl. etc. [0107] Other disorders which may be treated with a compound of this invention include metabolic disorders, inflammatory disorders and osteoporosis and other bone disorders. In such cases the compound of this invention may be used as a monotherapy or may be administered in conjunction with administration of another drug for the disorder, e.g., a bisphosphonate in the case of osteoporosis or other bone-related illnesses. [0108] Compounds of this invention are also useful as standards and reagents for characterizing various kinases, especially but not limited to kdr and Src family kinases, as well as for studying the role of such kinases in biological and pathological phenomena; for studying intracellular signal transduction pathways mediated by such kinases, for the comparative evaluation of new kinase inhibitors; and for studying various cancers in cell lines and animal models. [0109] In some embodiments, a pharmaceutical composition can include the compound of one of the embodiments provided herein and a pharmaceutically acceptable carrier having the compound. In some aspects, the composition can include an additional therapeutic agent. In some aspects, the additional therapeutic agent is a chemotherapeutic agent. In some aspects, the additional therapeutic agent is gemcitabine. In some aspects, the additional therapeutic agent is dasatinib. In some aspects, the additional therapeutic agent is irinotecan. [0110] In some embodiments, the pharmaceutically acceptable carrier includes at least one of a buffer, organic acid, salt, antioxidant, preservative, polymer, carbohydrate, chelating agent, sugar, or surfactant. In some aspects, the pharmaceutically acceptable carrier is configured for an administration route selected from topical, transdermal, pulmonary, oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, intratumora, intranasal, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, or intracranial. In some aspects, the pharmaceutically acceptable carrier is configured as a dosage form selected from, tablet, pill, capsule, powder, granule, solution, suspension, or suppository. In some aspects, the compound is contained in a liposome, microsphere, microemulsion, nano-particle, nano-capsule, sustained release matrix, or combination thereof. [0111] In some embodiments, a method of inhibiting a kinase can include providing the compound of one of the embodiments to the kinase such that the kinase is inhibited. In some aspects, the kinase is a receptor tyrosine kinase. In some aspects, the receptor tyrosine kinase is a discoidin domain receptor family member. In some aspects, the discoidin domain receptor family member is DDR1. In some aspects, the discoidin domain receptor family member is DDR2. In some aspects, the inhibition of the kinase inhibits transfer of a phosphate group from ATP to another molecule. In some aspects, the inhibition of the kinase inhibits a phosphorylation pathway. In some aspects, the inhibition of the receptor tyrosine kinase inhibits binding of the receptor tyrosine kinase with at least one of a growth factor, cytokine, or hormone. In some aspects, the inhibition of the discoidin domain receptor family member inhibits communication between cells. In some aspects, the inhibition of DDR1 and/or DDR2 inhibits binding of a substance to the DDR1. In some aspects, the inhibition of binding inhibits binding of the DDR1 and/or DDR2 with fibrillar collagen. In some aspects, the inhibition of binding of DDR1 and/or DDR2 with fibrillar collagen inhibits cellular attachment to an extracellular matrix or remodeling of the extracellular matrix. [0112] In some embodiments, the inhibition of DDR1 and/or DDR2 results in at least one of: inhibiting cell growth; inhibiting cell migration; inhibiting cell proliferation; or inhibiting cell migration. In some aspects, the inhibited DDR1 and/or DDR2 is present on an epithelial cell. In some aspects, the epithelial cell is selected from cells of a kidney, lung, gastrointestinal tract, or brain. In some aspects, the inhibited DDR1 and/or DDR2 inhibits an SRC signaling pathway. In some aspects, the inhibited DDR1 and/or DDR2 inhibits activation of a MAP kinase. In some aspects, the receptor tyrosine kinase (RTK) is at least one of the classes recited herein. [0113] 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 aspects, the cell is inhibited from interacting with a cell growth regulating substance. In some aspects, the cell is inhibited from interacting with a differentiation regulating substance. In some aspects, the cell is inhibited from interacting with a metabolism regulating substance. In some aspects, the compound binds with a discoidin domain receptor family member. [0114] 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 and/or DDR2 receptor of the cell to inhibit the DDR1 and/or DDR2 from interacting with fibrillar collagen. In some aspects, the inhibition of DDR1 and/or DDR2 inhibits remodeling of an extracellular matrix around the cell. 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 aspects, the biological function of the cell is at least one of: cell growth; differentiation; cell migration; cell proliferation; or cell metabolism. In some aspects, the compound inhibits a discoidin domain receptor family member of the cell. In some aspects, the discoidin domain receptor family member is DDR1 or DDR2. In some aspects, the discoidin domain receptor family member is DDR1. In some aspects, the cell is an epithelial cell. In some aspects, the epithelial cell is selected from a cell from a kidney, lung, gastrointestinal tract, or brain. [0115] 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 and/or DDR2 so as to cause upregulation of a matrix metalloproteinase. In some aspects, the matrix metalloproteinase is selected from MMP2, MMP7 or MMP9. In some aspects, the upregulation of a matrix metalloproteinase causes cellular migration. In some aspects, the upregulation of a matrix metalloproteinase causes wound healing. [0116] In some embodiments, a method of inhibiting blastocyte implantation, such as during pregnancy, can include providing the compound of one of the embodiments to a DDR1 and/or DDR2 receptor of an undifferentiated cell in a blastula stage of an embryo. In some embodiments, the embryo is in a pregnant female. In some aspects, the method includes administering a sufficient amount of the compound to the pregnant female so as to cause abortion of the embryo. [0117] In some embodiments, a method of inhibiting mammary gland differentiation can include providing the compound of one of the embodiments to a DDR1 and/or DDR2 of a mammary gland so as to inhibit differentiation of cells of the mammary gland. In some aspects, the mammary gland is in a pregnant female. In some aspects, the method can include administering a sufficient amount of the compound to the pregnant female to inhibit development of the mammary gland. In some aspects, the compound inhibits lactation from the mammary gland. In some aspects, the mammary gland is in a non- pregnant female. In some aspects, the method can include administering a sufficient amount of the compound to the non-pregnant female to inhibit development of breast cancer. [0118] 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 aspects, the administering includes a therapeutically effective amount of the compound sufficient to: inhibit cancer cell growth; inhibit cancer cell migration; inhibit cancer cell proliferation; inhibit cancer cell migration; or inhibit cancer cell metabolism. In some aspects, the cancer cell is in a subject that has been diagnosed with cancer prior to the administration of the compound. In some aspects, the cancer cell is in a subject that has not been diagnosed with cancer prior to the administration of the compound. In some aspects, the cancer cell is in a breast tumor, colorectal tumor, hepatic tumor, renal tumor, lung tumor, pancreatic tumor, gastrointestinal tumor, ovarian tumor, prostate tumor, skin tumor, bladder tumor, cervical tumor, or head and neck tumor. In some aspects, the method can include administering at least one additional chemotherapeutic agent to the cancer cell with the kinase inhibitor. [0119] 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 aspects, the method can include administering a sufficient amount of the compound to inhibit a kinase of a cancer cell. In some aspects, the kinase is a receptor tyrosine kinase. In some aspects, the receptor tyrosine kinase is a discoidin domain receptor family member. In some aspects, the discoidin domain receptor family member is DDR1. In some aspects, the discoidin domain receptor family member is DDR2. In some aspects, the method can include administering a sufficient amount of the compound to inhibit a phosphorylation pathway of the cancer cell. In some aspects, the method can include administering a sufficient amount of the compound to inhibit binding of the receptor tyrosine kinase with at least one of a growth factor, cytokine, or hormone. In some aspects, the method can include administering a sufficient amount of the compound to inhibits chemical communication between cancer cells. In some aspects, the inhibition of DDR1 and/or DDR2 inhibits binding of a substance to the cancer cell. In some aspects, the inhibition of binding inhibits binding of the cancer cell with fibrillar collagen. In some aspects, the inhibition of binding of DDR1 and/or DDR2with fibrillar collagen inhibits cellular attachment to an extracellular matrix or remodeling of the extracellular matrix. In some aspects, the inhibition of DDR1 and/or DDR2 results in at least one of: inhibiting cancer cell growth; inhibiting cancer cell migration; inhibiting cancer cell proliferation; inhibiting cancer cell metabolism; inhibiting cancer cell metastasis; or inhibiting cancer cell migration. In some aspects, the cancer cell is inhibited from interacting with a cell growth regulating substance. In some aspects, the cancer cell is inhibited from interacting with a differentiation regulating substance. In some aspects, the cancer cell is inhibited from interacting with a metabolism regulating substance. In some aspects, the cancer is in a subject that has been diagnosed with cancer prior to the administration of the compound. In some aspects, the cancer is in a subject that has not been diagnosed with cancer prior to the administration of the compound. In some aspects, the subject desires to avoid contracting cancer and takes the compound as a prophylactic. In some aspects, the cancer is a breast cancer, colorectal cancer, hepatic cancer, renal cancer, lung cancer, pancreatic cancer, gastrointestinal cancer, ovarian cancer, prostate cancer, skin cancer, bladder cancer, cervical cancer, or head and neck cancer. In some aspects, the method can include administering at least one additional chemotherapeutic agent to the subject with the kinase inhibitor, which can provide a combination therapy. In some aspects, the method can include administering a sufficient amount of the compound to reduce a number of cancer cells in the cancer. In some aspects, the method can include administering a sufficient amount of the compound to reduce a number of cancer stem cells in the cancer. [0120] In view of the synthetic protocols described herein, it should be recognized that the reagents that are used can be modified in accordance with the structures of the compounds recited herein. As such, the reagents and reactants can be modified to include the features of reactants to result in the specific compounds provided herein. This includes the reactants having the R group substituents in order to arrive at the synthesized compounds having corresponding R group substituents, and thereby the defined compounds can be used as a roadmap for modifying the synthesis provided herein to arrive at the compounds defined herein and provided by the formulae. [0121] EXAMPLES [0122] Six molecules were generated, selected, and synthesized and were submitted for biological testing (e.g., within 35 days). Among the tested samples four compounds have demonstrated moderate to high activity (see dose-response curves in Fig.1A). Compound 1 (i.e., INS015_036) and Compound 2 (i.e., INS015_37) showed strong inhibition of DDR1 activity with an IC50 value of 10 and 21 nM, respectively. Compound 3 (i.e., INS015_030) and Compound 4 (i.e., INS015_032) demonstrated moderate potency (1 mM and 278 nM, respectively), while Compound 5 (i.e., INS015_039) and Compound 6 (i.e., INS015_038) were inactive. Since the dose-response curves for Compounds 2 and 4 seemed likely inconsistent, additional experiments were performed to confirm the activity of these molecules towards DDR1 kinase (see Fig.1B). In these studies, Compound 2 has demonstrated an IC50 value of 37 nM, while Compound 4 was 4-times less active (IC50=156 nM). Thus, nanomolar activity of both compounds was proved in two different biochemical assays. Compounds 1 and 2 were also evaluated towards DDR2 kinase. According to the results depicted in Fig. 1A, the activity of Compound 1 was 23- times weaker than for DDR1, while Compound 2 showed an IC50 value of 76 nM. Based on these results, it was concluded that two the most active DDR1 inhibitors (Compounds 1 and 2) are interesting structures for further investigation and optimization. [0123] Figs. 1A-1B show the structures and dose-response curves for the generated molecules. The six generated compounds were tested in a dose-dependent manner against DDR1 tyrosine kinase. Compounds 1 and 2 demonstrated the IC50 values in the low nanomolar range (Fig. 1A). Compounds 2 and 4 were additionally rescreened towards DDR1 kinase using another biochemical assay (Thermo Fisher-PR6913A) and have demonstrated the IC50 values of 37.12 and 155.6 nM respectively (Fig.1B). [0124] Fig. 1C shows the structure and the IC50 against DDR1 and DDR2 for Compounds 1-6, as identified by their compound number. which are also shown in Fig. 1A. [0125] The kinase inhibitors described herein can be specific for DDR1 kinase. The issue of selectivity is of vital importance for a lead compound to estimate possible off-target effects that can influence the pre-clinical evaluation success. The protocol can be configured to assess a selectivity index (SI) for the most active generated compound, such as in enzymatic assay using the scanMAX Delta Kinase Panel by Eurofins. Compound 1 was tested at 10 µM concentration and showed a relatively high SI over 44 kinases, including serine/threonine protein kinases (e.g. CDKs, PKCb2, MAPKAPK3, TSSKs, TTBK1, A-Raf, etc.), lipid and atypical kinases, as well as dual-specificity protein kinases, as shown in Fig.2. The highest inhibition potency within the panel was revealed against eEF-2K (INH%=37), while the activity of DDR1 kinase was completely inhibited at this concentration. DDR1 kinase is mostly expressed in epithelial cells, whereas the expression of DDR2 is generally observed in interstitial cells of Leydig. Even though that the prevention of fibrosis is the primary goal, the selectivity over DDR2 kinase is also a very important consideration. The inhibition activity of molecules Compound 1 and Compound 2 towards DDR2 kinase isoform was evaluated as well. Compounds 1 and 2 were found to have good and moderate SI: 23.4 and 3.6, respectively. Subsequent optimization of Compound 1 via a follow up synthesis of close structural analogues may results in an increase in selectivity. The detailed selectivity profile is presented in Fig.2. [0126] The ability of Compounds 1 and 2 to inhibit DDR1 autophosphorylation was studied in U2OS cells stimulated with collagen. The amount of activated DRR1 (Y543) was measured using Western blot analysis, the obtained data were normalized to HA and GAPDH protein levels. Dasatinib served as a positive control and showed high potency with an IC50 value of 1 nM. It was found that Compounds 1 and 2 significantly block DDR1 autophosphorylation in a dose-dependent manner with IC50 values of 10.3 and 5.8 nM, respectively (Figs. 3A-3I). These values are close to the activities observed in biochemical assays for both compounds. [0127] Antifibrotic activity of Compounds 1 and 2 was assessed using MRC-5 cell line as shown in Figs. 4A-4F. Four antibodies were used to assess the antifibrotic effect of the selected molecules in comparison with two reference compounds, SB-525334 (TGFBR1 inhibitor, IC₅₀=5-15 nM) and dasatinib (unselective kinase inhibitor, including DDR1 and DDR2, IC50~15-30 nM), which were used as a positive control, while DMSO (0.1%) was used as a negative control. The obtained Western Blot results are depicted in Fig. 4A. As shown in Figs. 4B-4C, DMSO demonstrated no effect in the test system, while the addition of TGF-b (10 ng) led to enhanced a-actin expression (up to 9.3-fold) and CTGF expression (2-fold). Unclear dose-dependent effect was observed for SB-525334, the maximum inhibition rate close to the negative control baseline was achieved at 10 µM (as for dasatinib), while at 0.5 µM we observed 2-fold reduction in a-actin expression level as compared to TGF+DMSO stimulation. In contrast, at 0.5 µM and upper concentrations dasatinib showed a significant stimulation effect. SB-525334 (10 µM) slightly reduced CTGF expression (by 1.5-fold), whereas at 0.5 µM it had no effect (Figs. 4E-4F). Dasatinib, at all the concentrations used, demonstrated only stimulation effect with no signs of inhibition. For Compound 1 the most inhibition potency against a-actin expression was achieved at 10 µM close to that determined for SB-525334 and dasatinib, while Compound 2 was less active. The maximum effect was observed at 0.37 µM (1.5- fold). Compound 1 demonstrated a robust dose-dependent effect in contrast to other molecules. In CTGF assay, Compound 1 had no inhibition potency at all the concentrations used, however, at 0.013 µM it demonstrated antifibrotic activity equal to that determined for SB-525334 at 38-fold higher concentration. Compound 2 showed the highest activity close to the negative control at 0.041 µM, and it was more active than both SB- 525334 and dasatinib. [0128] Besides the lung fibrosis model, the antifibrotic effect of the inhibitors Compound 1 and Compound 2 was also studied in a human hepatic stellate cell line LX-2 assay. Сollagen a1, a-SMA, CTGF and GAPDH were traced using Western blot analysis. DMSO and SB-525334 were used as negative and positive controls, respectively. The unshown data shows the effects of Compounds 1 and 2 on cellular fibrosis markers collagen a1, a-actin and CTGF (normalized to GAPDH) in LX-2 cells. [0129] Treatment with TGF-b induced collagen a1, a-SMA and CTGF production in LX- 2 cells. SB-525334 strongly inhibited collagen a1 and a-actin expression in the concentration range from 0.5 to 10 mM, however at lower concentrations we observed a significant decrease in activity. The data normalized to GAPDH level has clearly demonstrated, that Compound 1 strongly inhibits collagen production in a dose-dependent manner with an IC50 value of 13 nM in TGF-b stimulated LX-2 cells. The highest inhibition of a-actin production was observed at a concentration of 41 nM, while in CTGF assay Compound 1 did not show the inhibition effect. Taking into account nanomolar potency of the molecule in enzymatic, autophosphorylation and fibrotic assays, the consistent translation from the biochemical to cellular activities has been clear and firm. Noteworthy, the IC50 value of Compound 1 in LX-2 assay significantly exceeds cytotoxicity (CC50=3.3 mM) against the same cell line. It was found that Compound 2 has micromolar activity (IC50 > 10 mM) in collagen assay. At a lower concentration between 3.3 and 0.014 mM, Compound 2 did not inhibit collagen a1 production. At the concentration of 14 nM it prevented almost a half of CTGF production (43%) and slightly inhibited a-SMA (15%). However, these effects diminished with increasing concentration. Compound 2 demonstrated low cytotoxicity in LX-2 cells with a CC50 value of 7.3 mM. Based on these preliminary results, it can be tentatively concluded that novel compounds can be reasonably regarded as having good antifibrotic activity. [0130] Since Compound 2 contains an imidazolidine fragment typically unusual in drug discovery we experimentally assessed key properties for this molecule. Thus, kinetic solubility for Compound 2 at pH=7.4 was 1.09 µg/ml, while thermodynamic solubility was <0.59 µg/ml, logD7.4 was 4.07 (TFA salt), and pKa=6.99. The inhibition activity of Compounds 1 and 2 towards a small panel of key cytochrome P450 (CYP450) isoforms was also assessed in vitro (Table 1). Table 1 – IC50

[0131] It was found that Compound 1 inhibited the activity of CYP1A2 with an IC50 value of 7.36 µM, while it was inactive against CYP2C9, CYP2C₁9, CYP2D6, and CYP3A4 (IC50>50 µM). Compound 2 demonstrated higher inhibition with IC50 values of 10.6, 2.70, 6.56, 6.97, and 7.36 µM, respectively. Both compounds did not show a significant CYP450 inhibition. Their CYP450 activities are much lower than the target nanomolar potency thereby providing a good selectivity index which is comparable to that observed for many drugs including kinase inhibitors. The detailed description of the performed assay is provided in supporting information. Metabolic stability of Compound 2 (10 µM) was evaluated in human, SD rat, CD-1 mouse, and beagle dog liver microsomes (Table 2). [0132] Table 3 - Microsomal stability results summary for Compound 2

*NCF: the abbreviation of no co-factor. No NADPH regenerating system is added into NCF sample (replaced by buffer) during the 60 min-incubation, if the NCF remaining is less than 60%, then Non- NADPH dependent occurs R₂ is the correlation coefficient of the linear regression for the determination of kinetic constant (see raw data worksheet) T_1/2 is half life and CL_int(mic) is the intrinsic clearance CL_int(mic) = 0.693/half life/mg microsome protein per mL CL_int(liver) = CL_int(mic) * mg microsomal protein/g liver weight * g liver weight/kg body weight mg microsomal protein / g liver weight: 45 mg/g for 5 species Liver weight: 88 g/kg, 40g/kg, 32 g/kg, 30 g/kg and 20 g/kg for mouse, rat, dog, monkey and human. [0133] In human microsomes, Compound 2 demonstrated the half life time (t1/2) of 12.8 min and an intrinsic clearance value (human liver weight 20 g/kg, Clint/liver) of 97.3 mL/min/kg. For instance, under the same conditions, testosterone, diclofenac, and propafenone showed the following values: t1/2=15.6, 10.7, 8.3 min, and Clint/liver=79.7, 116.9, 149.7 mL/min/kg, respectively. Based on the obtained results, it is concluded that Compound 2 shows a relatively good metabolic stability as compared to the control molecules. It should be especially noted that the metabolic reaction for all the tested compounds proceeded only in the presence of NADPH regenerating system which was added into the sample (2.8% of Compound 2 was remained after 60 min-incubation), while without NADPH we observed that 88.7% of Compound 2 was unmodified based on LC/MS/MS data. The remaining amounts of testosterone, diclofenac, and propafenone were 6.9%, 1.9%, and 0.7%, respectively. This clearly indicates that Compound 2 is quite stable under the assay conditions. The detailed summary of the metabolic stability of Compound 2 as well as the control molecules is presented in supporting information. In addition, we assessed the stability of Compound 2 (10 µM) in phosphate buffer (50 mM, pH=7.4) and MOPS/EDTA (8 mM/0.2 mM, pH=7.0). The samples were incubated for 0, 120, 240, 360, and 1440 min then subjected immediately for LC/MS/MS analysis. Thus, under the assay conditions Compound 2 was very stable (the remaining amount of the compound was close to 100% at each time point, see Table 3). Table 3 - Buffer stability results for Compound 2

[0134] Additionally, the binding interactions of Compound 1 in the target kinase were analyzed using the DDR1 crystal structure (PDB code: 3ZOS) by molecular docking. The putative binding mode reveals several characteristics featuring the type II inhibition mechanism of the protein kinase (data not shown). The procedure of molecular docking was performed using Schrodinger Maestro. It was found that the N1 of the imidazopyridazine scaffold forms the conserved hinge interaction with Met704. The C(2)H of the scaffold also engages a pseudo-hydrogen bond with the backbone of Asp702. Connected via the ethynyl linker, the 6-methyl-benzoisoxazole moiety exhibits an orthogonal geometry to the hinge element, a conformation required for the DFG-out pocket. Strong contacts are established by the isoxazole via hydrogen bond with Asp784 of the DFG motif, as well as pi-cation interaction with the catalytic Lys655. Occupying the hydrophobic pocket opened up by the DFG motif, the CF₃-phenyl group of Compound 1 further stabilizes the binding complex by close contacts with Ile675, Met676, Leu679, Ile684, Ile685, Leu757 and Ile782. The exocyclic amine hydrogen bonds with Glu672, which is part of the extensive hydrogen bond and/or charge network consisting of Lys655, Glu672 and Asp784. In total, Compound 1 forms multiple hydrogen bonds, favorable charge and hydrophobic interactions with the active site residues of DDR1 kinase. The outstanding complementarity of Compound 1 to the ATP site prerequisites corroborates its potent inhibitory activity against DDR1. [0135] Cytochrome inhibition. [0136] Water used in the assay and analysis was purified by ELGA Lab purification systems. Potassium phosphate buffer (PB) in concentration of 100 mM and MgCl2 in concentration of 33 mM were used. Test compounds (Compound 1 and Compound 2) and standard inhibitors (a-naphthoflavone, sulfaphenazole, (+)-N-3-benzylnirvanol, quinidine, ketoconazole) working solutions (100×) were prepared. Microsomes were pulled out of the –80°C freezer to thaw on ice, labeled the date and put back to freezer immediately after using.20 µL of the substrates solutions were added to corresponding wells. 20 µL PB were added to Blank wells. 2 µL of the test compounds and positive control working solution were added to corresponding wells. Then, HLM working solution was prepared. 158 µL of the HLM working solution was added to all wells of incubation plate. The plate was pre-warmed for about 10 min at 37°C water bath. Then, NADPH cofactor solution was prepared. 20 µL NADPH cofactor was added to all incubation wells. The solution was mixed and incubated for 10 minutes at 37°C water bath. At the time point, the reaction was terminated by adding 400 µL cold stop solution (200 ng/mL Tolbutamide and 200 ng/mL Labetalol in ACN). The samples were centrifuged at 4000 rpm for 20 minutes to precipitate protein.200 µL supernatant was transferred to 100 µL HPLC water and shaken for 10 min. XL fit was used to plot the percent of vehicle control versus the test compound concentrations, and for non-linear regression analysis of the data. IC₅₀ values were determined using 3- or 4-parameter logistic equation. IC50 values were reported as “>50 µM” when % inhibition at the highest concentration (50 µM) is less than 50%. See Table 1. [0137] Microsomal stability. [0138] Microsomal stability of Compound 2 was accessed as follows: working solutions of Compound 2 and control compounds (testosterone, diclofenac, propafenone) were prepared. The appropriate amount of NADPH powder (b-Nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt, NADPH·4Na, Vendor: Chem- impex international, Cat.No.00616) was weighed, and diluted into MgCl2 (10 mM) solution (work solution concentration: 10 unit/mL; final concentration in reaction system is 1 unit/mL). The appropriate concentration microsome working solutions (human: HLM, Cat No.452117, Corning; SD rat: RLM, Cat No. R1000, Xenotech; CD-1 mouse: MLM, Cat No. M1000, Xenotech; Beagle dog: DLM, Cat No. D1000, Xenotech) was prepared with 100 mM potassium phosphate buffer. Cold acetonitrile (ACN) including 100 ng/mL Tolbutamide and 100 ng/mL Labetalol as internal standard (IS) were used for stop solution. 10 mL compound or control working solution/well was added to all plates (T0, T5, T10, T20, T30, T60, NCF60) except matrix blank. Dispense 80 mL/well microsome solution was added to every plate by Apricot, the mixture of microsome solution and compound were incubated at 37 ^oC for about 10 min. After pre-warming, dispense 10 mL/well NADPH regenerating system was added to every plate by Apricot to start reaction. The solution was then incubated at 37 ^oC.300 (mL/well) stop solution (cold in 4 ^oC) was added to terminate the reaction. The sampling plates were shaken for approximately 10 min. Samples were centrifuged at 4000 rpm for 20 min under 4 ^oC. While centrifuging, 8×new 96-well plate were loaded with 300 mL HPLC water, then 100 mL supernatant was transferred and mixed for LC/MS/MS. See Table 2. [0139] Buffer stability. [0140] The stability of compound 2 was accessed in phosphate buffer (pH = 7.0 and pH = 7.4). Test compounds (at 10 mM) were incubated at 25°C with 50 mM phosphate buffer, pH=7.4 and 8 mM MOPS pH 7.0, 0.2 mM EDTA, pH=7.0. Duplicate samples were used. Time samples (0, 120, 240, 360 and 1440 min) were removed and immediately mixed with cold 50% acetonitrile/water containing internal standard (IS). Curcumin was used as positive control in this assay at neutral-basic condition. Samples were analyzed by LC/MS/MS, disappearance of test compound was assessed based on peak area ratios of analyte/IS (no standard curve). See Table 3. [0141] Biological studies. [0142] Biochemical assay. [0143] The experimental procedures were performed by Eurofins. The activity of the molecules against hDDR1 and hDDR2 kinases was assessed using KinaseProfiler (Eurofins Pharma Discovery Services. Available at: eurofinsdiscoveryservices.com/catalogmanagement/viewitem/DDR1-Human-TK-Kinase- Enzymatic-Radiometric-Assay-10-uM-ATP-KinaseProfiler/14-942KP10. (Accessed: 30th October 2018). [0144] The enzyme sample was incubated with 8 mM MOPS buffer (pH = 7.0), 0.2 mM EDTA, 250 µM target protein hDDR1 and hDDR2 kinases, 10 mM Magnesium acetate/Manganese chloride, respectively, and [ɣ-³³P] - ATP. The enzymatic reaction processed in the presence of Mg²⁺ cations and ATP at room temperature for 40 minutes and terminated by addition of phosphoric acid. The reaction mixture (10 µL) was spotted onto a P30 filtermat and washed four times using 0.425% phosphoric acid and once with methanol. All the compounds were prepared in 100% DMSO. Staurosporine was used as a reference inhibitor and was added to each plate at an estimated concentration resulted in complete inhibition. The biological evaluation of selectivity against non-target kinases was performed in Dundee Eurofins, using Scan Max Delta Panel [10µM ATP] KinaseProfiler (Eurofins Pharma Discovery Services. Available at: eurofinsdiscoveryservices.com/catalogmanagement/viewitem/scanMAX-Delta-Panel- 10uM-ATP/50-100KP10. (Accessed: 30th October 2018). [0145] Auto-phosphorylation. [0146] Human DDR1b gene with HA-tag was cloned into pCMV Tet-On vector (Clontech) and stable inducible cell lines established in U2OS were used for the IC50 test. The cells were seeded in 12-well plates and DDR1b expression was induced with 10 µg/ml doxycycline (Selleckchem#S4163) for 48 h at 37^oC in a humidity controlled incubator with 5% CO2 prior to DDR1 activation by rat tail collagen I (sigma#11179179001). The cells were detached with trypsinization and transferred to a 15-ml tube. Then, after being pre-treated with compound for 0.5 h, the cells were treated with compounds in the presence of 10 µg/ml rat tail collagen I for 1.5 h at 37^oC. At the end of the treatment, each sample was washed with cold PBS one time and lysed in RIPA buffer with protease and phosphatase inhibitors (Sigma#0278, Sigma#P5726 and Sigma#P0044) for 20 min at 4℃. The lysates were cleared by centrifugation and the supernatants were subject to Western blot analysis for the activated human DDR1b (Y513) (Cell Signaling#14531S), total DDR1b (HA-tag, sigma#H9658) after stripping, and GAPDH. The integrated intensity of each band was quantified and the IC50 values of the evaluated compounds were calculated on a 10-point 3-fold dilution series. [0147] MRC-5 Fibrosis Assay. [0148] MRC-5 cells were grown in Minimum Essential Medium Eagle (Sigma, M2279) supplied with 1% MEM Non-Essential Amino Acids (Invitrogen, 11140-050), 10% fetal bovine serum (Hyclone, SV30087.03), Penicillin (100 U/mL)-streptomycin (100 µg/mL) (Millipore, TMS-AB2-C) and 2 mM L-Glutamine (Invitrogen, 25030-001). After the cells grew in 12-well plates for 24 h, the cell culture medium was changed to the same as above except using 2% fetal bovine serum. After 20 h growth in the reduced serum medium, the cells were treated with indicated doses of compounds for 30 minutes. Subsequently, the cells were stimulated with 10 ng/mL TGF-b (R&D Systems, 240-B- 002) for 48 or 72 hours. The cells were rinsed twice with DPBS before being harvested with 100 mL RIPA buffer (Sigma, R0278) supplemented with protease inhibitor cocktail (Roche, 04693132001) at 4 ^oC. The total protein content in each sample was quantified using BCA Protein Assay Kit (Pierce™, 23227) and equal amount of total protein of each sample was loaded onto WES Automatic Western Blot System (ProteinSimple, Bio- techne) following the manufacturer’s instruction. Antibodies used were mouse anti-a- Actin (SPM332) (sc-365970) and mouse anti-CTGF (E5) (sc-365970), from Santa Cruz Biotechnologies; and mouse anti-GAPDH (6C5) (EMD Millipore, MAB374). [0149] LX-2 Fibrosis Assay. [0150] Human hepatic stellate cells LX-2 were grown in DMEM (Invitrogen, 11960) supplied with 1% MEM Non-Essential Amino Acids (Invitrogen, 11140-050), 2% fetal bovine serum (Hyclone, SV30087.03), Penicillin (100 U/mL)-streptomycin (100 mg/mL) (Millipore, TMS-AB2-C) and 2 mM L-Glutamine (Invitrogen, 25030-001). After the cells grew in 12-well plates for 24 h, the cell culture medium was changed to the same as above except using 0.4% fetal bovine serum. After 20 h growth in the reduced serum medium, the cells were treated with indicated doses of compounds for 30 minutes. Subsequently, the cells were stimulated with 4 ng/mL TGF-b (R&D Systems, 240-B-002) for 48 h. The cells were rinsed twice with DPBS before being harvested with 100 mL RIPA buffer (Sigma, R0278) supplemented with protease inhibitor cocktail (Roche, 04693132001) at 4°C. The total protein in each sample was quantified using BCA Protein Assay Kit (Pierce™, 23227) and equal amount of total protein of each sample was subject to Western blot analysis. Antibodies used were mouse anti-a-Actin (SPM332) (sc- 365970), mouse anti-CTGF (E5) (sc-365970), and mouse anti-collagen a1 (3G3) (sc- 293182), from Santa Cruz Biotechnologies; and mouse anti-GAPDH (6C5) (EMD Millipore, MAB374). [0151] Cytotoxicity. [0152] LX-2 cells were seeded into 96 well plates in the presence of a compound and allowed to grow for 72 h before CellTiter-Glo® Luminescent Cell Viability Assay was carried out according the manufacturer’s instruction. Cytotoxicity (CC₅₀) was calculated on a 10 dose 3-fold compound dilution series using GraphPad Prism software. [0153] Physicochemical properties of Compounds 1 and 2 are shown in Table 4. Table 4

*Predicted **LE = 1.4*(pIC50)/N, N – number of heavy atoms [0154] Full mouse PK study results for 10mg/kg Compound 1 IV administration. Formulation: 5 mg/mL in NMP/PEG400/H20=1：7：2, clear solution are shown in Table 5. Table 5

ND = Not determined (Parameters not determined due to inadequately defined terminal elimination phase) BQL = Below the lower limit of quantitation (LLOQ) If the adjusted rsq (linear regression coefficient of the concentration value on the terminal phase) is less than 0.9, T1/2 might not be accurately estimated. If the % AUC_Extra > 20%, AUC_0-inf, Cl, MRT_0-inf and Vd_ss might not be accurately estimated. If the % AUMC_Extra > 20%, MRT_0-inf and Vd_ss might not be accurately estimated. The adjusted linear regression coefficient of the concentration value on the terminal phase is less than 0.9, T1/2 might not be accurately estimated. a: Bioavailability (%) was calculated using AUC_0-inf (% AUC_Extra < 20%) or AUC_0-last (% AUC_Extra > 20%) with administered dose [0155] Full mouse PK study results for 15mg/kg Compound 1 PO administration. Formulation: 3 mg/mL in NMP/PEG400/H20=1：7：2, clear solution are shown in Table 6. Table 6

ND = Not determined (Parameters not determined due to inadequately defined terminal elimination phase) BQL = Below the lower limit of quantitation (LLOQ) If the adjusted rsq (linear regression coefficient of the concentration value on the terminal phase) is less than 0.9, T1/2 might not be accurately estimated. If the % AUC_Extra > 20%, AUC_0-inf, Cl, MRT_0-inf and Vd_ss might not be accurately estimated. If the % AUMC_Extra > 20%, MRT_0-inf and Vd_ss might not be accurately estimated. The adjusted linear regression coefficient of the concentration value on the terminal phase is less than 0.9, T1/2 might not be accurately estimated. a: Bioavailability (%) was calculated using AUC_0-inf (% AUC_Extra < 20%) or AUC_0-last (% AUC_Extra > 20%) with administered dose [0156] Chemical Synthesis [0157] NMR spectra were recorded on a Bruker 400 (400 MHz ¹H, 100 MHz ¹³C, 400 MHz ¹⁹F). Proton chemical shifts are reported in ppm (d) referenced to the NMR solvent. Data are reported as follows: chemical shifts, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet; coupling constant(s) in Hz; integration). NMR data were collected at 25°C. Analytical TLC was performed on 0.25 mm silica gel 60-F plates. Visualization was accomplished with UV light and I₂. Flash chromatography was performed using ISCO Combiflash. Reverse phase chromatography was performed using ISCO Combiflash (column: C₁8 (20-35mm)). Acidic condition: Mobile Phase A: 0.1% FA in water (v/v). Mobile Phase B: 0.1% FA in acetonitrile (v/v). Basic condition: Mobile Phase A: 0.1% NH₃·H₂O in water (v/v). Mobile Phase B: 0.1% in Acetonitrile(v/v). LC/MS spectra were obtained using Agilent 1200\G1956A or SHIMADZU LCMS-2020. Standard LC/MS conditions were as follows (running time 1.55 minutes): Acidic condition: Mobile Phase A: 0.0375% TFA in water (v/v). Mobile Phase B: 0.01875% TFA in acetonitrile (v/v); Column: Kinetex EVO C₁830*2.1mm, 5 mm. Basic condition: Mobile Phase A: 0.025% NH₃·H₂O in water (v/v). Mobile Phase B: Acetonitrile; Column: Kinetex EVO C₁82.1X30mm, 5 mm. The gradient ran from 5% to 95% mobile phase B or 0 to 60% mobile phase B. HPLC spectra were obtained using SHIMADZU LC-20AB, Standard HPLC conditions were as follows (running time 4 minutes): Acidic condition: Mobile Phase A: 0.0375% TFA in water (v/v). Mobile Phase B: 0.01875% TFA in acetonitrile (v/v); Column: Kinetex EVO C₁8 50*4.6mm, 5 mm. Basic condition: Mobile Phase A: 0.025% NH₃·H₂O in water (v/v). Mobile Phase B: Acetonitrile; Column: XBridge C₁82.1X50mm, 5 mm. The gradient ran from 5% to 95% mobile phase B or 0 to 60% mobile phase B. The final product was purified by Prep- HPLC using Gilson 281. [0158] Chemical Synthesis of INS015_030 (Compound 3) [0159] The synthesis of INS015_030 (Compound 3) is shown as Scheme 1 in Fig. 5, and described in connection to the reagents and products below. (3-bromo-4-methylphenyl)methanamine

[0160] To a solution of 3-bromo-4-methylbenzamide (12 g, 56.06 mmol, 1 eq) in THF (100 mL) was added BH₃-Me₂S (10M, 14.01 mL, 2.5 eq) at 0°C, and then the mixture was heated up to 70°C and stirred for 16 h. Then the mixture was cooled to 25 °C and quenched with MeOH, and then adjusted the pH=2 with HCl/EA (4M). The mixture was heated to 80 °C and stirred for 2 h. TLC (PE/EA=1/1) showed starting material (Rf=0.50) was consumed completely and new point (Rf=0.0) was formed. The mixture was washed with 1N NaOH solution to adjust the pH=10 and extracted with EA (50 mL*3). The combined organic layers were washed with brine (50 mL*2), dried over Na₂SO₄, filtered and concentrated in vacuum to get the residue. The residue was used into next step without purification. (3-bromo-4-methylphenyl)methanamine (10 g, 49.98 mmol, 89.16% yield) was obtained as a white solid. LCMS: Retention time: 0.913 min, [M+H]⁺ calcd. for C₈H₁₀BrN 200.0; found 200.1. [0161] N-(3-bromo-4-methylbenzyl)-2-(3-fluorophenyl)acetamide

[0162] To a solution of 2-(3-fluorophenyl)acetic acid (2.3 g, 14.92 mmol, 1.0 eq) and (3- bromo-4-methylphenyl)methanamine (3.6 g, 17.99 mmol, 1.21 eq) in DCM (20 mL) was added Et3N (4.53 g, 44.77 mmol, 6.23 mL, 3 eq) and T3P (7.12 g, 22.38 mmol, 6.66 mL, 1.5 eq) .The reaction mixture was stirred at 30°C for 2 h. LCMS showed desired MS. The mixture was washed with water (30 mL) and extracted with DCM (50 mL*3). The combined organic layers were washed with brine (30 mL*2), dried over Na2SO4, filtered and concentrated in vacuum to get the residue confirmed by ¹H-NMR. The crude product N-(3-bromo-4-methylbenzyl)-2-(3-fluorophenyl)acetamide (4 g, 11.90 mmol, 79.73% yield) as white solid was used into the next step without further purification.. ¹H-NMR (400MHz, METHANOL-d4) d = 7.40 (d, J=1.2 Hz, 1H), 7.31 (dt, J=6.1, 7.9 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 7.10 (d, J=7.7 Hz, 2H), 7.05 (dd, J=2.1, 9.9 Hz, 1H), 6.98 (dt, J=2.1, 8.6 Hz, 1H), 4.30 (s, 2H), 3.55 (s, 2H), 2.34 (s, 3H). LCMS: Retention time: 0.926 min, [M+H]⁺ calcd. for C₁6H15BrFNO 337.0; found 337.7. [0163] N-(3-(1H-indazol-5-yl)-4-methylbenzyl)-2-(3-fluorophenyl)acetamide (INS015_030) (Compound 3)

[0164] To a mixture of N-(3-bromo-4-methylbenzyl)-2-(3-fluorophenyl)acetamide (2 g, 5.95 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (2.32 g, 9.52 mmol, 1.6 eq) and K2CO3 (2.47 g, 17.85 mmol, 3 eq) in H₂O (2 mL) and dioxane (20 mL) was added Pd(dppf)Cl₂ (217.64 mg, 297.44 µmol, 0.05 eq) Degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100°C for 16 hr under N₂ atmosphere. TLC (PE/EA=1/2) showed starting material (Rf=0.60) was consumed completely and new main point (Rf=0.20) was formed. The mixture was washed with water (20 mL) and extracted with EA (30mL*3). The combined organic layers were washed with brine (20 mL*2), dried over Na₂SO₄, filtered and concentrated in vacuum to get the crude product confirmed by LCMS. The crude product (4.25 g, crude) was obtained without purification. 250mg of the crude product was purified by prep-HPLC (column: Waters Xbridge 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 52%-82%,10min) and lyophilized to get the product. N-(3-(1H-indazol- 5-yl)-4-methylbenzyl)-2-(3-fluorophenyl)acetamide (120.68 mg, 320.83 µmol, 5.39% yield, 99.275% purity) was obtained as a white solid. HPLC: Retention time: 2.271 min. 1H-NMR (400MHz, METHANOL-d4) d = 8.06 (s, 1H), 7.62 - 7.53 (m, 2H), 7.31 - 7.17 (m, 3H), 7.15 - 7.01 (m, 4H), 6.89 (dt, J=2.0, 8.6 Hz, 1H), 4.37 (s, 2H), 3.53 (s, 2H), 2.21 (s, 3H). ¹⁹F NMR (400MHz, METHANOL-d4) d =115.38. ¹³C NMR (400MHz, METHANOL-d4) d= 171.88, 164.02, 161.60, 142.23, 139.27, 138.30, 138.21, 135.91, 134.62, 134.22, 133.69, 130.07, 129.81, 129.73, 128.77, 128.36, 125.94, 124.57, 124.53, 122.99, 120.26, 115.53, 115.31, 113.28, 113.06,109.24, 42.50, 42.13, 42.11, 18.95. LCMS: Retention time: 0.973 min, [M+H]⁺ calcd. for C₂3H20FN3O 374.2; found 374.3. [0165] Chemical Synthesis of INS015_032 (Compound 4) [0166] The synthesis of INS015_032 (Compound 4) is shown as Scheme 2 in Fig. 6, and described in connection to the reagents and products below. [0167] 4-Iodo-5-methyl-2-nitroaniline

[0168] 5-Methyl-2-nitroaniline (1 g, 6.57 mmol, 1 eq) and NIS (1.40 g, 6.24 mmol, 0.95 eq) in AcOH (60 mL) was refluxed at 120°C for 70 min. TLC (petroleum ether: ethyl acetate =10:1, twice, Rf= 0.55) showed 5-methyl-2-nitroaniline was consumed and a new spot was detected. The reaction mixture was cooled to room temperature and poured into ice-water (120 mL). The precipitate was collected by filtration. The filtered cake was washed with water (50 mL), petroleum ether (50 mL) and dried under the reduced pressure. 4-Iodo-5-methyl-2-nitroaniline (1.1 g, 3.96 mmol, 60.19% yield) was obtained as red solid. ¹H-NMR (400MHz, DMSO-d6) ppm= 8.28 (s, 1H), 7.44 (br s, 2H), 6.96 (s, 1H), 2.28 (s, 3H). [0169] 4-Iodo-5-methylbenzene-1,2-diamine

[0170] A suspension of 4-iodo-5-methyl-2-nitroaniline (1.1 g, 3.96 mmol, 1 eq), Fe (883.73 mg, 15.82 mmol, 4 eq) and NH4Cl (2.12 g, 39.56 mmol, 10 eq) in EtOH (100 mL) and H₂O (20 mL) was stirred at 80°C for 3 h. The reaction mixture was cooled to room temperature and filtered through the celite. The filtrate was concentrated; the residue was dissolved in ethyl acetate (30 mL). The mixture was washed with water (10 mL*2), brine (10 mL) and dried over Na2SO4. After filtration and concentration, 4- iodo-5-methylbenzene-1,2-diamine (1.24 g, crude) was obtained as gray solid and was confirmed by ¹H-NMR. The crude product was used to the next step directly. ¹H-NMR (400MHz, METHANOL-d4) ppm = 6.90 (s, 1H), 6.47 (s, 1H), 4.63 (br s, 4H), 2.11 (s, 3H). [0171] 5-Iodo-6-methyl-1H-benzo[d]imidazole-2-thiol

[0172] A solution of 4-iodo-5-methylbenzene-1,2-diamine (1.24 g, 5.00 mmol, 1 eq), CS2 (3.81 g, 49.99 mmol, 3.02 mL, 10 eq) and NaOH (399.87 mg, 10.00 mmol, 2 eq) in EtOH (12 mL) and H₂O (3 mL) was stirred at 80°C for 6 h. LCMS showed 4-iodo-5- methylbenzene-1,2-diamine was consumed and the desired mass was detected. The reaction mixture was concentrated under the reduced pressure, the residue was dissolved in saturated NH₄Cl (20 mL). The precipitate was collected by the filtration. 5-Iodo-6- methyl-1H-benzo[d]imidazole-2-thiol (0.98 g, 3.38 mmol, 67.57% yield, 100% purity) was obtained as gray solid. ¹H-NMR (400 MHz, DMSO-d6) ppm = 7.51 (s, 1H), 7.13 (s, 1H), 2.39 (s, 3H). LCMS: Retention time: 0.813 min, [M+H]⁺ calcd. for C₈H₇IN₂S 290,9; found 290.9. [0173] 2-Bromo-5-iodo-6-methyl-1H-benzo[d]imidazole

[0174] A suspension of 5-iodo-6-methyl-1H-benzo[d]imidazole-2-thiol (0.5 g, 1.72 mmol, 1 eq) in HBr (29.80 g, 121.54 mmol, 20 mL, 33% in AcOH, 70.52 eq) was cooled to 0°C and Br2 (1.10 g, 6.89 mmol, 355.37 µL, 4 eq) in AcOH (5 mL) was added slowly dropwise. The mixture was stirred for 2 h at 0°C. LCMS showed 5-iodo-6-methyl-1H- benzo[d]imidazole-2-thiol was consumed and a major peak with desired MS was detected. Water (100 mL) was added to the mixture slowly and the solid was precipitated. The solid was obtained by filtration. The solid was washed with water (20 mL) and EA (20 mL). 2-Bromo-5-iodo-6-methyl-1H-benzo[d]imidazole (380 mg, 1.13 mmol, 65.44% yield) was obtained as gray solid. ¹H-NMR (400 MHz, MeOD) ppm = 8.24 - 8.13 (m, 1H), 7.66 (d, J = 4.0 Hz, 1H), 2.61 (s, 3H). LCMS: Retention time: 0.886 min, [M+H]⁺ calcd. for C8H6BrIN2337.8; found 337.0 [0175] 2-Bromo-6-methyl-5-(pyrimidin-5-ylethynyl)-1H-benzo[d]imidazole

[0176] To the solution of 2-bromo-5-iodo-6-methyl-1H-benzo[d]imidazole (380 mg, 1.13 mmol, 1 eq) and 5-ethynylpyrimidine (234.82 mg, 2.26 mmol, 2 eq) in THF (6 mL) was added Pd(PPh3)2Cl2 (79.16 mg, 112.77 µmol, 0.1 eq), CuI (21.48 mg, 112.77 µmol, 0.1 eq) and TEA (1.14 g, 11.28 mmol, 1.57 mL, 10 eq). The mixture was stirred at 28°C for 2 h. LCMS showed 2-bromo-5-iodo-6-methyl-1H-benzo[d]imidazole remained and desired MS was detected. The reaction mixture was quenched by addition water 10 mL, and then extracted with EA (10 mL*3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1 to 1:1) to give 2-bromo-6-methyl-5-(pyrimidin-5-ylethynyl)-1H- benzo[d]imidazole (150 mg, 411.39 µmol, 36.48% yield, 85.885% purity) as yellow solid. LCMS: Retention time: 0.797 min, [M+H]⁺ calcd. for C₁₄H₉BrN₄314.0; found 315.1. [0177] 3-(6-methyl-5-(pyrimidin-5-ylethynyl)-1H-benzo[d]imidazol-2-yl)-5- (trifluoromethyl)benzaldehyde

[0178] A mixture of 2-bromo-6-methyl-5-(pyrimidin-5-ylethynyl)-1H-benzo[d]imidazole (150 mg, 479.00 µmol, 1 eq), 3-formyl-5-(trifluoromethyl)phenylboronic acid (156.59 mg, 718.50 µmol, 1.5 eq), Pd(dppf)Cl₂ (35.05 mg, 47.90 µmol, 0.1 eq), and K₂CO₃ (132.40 mg, 958.00 µmol, 2 eq) in dioxane (2 mL) and H₂O (1 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 80°C for 16 hr under N2 atmosphere. LCMS showed 2-bromo-6-methyl-5-(pyrimidin-5-ylethynyl)-1H- benzo[d]imidazole was consumed and desired MS was detected. The reaction mixture was quenched by adding water 5 mL, and then extracted with EA (5 mL*3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The product was used for next step without purification. 3-(6-methyl-5-(pyrimidin-5-ylethynyl)-1H-benzo[d]imidazol-2-yl)-5- (trifluoromethyl)benzaldehyde (180 mg, crude) was obtained as black brown solid. LCMS: Retention time: 1.026 min, [M+H]⁺ calcd. for C₂₂H₁₃F₃N₄O 407.1; found 407.3. [0179] N,N-Dimethyl-1-(3-(6-methyl-5-(pyrimidin-5-ylethynyl)-1H- benzo[d]imidazol-2-yl)-5-(trifluoromethyl)phenyl)methanamine INS015_032

[0180] 3-(6-methyl-5-(pyrimidin-5-ylethynyl)-1H-benzo[d]imidazol-2-yl)-5- (trifluoromethyl)benzaldehyde (180 mg, 442.96 µmol, 1 eq) and dimethyl amine (72.24 mg, 885.92 µmol, 81.17 µL, 2 eq, HCl) were dissolved in MeOH (2 mL). TEA (89.65 mg, 885.92 µmol, 123.31 µL, 2 eq) was added to the mixture. The mixture was stirred at 0°C for 30 minutes. NaBH₃CN (55.67 mg, 885.92 µmol, 2 eq) and AcOH (79.80 mg, 1.33 mmol, 76.00 µL, 3 eq) were added to the mixture. The mixture was stirred at 0°C for another 30 minutes. LCMS showed 3-(6-methyl-5-(pyrimidin-5-ylethynyl)-1H- benzo[d]imidazol-2-yl)-5-(trifluoromethyl)benzaldehyde was consumed and desired MS was detected. The mixture was quenched with by adding water (1 mL). The mixture was purified by Prep-HPLC (column: Luna C₁8 150*25 5u; mobile phase: [water (0.075%TFA)-ACN]; B%: 18%-48%, 9min). N,N-Dimethyl-1-(3-(6-methyl-5- (pyrimidin-5-ylethynyl)-1H-benzo[d]imidazol-2-yl)-5- (trifluoromethyl)phenyl)methanamine (34.14 mg, 61.21 µmol, 13.82% yield, 98.517% purity, TFA) was obtained as yellow solid.¹H-NMR (400 MHz, METHANOL-d4) ppm= 9.15 - 9.02 (m, 1H), 9.00 - 8.85 (m, 2H), 8.58 - 8.50 (m, 2H), 8.11 (s, 1H), 7.93 -7.75 (m, 1H), 7.67 - 7.56 (m, 1H), 4.59 - 4.53 (m, 2H), 3.01 - 2.92 (m, 6H), 2.71 - 2.58 (m, 3H). LCMS: Retention time: 0.797 min, [M+H]⁺ calcd. for C₂₄H20F3N5436.2; found 436.2. [0181] Chemical Synthesis of INS015_036 (Compound 1) [0182] The synthesis of INS015_036 (Compound 1) is shown as Scheme 3 in Fig. 7, and described in connection to the reagents and products below. [0183] 2-Fluoro-3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide

[0184] To a solution of 2-fluoro-3-iodo-4-methylbenzoic acid (500 mg, 1.79 mmol, 1 eq) in DMF (6 mL) was added HATU (814.68 mg, 2.14 mmol, 1.2 eq) and DIEA (692.29 mg, 5.36 mmol, 933.00 uL, 3 eq). The mixture was stirred at 25°C for 30 min. Then 3- (trifluoromethyl)aniline (316.46 mg, 1.96 mmol, 245.31 uL, 1.1 eq) was added to the mixture. The mixture was stirred at 25°C for 16 h. TLC (PE: EA=5:1, Rf = 0.8) and LCMS showed a major peak with desired mass was detected. To the mixture was added water (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum) to afford 2-fluoro-3-iodo-4-methyl- N-(3-(trifluoromethyl)phenyl)benzamide (500 mg, 1.18 mmol, 66.18% yield) as a white solid. LCMS: Retention time: 1.085 min, [M+H]⁺ calcd. for C₁5H10F4INO 424.0; found 424.0. [0185] 2-Fluoro-3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzothioamide

[0186] A solution of 2-fluoro-3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (500 mg, 1.18 mmol, 1 eq) in toluene (6 mL) was added LAWESSON'S REAGENT (477.93 mg, 1.18 mmol, 1 eq). The mixture was stirred at 100°C for 16 h. LCMS (the mixture was stirred at 100°C for 3 h) showed most of starting material was consumed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove toluene. The residue was diluted with DCM 3 mL. The solution was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford 2- fluoro-3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzothioamide (400 mg, 901.62 µmol, 76.30% yield, 99% purity) as a yellow solid. ¹H-NMR (400MHz, DMSO-d₆) ppm = 12.30 (s, 1H), 8.45 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.74 - 7.63 (m, 2H), 7.52 (t, J=7.6 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 2.48 (s, 3H). LCMS: Retention time: 1.134 min, [M+H]⁺ calcd. for C₁5H10F4INS 440.0; found 440.0. [0187] 2-Fluoro-N'-hydroxy-3-iodo-4-methyl-N-(3- (trifluoromethyl)phenyl)benzimidamide

[0188] To a solution of 2-fluoro-3-iodo-4-methyl-N-(3- (trifluoromethyl)phenyl)benzothioamide (400 mg, 910.73 µmol, 1 eq) in EtOH (5 mL) was added NH₂OH^.HCl (2.53 g, 18.21 mmol, 50% purity, 20 eq). The mixture was stirred at 25°C for 2 h. LCMS showed a major peak with desired mass was detected. The mixture was diluted with ACN (1 mL). The solution was purified by reversed-phase column (0.1% NH₃•H₂O) to give 2-fluoro-N'-hydroxy-3-iodo-4-methyl-N-(3- (trifluoromethyl)phenyl)benzimidamide (350 mg, 772.44 µmol, 84.82% yield, 96.7% purity) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆) ppm = 10.75 (s, 1H), 8.90 (s, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.30 - 7.20 (m, 2H), 7.11 (br d, J=8.0 Hz, 1H), 6.96 - 6.86 (m, 2H), 2.42 (s, 3H). LCMS: Retention time: 1.010 min, [M+H]⁺ calcd. for C₁5H11F4IN2O 439.0; found 439.0. [0189] 7-Iodo-6-methyl-N-(3-(trifluoromethyl)phenyl)benzo[d]isoxazol-3-amine

[0190] To a solution of 2-fluoro-N'-hydroxy-3-iodo-4-methyl-N-(3- (trifluoromethyl)phenyl)benzimidamide (160 mg, 365.17 µmol, 1 eq) in NMP (5 mL) was added t-BuOK (45.07 mg, 401.68 µmol, 1.1 eq). The mixture was stirred at 100°C for 0.5 h. LCMS showed a major peak with desired mass. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (8 mL*3). The combined organic phase was concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether gradient @ 40 mL/min) to afford 7-iodo-6-methyl-N-(3- (trifluoromethyl)phenyl)benzo[d]isoxazol-3-amine (130 mg, 301.57 µmol, 82.58% yield, 97% purity) as a yellow solid.. ¹H-NMR (400MHz, DMSO-d₆) ppm = 9.96 (s, 1H), 8.09 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.90 (br d, J=8.4 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.38 - 7.31 (m, 2H), 2.55 (s, 3H). LCMS: Retention time: 1.144 min, [M+H]⁺ calcd. for C₁5H10F3IN2O 419.0; found 419.0 [0191] 7-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-6-methyl-N-(3- (trifluoromethyl)phenyl)benzo[d]isoxazol-3-amine (INS015_036)

[0192] A mixture of 7-iodo-6-methyl-N-(3-(trifluoromethyl)phenyl)benzo[d]isoxazol-3- amine (101 mg, 241.54 µmol, 1 eq), XPhos Pd G3 (122.67 mg, 144.92 µmol, 0.6 eq), Cs₂CO₃ (204.62 mg, 628.00 µmol, 2.6 eq) and CuI (23.00 mg, 120.77 µmol, 0.5 eq) in anhydrous ACN (2.5 mL). 3-Ethynylimidazo[1,2-b]pyridazine (55.32 mg, 386.46 µmol, 1.6 eq) was then added and the reaction mixture was stirred for 2 h at 80°C under nitrogen atmosphere. LCMS showed desired mass. Reaction mixture was poured into water (20 mL), extracted with ethyl acetate (8 mL*3). The combined organic phase was concentrated in vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 40 mL/min). LCMS and HPLC showed the purity about 75%. After concentration, the residue was purified by prep-HPLC (neutral condition) and lyophilization to afford 7-(Imidazo[1,2-b]pyridazin-3-ylethynyl)-6-methyl- N-(3-(trifluoromethyl)phenyl)benzo[d]isoxazol-3-amine (14.11 mg, 32.56 µmol, 13.48% yield, 100% purity) as yellow solid.¹H-NMR (400 MHz, DMSO-d6) ppm= 10.04 (s, 1H), 8.79 - 8.71 (m, 1H), 8.31 - 8.26 (m, 2H), 8.12 (s, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.92 (br d, J=8.4 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.35 (br d, J=7.6 Hz, 1H), 2.70 (s, 3H). LCMS: Retention time: 1.051 min, [M+H]⁺ calcd. for C₂₃H₁₄F₃N₅O 434.1; found 434.2. [0193] Chemical Synthesis of INS015_037 (Compound 2) [0194] The synthesis of INS015_037 (Compound 2) is shown as Scheme 4 in Fig. 8, and described in connection to the reagents and products below. [0195] 3-(3-(trifluoromethyl)benzamido)benzoic acid

[0196] To a solution of 3-aminobenzoic acid (1.17 g, 5.61 m mol, 829.48 u L, 1 eq) in DCM (5 mL) 3-(trifluoromethyl)benzoyl chloride (1 g, 7.29 mmol, 1.3 eq) was added at 0°C. And then was added DIEA (3.62 g, 28.04 mmol, 4.88 mL, 5 eq). The mixture was stirred at 25°C for 16 h. LCMS showed the 3-aminobenzoic acid was consumed and the desired MS (M+1, 310.1) was detected. The reaction mixture was concentrated under vacuum, and was poured into H₂O (30 mL) and extracted with MTBE (15 mL*3). And then was added citric acid to pH=3. The mixture was filtered and concentrated to give a white solid. The residue was used into the next step without purification. 3-(3-(trifluoromethyl)benzamido)benzoic acid (1.3 g, 4.20 mmol, 74.97% yield) as a white solid.¹H-NMR (400MHz, DMSO-d₆) ppm = 10.72 - 10.45 (m, 1H), 8.51 - 8.12 (m, 4H), 8.07 (td, J=1.1, 7.1 Hz, 1H), 7.97 (br d, J=7.7Hz, 1H), 7.83 - 7.67 (m, 2H), 7.59 - 7.44 (m, 1H). LCMS: Retention time: 0.918 min, [M+H]⁺ calcd. for C₁5H10F3NO3310.0; found 310.1. [0197] Tert-butyl 3-benzylimidazolidine-1-carboxylate

[0198] To a solution of N¹-benzylethane-1,2-diamine (2 g, 13.31 mmol, 2.00 mL, 1 eq) and MgSO4 (6.41 g, 53.25 mmol, 4 eq) , K2CO3 (5.52 g, 39.94 mmol, 3 eq) and PARAFORMALDEHYDE (400 mg) in CHCl₃ (50 mL) was stirred at 25°C for 18 h. (Boc)2O (2.91 g, 13.31 mmol, 3.06 mL, 1 eq) was added and the mixture was stirred at 25°C for a further 18 h. LCMS showed the starting material was consumed and the desired MS (M+1,263.3) was detected. The reaction mixture was poured into H₂O (40 mL) and extracted with EA (20 mL*3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 35 m L/min) to give a spot (R f=0.4) as a white oil. Tert-butyl 3-benzylimidazolidine-1-carboxylate (2.8 g, 10.67 mmol, 80.16% yield) as a white oil was obtained. ¹H-NMR (400 MHz, CHLOROFORM-d) d= 7.38 - 7.28 (m, 4H), 3.99 (br d, J=19.6 Hz, 2H), 3.64 (s, 2H), 3.43 (td, J=6.2, 18.6Hz, 2H), 2.83 (t, J=6.4 Hz, 2H), 1.45 (s, 9H). LCMS: Retention time: 1.025 min, [M+H]⁺ calcd. for C₁₅H₂₂N₂O₂263.2; found 263.3 [0199] Tert-butyl imidazolidine-1-carboxylate

[0200] To a solution of tert-butyl 3-benzylimidazolidine-1-carboxylate (1 g, 3.81 mmol, 1 eq) in EtOH (5 mL) was added Pd/C (200 mg, 20% purity). The mixture was stirred at 25°C for 16 h under H2 (15 psi). TLC (PE:EA=1:1) showed that most of starting material (R f=0.5) was consumed and a large new spot (R f=0.3) was formed. The reaction mixture was filtered and concentrated. The residue was used into the next step without purification. The crude product tert-butyl imidazolidine-1-carboxylate (600 mg, 3.48 m mol, 91.40% yield) as a white oil was obtained.¹H-NMR (400 MHz, CHLOROFORM-d) ppm = 4.32 - 4.06 (m, 2H), 3.26 (br s, 2H), 3.20 - 3.05 (m, 2H), 2.05 - 2.00 (m, 1H), 1.49- 1.44 (m, 9H). [0201] Tert-butyl 3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazolidine-1-carboxylate

[0202] A mixture of tert-butyl imidazolidine-1-carboxylate (300 mg, 1.74 mmol, 1 eq), 4- bromo-1H-pyrrolo[2,3-b]pyridine (514.82 mg, 2.61 mmol, 1.5 eq) , Cs2CO3 (1.14 g, 3.48 mmol, 2 eq) , RuPhos Pd G3 (72.84 mg, 87.10 µmol, 0.05 eq) in THF (3 mL) and t- BuOH (3 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 80°C for 16 h under N2 atmosphere. LCMS showed the starting material was consumed and the desired MS (M+1,289.3) was detected. The reaction mixture was poured into H₂O (30 mL) and extracted with EA (20 mL*3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; X g SepaFlash® Silica Flash Column, Eluent of 0~80% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give a spot (R f=0.5) as a yellow solid. LCMS showed the yellow solid tert-butyl 3-(1H- pyrrolo[2,3-b]pyridin-4-yl)imidazolidine-1-carboxylate (120 mg, 416.17 µmol, 23.89% yield, N/A purity) the desired MS was detected. LCMS: Retention time: 0.961 min, [M+H]⁺ calcd. for C₁₅H₂₀N₄O₂289.2; found 289.3. [0203] 4-(Imidazolidin-1-yl)-1H-pyrrolo[2,3-b]pyridine

[0204] A solution of tert-butyl 3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazolidine-1- carboxylate 346.81 µmol, 1 eq) in TFA (1 mL) and DCM (3 mL) was stirred at 25°C for 0.5 h. LCMS showed the starting material was consumed and the desired MS (M+1,189.3) was detected. The reaction mixture was concentrated under vacuum. The residue was used into the next step without purification. The crude product 4- (imidazolidin-1-yl)-1H-pyrrolo[2,3-b]pyridine (90 mg, 297.77 µmol, 85.86% yield, TFA) as a yellow oil was used into the next step without further purification. LCMS: Retention time: 0.704 min, [M+H]⁺ calcd. for C₁0H12N4189.1; found 189.3. [0205] N-(3-(3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazolidine-1-carbonyl)phenyl)-3- (trifluoromethyl)benzamide (INS015_037)

[0206] To a solution of 4-(Imidazolidin-1-yl)-1H-pyrrolo[2,3-b]pyridine (90 mg, 297.77 µmol, 1 eq, TFA) and 3-(3-(trifluoromethyl)benzamido)benzoic acid (73.66 mg, 238.21 µmol, 0.8 eq) in DMF (2 mL) was added HATU (169.83 mg, 446.65 µmol, 1.5 eq) and DIEA (115.45 mg, 893.30 µmol, 155.60 uL, 3 eq). The mixture was stirred at 25°C for 1h. LCMS showed the 4-(imidazolidin-1-yl)-1H-pyrrolo[2,3-b]pyridine was consumed and the desired MS (M+1,480.2) was detected. The reaction mixture was poured into H₂O (40 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC (column: Phenomenex Synergi C₁8 150*25*10um; mobile phase: [water (0.1%TFA)-ACN]; B%: 23%-43%, 10min). N-(3-(3-(1H-pyrrolo[2,3-b]pyridin-4- yl)imidazolidine-1-carbonyl)phenyl)-3-(trifluoromethyl)benzamide (19.58 mg, 40.66 µmol, 13.66% yield, 99.571% purity) as a yellow solid was obtained. ¹H-NMR (400 MHz, METHANOL-d₄) d = 8.39 - 8.10 (m, 3H), 7.99 - 7.69 (m, 4H), 7.60 - 7.41 (m, 2H), 7.38 - 7.19 (m, 1H), 7.04 - 6.78 (m, 1H), 6.65 - 6.38 (m, 1H), 5.73 - 5.25 (m, 2H), 4.46 - 3.82 (m, 4H). LCMS: Retention time: 0.814 min, [M+H]⁺ calcd. for C₂₅H₂₀F₃N₅O₂480.2; found 480.2 [0207] Chemical Synthesis of INS015_038 (Compound 5) [0208] The synthesis of INS015_038 (Compound 5) is shown as Scheme 5 in Fig. 9, and described in connection to the reagents and products below. [0209] Tert-butyl 3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamido)-4- methylphenylcarbamate

[0210] To a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid (164.28 mg, 1.08 mmol, 1.2 eq) in DMF (3 mL) was added HATU (513.17 mg, 1.35 mmol, 1.5 eq) stirred at 25°C for 10 min. And then was added DIEA (348.86 mg, 2.70 mmol, 470.16 µL, 3 eq) and tert-butyl 3-amino-4-methylphenylcarbamate (200 mg, 899.75 µmol, 1 eq). The mixture was stirred at 25°C for 1h. LCMS showed the starting material was consumed and the desired MS (M+1,357.2) was detected. Reaction mixture was added to the H₂O (30 mL) with stirred. And then was filtered and concentrated to give a white solid. The residue was used into the next step without purification. The crude product tert-butyl 3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamido)-4- methylphenylcarbamate (300 mg, 841.71 µmol, 93.55% yield) as a white solid was obtained. ¹H-NMR (400 MHz, METHANOL-d4) ppm = 7.79 - 7.70 (m, 1H), 7.27 - 7.09 (m, 2H), 6.59 - 6.51 (m, 1H), 4.24 - 4.16 (m, 2H), 3.00 - 2.95 (m, 2H), 2.72 - 2.60 (m, 2H), 2.26 - 2.23 (m, 3H), 1.53 - 1.50 (m, 9H). LCMS: Retention time: 0.993 min, [M+H]⁺ calcd. for C₁₉H₂₄N₄O₃357.2; found 357.4. [0211] N-(5-amino-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3- carboxamide

[0212] A solution of tert-butyl 3-(5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3- carboxamido)-4-methylphenylcarbamate (200 mg, 561.14 µmol, 1 eq) in TFA (0.4 mL) and DCM (1.2 mL) was stirred at 25°C for 0.5 h. LCMS showed the starting material was consumed and the desired MS (M+1,257.1) was detected. The reaction mixture was concentrated under vacuum. The crude product N-(5-amino-2-methylphenyl)-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide (180 mg, 486.06 µmol, 86.62% yield, TFA) as a yellow oil was used into the next step without further purification. LCMS: Retention time: 0.819 min, [M+H]⁺ calcd. for C₁4H16N4O 257.2; found 257.1 [0213] N-(5-(2-chloroacetamido)-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-3-carboxamide

[0214] To a solution of N-(5-amino-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[1,2- b]pyrazole-3-carboxamide (180 mg, 486.06 µmol, 1 eq, TFA) in DCM (2 mL) was added DIEA (188.46 mg, 1.46 mmol, 253.99 µL, 3 eq) and 2-chloroacetyl chloride (109.79 mg, 972.12 µmol, 77.32 µL, 2 eq) at 0°C. The mixture was stirred at 25°C for 1 h. LCMS showed the starting material was consumed and the desired MS (M+1,333.1) was detected. The reaction mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give a spot (R f=0.3) as a white solid. LCMS showed the white solid N-(5-(2- chloroacetamido)-2-methylphenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3- carboxamide (150 mg, 435.64 µmol, 89.63% yield, 96.650% purity) the desired MS was detected. LCMS: Retention time: 0.871 min, [M+H]⁺ calcd. for C₁6H17ClN4O2333.1; found 333.1. [0215] N-(2-methyl-5-(2-(2-(trifluoromethyl)azetidin-1-yl)acetamido)phenyl)-5,6- dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxamide (INS015_038)

[0216] To a solution of N-(5-(2-chloroacetamido)-2-methylphenyl)-5,6-dihydro-4H- pyrrolo[1,2-b]pyrazole-3-carboxamide (100 mg, 300.50 µmol, 1 eq) and 2- (trifluoromethyl)azetidine (97.09 mg, 600.99 µmol, 2 eq, HCl) in MeCN (1 mL) was added K₂CO₃ (124.59 mg, 901.49 µmol, 3 eq) .The mixture was stirred at 80°C for 16 h. LCMS showed the starting material was consumed and desired MS (M+1,422.2) was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with EA (10 mL*3). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge 150*25 5u; mobile phase: [Water-ACN]; B%: 35%-62%, 9min). Compound INS015_038 (31.17 mg, 73.41 µmol, 24.43% yield, 99.244% purity) as a yellow solid was obtained. ¹H-NMR (400 MHz, METHANOL-d₄) ppm = 7.92 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 2.2, 8.2 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.54(s, 1H), 4.17 (t, J = 7.3 Hz, 2H), 4.11 - 3.96 (m, 1H), 3.67 - 3.59 (m, 1H), 3.47 - 3.32 (m, 2H), 3.29 - 3.26 (m, 1H), 2.98 - 2.88(m, 2H), 2.72 - 2.55 (m, 2H), 2.38 - 2.23 (m, 5H). LCMS: Retention time: 0.955min, [M+H]⁺ calcd. for C₂0H22F3N5O2422.2; found 422.2. [0217] Chemical Synthesis of INS015_039 (Compound 6) [0218] The synthesis of INS015_039 (Compound 6) is shown as Scheme 6 in Fig.10, and described in connection to the reagents and products below. [0219] Tert-butyl 1-benzyl-5-oxo-1,4,9-triazaspiro[5.5]undecane-9-carboxylate

[0220] To a solution of tert-butyl 5-oxo-1,4,9-triazaspiro[5.5]undecane-9-carboxylate (250 mg, 928.20 µmol, 1 eq.) and BnBr (238.13 mg, 1.39 mmol, 165.37 µL, 1.5 eq.) in MeCN (5 mL) was added K₂CO₃ (256.57 mg, 1.86 mmol, 2 eq.), the mixture was stirred at 80°C for 1 h. LC-MS showed desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give a residue and purified by column (SiO₂, PE:EA =5:1 to 1:2) to give tert-butyl 1-benzyl-5-oxo-1,4,9-triazaspiro[5.5]undecane-9- carboxylate (290 mg, 806.76 µmol, 86.92% yield). The white solid was confirmed by ¹H- NMR. ¹H-NMR (400 MHz, METHANOL-d₄) d = 7.45 - 7.38 (m, 2H), 7.37 - 7.30 (m, 2H), 7.28 - 7.19 (m, 1H), 3.87 - 3.75 (m, 4H), 3.48 - 3.32 (m, 4H), 2.91 (t, J = 6.0 Hz, 2H), 2.03 - 1.91 (m, 2H), 1.67 - 1.60 (m, 2H), 1.47 (s, 9H). [0221] Tert-butyl 1-benzyl-4-(2-(3-fluorophenylamino)-2-oxoethyl)-5-oxo-1,4,9- triazaspiro[5.5]undecane-9-carboxylate

[0222] To a solution of 1-benzyl-5-oxo-1,4,9-triazaspiro[5.5]undecane-9-carboxylate (290 mg, 806.76 µmol, 1 eq.) in THF (10 mL) was added NaH (64.53 mg, 1.61 mmol, 60% purity, 2 eq.) at 0°C, the mixture was stirred at 25°C for 30 min, 2-chloro-N-(3- fluorophenyl)acetamide (227.02 mg, 1.21 mmol, 1.5 eq.) in THF (5 mL) was added dropwise to the mixture. The mixture was stirred at 25°C for 1 h. LC-MS showed desired MS was detected. The mixture was quenched by NH₄Cl (saturation, 10 mL), diluted with EA (50 mL), washed with brine (10 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to give a residue and purified by column (SiO₂, PE:EA = 5:1 to 1:1) to give tert-butyl 1-benzyl-4-(2-(3-fluorophenylamino)-2-oxoethyl)-5-oxo-1,4,9- triazaspiro[5.5]undecane-9-carboxylate (300 mg, 587.55 µmol, 72.83% yield) as a white solid. ¹H-NMR (400 MHz, METHANOL-d₄) d = 8.88 - 8.62 (m, 1H), 7.54 - 7.45 (m, 1H), 7.41 - 7.28 (m, 5H), 7.26 - 7.18 (m, 1H), 7.17 - 7.03 (m, 1H), 6.88 - 6.72 (m, 1H), 4.12 - 4.07 (m, 2H), 3.96 - 3.68 (m, 4H), 3.60 - 3.20 (m, 4H), 3.06 - 2.85 (m, 2H), 2.15 - 2.05 (m, 4H), 1.51 - 1.39 (m, 9H). [0223] 2-(1-benzyl-5-oxo-1,4,9-triazaspiro[5.5]undecan-4-yl)-N-(3- fluorophenyl)acetamide

[0224] To a solution of tert-butyl 1-benzyl-4-(2-(3-fluorophenylamino)-2-oxoethyl)-5- oxo-1,4,9-triazaspiro[5.5]undecane-9-carboxylate (300 mg, 587.55 µmol, 1 eq.) in DCM (9 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL, 68.96 eq.), the mixture was stirred at 25°C for 0.5 h. LC-MS showed desired MS was detected. The mixture was concentrated under reduced pressure to give 2-(1-benzyl-5-oxo-1,4,9-triazaspiro[5.5]undecan-4-yl)-N- (3-fluorophenyl)acetamide (300 mg, 571.97 µmol, 97.35% yield, TFA) as a colorless oil. [0225] 2-(1-benzyl-9-(2H-indazole-5-carbonyl)-5-oxo-1,4,9-triazaspiro[5.5]undecan- 4-yl)-N-(3-fluorophenyl)acetamide

[0226] To a solution 2-(1-benzyl-5-oxo-1,4,9-triazaspiro[5.5]undecan-4-yl)-N-(3- fluorophenyl)acetamide (300 mg, 571.97 µmol, 1 eq., TFA) and DIEA (221.77 mg, 1.72 mmol, 298.88 µL, 3 eq.) in DCM (8 mL) and DMF (2 mL) was added 2H-indazole-5- carboxylic acid (111.29 mg, 686.36 µmol, 1.2 eq.) and HATU (260.97 mg, 686.36 µmol, 1.2 eq.), the mixture was stirred at 25°C for 2 h. LC-MS showed desired MS was detected. The mixture was concentrated under reduced pressure to give a residue and purified by column (SiO₂, DCM:MeOH = 1:0 to 5:1) to give 2-(1-benzyl-9-(2H-indazole- 5-carbonyl)-5-oxo-1,4,9-triazaspiro[5.5]undecan-4-yl)-N-(3-fluorophenyl)acetamide (250 mg, 450.76 µmol, 78.81% yield) as a colorless oil. [0227] 2-(9-(2H-indazole-5-carbonyl)-5-oxo-1,4,9-triazaspiro[5.5]undecan-4-yl)-N- (3-fluorophenyl)acetamide (INS015_039)

[0228] A mixture of 2-(1-benzyl-9-(2H-indazole-5-carbonyl)-5-oxo-1,4,9- triazaspiro[5.5]undecan-4-yl)-N-(3-fluorophenyl)acetamide (250 mg, 450.76 µmol, 1 eq.) and Pd/C (250 mg, 450.76 µmol, 10% purity, 1 eq.), in EtOH (10 mL) was degassed and purged with H₂ for 3 times, and then the mixture was stirred at 25°C for 2 h under H₂ (15 psi) atmosphere. LC-MS showed desired MS was detected. The mixture was filtered and concentrated under reduced pressure to give a residue and purified by pre-HPLC (water (10 mM NH4HCO3)-ACN) to give 2-(9-(2H-indazole-5-carbonyl)-5-oxo-1,4,9- triazaspiro[5.5]undecan-4-yl)-N-(3-fluorophenyl)acetamide (35.79 mg, 73.50 µmol, 16.31% yield, 95.387% purity) as a white solid. HPLC: Retention time: 1.675 min. ¹H- NMR (400 MHz, METHANOL-d4) d = 8.14 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.35 - 7.20(m, 2H), 6.87 - 6.76 (m, 1H), 4.47 - 4.07 (m, 3H), 3.79 - 3.34 (m, 5H), 3.20 - 2.99 (m, 2H), 2.38 - 1.53 (m, 4H). ¹⁹F-NMR (400MHz, METHANOL-d4) d =114.135. ¹³C-NMR (400MHz, METHANOL-d4) d= 174.48, 171.53, 167.36, 164.11, 161.69, 140.48, 140.10, 139.99, 134.29, 129.89, 129.80, 128.13, 125.34, 122.37, 119.90, 114.82, 114.80, 110.18, 109.95, 106.63, 106.36, 56.81, 50.66, 50.34, 48.30, 48.09, 47.88, 47.66, 37.06. LCMS: Retention time: 0.800 min, [M+H]⁺ calcd. for C₂₄H25FN6O3465.2; found 465.2. [0229] The foregoing synthetic routes show that a number of synthetic pathways and protocols can be used to prepare the compounds described herein. [0230] DEFINITIONS [0231] The term “alkyl” or “aliphatic” as used herein refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 18 carbon atoms, or 1 to about 12 carbon atoms. The term “lower alkyl” intends an alkyl group of 1 to 6 carbon atoms. Substituents identified as “C 1 -C 6 alkyl” or “lower alkyl” contains 1 to 3 carbon atoms, and such substituents contain 1 or 2 carbon atoms (i.e., methyl and ethyl). “Substituted alkyl” refers to alkyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, the terms “alkyl” and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl or lower alkyl, respectively. Examples of Alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl tert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, etc. Alkyl may be substituted or unsubstituted. Illustrative substituted alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl, substituted phenethyl, etc. [0232] The terms “alkenyl” as used herein refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like. Generally, although again not necessarily, alkenyl groups herein contain 2 to about 18 carbon atoms, or 2 to 12 carbon atoms. The term “lower alkenyl” intends an alkenyl group of 2 to 6 carbon atoms, and the specific term “cycloalkenyl” intends a cyclic alkenyl group, or having 5 to 8 carbon atoms. The term “substituted alkenyl” refers to alkenyl substituted with one or more substituent groups, and the terms “heteroatom-containing alkenyl” and “heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkenyl” and “lower alkenyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively. [0233] The term “alkynyl” as used herein refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n- propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein contain 2 to about 18 carbon atoms, or 2 to 12 carbon atoms. The term “lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms. The term “substituted alkynyl” refers to alkynyl substituted with one or more substituent groups, and the terms “heteroatom- containing alkynyl” and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms “alkynyl” and “lower alkynyl” include linear, branched, unsubstituted, substituted, and/or heteroatom- containing alkynyl and lower alkynyl, respectively. [0234] The term “alkoxy” as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an “alkoxy” group may be represented as —O-alkyl where alkyl is as defined above. A “lower alkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, t- butyloxy, etc. Substituents identified as “C₁ -C₆ alkoxy” or “lower alkoxy” herein contain 1 to 3 carbon atoms, and such substituents contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy). [0235] The term “aryl” as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety). Examples of aryl groups contain 5 to 20 carbon atoms, and aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. “Substituted aryl” refers to an aryl moiety substituted with one or more substituent groups, and the terms “heteroatom-containing aryl” and “heteroaryl” refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra. If not otherwise indicated, the term “aryl” includes unsubstituted, substituted, and/or heteroatom-containing aromatic substituents. [0236] The term “aryloxy” as used herein refers to an aryl group bound through a single, terminal ether linkage, wherein “aryl” is as defined above. An “aryloxy” group may be represented as —O-aryl where aryl is as defined above. Examples of aryloxy groups contain 5 to 20 carbon atoms, and aryloxy groups contain 5 to 14 carbon atoms. Examples of aryloxy groups include, without limitation, phenoxy, o-halo-phenoxy, m-halo- phenoxy, p-halo-phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy, p-methoxy- phenoxy, 2,4-dimethoxy-phenoxy, 3,4,5-trimethoxy-phenoxy, and the like. [0237] The term “alkaryl” refers to an aryl group with an alkyl substituent, and the term “aralkyl” refers to an alkyl group with an aryl substituent, wherein “aryl” and “alkyl” are as defined above. Examples of aralkyl groups contain 6 to 24 carbon atoms, and aralkyl groups contain 6 to 16 carbon atoms. Examples of aralkyl groups include, without limitation, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4- phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4- benzylcyclohexylmethyl, and the like. Alkaryl groups include, for example, p- methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethyinaphthyl, 7- cyclooctylnaphthyl, 3-ethyl-cyclopenta-1,4-diene, and the like. [0238] The term “cyclic” refers to alicyclic or aromatic substituents that may or may not be substituted and/or heteroatom containing, and that may be monocyclic, bicyclic, or polycyclic. [0239] The terms “halo” and “halogen” are used in the conventional sense to refer to a chloro, bromo, and fluoro or iodo substituent. [0240] The term “heteroatom-containing” as in a “heteroatom-containing alkyl group” (also termed a “heteroalkyl” group) or a “heteroatom-containing aryl group” (also termed a “heteroaryl” group) refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur. Similarly, the term “heteroalkyl” refers to an alkyl substituent that is heteroatom-containing, the term “heterocyclic” refers to a cyclic substituent that is heteroatom-containing, the terms “heteroaryl” and heteroaromatic” respectively refer to “aryl” and “aromatic” substituents that are heteroatom-containing, and the like. Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., and examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, etc. [0241] The term “hydrocarbyl” refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, or 1 to about 24 carbon atoms, or 1 to about 18 carbon atoms, or about 1 to 12 carbon atoms, including linear, branched, cyclic, saturated, and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. “Substituted hydrocarbyl” refers to hydrocarbyl substituted with one or more substituent groups, and the term “heteroatom-containing hydrocarbyl” refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term “hydrocarbyl” is to be interpreted as including substituted and/or heteroatom-containing hydrocarbyl moieties. [0242] The term “boron compound” can include any compound having boron or radical thereof, or chemical having a boron substituent. Examples of boron compounds that can be included as the R groups defined herein are boron tri alkyl or radical thereof, boron di- alkyl radical, hydrogen boron di-alkyl, hydrogen boron alkyl radical, boric acid (e.g., ^{H3BO3 or H2BO3 radical)}, borax (e.g., ^{B4Na2O7.10H2O or radical thereof)}, boron sodium oxide (e.g., B4Na2O7 or radical thereof), boron oxide (e.g. B2O3 or radical thereof), boron acid zinc salt, cobalt borate neodecanoate complexes, boron zinc oxide ^{(e.g., B6Zn2O11 or} radical thereof), boric acid sodium salt, perboric acid sodium salt, boron lithium oxide, ammonium boron oxide, boron silver oxide, boric acid lithium salt, boron trifluoride, boron difluoride radical, boron dihydroxy, potassium boron trifluoride, 4,4,5,5- tetramethyl-3,2-dioxaboralane, and radicals thereof. The radicals can be the R group and conjugated to the chemical scaffolds described herein. [0243] An example boron compound includes the radical of (lose hydrogen):

[0244] By “substituted” as in “substituted alkyl,” “substituted aryl,” and the like, as alluded to in some of the aforementioned definitions, is meant that in the alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents. [0245] In addition, the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above. Analogously, the above-mentioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically enumerated. [0246] When the term “substituted” appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. For example, the phrase “substituted alkyl, alkenyl, and aryl” is to be interpreted as “substituted alkyl, substituted alkenyl, and substituted aryl.” Analogously, when the term “heteroatom-containing” appears prior to a list of possible heteroatom-containing groups, it is intended that the term apply to every member of that group. For example, the phrase “heteroatom- containing alkyl, alkenyl, and aryl” is to be interpreted as “heteroatom-containing alkyl, heteroatom-containing alkenyl, and heteroatom-containing aryl.” [0247] All other chemistry terms are defined as known in the art. [0248] The term “discoidin domain receptor 1” or “DDR1” as used herein refers to all isoforms and variants of the DDR1 protein, including DDR1a, DDR1b, DDR1c, DDR1d and DDR1e. [0249] As used herein, the terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancers. [0250] “Tumor” and “neoplasm” as used herein refer to any mass of tissue that results from excessive cell growth or proliferation, either benign (noncancerous) or malignant (cancerous), including pre-cancerous lesions. [0251] “Metastasis” as used herein refers to the process by which a cancer spreads or transfers from the site of origin to other regions of the body with the development of a similar cancerous lesion at the new location. A “metastatic” or “metastasizing” cell is one that loses adhesive contacts with neighboring cells and migrates via the bloodstream or lymph from the primary site of disease to invade neighboring body structures. [0252] The terms “cancer stem cell”, “tumor stem cell”, or “solid tumor stem cell” are used interchangeably herein and refer to a population of cells from a solid tumor that: (1) have extensive proliferative capacity; 2) are capable of asymmetric cell division to generate one or more kinds of differentiated progeny with reduced proliferative or developmental potential; and (3) are capable of symmetric cell divisions for self-renewal or self-maintenance. These properties of “cancer stem cells”, “tumor stem cells” or “solid tumor stem cells” confer on those cancer stem cells the ability to form palpable tumors upon serial transplantation into an immunocompromised mouse compared to the majority of tumor cells that fail to form tumors. Cancer stem cells undergo self-renewal versus differentiation in a chaotic manner to form tumors with abnormal cell types that can change over time as mutations occur. The terms “cancer cell,” “tumor cell,” and grammatical equivalents refer to the total population of cells derived from a tumor or a pre-cancerous lesion, including both non-tumorigenic cells, which comprise the bulk of the tumor cell population, and tumorigenic stem cells (cancer stem cells). As used herein, the term “tumor cell” will be modified by the term “non-tumorigenic” when referring solely to those tumor cells lacking the capacity to renew and differentiate to distinguish those tumor cells from cancer stem cells. [0253] As used herein “tumorigenic” refers to the functional features of a solid tumor stein cell including the properties of self-renewal (giving rise to additional tumorigenic cancer stem cells) and proliferation to generate all other tumor cells (giving rise to differentiated and thus non-tumorigenic tumor cells) that allow solid tumor stem cells to form a tumor. These properties of self-renewal and proliferation to generate all other tumor cells confer on cancer stem cells the ability to form palpable tumors upon serial transplantation into an immunocompromised mouse compared to non-tumorigenic tumor cells, which are unable to form tumors upon serial transplantation. It has been observed that non-tumorigenic tumor cells may form a tumor upon primary transplantation into an immunocompromised mouse after obtaining the tumor cells from a solid tumor, but those non-tumorigenic tumor cells do not give rise to a tumor upon serial transplantation. [0254] As used herein, the terms “stem cell cancer marker(s)”, “cancer stem cell marker(s)”, “tumor stem cell marker(s)”, or “solid tumor stem cell marker(s)” refer to a gene or genes or a protein, polypeptide, or peptide expressed by the gene or genes whose expression level, alone or in combination with other genes, is correlated with the presence of tumorigenic cancer cells compared to non-tumorigenic cells. The correlation can relate to either an increased or decreased expression of the gene (e.g. increased or decreased levels of mRNA or the peptide encoded by the gene). [0255] As used herein, the terms “biopsy” and “biopsy tissue” refer to a sample of tissue or fluid that is removed from a subject for the purpose of determining if the sample contains cancerous tissue. In some embodiments, biopsy tissue or fluid is obtained because a subject is suspected of having cancer, and the biopsy tissue or fluid is then examined for the presence or absence of cancer. [0256] As used herein, the term “subject” refers to any animal (e.g., a mammal), including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject. [0257] “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans. [0258] “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. [0259] “Pharmaceutically acceptable excipient, carrier or adjuvant” refers to an excipient, carrier or adjuvant that can be administered to a subject, together with at least one DDR1 inhibitor of the present disclosure, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the DDR1 inhibitor. [0260] “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient, or carrier with which at least one DDR1 inhibitor of the present disclosure is administered. [0261] The term “effective amount,” “therapeutically effective amount” or “therapeutic effect” refers to an amount of a DDR1 inhibitor, polypeptide, polynucleotide, small organic molecule, or other drug effective to “treat” a disease or disorder in a subject or mammal. In the case of cancer, the therapeutically effective amount of the drug has a therapeutic effect and as such can reduce the number of cancer cells; decrease tumorigenicity, tumorigenic frequency or tumorigenic capacity; reduce the number or frequency of cancer stem cells; reduce the tumor size; inhibit or stop cancer cell infiltration into peripheral organs including, for example, the spread of cancer into soft tissue and bone; inhibit and stop tumor metastasis; inhibit and stop tumor growth; relieve to some extent one or more of the symptoms associated with the cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects. Methods to determine tumorigenicity or tumorigenic frequency or capacity are demonstrated in copending application U.S. Ser. No. 11/776,935, incorporated by reference herein in its entirety. To the extent the drug prevents growth and/or kills existing cancer cells, it can be referred to as cytostatic and/or cytotoxic. [0262] Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” refer to both 1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and 2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder. Thus those in need of treatment include those already with the disorder; those prone to have the disorder, and those in whom the disorder is to be prevented. In certain embodiments, a subject is successfully “treated” according to the methods of the present invention if the patient shows one or more of the following: a reduction in the number of or complete absence of cancer cells; a reduction in the tumor size; inhibition of or an absence of cancer cell infiltration into peripheral organs including, for example, the spread of cancer into soft tissue and bone; inhibition of or an absence of tumor metastasis; inhibition or an absence of tumor growth; relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; reduction in tumorigenicity; reduction in the number or frequency of cancer stem cells; or some combination of effects. [0263] One skilled in the art will appreciate that, for this and other processes and methods disclosed herein, the functions performed in the processes and methods may be implemented in differing order. Furthermore, the outlined steps and operations are only provided as examples, and some of the steps and operations may be optional, combined into fewer steps and operations, or expanded into additional steps and operations without detracting from the essence of the disclosed embodiments. [0264] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. [0265] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. [0266] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g., “a” and/or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of "two recitations," without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.” [0267] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. [0268] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to groups having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth. [0269] From the foregoing, it will be appreciated that various embodiments of the present disclosure have been described herein for purposes of illustration, and that various modifications may be made without departing from the scope and spirit of the present disclosure. Accordingly, the various embodiments disclosed herein are not intended to be limiting, with the true scope and spirit being indicated by the following claims. [0270] Abbreviations [0271] DCM dichloromethane [0272] DMF dimethylformamide [0273] DMSO dimethylsulphoxide [0274] EA ethyl acetate [0275] HPLC high performance liquid chromatography methanol [0276] PBS phosphate buffered saline [0277] THF tetrahydrofuran [0278] TFA trifluoroacetic acid [0279] TLC thin layer chromatography [0280] Py pyridine [0281] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide [0282] ACN acetonitrile [0283] T3P 1-Propanephosphonic anhydride solution [0284] Pd(dppf)Cl2 [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) [0285] NIS N-Iodosuccinimide [0286] TEA triethylamine [0287] TFA trifluoroacetic acid [0288] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate [0289] DIEA diisopropylethylamine [0290] NMP N-Methyl-2-pyrrolidone [0291] XPhos Pd G3 (2-Dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2- (2-amino-1,1-biphenyl)]palladium(II) methanesulfonate [0292] MTBE Methyl-tert-butyl ether [0293] CDI 1,1'-Carbonyldiimidazole [0294] All references recited herein are incorporated herein by specific reference in their entirety for all that they teach..

Claims

CLAIMS 1. A compound comprising a structure of Formula 1, Formula 2, Formula 3, or Formula 4, or derivative thereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof, or solvate thereof, or having any chirality at any chiral center,

wherein: Fluorine Group is a chemical moiety having at least one F; R¹, R², and R³ are each individually a substituent; X¹, X², X³, X⁴, and X⁵ are independently CH, N, O, or S; Y¹ is a linker or a bond; Y² is a linker or a bond; n is from 0 to 6; m is from 0 to 5; and o is from 0 to 4. 2. The compound of claim 1, comprising a structure of Formula 1A, Formula 2A, Formula 3A, or Formula 4A, or derivative thereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof, or solvate thereof, or having any chirality at any chiral center,

3. The compound of claim 1, comprising a structure of Formula 1B, Formula 2B, Formula 3B, or Formula 4B, or derivative thereof, prodrug thereof, salt thereof, stereoisomer thereof, tautomer thereof, polymorph thereof, or solvate thereof, or having any chirality at any chiral center,

4. The compound of claim 1, wherein R¹, R², and R³ 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, peptides, polypeptides, derivatives thereof, substituted or unsubstituted, or combinations thereof. 5. The compound of claim 1, wherein R¹, R², and R³ are 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, alkylsulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, any with or without hetero atoms, derivatives thereof, and combinations thereof. 6. The compound of claim 1, wherein R¹, R², and R³ are each independently hydrogen, C₁ -C₂₄ alkyl, C₂ -C₂₄ alkenyl, C₂ -C₂₄ alkynyl, C₅ -C₂₀ aryl, C₆ -C₂₄ alkaryl, C₆ - C₂₄ aralkyl, halo, hydroxyl, sulfhydryl, C₁ -C₂₄ alkoxy, C₂ -C₂₄ alkenyloxy, C₂ -C₂₄ alkynyloxy, C₅-C₂₀ aryloxy, acyl, acyloxy, C₂-C₂₄ alkoxycarbonyl, C₆-C₂₀ aryloxycarbonyl, halocarbonyl, C₂-C₂₄ alkylcarbonato, C₆-C₂0 arylcarbonato, carboxy, carboxylato, carbamoyl, mono-(C₁ -C₂₄ alkyl)-substituted carbamoyl, di-(C₁ -C₂₄ alkyl)- substituted carbamoyl, mono-substituted arylcarbamoyl, di-substituted arylcarbamoyl, thiocarbamoyl, mono-(C₁ -C₂₄ alkyl)-substituted thiocarbamoyl, di-(C₁ -C₂₄ alkyl)- substituted thiocarbamoyl, mono-substituted arylthiocarbamoyl, di-substituted arylthiocarbamoyl, carbamido, mono-(C₁ -C₂₄ alkyl)-substituted carbamido, di-(C₁ -C₂₄ alkyl)-substituted carbamido, mono-substituted aryl carbamido, di-substituted aryl carbamido, isocyano, cyanato, isocyanato, thiocyanato, isothiocyanato, azido, formyl, thioformyl, amino, mono- and di-(C₁ -C₂₄ alkyl)-substituted amino, mono- and di-(C5 -C₂0 aryl)-substituted amino, C₂ -C₂₄ alkylamido, C₆ -C₂₀ arylamido, imino, alkylimino, arylimino, nitro, nitroso, sulfonic acid, sulfonate, C₁ -C₂₄ alkylsulfanyl, C5 -C₂0 arylsulfanyl, C₁ -C₂₄ alkylsulfinyl, C₅ -C₂₀ arylsulfinyl, C₁ -C₂₄ alkylsulfonyl, C₅ -C₂₀ arylsulfonyl, phosphono, phosphonato, phosphinato, phospho, phosphino, any with or without hetero atoms, derivatives thereof, and combinations thereof. 7. The compound of claim 1, wherein: X¹ is N; X² is N; X³ is N; X⁴ is O; and X⁵ is N. 8. The compound of claim 1, wherein: for Formula 1, Y¹ includes an alkylene; for Formula 2, Y¹ is a bond; for Formula 3, Y¹ is a bond; and for Formula 4, Y¹ includes an alkylene. 9. The compound of claim 1, wherein: for Formula 1, Y² includes an amino; for Formula 2, Y² includes an amide; for Formula 3, Y² is a bis-alkyl amide; and for Formula 4, Y² includes a bond. 10. The compound of claim 1, wherein: for Formula 1, R¹ is H, R² is methyl, and R³ is H; for Formula 2, R¹ is H, R² is H, and R³ is H; for Formula 3, R¹ is H, R² is methyl, and R³ is H; and for Formula 4, R¹ is H, R² is methyl, and R³ is dimethyl amine. 11. The method of claim 1,`comprising a structure of Compound 1,

Com pound 1. 12. The compound of claim 1, comprising a structure of Compound 2,

Co mpound 2. 13. The compound of claim 1, comprising a structure of Compound 3,

Compound 3. 14. The compound of claim 1, comprising a structure of Compound 4,

Com pound 4. 15. A pharmaceutical composition comprising: the compound of claim 1; and a pharmaceutically acceptable carrier having the compound. 16. A method of inhibiting a kinase, comprising: providing the compound of claim 1 to the kinase such that the kinase is inhibited. 17. A method of inhibiting cellular communication, the method comprising: providing the compound of claim 1 to a cell so as to inhibit communication of the cell with a surrounding environment of the cell. 18. A method of inhibiting a cell attachment to an extracellular matrix, the method comprising: providing the compound of claim 1 to a DDR1 and/or DDR2 of the cell to inhibit the DDR1 receptor from interacting with fibrillar collagen. 19. A method of inhibiting cell activity, comprising: providing the compound of claim 1 to a cell so as to inhibit at least one biological function of the cell. 20. A method of promoting remodeling of an extracellular matrix, the method comprising: providing the compound of claim 1 to a DDR1 and/or DDR2 so as to cause upregulation of a matrix metalloproteinase. 21. A method of inhibiting fibrosis, the method comprising: providing the compound of claim 1 to a DDR1 and/or DDR2 to inhibit formation of excess fibrous tissue. 22. A method of inhibiting mammary gland differentiation, the method comprising: providing the compound of claim 1 to a DDR1 and/or DDR2 of a mammary gland so as to inhibit differentiation of cells of the mammary gland. 23. A method of inhibiting activity of a cancer cell, comprising: administering the compound of claim 1 to the cancer cell so as to inhibit a biological activity of the cancer cell. 24. A method of treating cancer in a subject, the method comprising: administering the compound of claim 1 to a subject that has cancer. 25. A method of inhibiting a DDR1 and/or DDR2, comprising: providing the compound of claim 1 to the DDR1 and/or DDR2 such that the DDR1 kinase is inhibited.

26. A method of inhibiting a disease related to DDR1 and/or DDR2 in a subject, the method comprising: providing the compound of claim 1 to the DDR1 and/or DDR2 of the subject such that the DDR1 and/or DDR2 is inhibited in the subject.