Imidazopyridine inhibitors of tyrosine kinases

Abstract

The present disclosure provides compounds and compositions thereof that are useful as inhibitors of tyrosine kinases and that exhibit desirable characteristics for tyrosine kinase inhibitors. Further disclosed herein are methods of treating cancer using these tyrosine kinase inhibitor compounds.

Description

[Technical field]

[0001] The present disclosure relates generally to the field of compounds, pharmaceutical compositions, and methods of using the compounds and compositions containing the compounds.The present disclosure specifically relates to imidazopyridine compounds that are tyrosine kinase inhibitor compounds, and compositions containing the compounds, and the use of the compounds and compositions to treat cancer. [Background technology]

[0002] In recent years, inhibition of certain cancer-related tyrosine kinases has emerged as an important approach for cancer treatment. Tyrosine kinases, as mediators of cell signaling, play important roles in many diverse physiological pathways, including cell growth and differentiation. Deregulation of tyrosine kinase activity can lead to cell transformation that leads to the development of cancer. Summary of the Invention

[0003] Disclosed herein are compounds for use as tyrosine kinase inhibitors, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions to treat cancer. Many of the disclosed compounds are capable of covalently inhibiting certain tyrosine kinases, and therefore exhibit high potency and remarkable selectivity for these kinases. In some embodiments, the disclosure provides compounds of the following formula (I): [ka] Compound or an optically pure stereoisomer, a pharma- ceutically acceptable salt, or a solvate thereof. In some embodiments, m can be an integer ranging from 0 to 4. In formula (I), Ar is phenyl, [ka] selected from the group consisting of; Z is -CO-, -COO-, -CONR 4 -, -NR 4 -, -(CH2) 1~5 selected from the group consisting of -, -O-, -OPO-, -OPO2-, -S-, -SO-, or -SO2-; L is -CONR 4 (CH2)-NR 4 -, -NR 4 CO(CH2) 1~5 NR 4 -, -(CH2) 1~5 NR 4 -, -(CH2)1~5O-, -(CH2)1~5OCO-, -(CH2)1~5CONR 4 -, [ka] (Each of these can be optionally 6 (may be replaced by It may be the case. A.A. [ka] (In these formulas, R 1 is selected from the group consisting of H, -F, -CF3, -CN, -NH2, -OH, -OCH3, -OEt, methyl, ethyl, propyl, isopropyl, and cyclopropyl. The ring is a natural or unnatural amino acid selected from the group consisting of: 1 may have. R 2 are H, -F, -Br, -Cl, -CF3, -CN, -N3, -NH2, -NO2, -OH, -OCH3, methyl, ethyl, propyl, isopropyl, [ka] (Each of these can have one, two, three, or four R 6 (may be replaced by is selected from the group consisting of: R 3is -CO(CH2)0~5CH3, -CONR 4 (CH2) 0~5CH3, -COO(CH2)0~5CH3, -SO2(CH2)0~5CH3, -CO(CH2)0~5CH=CH2, -CONR 4 (CH2) 0-5CH = CH2, -COO(CH2)0~5CH=CH2, -SO2(CH2)0~5CH=CH2, -CO(CH2)0~5CH=CHCH3, -COO(CH2)0~5CH=CHCH3, -CONR 4 (CH2)0~5CH=CHCH3, -SO2(CH2)0~5CH=CHCH3, -CO(CH2)0~5C≡CH, -COO(CH2)0~5C≡CH, -CONR 4 (CH2)0~5C≡CH, -SO2(CH2)0~5C≡CH, -CO(CH2)0~5C≡CCH3, -COO(CH2)0~5C≡CCH3, -CONR 4 (CH2)0-5C≡CCH3, and -SO2(CH2)0-5C≡CCH3, each of the foregoing groups being selected from the group consisting of one, two, three, or four R 6 may be substituted by: In some embodiments, R 3 teeth, [ka] may be selected from the group consisting of; R 4 may be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. R 5 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2SCH3, -CH2Ph, -CH2PhOH, -CH2OH, -CHOHCH3, -CH2CONH2, -CH2CH2CONH2, -CH2SH, -CH2SeH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2CH2NH2, [ka] It may be; Each R 6 may be independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an unsubstituted amino group or an amino group substituted with methyl, ethyl, or propyl.

[0004] In a preferred embodiment, the compound of formula (I) as discussed above is represented by the following formula (II): [ka]

[0005] In a further preferred embodiment, the compound of the present invention specifically has the following formula (III): [ka] As shown in or an optically pure stereoisomer, a pharma- ceutically acceptable salt, or a solvate thereof. [ka] may be a naturally occurring or unnatural amino acid selected from the group consisting of: R 2 teeth, [ka] (each of which may be substituted by 1, 2, 3, or 4 R6). The ion exchange resin may be selected from the group consisting of: In some embodiments, R 3 teeth, [ka] selected from the group consisting of; R4 may be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. Each R6 may independently be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, OCH3, CN, or an unsubstituted amino group or an amino group substituted with methyl, ethyl, or propyl.

[0006] Also disclosed herein are pharmaceutical compositions comprising compounds according to formula (I).

[0007] Further disclosed herein is a method for treating cancer in a subject, comprising administering a compound of formula (I). In some embodiments, the cancer may be selected from the group consisting of breast, lung, bladder, prostate, ovarian, endometrium, rhabdomyosarcoma, liver and stomach. In some embodiments, the method also comprises administering a chemotherapeutic agent, and the compound may be administered prior to, simultaneously with, or after the administration of the chemotherapeutic agent.

[0008] Also disclosed herein is a method of inhibiting tyrosine kinase activity comprising contacting a cell with a compound of formula (I). In some embodiments, the disclosed compounds exhibit covalent inhibition of FLT-3 and / or KIT.

[0009] Other features and advantages may become apparent from the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The following are some acronyms used in this disclosure: n-BuOK denotes potassium tert-butoxide; DMF denotes dimethylformamide; Boc denotes tert-butyloxycarbonyl protecting group; DMSO denotes dimethylsulfoxide; HATU denotes 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; DIEA denotes N,N-diisopropylethylamine; DIPEA denotes N,N-diisopropylethylamine; TFA denotes trifluoroacetic acid; PyBOP denotes benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate.

[0011] The term "about" will be understood by those of ordinary skill in the art. Any quantity given herein, whether or not the term "about" is explicitly used, is meant to indicate the actual given value, and also to indicate an approximation to such given value that might be reasonably estimated based on ordinary skill in the art.

[0012] An alkyl group refers to a monovalent group derived from an alkane by removing one hydrogen atom from any carbon atom, where the alkyl group includes straight and branched chains having 1 to 12 carbon atoms, typically 1 to about 10 carbons, or in some embodiments 1 to about 6 carbon atoms, or in other embodiments 1, 2, 3, or 4 carbon atoms. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl groups. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, and tert-butyl groups. An alkyl group may be substituted or unsubstituted. Representative substituted alkyl groups may be mono-substituted or substituted two or more times, such as, but not limited to, di- or tri-substituted. As used herein, the term alkyl refers to both cyclic and non-cyclic groups, unless otherwise specified.

[0013] The term "cyclic alkyl" or "cycloalkyl" refers to a monovalent group derived from a cycloalkane by removing one hydrogen atom from a ring carbon atom. Cycloalkyl groups are saturated or partially saturated non-aromatic structures having only one ring or multiple rings, including isolated ring systems, fused ring systems, bridged ring systems, and spiro ring systems, having 3 to 14 carbon atoms, or in some embodiments 3 to 12, or 3 to 10, or 3 to 8, or 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl groups may be substituted or unsubstituted. Representative substituted cycloalkyl groups may be mono-substituted or substituted two or more times, such as, but not limited to, di- or tri-substituted. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. Examples of polycyclic ring systems include, but are not limited to, bicyclo[4.4.0]decane, bicyclo[2.2.1]heptane, spiro[2.2]pentane, and the like.

[0014] Alkenyl groups refer to straight and branched chain groups as defined above, as well as cycloalkyl groups, having one or more double bonds between two carbon atoms. Alkenyl groups may have from 2 to about 12 carbon atoms, or in some embodiments from 2 to about 10 carbons, or in other embodiments from 2 to about 6 carbon atoms, or in other embodiments from 2, 3, or 4 carbon atoms. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or substituted two or more times, such as, but not limited to, di- or tri-substituted. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, cyclopentenyl, cyclohexenyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0015] Alkynyl groups refer to straight and branched chain groups as well as cycloalkyl groups as defined above, having one or more triple bonds between two carbon atoms. Alkynyl groups can have from 2 to about 12 carbon atoms, or in some embodiments from 2 to about 10 carbons, or in other embodiments from 2 to about 6 carbon atoms, or in other embodiments from 2, 3, or 4 carbon atoms. Alkynyl groups can be substituted or unsubstituted. Representative substituted alkynyl groups can be mono-substituted or substituted two or more times, such as, but not limited to, di- or tri-substituted. Exemplary alkynyl groups include, but are not limited to, ethynyl, propargyl, and -C≡C(CH3), among others.

[0016] Aryl groups are cyclic aromatic hydrocarbons including single ring compounds and polycyclic compounds including polycyclic compounds containing separate and / or fused aryl groups. Aryl groups may contain 6 to about 18 ring carbons, or in some embodiments 6 to 14 ring carbons, or even in other embodiments 6 to 10 ring carbons. Aryl groups also include heteroaryl groups, which are aromatic ring compounds containing 5 or more ring atoms in which one or more ring carbon atoms are replaced by a heteroatom (such as, but not limited to, N, O, and S). Aryl groups may be substituted or unsubstituted. Representative substituted aryl groups may be mono-substituted or substituted two or more times, such as, but not limited to, di- or tri-substituted. Aryl groups include, but are not limited to, phenyl, biphenylenyl, triphenylenyl, naphthyl, anthryl, and pyrenyl groups.

[0017] Suitable heterocyclyl groups include cyclic groups having atoms of at least two different elements as ring members, one or more of which is a heteroatom (such as, but not limited to, N, O, or S). Heterocyclyl groups may contain from 3 to about 20 ring atoms, or in some embodiments, from 3 to 18, or from about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring atoms. The ring system in a heterocyclyl group may be unsaturated, partially saturated, and / or saturated. Heterocyclyl groups may be substituted or unsubstituted. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, di- or tri-substituted. Exemplary heterocyclyl groups include pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, aziridinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, triazolyl, and the like. Examples of thiazolyl groups include, but are not limited to, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxolanyl, dioxanyl, purinyl, quinolidinyl, cinnolinyl, phthalazinyl, pteridinyl, and benzothiazolyl groups.

[0018] A polycyclic or polycyclyl group denotes two or more rings in which two or more carbons are common to two adjacent rings, in which case the rings are "fused rings"; if the rings are linked by one common carbon atom, they are "spiro" ring systems. Rings that are linked through non-adjacent atoms are "bridged" rings. Polycyclic groups may be substituted or unsubstituted. Representative polycyclic groups may be substituted one or more times.

[0019] Halogen groups include F, Cl, Br, and I. Nitro groups refer to -NO2. Cyano groups refer to -CN. Isocyano groups refer to -N≡C. Epoxy groups encompass structures in which an oxygen atom is directly bonded to two adjacent or non-adjacent carbon atoms of a carbon chain or ring system, i.e., essentially a cyclic ether structure. Epoxides are cyclic ethers with a three-atom ring.

[0020] An alkoxy group is a substituted or unsubstituted alkyl group as defined above that is single-bonded to oxygen. An alkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, isopropoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0021] The terms "amine" and "amino" refer to derivatives of ammonia in which one or more hydrogen atoms have been replaced by substituents including, but not limited to, alkyl, alkenyl, aryl, and heterocyclyl groups. A carbamate group is represented by the formula -O(C=O)NR 11 R 12 (In the formula, R 11 and R 12 are independently hydrogen, an aliphatic group, an aryl group, or a heterocyclyl group.

[0022] Pharmaceutically acceptable salts of the compounds described herein include, for example, conventional non-toxic salts or quaternary ammonium salts of the compounds obtained from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and similar acids, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and similar acids. In other cases, the described compounds may contain one or more acidic functional groups, and therefore can form pharma- ceutically acceptable salts with pharma-ceutically acceptable bases. These salts may also be prepared in situ in the administration vehicle or during the dosage form manufacturing process, or may be prepared by separately reacting the purified compound in its free acid form with a suitable base (e.g., hydroxide, carbonate, or bicarbonate of a pharma-ceutically acceptable metal cation, etc.), with ammonia, or with a pharma-ceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and similar amines.

[0023] Those skilled in the art of organic chemistry will understand that many organic compounds may form complexes with the solvent in which the compound is reacted or from which the compound is precipitated or crystallized. These complexes are known as "solvates". For example, complexes with water are known as "hydrates". Solvates of the compound of formula (I) are within the scope of the present invention. Those skilled in the art of organic chemistry will also understand that many organic compounds may exist in more than one crystal form. For example, the crystal form may vary from one solvate to another. Thus, all crystal forms of the compound of formula (I) or its pharma- ceutical acceptable solvates are within the scope of the present invention.

[0024] Disclosed herein are compounds for use as tyrosine kinase inhibitors, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions to treat cancer. The disclosed compounds may provide covalent inhibition of certain tyrosine kinases; thus, the disclosed compounds exhibit high potency and remarkable selectivity against these kinases. In some embodiments, the disclosure provides compounds of formula (I): [ka] In formula (I), Ar is phenyl, [ka] selected from the group consisting of; Z is -CO-, -COO-, -CONR 4 -, -NR 4 -, -(CH2) 1~5 -, -O-, may be selected from the group consisting of -OPO-, -OPO2-, -S-, -SO-, or -SO2-; L is -CONR 4 (CH2)-NR 4 -, -NR 4 CO(CH2) 1~5 NR 4 -, -(CH2) 1~5 NR 4-, -(CH2)1~5O-, -(CH2)1~5OCO-, -(CH2)1~5CONR 4 -, [ka] (Each of these can be optionally 6 (may be replaced by It may be the case. A.A. [ka] (In these formulas, R 1 are H, -F, -CF3, -CN, -NH2, -OH, -OCH3, -OEt, methyl, ethyl, propyl, isopropyl, cyclopropyl The ring is a natural or unnatural amino acid selected from the group consisting of: 1 may have. R 2 are H, -F, -Br, -Cl, -CF3, -CN, -N3, -NH2, -NO2, -OH, -OCH3, methyl, ethyl, propyl, isopropyl, [ka] (Each of these can have one, two, three, or four R 6 (may be replaced by The ion exchange resin may be selected from the group consisting of: R 3 is -CO(CH2)0~5CH3, -CONR 4 (CH2) 0~5CH3, -COO(CH2)0~5CH3, -SO2(CH2)0~5CH3, -CO(CH2)0~5CH=CH2, -CONR 4 (CH2) 0-5CH = CH2, -COO(CH2)0~5CH=CH2, -SO2(CH2)0~5CH=CH2, -CO(CH2)0~5CH=CHCH3, -COO(CH2)0~5CH=CHCH3, -CONR 4 (CH2)0~5CH=CHCH3, -SO2(CH2)0~5CH=CHCH3, -CO(CH2)0~5C≡CH, -COO(CH2)0~5C≡CH, -CONR 4 (CH2)0~5C≡CH, -SO2(CH2)0~5C≡CH, -CO(CH2)0~5C≡CCH3, -COO(CH2)0~5C≡CCH3, -CONR 4 (CH2)0-5C≡CCH3, and -SO2(CH2)0-5C≡CCH3, each of these aforementioned groups being selected from the group consisting of one, two, three, or four R 6 may be substituted by: In some embodiments, R 3 teeth, [ka] may be selected from the group consisting of; R 4 may be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. R 5 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2SCH3, -CH2Ph, -CH2PhOH, -CH2OH, -CHOHCH3, -CH2CONH2, -CH2CH2CONH2, -CH2SH, -CH2SeH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2CH2NH2, [ka] It may be; Each R 6may be independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, -F, -Br, -Cl, -CF3, -NO2, -OH, -OCH3, -CN, or an unsubstituted amino group or an amino group substituted with methyl, ethyl, or propyl.

[0025] In certain embodiments, the compounds of the present invention are specifically 2 , Ar, Z, L, AA, m, and R 3 each of which has the following formula (II) as defined above: [ka] Those with or an optically pure stereoisomer, a pharma- ceutically acceptable salt, or a solvate thereof.

[0026] In certain embodiments, the compounds of the present invention are specifically 2 , A.A., and R. 3 each of which has the following formula (III) as defined above: [ka] As shown in or an optically pure stereoisomer, a pharma- ceutically acceptable salt, or a solvate thereof.

[0027] Various compounds of the present disclosure are generally synthesized by an appropriate combination of established synthetic methods. Various techniques useful in synthesizing the compounds of the present disclosure are readily apparent to those skilled in the relevant art, and are also available. The discussion below is provided to illustrate some of the various methods available for use in assembling the compounds of the present disclosure. However, the discussion is not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds of the present disclosure. A general synthesis of various compounds in the present application is shown in Scheme 1, but is not limited to this scheme: In Scheme 1, R and R 1may form a ring (e.g., pyrrolidine, morpholine, piperazine, or piperidine, which may be substituted); R 3 , R 4 , and R 5 may all be H, or one or more may independently be Me, F, CHN(CH), but are not limited to these substituents. 2 is as defined in Equation 1. [ka] [Table 1]

[0028] The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to both 1) therapeutic procedures or measures that cure, slow, or alleviate the symptoms of a diagnosed pathological condition, disease or disorder and / or halt the progression of a diagnosed pathological condition, disease or disorder, and 2) prophylactic / preventative measures. Those in need of treatment can include individuals who already have a particular medical disease or disorder, as well as those who may eventually suffer from the disorder (i.e., those in need of preventative measures).

[0029] The term "subject," as used herein, refers to any individual or patient upon which the subject method is performed. Generally, the subject is a human, although, as will be understood by one of skill in the art, the subject may be an animal.

[0030] The term "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," or similar terms refer to an amount of a compound of interest that will elicit the biological or medical response in a tissue, system, animal, or human that is being sought by administering said compound. Generally, the response is either an improvement in symptoms in a patient, or a desired biological outcome. Such an amount should be sufficient to inhibit the enzymatic activity of a tyrosine kinase.

[0031] Also disclosed herein are various pharmaceutical compositions comprising a compound having the structure of formula (I). The term "pharmaceutical acceptable carrier" refers to a non-toxic carrier that may be administered to a patient together with the compound of the present disclosure and does not destroy its pharmacological activity. Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin, etc.), buffer substances (e.g., phosphates, etc.), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, etc.), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0032] Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as, for example, human serum albumin), buffer substances (such as, for example, phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as, for example, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, etc.), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, and self-emulsifying drug delivery systems (SEDDS) (such as, for example, α-tocopherol, polyethylene glycol 1000 succinate, or other similar polymer-based delivery matrices).

[0033] In pharmaceutical compositions containing only the compounds described herein as active ingredients, the methods for administering these compositions may additionally include administering additional drugs or treatments to the subject. Such treatments include, but are not limited to, anemia treatments, diabetes treatments, hypertension treatments, cholesterol treatments, neuropharmacological drugs, drugs that regulate cardiovascular function, drugs that regulate inflammation, immune function, blood cell production, hormones and antagonists, drugs that affect gastrointestinal function, chemotherapeutic agents for microbial diseases, and / or chemotherapeutic agents for neoplastic diseases. Other pharmacological treatments may include any other drug or biologic found in any drug class. For example, other drug classes may include allergy / cold / ENT therapies, analgesics, anesthetics, anti-inflammatory agents, antibacterial agents, antiviral agents, asthma / pulmonary treatments, cardiovascular treatments, dermatological treatments, endocrine / metabolic treatments, gastrointestinal treatments, cancer treatments, immunological treatments, neurological treatments, ophthalmological treatments, psychiatric treatments, or rheumatological treatments. Other examples of drugs or treatments that may be administered in conjunction with the compounds described herein include matrix metalloprotease inhibitors, lipoxygenase inhibitors, cytokine antagonists, immunosuppressants, cytokines, growth factors, immunomodulators, prostaglandins, or anti-vascular hyperproliferative compounds.

[0034] The term "therapeutically effective amount," as used herein, refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, physician, or other clinician, where such response includes one or more of the following: (1) preventing a disease; e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder, but has not yet experienced or exhibited the pathology or symptomology of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomology); and (3) ameliorating a disease; e.g., ameliorating a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology).

[0035] The compounds of the present disclosure may be used in conventional manner to suppress the diseases described herein, including (but not limited to) cancer.Such methods of treatment, their dosage levels and requirements may be selected by those skilled in the art from available methods and techniques.For example, the compounds of the present disclosure may be combined with pharmaceutically acceptable adjuvants for administration to patients suffering from cancer in a pharmaceutically acceptable manner and in an amount effective for treating cancer.

[0036] Alternatively, the compounds of the present disclosure may be used in compositions and methods for treating or protecting individuals against diseases described herein, including, but not limited to, cancer, for extended periods of time. The compounds of the present disclosure may be used in such compositions, either alone or together with other compounds of the present disclosure, in a manner that is consistent with the conventional use of such compounds in pharmaceutical compositions. For example, the compounds of the present disclosure may be combined with pharma- ceutically acceptable adjuvants conventionally used in vaccines and administered in prophylactically effective amounts to protect individuals against diseases described herein, including, but not limited to, cancer, for extended periods of time.

[0037] As used herein, the term "combination," "combined," and related terms indicate that therapeutic agents are administered simultaneously or sequentially in accordance with the present disclosure. For example, the described compounds may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form that includes the described compounds, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "in combination" when a patient or individual is exposed to both agents simultaneously. In many embodiments, two or more agents are considered to be administered "in combination" when a patient or individual simultaneously exhibits therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., in the brain, serum, etc.).

[0038] When the compounds of the present disclosure are administered in combination therapy with other agents, they may be administered sequentially or concurrently to a patient. Alternatively, a pharmaceutical or prophylactic composition according to the present disclosure includes a combination of ivermectin, or any other compound described herein, and another therapeutic or prophylactic agent. Additional therapeutic agents that are normally administered to treat a particular disease or condition may be referred to as "agents appropriate for the disease or condition being treated."

[0039] The compounds utilized in the compositions and methods of the present disclosure may also be modified by appending appropriate functional groups to enhance selective biological properties. A variety of such modifications are known in the art and include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, or central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and / or alter excretion rate.

[0040] According to a preferred embodiment, the compositions of the present disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human. Such pharmaceutical compositions are used to ameliorate, treat, or prevent in a subject any of the diseases described herein, including, but not limited to, cancer.

[0041] The agents of the present disclosure are often administered as pharmaceutical compositions containing an active therapeutic agent, i.e., and various other pharma- ceutical acceptable ingredients. See Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred form depends on the intended mode of administration and therapeutic application. The composition may also contain pharma-ceutical acceptable non-toxic carriers or diluents, defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration, depending on the desired formulation. The diluents are selected so as not to affect the biological activity of the combination. Examples of such diluents include distilled water, physiological phosphate-buffered saline, Ringer's solution, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also contain other carriers, adjuvants, or non-toxic non-therapeutic non-immunogenic stabilizers and the like.

[0042] In some embodiments, the present disclosure provides pharma- ceutical acceptable compositions comprising a therapeutically effective amount of one or more of the described compounds formulated together with one or more pharma- ceutical acceptable carriers (additives) and / or diluents for use in treating diseases described herein, including but not limited to cancer. While it is possible for the described compounds to be administered alone, it is preferred to administer the described compounds as a pharmaceutical formulation (composition) as described herein. The described compounds may be formulated for administration in any convenient manner for use in human or veterinary medicine, by analogy with other pharmaceuticals.

[0043] As described in detail, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for: oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., tablets intended for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., by sterile solution or suspension, or such injection as a sustained release formulation; topical application, e.g., as a cream, ointment, or controlled release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or rectally, e.g., as a pessary, cream, or foam; sublingually; ophthalmically; transdermally; or intranasally, to the lungs, and other mucosal surfaces.

[0044] Wetting agents, emulsifying agents and lubricating agents, such as, for example, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0045] Examples of pharma- ceutically acceptable antioxidants include water soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0046] Formulations for use according to the present disclosure include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be provided in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of the active ingredient. In some embodiments, this amount will range from about 5% to about 70%, from about 10% to about 50%, or from about 20% to about 40%.

[0047] In certain embodiments, the formulations as described herein comprise an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents (such as bile acids), and polymeric carriers (such as polyesters and polyanhydrides) and a compound of the present disclosure. In certain embodiments, the formulations render the compounds described of the present disclosure orally bioavailable.

[0048] Methods of preparing formulations or compositions containing the described compounds include the step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations may be prepared by uniformly and intimately bringing into association a compound of the present disclosure with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0049] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oily solutions or suspensions may also contain a diluent or dispersant that is a long-chain alcohol, such as those listed in the Pharmacopeia Helvetica (Swiss Pharmacopoeia), or a similar alcohol. Other commonly used surfactants, such as Tween, Spans, and other emulsifiers or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid dosage forms, liquid dosage forms, or other dosage forms, may also be used for formulation purposes.

[0050] In some cases, it may be desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong the effect of the drug.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The rate of absorption of the drug then depends on its dissolution rate, which in turn can depend on crystal size and crystalline form.In an alternative, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0051] Injectable depot forms are made by forming microencapsule matrices of the described compounds in biodegradable polymers, such as, for example, polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0052] The pharmaceutical composition of the present disclosure may be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, and aqueous suspensions and solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and solutions and propylene glycol are orally administered, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0053] Formulations described herein that are suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or tragacanth), powders, granules, or as a solution or suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a flavoring (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic), and / or as a mouthwash, and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. The compounds described herein may also be administered as a bolus, electuary, or paste.

[0054] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers (such as, for example, sodium citrate or dicalcium phosphate) and / or any of the following: fillers or extenders, such as, for example, starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; wetting agents, such as, for example, glycerol; disintegrating agents. Examples of suitable additives include, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders, for example, paraffin; absorption accelerators, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol monostearate, and nonionic surfactants; absorbents, for example, kaolin and bentonite clay; lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-shelled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0055] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets may be made in a suitable machine in which a mixture of powdered compounds is moistened with an inert liquid diluent. If a solid carrier is used, the preparation may be in tablet form, or may be placed in a hard gelatin capsule in powder or pellet form, or may be in the form of a troche or lozenge. The amount of solid carrier may range, for example, from about 25 to 800 mg, and preferably from about 25 to 400 mg. When a liquid carrier is used, the preparation may be in the form of, for example, a syrup, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., an ampoule or non-aqueous liquid suspension, etc.). Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the above-mentioned carriers in a hard gelatin capsule shell.

[0056] Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, may be scored as required, or may be prepared with coatings and shells, such as enteric coatings and other coatings that are well known in the pharmaceutical compounding art. Alternatively or additionally, they may be formulated to provide slow or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres in various proportions to provide the desired release profile. They may be formulated for rapid release, for example, lyophilized. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that may be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also contain opacifying agents as required, and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Various examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0057] The liquid dosage form for oral administration of the compounds of the present disclosure includes pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in this technical field, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0058] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0059] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0060] The pharmaceutical composition of the present disclosure may also be administered in the form of suppositories for rectal administration.These compositions may be prepared by mixing the compound of the present disclosure with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore will melt in the rectum and release the active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycol.

[0061] Topical administration of the pharmaceutical composition of the present disclosure is particularly useful when the desired treatment involves areas or organs that are easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petroleum oil, white petroleum oil, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutical composition may be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical composition of the present disclosure may also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically administered transdermal patches are also included in the present disclosure.

[0062] The pharmaceutical compositions of the present disclosure may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical compounding and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0063] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, either with or without a preservative (such as, for example, benzylalkonium chloride), or, preferably, as a solution in isotonic, pH-adjusted, sterile saline. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated in an ointment (such as, for example, petrolatum).

[0064] Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present disclosure to the body.Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium.Absorption enhancers may also be used to increase the flux of the compound across the skin.The rate of such flux may be controlled, whether by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0065] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate, etc. Proper fluidity can be maintained, for example, by the use of coating materials (e.g., lecithin, etc.), by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0066] Such compositions may also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. It may be desirable in certain embodiments to include one or more antibacterial and / or antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, and the like. Alternatively or additionally, it may be desirable to include isotonic agents, such as sugars, sodium chloride, and the like, in the composition. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0067] In certain embodiments, the described compounds or pharmaceutical preparations are administered orally. In other embodiments, the described compounds or pharmaceutical preparations are administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administration.

[0068] When the compounds described herein are administered as pharmaceuticals to humans and animals, the compounds may be given per se or as pharmaceutical compositions, e.g., pharmaceutical compositions containing 0.1% to 99.5% of the active ingredient in combination with a pharma- ceutically acceptable carrier. In some embodiments, 0.5% to 90% of the active ingredient may be used. The preparations described herein may be given orally, parenterally, topically, or rectally. The preparations are, of course, given in a form suitable for the appropriate route of administration. For example, the preparations are given in tablet or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., by administration by injection, infusion or inhalation, by topical administration by lotion or ointment, and by rectal administration by suppository. Oral administration is preferred.

[0069] Such compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally (e.g., by aerosol), rectally, intravaginally, parenterally, intracisternally, and topically (including bucally and sublingually) such as by powders, ointments or drops.

[0070] Regardless of the route of administration selected, the compounds described herein, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present disclosure are formulated into pharma- ceutical acceptable dosage forms by conventional methods known to those of skill in the art.

[0071] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0072] The term "administration" and / or "administering" should be understood to mean providing a pharmaceutical composition in a therapeutically effective amount to a subject in need of treatment. The route of administration may be enteral, topical or parenteral. As such, the routes of administration include, but are not limited to, intradermal, subcutaneous, intravenous, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal administration, oral, sublingual buccal, rectal, vaginal, nasal ocular, as well as injection, inhalation, and spray.

[0073] The term "cancer" refers to a group of diseases characterized by abnormal and uncontrolled cell proliferation that begins at one site (primary site) and has the potential to invade and spread to other sites (secondary sites, metastases), which distinguishes cancer (malignant tumors) from benign tumors. Virtually every organ can be affected, resulting in over 100 types of cancer that can affect humans. Cancer can result from many causes, including genetic predisposition, viral infection, exposure to ionizing radiation, exposure to environmental pollutants, tobacco and / or alcohol use, obesity, poor diet, lack of physical activity, or any combination thereof.

[0074] Exemplary cancers include: acute lymphoblastic leukemia, adult; acute lymphoblastic leukemia, pediatric; acute myeloid leukemia, adult; adrenocortical carcinoma; adrenocortical carcinoma, pediatric; AIDS-related lymphoma; AIDS-related malignancies; anal cancer; astrocytoma, pediatric cerebellum; astrocytoma, pediatric brain; cholangiocarcinoma, extrahepatic; bladder cancer; bladder cancer, pediatric; bone cancer, osteosarcoma / malignant fibrous histiocytoma; brain stem glioma, pediatric ;Brain tumors, adults;Brain tumors, brain stem gliomas, children;Brain tumors, cerebellar astrocytoma, children;Brain tumors, brain astrocytoma / malignant glioma, children;Brain tumors, ependymoma, children;Brain tumors, medulloblastoma, children;Brain tumors, supratentorial primitive neuroectodermal tumor, children;Brain tumors, visual pathway and hypothalamic glioma, children;Brain tumors, children (other);Breast cancer;Breast cancer and pregnancy;Breast cancer, children;Breast cancer, male;Bronchial adenoma / carcinoma id, pediatric;carcinoid tumor, pediatric;carcinoid tumor, gastrointestinal;carcinoma, adrenal cortex;carcinoma, pancreatic islet cell;carcinoma of unknown primary;central nervous system lymphoma, primary;cerebellar astrocytoma, pediatric;cerebral astrocytoma / malignant glioma, pediatric;cervical cancer;pediatric cancer;chronic lymphocytic leukemia;chronic myeloid leukemia;chronic myeloproliferative disorder;clear cell sarcoma of tendon sheath;colon cancer;colorectal cancer, pediatric;cutaneous T-cell lymphoma;child Endometrial cancer;Ependymoma, pediatric;Epithelial carcinoma, ovarian;Esophageal cancer;Esophageal cancer, pediatric;Ewing's family of tumors;Extracranial germ cell tumors, pediatric;Extragonadal germ cell tumors;Extrahepatic bile duct cancer;Eye cancer, intraocular melanoma;Eye cancer, retinoblastoma;Gallbladder cancer;Gastric (stomach) cancer;Gastric (stomach) cancer, pediatric;Gastrointestinal carcinoid tumors;Germ cell tumors, extracranial, pediatric;Germ cell tumors, extragonadal;Germ cell tumors, ovarian;Gestational trophoblastic tumor;Glioma.Pediatric brain stem;Glioma. Visual pathway and hypothalamus in children;Hairy cell leukemia;Head and neck cancer;Hepatocellular (liver) cancer, adult (primary);Hepatocellular (liver) cancer, childhood (primary);Hodgkin's lymphoma, adult;Hodgkin's lymphoma, childhood;Hodgkin's lymphoma during pregnancy;Hypopharyngeal cancer;Glioma of the hypothalamus and visual pathway, childhood;Intraocular melanoma;Islet cell carcinoma (endocrine pancreas);Kaposi's sarcoma;Kidney cancer;Laryngeal cancer;Laryngeal cancer, childhood;Leukemia, acute lymphoblastic, adult;Leukemia, acute lymphoblastic, childhood;Leukemia, acute myeloid, adult;Leukemia, acute myeloid, childhood;Leukemia, chronic lymphocytic;Leukemia, chronic myeloid;Leukemia, hairy cell;Cancer of the lip and oral cavity;Liver cancer, adult (primary);Liver cancer, childhood (primary);Lung cancer, non-small cell;Lung cancer, small cell;Lymphoblastic leukemia, adult acute;Lymphoblastic leukemia, childhood acute;Lymphocytic leukemia, chronic;Lymphoma, AIDS-related;Lymphoma, central nervous system (primary);Lymphoma, cutaneous T-cell;Lymphoma, Hodgkin, adult;Lymphoma, Hodgkin;Childhood;Lymphoma, Hodgkin during pregnancy;Lymphoma, non-Hodgkin, adult;Lymphoma, non-Hodgkin, childhood;Lymphoma, non-Hodgkin during pregnancy;Lymphoma, primary central nervous system;Macroglobulinemia, Waldenstrom;Male breast cancer;Malignant mesothelioma, adult;Malignant mesothelioma, childhood;Malignant thymoma;Medulloblastoma, childhood;Melanoma;Melanoma, intraocular;Melanoma Luke's cell carcinoma;Mesothelioma, malignant;Metastatic squamous cell neck carcinoma of unknown primary;Multiple endocrine neoplasia syndrome, childhood;Multiple myeloma / plasma cell neoplasm;Mycosis fungoides;Myelodysplastic syndrome;Myeloid leukemia, chronic;Myeloid leukemia, childhood acute;Myeloma, multiple;Myeloproliferative disorder, chronic;Cancer of the nasal cavity and paranasal sinuses;Nasopharyngeal carcinoma;Nasopharyngeal carcinoma, childhood;Neuroblastoma;Non-Hodgkin's lymphoma, adult;Non-Hodgkin's lymphoma, childhood;Non-Hodgkin's lymphoma in pregnancy;Non-small cell lung cancer;Oral cavity cancer, childhood;Cancer of the oral cavity and lip;Oropharyngeal cancer;Osteosarcoma / malignant fibrous histiocytoma of bone;Ovarian cancer, childhood;Ovarian epithelial carcinoma;Ovarian germ cell tumor ;Ovarian low malignant potential tumor;Pancreatic cancer;Pancreatic cancer, children;Pancreatic cancer, islet cell;Cancer of the paranasal sinuses and nasal cavity;Parathyroid cancer;Penile cancer;pheochromocytoma;Pineal and supratentorial primitive neuroectodermal tumors, children;Pituitary tumors;Plasma cell neoplasm / multiple myeloma;Pleuropulmonary blastoma;Pregnancy and breast cancer;Pregnancy and Hodgkin's lymphoma;Pregnancy and non-Hodgkin's lymphoma;Primary central nervous system lymphoma;Primary liver cancer, adults;Primary liver cancer, children;Prostate cancer;Rectal cancer;Renal cell (kidney) cancer;Renal cell carcinoma, children;Renal pelvis and ureter, transitional cell carcinoma;Retinoblastoma;Rhabdomyosarcoma, children;Salivary gland cancer;Salivary gland cancer, children;Meat tumors, Ewing's family of tumors;sarcoma, Kaposi;sarcoma (osteosarcoma V) malignant fibrous histiocytoma of bone;sarcoma, rhabdomyosarcoma, childhood;sarcoma, soft tissue, adult;sarcoma, soft tissue, childhood;Sezary syndrome;skin cancer;skin cancer, childhood;skin cancer (melanoma);skin cancer, Merkel cell;small cell lung cancer;small intestine cancer;soft tissue sarcoma, adult;soft tissue sarcoma, childhood;squamous cell neck carcinoma of unknown primary, metastatic;gastric (stomach) cancer;gastric (stomach) cancer, childhood;supratentorial primitive neuroectodermal tumor, childhood;T-cell lymphoma, skin;testicular cancer;thymoma, childhood;thymoma, malignant;thyroid cancer;thyroid cancer, childhood;transitional cell carcinoma of the renal pelvis and ureter;Trophoblastic tumor, gestational; cancer of unknown primary site, childhood; uncommon cancer of childhood; ureter and renal pelvis, transitional cell carcinoma; urethral carcinoma; uterine sarcoma; vaginal carcinoma; glioma of the optic pathway and hypothalamus, childhood; vulvar carcinoma; Waldenstrom's macroglobulinemia; and Wilms' tumor.

[0075] In certain aspects, the cancer includes lung cancer, breast cancer, colorectal cancer, prostate cancer, gastric cancer, liver cancer, cervical cancer, esophageal cancer, bladder cancer, non-Hodgkin's lymphoma, leukemia, pancreatic cancer, kidney cancer, endometrial cancer, head and neck cancer, lip cancer, oral cavity cancer, thyroid cancer, brain cancer, ovarian cancer, melanoma, gallbladder cancer, laryngeal cancer, multiple myeloma, nasopharyngeal cancer, Hodgkin's lymphoma, testicular cancer, and Kaposi's sarcoma.

[0076] In certain embodiments, the method further comprises administering a chemotherapeutic agent. The compounds of the present disclosure may be administered in combination with one or more additional therapeutic agents. The phrases "combination therapy", "combined with" and similar phrases refer to the simultaneous use of two or more drug therapies or treatments to enhance response. The tyrosine kinase inhibitors of the present disclosure may be used in combination with other drugs or treatments, for example, in use to treat cancer. In various embodiments, the compounds are administered prior to, concurrently with, or after the administration of the chemotherapeutic agent.

[0077] The term "anti-cancer therapy" refers to any therapy or procedure that may be used to treat cancer. Anti-cancer therapy includes, but is not limited to, surgery, radiation therapy, chemotherapy, immunotherapy, and targeted therapy.

[0078] Examples of chemotherapeutic or anticancer agents include actinomycin, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fiuorouracil, gemcitabine, hydroxyurea, isoflurane, and cyclophosphamide. Darubicin, imatinib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, panitumamab, Erbitux (cetuximab), matuzumab, IMC-IIF8, TheraCIM h-R3, denosumab, Avastin (bevacizumab), Humira (adalimumab), Herceptin (trastuzumab), Remicade (infliximab), rituximab, Synagis (palivizumab), Mylotarg (gemtuzumab oxogamicin), Raptiva (efalizumab), Tysabri (natalizumab), Zenapax (dacliximab), Neutrospec (technetium (99mTc) fanolesomab), tocilizumab, Prostasint (indium-111 labeled capromab penicillin-2000). ndetide), Bexar (tositumomab), Zevalin (ibritumomab tiuxetan conjugated to yttrium-90 (IDEC-Y2B8)), Xolair (omalizumab), MabThera (rituximab), LeoPro (abciximab), MabCampus (alemtuzumab), Simulect (basiliximab), LeukoScan (sulesomab), CEA-Scan (arcitumomab), Verluma (nofetumomab), Panorex (edrecolomab), alemtuzumab, CDP870, natalizumab gilotrif (afatinib), Lynparza (olaparib), Perjeta (pertuzumab), Otdivo (nivolumab), Boslif (bosutinib), Cabometyx (cabozantinib), Ogivri (trastuzumab-dkst), Sutent (sunitinib malate), Adcetris (brentuximab vedotin), Alecensa (alectinib), Calque These include, but are not limited to, ALANCE (acalabrutinib), Yescarta (ciloleucel), Verzenio (abemaciclib), Keytruda (pembrolizumab), Aliqopa (copanlisib), Nerlynx (neratinib), Imfinzi (durvalumab), Darazlex (daratumumab), Tecentriq (atezolizumab), and Tarceva (erlotinib).

[0079] Examples of immunotherapeutic agents include, but are not limited to, interleukins (Il-2, Il-7, Il-12), cytokines (interferon, G-CSF, imiquimod), chemokines (CCL3, CCl26, CXCL7), and immunomodulatory imide drugs (thalidomide and its analogs).

[0080] In treatment, the dosage of the agent ranges from about 0.0001 mg / kg to about 100 mg / kg of the subject's body weight, from about 0.01 mg / kg to about 5 mg / kg of the subject's body weight, from about 0.15 mg / kg to about 3 mg / kg of the subject's body weight, from 0.5 mg / kg to about 2 mg / kg of the subject's body weight, and from about 1 mg / kg to about 2 mg / kg of the subject's body weight, as appropriate. In other embodiments, the dosage ranges from about 100 mg / kg to about 5 g / kg of the subject's body weight, from about 500 mg / kg to about 2 mg / kg of the subject's body weight, and from about 750 mg / kg to about 1.5 g / kg of the subject's body weight. For example, depending on the type and severity of the disease, about 1 μg / kg to 15 mg / kg of the agent (e.g., 0.1 to 20 mg / kg) is a candidate dosage for administration to a patient, whether by one or more separate administrations or by continuous infusion, for example. Typical daily dosages range from about 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administration over several days or more, depending on the condition, treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. Unit doses may, for example, range from about 5 mg to 500 mg: for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg. The progress of the treatment is monitored by conventional techniques and assays.

[0081] In some embodiments, the agent is administered to a human patient in an effective amount (or dose) of less than about 1 μg / kg, for example, about 0.35 to about 0.75 μg / kg or about 0.40 to about 0.60 μg / kg. In some embodiments, the dose of the agent is about 0.35 μg / kg, or about 0.40 μg / kg, or about 0.45 μg / kg, or about 0.50 μg / kg, or about 0.55 μg / kg, or about 0.60 μg / kg, or about 0.65 μg / kg, or about 0.70 μg / kg, or about 0.75 μg / kg, or about 0.80 μg / kg, or about 0.85 μg / kg, or about 0.90 μg / kg, or about 0.95 μg / kg, or about 1 μg / kg. In various embodiments, the absolute dose of drug is about 2 μg / subject to about 45 μg / subject, or about 5 to about 40 μg / subject, or about 10 to about 30 μg / subject, or about 15 to about 25 μg / subject. In some embodiments, the absolute dose of drug is about 20 μg, or about 30 μg, or about 40 μg.

[0082] In various embodiments, the dosage of the agent may be determined by the body weight of the human patient. For example, the absolute dose of the drug may be about 2 μg for a pediatric human patient weighing about 0 to about 5 kg (e.g., about 0 kg, or about 1 kg, or about 2 kg, or about 3 kg, or about 4 kg, or about 5 kg), or about 3 μg for a pediatric human patient weighing about 6 to about 8 kg (e.g., about 6 kg, or about 7 kg, or about 8 kg), or about 5 μg for a pediatric human patient weighing about 9 to about 13 kg (e.g., about 9 kg, or about 10 kg, or about 11 kg, or about 12 kg, or about 13 kg), or about 8 μg for a pediatric human patient weighing about 14 to about 20 kg (e.g., about 14 kg, or about 16 kg, or about 18 kg, or about 20 kg), or about 8 μg for a pediatric human patient weighing about 21 to about 30 kg (e.g., about 21 kg, or about 23 kg, or about 25 kg, or about 27 kg, or about 30 kg). or about 12 μg for a pediatric human patient weighing about 31 to about 33 kg (e.g., about 31 kg, or about 32 kg, or about 33 kg); or about 13 μg for an adult human patient weighing about 34 to about 50 kg (e.g., about 34 kg, or about 36 kg, or about 38 kg, or about 40 kg, or about 42 kg, or about 44 kg, or about 46 kg, or about 48 kg, or about 50 kg); or about 20 μg for an adult human patient weighing about 51 to about 75 kg (e.g., about 51 kg, or about 55 kg, or about 60 kg, or about 65 kg, or about 70 kg, or about 75 kg); or about 45 μg for an adult human patient weighing more than about 114 kg (e.g., about 114 kg, or about 120 kg, or about 130 kg, or about 140 kg, or about 150 kg).

[0083] In certain embodiments, the agents according to the methods provided herein are administered subcutaneously (sc), intravenously (iv), intramuscularly (im), intranasally, or topically. Administration of the agents described herein may be independently 1-4 times per day, or 1-4 times per month, or 1-6 times per year, or once every 2 years, 3 years, 4 years, or 5 years. Administration may be daily or over a period of 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, or even over the life of the human patient. The dosage may be administered as a single dose or may be divided into multiple doses. In some embodiments, the agent is administered about 1 to about 3 times (e.g., 1 time or 2 or 3 times).

[0084] Below are presented examples that discuss the design of novel tyrosine kinase inhibitors contemplated for the uses discussed and the efficacy of the tyrosine kinase inhibitors. The following examples are provided to further illustrate embodiments of the present disclosure, but are not intended to limit the scope of the disclosure. They are typical of those that might be used, but other procedures, methodologies, or techniques known to those of skill in the art may alternatively be used. EXAMPLES

[0085] Example 1 (3S)-4-Prop-2-enoyl-N-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide [ka] Synthesis of (3S)-4-prop-2-enoyl-N-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide [ka] Testing Procedure: [ka]

[0086] To a solution of 2,4-dichloro-5-nitro-pyridine (2 g, 10.36 mmol) in THF (50 mL) was added Et3N (1.36 g, 13.47 mmol) and tert-butyl N-(2-aminoethyl)carbamate (1.99 g, 12.44 mmol). The mixture was stirred at 0° C. for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give tert-butyl N-[2-[(2-chloro-5-nitro-4-pyridyl)amino]ethyl]carbamate (1.6 g, 49% yield) as a yellow solid. [ka]

[0087] To a solution of tert-butyl N-[2-[(2-chloro-5-nitro-4-pyridyl)amino]ethyl]carbamate (1.6 g, 5.05 mmol) in THF (5 mL) and HO (4 mL) was added NH4Cl (2.70 g, 50.51 mmol) and Fe (2.82 g, 50.51 mmol). The mixture was stirred at 65° C. for 3 h. The solution was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL), extracted with DCM (50 mL, 2 times), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-[2-[(5-amino-2-chloro-4-pyridyl)amino]ethyl]carbamate (1.48 g, crude) as a yellow solid. [ka]

[0088] To a solution of tert-butyl N-[2-[(5-amino-2-chloro-4-pyridyl)amino]ethyl]carbamate (1.48 g, 5.16 mmol) in toluene (20 mL) was added CH(OEt)3 (1.15 g, 7.74 mmol) and TsOH (17 mg, 0.103 mmol). The mixture was stirred at 110° C. for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-10% dichloromethane / methanol @ 60 mL / min) to give tert-butyl N-[2-[(6-chloroimidazo[4,5-c]pyridin-1-yl)ethyl]carbamate (1.2 g, 78% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ=8.73(s, 1H), 8.36(s, 1H), 7.76(s, 1H), 6.96(t, J=8Hz, 1H), 4.31-4.26(m, 2H), 3.31-3.30(m, 2H), 1.22(s, 9H). [ka]

[0089] A mixture of 5-(4-pyridyl)thiazol-2-amine (119 mg, 0.673 mmol), tert-butyl N-[2-(6-chloroimidazo[4,5-c]pyridin-1-yl)ethyl]carbamate (200 mg, 0.673 mmol), Xantphos (39 mg, 0.067 mmol), KOAc (132 mg, 1.35 mmol) and Pd(dba)2 (38 mg, 0.067 mmol) in dioxane (20 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 100° C. for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-10% ethyl acetate / petroleum ether gradient @ 60 mL / min) to give tert-butyl N-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (240 mg, 81% yield) as a yellow solid. [ka]

[0090] A solution of tert-butyl N-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (20 mg, 0.045 mmol) in HCl / dioxane (2 mL, 4 M) was stirred for 2 h at 25° C. The mixture was concentrated under reduced pressure to give N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-pyridyl)thiazol-2-amine (20 mg, crude) as a yellow solid. [ka]

[0091] To a solution of N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-pyridyl)thiazol-2-amine (250 mg, 0.740 mmol) in DMF (10 mL) was added HATU (338 mg, 0.889 mmol), (3S)-4-tert-butoxycarbonylmorpholine-3-carboxylic acid (171 mg, 0.740 mmol) and DIEA (287 mg, 2.22 mmol). The mixture was stirred at 25° C. for 2 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL, 2 times). The combined organic layers were washed with water (50 mL, 2 times), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, eluent: 0-15% dichloromethane / methanol @ 50 mL / min) to give tert-butyl (3S)-3-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morpholine-4-carboxylate (290 mg, 71% yield) as a yellow solid. [ka]

[0092] A solution of tert-butyl (3S)-3-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morpholine-4-carboxylate (290 mg, 0.526 mmol) in TFA (3 mL) and DCM (15 mL) was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18 150 * 40mm *Conditions: water (0.04% NH3.H2O+10 mM NH4HCO3)-ACN; B%, 10-40; gradient time: 10 min; flow rate: 25 mL / min) to give (3S)-N-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (180 mg, 76% yield) as a yellow solid. [ka]

[0093] To a solution of (3S)-N-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (50 mg, 0.111 mmol) in NMP (6 mL) was added DIEA (28 mg, 0.222 mmol) and prop-2-enoyl chloride (10 mg, 0.111 mmol). The mixture was stirred at 0° C. for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex luna 30 * 30mm * 10um; Conditions: water (0.225% FA)-ACN; B%, 0-38; Gradient time: 22 min; Flow rate: 25mL / min) to give (3S)-4-prop-2-enoyl-N-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (11 mg, 18% yield) as a yellow solid. LCMS:t R =0.740 min, 5~95AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=505.0[M+H] + . 1H NMR (400MHz, DMSO-d6): δ=11.50-11.38(m, 1H), 8.77(s, 1H), 8.50-8.48(m, 2H), 8.21-8.14(m, 2H), 8.10(s, 1H), 7.56-7.54(m, 2H), 7.18-7.15(m, 1H), 6 .82-6.28(m, 1H), 6.23-5.96(m, 1H), 5.76-5.47(m, 1H), 4.72-4.46(m, 1H), 4.33-4.29(m, 2H), 4.18-4.07(m, 1H), 3.83-3.72(m, 2H), 3.57-3.40(m, 5H). Chiral SFC: tR = 3.925 min (instrument column: Chiral MJ-3 100 × 4.6 mm ID, 3 um, mobile phase: A: CO2, B: ethanol (0.05% DEA); isocratic elution, 8 min, flow rate: 2.8 mL / min, column temperature: 40 °C, UV detection: 220 nm), ee% = 100%. [α] 20 =-89.0(c=0.10g / 100mL, MeOH). Example 2 (2S)-1-[(Z)-But-2-enoyl]-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide [ka] Synthesis of (2S)-1-[(Z)-but-2-enoyl]-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide [ka] Testing Procedure: [ka]

[0094] To a solution of tert-butyl N-[2-(6-chloroimidazo[4,5-c]pyridin-1-yl)ethyl]carbamate (300 mg, 1.01 mmol) and 5-(4-fluorophenyl)thiazol-2-amine (196 mg, 1.01 mmol) in NMP (8 mL) was added BrettPhos Pd G3 (92 mg, 0.10 mmol) and Cs2CO3 (659 mg, 2.02 mmol). The mixture was stirred at 100° C. for 3 h by microwave. The mixture was extracted with ethyl acetate (50 mL, 3 times) and washed with water (50 mL, 7 times). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in petroleum ether) to give tert-butyl N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (732 mg, 22% yield) as a brown oil. [ka]

[0095] A solution of tert-butyl N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (732 mg, 1.61 mmol) in HCl / dioxane (4 M, 8 mL) was stirred at 25° C. for 2 h. The mixture was concentrated and the residue was basified with saturated NaHCO3 until pH=8, then extracted with ethyl acetate (50 mL, 3 times). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and purified by flash column chromatography on silica gel (0% to 100% methanol in dichloromethane) to give N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-fluorophenyl)thiazol-2-amine (307 mg, 37% yield) as a yellow solid. [ka]

[0096] To a solution of (2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (270 mg, 1.26 mmol) in DMF (3 mL) was added HATU (567 mg, 1.49 mmol), DIEA (805 mg, 6.23 mmol) and N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-fluorophenyl)thiazol-2-amine (287 mg, 0.81 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-ACN; B%: 35-65%, 15min; flow rate (25ml / min)) to give tert-butyl (2S)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]pyrrolidine-1-carboxylate (138mg, 26% yield) as a yellow solid. [ka]

[0097] A solution of tert-butyl (2S)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]pyrrolidine-1-carboxylate (138 mg, 0.25 mmol) in HCl / dioxane (4 M, 2 mL) was stirred for 2 h at 25° C. The mixture was concentrated under reduced pressure to give (2S)—N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (140 mg, crude) as a yellow solid. [ka]

[0098] To a solution of (Z)-but-2-enoic acid (20 mg, 0.23 mmol) in DMF (1 mL) and NMP (1 mL) was added HATU (88 mg, 0.23 mmol), DIEA (200 mg, 1.55 mmol) and (2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (70 mg, 0.16 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-ACN; B%: 30-50%, 15 min; flow rate (25 ml / min)) to give (2S)-1-[(Z)-but-2-enoyl]-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (21.9 mg, 26% yield) as a white solid. LCMS:t R =1.401 min, 10~80AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=520.4[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.45-11.19(m, 1H), 8.77(s, 1H), 8.44-8.21(m, 1H), 8.20-8.01(m, 1H), 7.74(s, 1H), 7.68-7.56 (m, 2H), 7.30-7.13(m, 3H), 6.81-6.57(m, 1H), 6.31-5.77(m, 1H), 4.32-4.17(m, 3H), 3.60-3.48(m, 3H), 2.11-0.93(m, 8H). Example 3 (2S)-1-[(E)-4-(Dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide [ka] Synthesis of (2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide [ka]

[0099] Testing Procedure: To a solution of (2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (70 mg, 0.16 mmol) in DMF (2 mL) was added DIEA (200 mg, 1.55 mmol), (E)-4-(dimethylamino)but-2-enoic acid (22 mg, 0.17 mmol) and PyBOP (89 mg, 0.17 mmol). The mixture was stirred at 25° C. for 2 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-ACN; B%: 0-50%, 15 min; flow rate (25 ml / min)) to give (2S)-1-[(E)-4-(dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (18.1 mg, 21% yield) as a yellow solid. LCMS:t R =1.172 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=563.2[M+H] + . 1H NMR (400MHz, DMSO-d6): δ=11.49-10.88(m, 1H), 8.76-8.70(m, 1H), 8.26-8.01(m, 2H), 7.74-7.69(m, 1H), 7.67-7.57(m, 2H), 7.31-7.08(m, 3H), 6.75-6.50(m, 1H), 6.43-5.93(m, 1H), 4.37-4.18(m, 3H), 3.69-3 .54(m, 4H), 3.12-2.96(m, 2H), 2.29-2.01(m, 6H), 2.01-1.09(m, 4H). Example 4 (2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-(2-fluoroprop-2-enoyl)pyrrolidine-2-carboxamide [ka] Synthesis of (2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-(2-fluoroprop-2-enoyl)pyrrolidine-2-carboxamide [ka]

[0100] Testing Procedure: To a solution of 2-fluoroprop-2-enoic acid (21 mg, 0.23 mmol) in DMF (1 mL) and NMP (1 mL) was added HATU (88 mg, 0.23 mmol), DIEA (200 mg, 1.55 mmol) and (2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (70 mg, 0.16 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: C18-6 100 * 30mm *5um; mobile phase: water (FA)-ACN; B%: 30-50%, 15 min; flow rate (25 ml / min)) to give (2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-(2-fluoroprop-2-enoyl)pyrrolidine-2-carboxamide (17.5 mg, 20% yield) as a white solid. LCMS:t R =1.365 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=524.3[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.59-11.16(m, 1H), 8.80(s, 1H), 8.44-8.27(m, 1H), 8.21-8.10(m, 1H), 7.76(s, 1H), 7.64( dd. Example 5 2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Synthesis of (2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka]

[0101] Testing Procedure: To a solution of (2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (77 mg, 0.17 mmol) in DCM (2 mL) was added DIEA (220 mg, 1.71 mmol) and prop-2-enoyl chloride (17 mg, 0.19 mmol) at 0° C. Then the mixture was stirred at 25° C. for 1 h. The mixture was filtered and the filtrate was concentrated and purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-ACN; B%: 10-80%, 15 min; flow rate (25 ml / min)) to give (2S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide (4.6 mg, 5% yield) as a white solid. LCMS:t R =1.406 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=506.2[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.33-11.02(m, 1H), 8.73(s, 1H), 8.28-8.01(m, 2H), 7.84-7.51(m, 3H), 7.30-7.13(m, 3H) ), 6.66-6.49(m, 1H), 6.27-6.00(m, 1H), 5.77-5.45(m, 1H), 4.38-4.17(m, 3H), 3.68-3.44(m, 3H), 2.14-1.10(m, 5H). Example 6 (3S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide [ka] Synthesis of (3S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide [ka] Testing Procedure: [ka]

[0102] To a solution of (3S)-4-tert-butoxycarbonylmorpholine-3-carboxylic acid (261 mg, 1.13 mmol) in DMF (3 mL), HATU (509 mg, 1.34 mmol) and DIEA (724 mg, 5.60 mmol), N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-fluorophenyl)thiazol-2-amine (258 mg, 0.73 mmol) were added. The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-ACN; B%: 35-65%, 15 min; flow rate (25 ml / min)) to give tert-butyl (3S)-3-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morpholine-4-carboxylate (246 mg, 57% yield) as a yellow oil. [ka]

[0103] A solution of tert-butyl (3S)-3-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morpholine-4-carboxylate (246 mg, 0.43 mmol) in HCl / dioxane (4 M, 3 mL) was stirred for 2 h at 25° C. The reaction mixture was concentrated under reduced pressure to give (3S)—N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (249 mg, crude) as a yellow solid. [ka]

[0104] To a solution of (3S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (149 mg, 0.32 mmol) in NMP (2 mL) was added DIEA (412 mg, 3.19 mmol) and prop-2-enoyl chloride (32 mg, 0.35 mmol) at 0° C. The mixture was then stirred at 25° C. for 1 h. The mixture was purified by prep-HPLC (column: Phenomenex C18 75 * 30mm * 3um; mobile phase: water (NH3.H2O+NH4HCO3)-ACN; B%: 24-54%, 11 min; flow rate (25 ml / min)) to give (3S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide (10.2 mg, 6% yield) as a white solid. LCMS:t R =1.356 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=522.1[M+H] + . 1H NMR (400MHz, DMSO-d6): δ=11.26-11.08(m, 1H), 8.77-8.69(m, 1H), 8.25-8.08(m, 2H), 7.72(s, 1H), 7.62(dd, J= 8.8, 5.2Hz, 2H), 7.28-7.11(m, 3H), 6.87-5.46(m, 3H), 4.75-3.46(m, 9H), 2.81-2.67(m, 1H), 2.21-0.83(m, 1H). Example 7 (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-azetidine-2-carboxamide [ka] Synthesis of (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-azetidine-2-carboxamide [ka] Testing Procedure: [ka]

[0105] To a mixture of tert-butyl N-(5-bromothiazol-2-yl)carbamate (25 g, 89 mmol), (4-methoxyphenyl)methanol (24 g, 179 mmol), PPh3 (51 g, 197 mmol) in THF (500 mL) was added DIAD (40 g, 197 mmol) under N2 at 0 °C. The resulting mixture was stirred at 25 °C under N2 atmosphere for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (0% to 5% ethyl acetate in petroleum ether) to give tert-butyl N-(5-bromothiazol-2-yl)-N-[(4-methoxyphenyl)methyl]carbamate (29.28 g, 77% yield) as an off-white solid. [ka]

[0106] A solution of tert-butyl N-(5-bromothiazol-2-yl)-N-[(4-methoxyphenyl)methyl]carbamate (5 g, 12.52 mmol) in dry THF (80 mL) was cooled to −78° C. under N2 atmosphere, and then n-BuLi (2.5 M, 5.5 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 0.5 h, after which 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2 g, 15.70 mmol) was added and stirred at −78° C. for another 0.5 h. The mixture was warmed to 25 °C, quenched with saturated aqueous NH4Cl (200 mL), extracted with EtOAc (200 mL x 3), then the combined organic layers were dried over Na2SO4, filtered, concentrated and purified by flash column chromatography on silica gel (0% to 7% ethyl acetate in petroleum ether) to give tert-butyl N-[(4-methoxyphenyl)methyl]-N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl]carbamate (3.9 g, 68% yield) as an off-white solid. [ka]

[0107] A solution of tert-butyl N-[(4-methoxyphenyl)methyl]-N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl]carbamate (4 g, 9.0 mmol), 2-bromo-3-fluoro-pyridine (2.8 g, 15.8 mmol), Pd(dppf)Cl2 (1.5 g, 2.0 mmol), K2CO3 (4.2 g, 30.0 mmol) in dioxane (120 mL) and H2O (24 mL) was stirred at 80° C. under N2 atmosphere for 1 h. The mixture was concentrated under reduced pressure to give a residue. The mixture was diluted with saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (200 mL, 3 times), then the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0% to 17% ethyl acetate in petroleum ether) to give tert-butyl N-(5-(3-fluoro-2-pyridyl)thiazol-2-yl)-N-[(4-methoxyphenyl)methyl]carbamate (874 mg, 19% yield) as a yellow solid. [ka]

[0108] A solution of tert-butyl N-(5-(3-fluoro-2-pyridyl)thiazol-2-yl)-N-[(4-methoxyphenyl)methyl]carbamate (873 mg, 2.1 mmol) in TFA (10 mL) was stirred at 75° C. for 12 h. The mixture was concentrated and the residue was adjusted to pH=8 by addition of saturated aqueous NaHCO3, then extracted with EtOAc (20 mL, 3 times). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0% to 58% ethyl acetate in petroleum ether) to give 5-(3-fluoro-2-pyridyl)thiazol-2-amine (353 mg, 78% yield) as a yellow solid. [ka]

[0109] A solution of 5-(3-fluoro-2-pyridyl)thiazol-2-amine (353 mg, 1.8 mmol), tert-butyl N-[2-(6-chloroimidazo[4,5-c]pyridin-1-yl)ethyl]carbamate (536 mg, 1.8 mmol), Cs2CO3 (1.2 g, 3.6 mmol), BrettPhos Pd G3 (164 mg, 0.18 mmol) in dioxane (30 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 90° C. for 12 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (0% to 13% methanol in dichloromethane) to give tert-butyl N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (359 mg, 36% yield) as a yellow solid. [ka]

[0110] A solution of tert-butyl N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (358 mg, 0.78 mmol) in 4M HCl / dioxane (5 mL) was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure to give N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2-pyridyl)thiazol-2-amine (279 mg, crude) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0111] To a solution of (2S)-1-tert-butoxycarbonylazetidine-2-carboxylic acid (96 mg, 0.47 mmol) in DMF (7 mL), HATU (272 mg, 0.71 mmol) and DIEA (185 mg, 1.44 mmol) were added, followed by N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2-pyridyl)thiazol-2-amine (170 mg, 0.47 mmol). The mixture was stirred at 25° C. for 1 h. Water (10 mL) was added to the mixture, and then the mixture was extracted with ethyl acetate (10 mL, 3 times). The combined organic layers were concentrated. The residue was purified by flash column chromatography on silica gel (0% to 8% methanol in dichloromethane) to give tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]azetidine-1-carboxylate (214 mg, 80% yield) as a yellow solid. [ka]

[0112] A solution of tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]azetidine-1-carboxylate (214 mg, 0.39 mmol) in 4M HCl / dioxane (5 mL) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]azetidine-2-carboxamide (170 mg, crude) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0113] To a solution of (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]azetidine-2-carboxamide (170 mg, 0.38 mmol) in NMP (2 mL) was added DIEA (1 g, 7.75 mmol) followed by prop-2-enoyl chloride (56 mg, 0.62 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h. Then, additional prop-2-enoyl chloride (56 mg, 0.62 mmol) was added and the mixture was stirred at 25° C. for another 0.5 h. The mixture was analyzed by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 0-50%, 15 min; flow rate (25 ml / min)) to give (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-azetidine-2-carboxamide (6.3 mg, 3% yield) as an off-white solid. LCMS:t R =1.302 min, 5~95AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=493.1[M+H]+. 1 H NMR (400MHz, DMSO-d6): δ=11.46, 11.38(s, s, 1H), 9.02-8.79(m, 1H), 8.40-8.39(m, 1H), 8.28-8.18(m, 2H), 7.96(d, J=2.0 HZ, 1H), 7.79-7.74(m, 1H), 7.30-7.18(m, 2H), 6.32-5.46(m, 3H), 4.74-7.07(m, 4H), 3.78-3.35(m, 4H), 1.97-1.94(m, 1H). Example 8 (2S)-N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Synthesis of (2S)-N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Testing Procedure: [ka]

[0114] To a solution of tert-butyl N-[(4-methoxyphenyl)methyl]-N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl]carbamate (7 g, 15.68 mmol) and 3-fluoro-4-iodo-pyridine (6.99 g, 31.36 mmol) in dioxane (140 mL) and H2O (30 mL) was added Pd(dppf)Cl2 (1.72 g, 2.35 mmol) and K2CO3 (4.33 g, 31.36 mmol). The mixture was stirred at 80 °C under N2 atmosphere for 2 h. The mixture was concentrated under reduced pressure. Water (50 mL) was added to the mixture, which was then extracted with ethyl acetate (50 mL, 3 times). The combined organic phase was washed with brine (30 mL, 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-18% ethyl acetate in petroleum ether) to give tert-butyl N-[5-(3-fluoro-4-pyridyl)thiazol-2-yl]-N-[(4-methoxyphenyl)methyl]carbamate (2.62 g, 32% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): δ=8.64(d, J=2.8Hz, 1H), 8.43-8.42(m, 1H), 8.24(s, 1H), 7.86-7.83 (m, 1H), 7.26 (d, J=8.8Hz, 2H), 6.90 (d, J=8.8Hz, 2H), 5.22 (s, 2H), 3.71 (s, 3H), 1.52 (s, 9H). [ka]

[0115] A solution of tert-butyl N-[5-(3-fluoro-4-pyridyl)thiazol-2-yl]-N-[(4-methoxyphenyl)methyl]carbamate (2.62 g, 6.31 mmol) in TFA (25 mL) was stirred at 75° C. for 12 h. The mixture was concentrated and the residue was adjusted to pH=8 with saturated aqueous NaHCO3, then extracted with ethyl acetate (150 mL, 3 times). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-4% methanol in dichloromethane) to give 5-(3-fluoro-4-pyridyl)thiazol-2-amine (1.17 g, 67% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ = 8.50 (d, J = 3.6Hz, 1H), 8.31-8.29 (m, 1H), 7.76 (s, 1H), 7.57-7.55 (m, 3H). [ka]

[0116] A mixture of 5-(3-fluoro-4-pyridyl)thiazol-2-amine (250 mg, 1.28 mmol), tert-butyl N-[2-(6-chloroimidazo[4,5-c]pyridin-1-yl)ethyl]carbamate (380 mg, 1.28 mmol), BrettPhos Pd G3 (116 mg, 0.13 mmol), Cs2CO3 (834 mg, 2.56 mmol) in NMP (6 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere in a microwave at 100° C. for 3 h. Water (5 mL) was added to the mixture, then extracted with ethyl acetate (10 mL, 3 times). The organic phase was separated and the organic phase was extracted with water (10 mL, 5 times). The combined organic layers were concentrated and purified by flash column chromatography on silica gel (0% to 9% methanol in dichloromethane) to give tert-butyl N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (172 mg, 7% yield) as a yellow solid. [ka]

[0117] A solution of tert-butyl N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (170 mg, 0.37 mmol) in 4M HCl / dioxane (5 mL) was stirred at 25° C. for 1 h. The mixture was concentrated, water (10 mL) was added to the residue, and the mixture was adjusted to pH=8 by addition of saturated aqueous NaHCO3. The mixture was concentrated in vacuo to give a residue that was then diluted with MeOH (10 mL) and washed with MeOH (10 mL, 3 times). The mixture was filtered and the filtrate was evaporated to give N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-4-pyridyl)thiazol-2-amine (130 mg, 79% yield) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0118] To a solution of (2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (122 mg, 0.57 mmol) in DMF (2 mL) was added HATU (208 mg, 0.55 mmol), DIEA (472 mg, 3.66 mmol) and N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-4-pyridyl)thiazol-2-amine (130 mg, 0.366 mmol). The mixture was stirred at 25° C. for 1 h. Water (10 mL) was added to the mixture, which was then extracted with ethyl acetate (10 mL, 3 times). The organic phase was separated, then washed with brine (30 mL, 5 times), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel (0% to 8% methanol in dichloromethane) to give tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]pyrrolidine-1-carboxylate (176 mg, 84% yield) as a yellow solid. [ka]

[0119] A solution of tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]pyrrolidine-1-carboxylate (176 mg, 0.32 mmol) in 4M HCl / dioxane (3 mL) was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give (2S)-N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (144 mg, 88% yield) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0120] To a solution of (2S)-N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (144 mg, 0.32 mmol) in DCM (3 mL) was added DIEA (411 mg, 3.18 mmol) followed by prop-2-enoyl chloride (31 mg, 0.35 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100 * 30mm * 5um; mobile phase: water (0.05% HCl)-ACN; B%: 20-50%, 9 min; flow rate (25 ml / min)) and lyophilized to give (2S)-N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide (37.9 mg, 23% yield) as a yellow solid. LCMS:t R =0.913 min, at 10~80AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=507.4[M+H]+.1 H NMR (400MHz, DMSO-d6): δ=11.62, 11.53(s, 1H), 8.77(s, 1H), 8.57(d, J=2.4Hz, 1H), 8.36(d, J=4.8Hz, 1H), 8.24-8.09(m, 3H), 7.75(t, J=6.0Hz) , 1H), 7.23, 7.18(s, s, 1H), 6.62-6.01(m, 2H), 5.72-5.46(m, 1H), 4.34 -4.21(m, 3H), 3.65-3.47(m, 4H), 2.05-1.89(m, 1H), 1.76-1.20(m, 3H). Chiral SFC: tR=2.166 min (Instrument column: Chiralpak AS-3 50×4.6 mm ID, 3 um, Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: 5% to 40% B in 2.5 min and hold at 40% for 0.5 min, then hold at 5% B for 1 min; Flow rate: 4 ml / min; Column temperature: 35°C; ABPR: 1500 psi), ee%=99.04%; [α] 20 =+39.0(c=0.1g / 100mL, MeOH). Example 9 (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Synthesis of (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Testing Procedure: [ka]

[0121] To a solution of (2S)-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (103 mg, 0.47 mmol) in DMF (7 mL) was added HATU (217 mg, 0.57 mmol) and DIEA (308 mg, 2.38 mmol), followed by addition of N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2-pyridyl)thiazol-2-amine (169 mg, 0.31 mmol). The mixture was stirred at 25° C. for 1 h. Water (10 mL) was added to the mixture, followed by extraction with ethyl acetate (10 mL, 3 times). The combined organic phase was washed with brine (10 mL, 5 times), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel (0% to 7% methanol in dichloromethane) to give tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]pyrrolidine-1-carboxylate (125 mg, 65% yield) as a yellow solid. [ka]

[0122] A solution of tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]pyrrolidine-1-carboxylate (125 mg, 0.22 mmol) in 4M HCl / dioxane (2 mL) was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (100 mg, crude) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0123] To a solution of (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (100 mg, 0.22 mmol) in DCM (4 mL) was added DIEA (287 mg, 2.22 mmol) followed by prop-2-enoyl chloride (21 mg, 0.23 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 100 * 30mm * 10um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10min; flow rate (25ml / min)) and lyophilized to give (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-1-prop-2-enoyl-pyrrolidine-2-carboxamide (37.7mg, 32% yield) as a yellow solid. LCMS:t R =0.972 min, at 10~80AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=507.0[M+H]+. 1 H NMR (400MHz, DMSO-d6): δ=11.47, 11.38(s, 1H), 8.80(s, 1H), 8.40-8.39(m, 1H), 8.23-8.08(m, 2H), 7.96-7.95(m, 1H), 7.79-7.74(m, 1H), 7.30-7 .26(m, 1H), 7.23-7.17(m, 1H), 6.63-6.02(m, 2H), 5.72-5.47(m, 1H), 4.3 4-4.22(m, 3H), 3.63-3.45(m, 4H), 2.07-1.90(m, 1H), 1.80-1.53(m, 3H). Chiral SFC:t R= 1.660 min (Instrument column: Chiralpak OJ-3 50 × 4.6 mm ID, 3 μm. Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: 5% to 40% B in 2.5 min, and hold 40% for 0.5 min, then hold 5% B for 1 min; Flow rate: 4 ml / min; Column temperature: 35 °C; ABPR: 1500 psi), ee% = 100%; [α]20 = + 29.0 (c = 0.10 g / 100 mL, MeOH). Example 10 (2S)-1-(2-Fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide [ka] Synthesis of (2S)-1-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide [ka]

[0124] Testing Procedure: To a solution of 2-fluoroprop-2-enoic acid (15 mg, 0.17 mmol) in DMF (2 mL) was added HATU (64 mg, 0.17 mmol) and DIEA (146 mg, 1.13 mmol), followed by (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (51 mg, 0.11 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm *5um; mobile phase: [water (FA)-ACN]; B%: 28%-42%, 8 min; flow rate (25 ml / min)) to give (2S)-1-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (10.8 mg, 18% yield) as a yellow solid. LCMS:t R =1.316 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=525.1[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=8.87-8.86(m, 1H), 8.52-8.34(m, 2H), 8.16-8.12(m, 1H), 8.00-7.94(m, 1H), 7.80-7.75(m, 1H), 7. 35-7.21(m, 2H), 5.50-5.08(m, 2H), 4.42-4.20(m, 3H), 3.60(m, 3H), 2.09-1.91(m, 1H), 1.83-1.44(m, 3H), 1.29-1.14(m, 1H). Chiral SFC: tR=1.640 min (Instrument column: Chiralpak OJ-3 50×4.6 mm ID, 3 μm. Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: 5% to 40% B in 2.5 min and hold at 40% for 0.5 min, then hold 5% B for 1 min; Flow rate: 4 ml / min; Column temperature: 35 °C; ABPR: 1500 psi), ee%=100%; [α] 20 =+11.0(c=0.10g / 100mL, MeOH). Example 11 (2S)-1-[(Z)-But-2-enoyl]-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide [ka] Synthesis of (2S)-1-[(Z)-but-2-enoyl]-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide [ka]

[0125] Testing Procedure: To a solution of (Z)-but-2-enoic acid (7 mg, 0.08 mmol) in DMF (2 mL) was added HATU (32 mg, 0.08 mmol) and DIEA (71 mg, 0.55 mmol), followed by (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (25 mg, 0.05 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: Phenomenex C18 75 * 30mm * 3um; mobile phase: [water (NH3.H2O+NH4HCO3)-ACN]; B%: 23%-49%, 9 min; flow rate (25 ml / min)) to give (2S)-1-[(Z)-but-2-enoyl]-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]pyrrolidine-2-carboxamide (11.6 mg, 40% yield) as a white solid. LCMS:t R =1.545 minutes, 10~80CD_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=521.4[M+H] + . 1H NMR (400MHz, DMSO-d6): δ=11.44, 11.37(s, s, 1H), 8.78(s, 1H), 8.40-8.38(m, 1H), 8.23-7.95(m, 3H), 7.78-7.73(m, 1 H), 7.30-7.18(m, 2H), 6.79-6.60(m, 1H), 6.28-5.78(m, 1H), 4.30-4.19(m, 3H), 3.66-3.48(m, 3H), 2.03-1.14(m, 8H). Chiral SFC: tR=1.987 min (Instrument column: Chiralpak OD-3 50×4.6 mm ID, 3 um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: 40% EtOH (0.05% DEA); Flow rate: 4 ml / min; Column temperature: 35° C.; ABPR: 1500 psi), ee%=98.46%; [α] 20 =+14.0(c=0.067g / 100mL, MeOH). Example 12 (3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide [ka] Synthesis of (3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide [ka] Testing Procedure: [ka]

[0126] To a solution of N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2-pyridyl)thiazol-2-amine (420 mg, 1.18 mmol) in DMF (25 mL) was added HATU (696 mg, 1.83 mmol) and DIEA (1.5 g, 11.82 mmol), followed by (3S)-4-tert-butoxycarbonylmorpholine-3-carboxylic acid (410 mg, 1.77 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was added with water (10 mL) and then extracted with ethyl acetate (10 mL, 3 times). The combined organic phase was washed with brine (10 mL, 5 times), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0% to 8% methanol in dichloromethane) to give tert-butyl (3S)-3-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morpholine-4-carboxylate (28 mg, 4% yield) as a white solid. [ka]

[0127] A solution of tert-butyl (3S)-3-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morpholine-4-carboxylate (28 mg, 0.05 mmol) in 4M HCl / dioxane (2 mL) was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give (3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (23 mg, 99% yield) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0128] To a solution of (3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (23 mg, 0.05 mmol) in DCM (2 mL) was added DIEA (63 mg, 0.49 mmol) followed by prop-2-enoyl chloride (5 mg, 0.06 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 108%-80%, 15 min; flow rate (25 ml / min)) and lyophilized to give the product (3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide (1.9 mg, 7% yield) as an off-white solid. LCMS:t R =1.212 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=523.1[M+H] + . 1H NMR (400MHz, DMSO-d6): δ=11.44, 11.33(s, 1H), 8.80-8.79(m, 1H), 8.40-8.39(m , 1H), 8.21-8.14(m, 2H), 7.96(d, J=2.0Hz, 1H), 7.79-7.74(m, 1H), 7.30-7.26(m , 1H), 7.18-7.15(s, s, 1H), 6.84-6.19(m, 1H), 6.00-5.46(m, 1H), 4.71-4.45(m, 1H), 4.34-4.29(m, 2H), 4.18-4.07(m, 2H), 3.83-3.54(m, 3H), 1.33-0.83(m, 4H). Chiral SFC: tR=1.813 min (Instrument column: Chiralpak OJ-3 50×4.6 mm ID, 3 um, Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: 5% to 40% B in 2.5 min and hold at 40% for 0.35 min, then hold at 5% B for 0.15 min; Flow rate: 4 ml / min; Column temperature: 35 °C; ABPR: 1500 psi), ee%=99.12%. Example 13 (2S,4R)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoylpyrrolidine-2-carboxamide [ka] Synthesis of (2S,4R)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoylpyrrolidine-2-carboxamide [ka] Testing Procedure: [ka]

[0129] To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (233 mg, 1.01 mmol) in DMF (2 mL) was added HATU (454 mg, 1.19 mmol), DIEA (645 mg, 4.99 mmol) and N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-fluorophenyl)thiazol-2-amine (230 mg, 0.65 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was extracted with ethyl acetate (50 mL, 3 times). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 75 * 30mm * 3um; mobile phase: water (NH3.H2O+NH4HCO3)-ACN; B%: 26-56%, 11 min; flow rate (25 ml / min)) to give tert-butyl (2S,4R)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-4-hydroxypyrrolidine-1-carboxylate (50 mg, 13% yield) as a colorless oil. [ka]

[0130] A solution of tert-butyl (2S,4R)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (50 mg, 0.088 mmol) in HCl / dioxane (4 M, 1 mL) was stirred for 2 h at 25° C. The mixture was concentrated in vacuo to give (2S,4R)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (50 mg, crude) as a white solid. [ka]

[0131] To a solution of (2S,4R)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxypyrrolidine-2-carboxamide (50 mg, 0.18 mmol) in NMP (2 mL) was added DIEA (138 mg, 1.07 mmol) and prop-2-enoyl chloride (11 mg, 0.12 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-ACN; B%: 10-40%, 15 min; flow rate (25 ml / min)) to give (2S,4R)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoylpyrrolidine-2-carboxamide (3.2 mg, 5% yield) as a white solid. LCMS:t R =1.150 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=522.3[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.30-11.12(m, 1H), 8.81-8.70(m, 1H), 8.34-8.16(m, 2H), 7.72(s, 1H), 7.67-7.57(m, 2H), 7.35-7 .10(m, 3H), 6.64-6.52(m, 1H), 6.28-5.45(m, 2H), 5.15-4.97(m, 1H), 4.45-4.09(m, 4H), 3.66-3.47(m, 3H), 1.97-1.14(m, 3H). Example 14 (2S,4S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoylpyrrolidine-2-carboxamide [ka] Synthesis of (2S,4S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoylpyrrolidine-2-carboxamide [ka] Testing Procedure: [ka]

[0132] To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (243 mg, 1.05 mmol) in DMF (2 mL) was added HATU (474 ​​mg, 1.25 mmol) and DIEA (673 mg, 5.21 mmol), followed by N-[1-(2-aminoethyl)imidazo[4,5-c]70-iridin-6-yl]-5-(4-fluorophenyl)thiazol-2-amine (240 mg, 0.68 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-CAN; B%: 24-54%, 15 min; flow rate (25 ml / min)) to give tert-butyl (2S,4S)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-4-hydroxypyrrolidine-1-carboxylate (200 mg, 39% yield) as a white solid. [ka]

[0133] A solution of tert-butyl (2S,4S)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]71-yridin-1-yl]ethylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (200 mg, 0.35 mmol) in HCl / dioxane (4 M, 2 mL) was stirred for 2 h at 25° C. The mixture was concentrated in vacuo to give (2S,4S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]71-yridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (190 mg, crude) as a white solid. [ka]

[0134] To a solution of (2S,4S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]71-ylidin-1-yl]ethyl]-4-hydroxypyrrolidine-2-carboxamide (100 mg, 0.21 mmol) in NMP (2 mL) was added DIEA (276 mg, 2.14 mmol) and prop-2-enoyl chloride (21 mg, 0.24 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-CAN; B%: 16-46%, 15 min; flow rate (25 ml / min)) to give (2S,4S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]71-ylidin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoylpyrrolidine-2-carboxamide (6.2 mg, 6% yield) as a white solid. LCMS:t R=1.311 min, 10~80AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=522.1[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.27-11.13(m, 1H), 8.80-8.69(m, 1H), 8.31-8.13(m, 2H), 7.72(s, 1H), 7.66-7.48(m, 2H), 7.30-7 .15(m, 3H), 6.65-6.52(m, 1H), 6.31-5.39(m, 2H), 5.33-5.03(m, 1H), 4.48-4.10(m, 4H), 3.82-3.45(m, 3H), 2.30-1.10(m, 3H). Example 15 (2S,3S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]72-ylidin-1-yl]ethyl]-3-hydroxy-1-prop-2-enoylpyrrolidine-2-carboxamide [ka] Synthesis of (2S,3S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]72-yridin-1-yl]ethyl]-3-hydroxy-1-prop-2-enoylpyrrolidine-2-carboxamide [ka] Testing Procedure: [ka]

[0135] To a solution of (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-2-carboxylic acid (150 mg, 0.65 mmol, 1.55 equiv.) in DMF (2 mL) was added HATU (293 mg, 0.77 mmol), DIEA (416 mg, 3.22 mmol) and N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-fluorophenyl)thiazol-2-amine (148 mg, 0.42 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-ACN; B%: 24-54%, 15min; flow rate (25ml / min)) to give tert-butyl (2S,3S)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-3-hydroxypyrrolidine-1-carboxylate (59mg, 24% yield) as a yellow solid. [ka]

[0136] A solution of tert-butyl (2S,3S)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-3-hydroxy-pyrrolidine-1-carboxylate (59 mg, 0.10 mmol) in HCl / dioxane (4 M, 1 mL) was stirred for 2 h at 25° C. The mixture was concentrated in vacuo to give (2S,3S)—N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide (70 mg, crude) as a yellow solid. [ka]

[0137] To a solution of (2S,3S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxypyrrolidine-2-carboxamide (70 mg, 0.15 mmol) in NMP (2 mL) was added DIEA (194 mg, 1.50 mmol) and prop-2-enoyl chloride (15 mg, 0.16 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: water (FA)-ACN; B%: 16-46%, 15 min; flow rate (25 ml / min)) to give (2S,3S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-1-prop-2-enoylpyrrolidine-2-carboxamide (17.7 mg, 22% yield) as a white solid. LCMS:t R =1.291 min, 10~80AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=522.1[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.28-11.15(m, 1H), 8.79-8.66(m, 1H), 8.35-8.12(m, 2H), 7.72(s, 1H), 7.67-7.48(m, 2H), 7.2 7-7.13(m, 3H), 6.62(dd, J=16.4, 10.4Hz, 1H), 6.25-5.24(m, 3H), 4.30-3.96(m, 4H), 3.73-3.48(m, 3H), 2.09-1.13(m, 3H). Example 16 (3S)-4-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide [ka] Synthesis of (3S)-4-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide [ka] Testing Procedure: [ka]

[0138] To a solution of (3S)-4-tert-butoxycarbonylmorpholine-3-carboxylic acid (93 mg, 0.4 mmol) in DMF (25 mL) was added HATU (157 mg, 0.4 mmol) and DIEA (691 mg, 5.3 mmol), followed by N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2-pyridyl)thiazol-2-amine (95 mg, 0.3 mmol). The mixture was stirred at 25° C. for 1 h. Water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL, 3 times). The combined organic phase was washed with brine (10 mL, 5 times), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel (0% to 8% methanol in dichloromethane) to give tert-butyl (3S)-3-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morpholine-4-carboxylate (84 mg, 51% yield) as a yellow solid. [ka]

[0139] A solution of tert-butyl (3S)-3-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morpholine-4-carboxylate (84 mg, 0.14 mmol) in 4M HCl / dioxane (2 mL) was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give (3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (158 mg, HCl salt) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0140] To a solution of 2-fluoroprop-2-enoic acid (17 mg, 0.18 mmol) in DMF (2 mL) was added HATU (96 mg, 0.25 mmol) and DIEA (435 mg, 3.36 mmol) followed by (3S)—N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (79 mg, 0.17 mmol). The mixture was stirred at 25° C. for 1 h, then 2-fluoroprop-2-enoic acid (17 mg, 0.18 mmol), HATU (96 mg, 0.25 mmol), DIEA (222 mg, 1.72 mmol) and 2-fluoroprop-2-enoic acid (34 mg, 0.38 mmol) were added and the mixture was stirred at 25° C. for another 1 h. The mixture was analyzed by prep-HPLC (column: C18-6 100 * 30mm *5um; mobile phase: [water (FA)-ACN]; B%: 0%-50%, 15min; flow rate (25ml / min)) to give (3S)-4-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (4.7mg, 5% yield) as an off-white solid. LCMS: tR=1.336min, 5-5AB_4min_220&254_Shimadzu.lcm; MS(ESI) m / z=541.2[M+H]+. 1 H NMR (400MHz, DMSO-d6): δ=11.43-11.37(m, 1H), 8.81-8.79(m, 1H), 8.41-8.40(m, 1 H), 8.31-8.20(m, 1H), 8.13(s, 1H), 7.97(d, J=2.4Hz, 1H), 7.80-7.75(m, 1H), 7.31 -7.27(m, 1H), 7.19-7.12(m, 1H), 5.34-4.61(m, 2H), 4.30(t, J=5.6Hz, 2H), 4.20(m , 1H), 3.87-3.85(m, 1H), 3.77-3.61(m, 2H), 3.53-3.44(m, 4H), 3.15-2.87(m, 2H). Example 17 (3S)-4-[(E)-4-(Dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide [ka] Synthesis of (3S)-4-[(E)-4-(dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide [ka]

[0141] Testing Procedure: To a solution of (3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (78.8 mg, 0.168 mmol) in DMF (2 mL) was added DIEA (435 mg, 3.36 mmol) and PyBOP (96 mg, 0.18 mmol). The mixture was stirred at 25° C. for 1 h, after which (E)-4-(dimethylamino)but-2-enoic acid (24 mg, 0.18 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (50 mg, 0.38 mmol) were added in two portions. DIEA (222 mg, 1.72 mmol) and PyBOP (96 mg, 0.18 mmol) were added. The mixture was stirred at 25° C. for an additional hour. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 0%-45%, 15 min; flow rate (25 ml / min)) to give (3S)-4-[(E)-4-(dimethylamino)but-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (8.2 mg, 8% yield) as an off-white solid. LCMS:t R =0.972 min, 10~80AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=580.4[M+H] + . 1H NMR (400MHz, DMSO-d6): δ=11.49-11.30(m, 1H), 8.80(s, 1H), 8.40-8.39(m, 1H), 8.22 -8.06(m, 3H), 7.96(m, 1H), 7.79-7.74(m, 1H), 7.30-7.26(m, 1H), 7.18-7.16(m, 1H), 6 .74-6.20(m, 2H), 4.71-4.46(m, 1H), 4.29-4.25(m, 3H), 4.18-4.09(m, 1H), 3.80-3.7 1(m, 2H), 3.62-3.55(m, 2H), 3.14-2.95(m, 3H), 2.79-2.67(m, 1H), 2.37-2.12(m, 6H). Example 18 (2S,4R)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Synthesis of (2S,4R)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Testing Procedure: [ka]

[0142] To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (222 mg, 0.96 mmol) in DMF (10 mL) was added HATU (497 mg, 1.31 mmol) and DIEA (2.25 g, 17.45 mmol), followed by N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2-pyridyl)thiazol-2-amine (310 mg, 0.872 mmol). The mixture was stirred at 25° C. for 2 h. The mixture was analyzed by prep-HPLC (column: Xtimate C18 150 * 40mm * 10um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10min; flow rate (25ml / min)) to give tert-butyl (2S,4R)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (300mg, 59% yield) as a brown solid. [ka]

[0143] A solution of tert-butyl (2S,4R)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (300 mg, 0.53 mmol) in 4M HCl / dioxane (10 mL) was stirred at 25° C. for 0.5 h. The mixture was concentrated under reduced pressure to give (2S,4R)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (245 mg, crude) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0144] To a solution of (2S,4R)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (80 mg, 0.17 mmol) in NMP (2 mL) was added DIEA (278 mg, 2.15 mmol) and prop-2-enoyl chloride (22 mg, 0.24 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 0%-50%, 15 min; flow rate (25 ml / min)) to give (2S,4R)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoyl-pyrrolidine-2-carboxamide (6.2 mg, 7% yield) as a yellow solid. LCMS:t R =1.220 minutes, 5~95AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=523.2[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.47, 11.38(s, s, 1H), 8.80(m, 1H), 8.40-8.14(m, 3H), 7.96(m, 1H), 7.79-7.74(m, 1H), 7.31-7.1 7(m, 2H), 6.61-6.02(m, 2H), 5.73-5.50(m, 1H), 5.09-4.99(m, 1H), 4.63-4.13(m, 4H), 3.65-3.38(m, 4H), 1.94-1.66(m, 2H). Example 19 (2S,4R)-1-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide [ka] Synthesis of (2S,4R)-1-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide [ka]

[0145] Testing Procedure: To a solution of 2-fluoroprop-2-enoic acid (23 mg, 0.25 mmol) in DMF (2 mL) was added HATU (122 mg, 0.32 mmol), DIEA (278 mg, 2.15 mmol) and (2S,4R)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (80 mg, 0.17 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 0%-50%, 15 min; flow rate (25 ml / min)) and freeze-dried to obtain the crude product, which was then purified by prep-HPLC (column: Phenomenex C18 75 * 30mm * 3um; mobile phase: [water (NH3.H2O+NH4HCO3)-ACN]; B%: 10%-40%, 14 min; flow rate (25 ml / min)) to give (2S,4R)-1-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (5.5 mg, 6% yield) as an off-white solid. LCMS:t R=1.059 minutes, 5~95AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=541.0[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.47, 11.39(s, s, 1H), 8.80(s, 1H), 8.40-8.39(m, 1H), 8.26-8.17(m, 2H), 7.96(d, J=2.0Hz, 1H), 7.79-7.74(m, 1H), 7.31-7.26(m, 1H), 7.20-7.17(m, 1H), 5.51-5.05(m, 3H), 4.34-4 .13(m, 4H), 3.67-3.39(m, 4H), 2.08-1.89(m, 1H), 1.76-1.60(m, 1H). Example 20 (2S,4R)-1-[(E)-4-(Dimethylamino)but-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide [ka] Synthesis of (2S,4R)-1-[(E)-4-(dimethylamino)but-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide [ka]

[0146] Testing Procedure: To a solution of (2S,4R)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (80 mg, 0.17 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (39 mg, 0.30 mmol) in DMF (2 mL) was added (276 mg, 2.14 mmol) and PyBOP (123 mg, 0.23 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 0%-25%, 15 min; flow rate (25 ml / min)) to give (2S,4R)-1-[(E)-4-(dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (28.9 mg, 29% yield) as a yellow solid. LCMS:t R =1.127 minutes, 5~95AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=580.3[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.3(s, 1H), 8.80, 8.79(s, s, 1H), 8.40-8.15(m, 3H), 7 .97-7.95(m, 1H), 7.79-7.74(m, 1H), 7.30-7.14(m, 2H), 6.73-6.51(m, 1H), 6.38- 5.94(m, 1H), 5.04(s, 1H), 4.39-4.03(m, 5H), 3.63-3.58(m, 2H), 3.06(d, J=6.0Hz) , 2H), 2.97-2.84(m, 1H), 2.34-2.10(m, 6H), 2.03-1.83(m, 1H), 1.78-1.65(m, 1H). Example 21 (2S,4R)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Synthesis of (2S,4R)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Testing Procedure: [ka]

[0147] To a solution of tert-butyl N-[(4-methoxyphenyl)methyl]-N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl]carbamate (5.6 g, 12.55 mmol) and 4-chloro-5-fluoro-pyridine (2.49 g, 18.82 mmol) in dioxane (100 mL) and H2O (20 mL) was added Pd(dppf)Cl2 (918 mg, 1.25 mmol) and K2CO3 (5.20 g, 37.64 mmol). The mixture was stirred at 80 °C under N2 atmosphere for 1 h. The mixture was concentrated and the residue was diluted with H2O (30 mL) and extracted with ethyl acetate (60 mL, 3 times). The combined organic layers were then washed with saturated aqueous NaCl (20 mL, 2 times), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0% to 15% EtOAc in PE) to give tert-butyl N-[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]-N-[(4-methoxyphenyl)methyl]carbamate (2.8 g, 51% yield) as a yellow solid. [ka]

[0148] A solution of tert-butyl N-[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]-N-[(4-methoxyphenyl)methyl]carbamate (2.8 g, 6.72 mmol) in TFA (43.12 g, 378.17 mmol) was stirred at 75° C. for 12 h. The mixture was concentrated, the residue was basified with saturated aqueous Na2CO3 until pH=9, then extracted with ethyl acetate (60 mL, 3×), and then the combined organic layers were washed with saturated aqueous NaCl (20 mL, 2×), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0% to 7% DCM in MeOH ether) to give 5-(5-fluoropyrimidin-4-yl)thiazol-2-amine (856 mg, 58% yield) as a yellow solid. [ka]

[0149] To a solution of 5-(5-fluoropyrimidin-4-yl)thiazol-2-amine (856 mg, 4.36 mmol) and tert-butyl N-[2-(6-chloroimidazo[4,5-c]pyridin-1-yl)ethyl]carbamate (1.29 g, 4.36 mmol) in dioxane (50 mL) was added [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (395 mg, 0.4 mmol), Cs2CO3 (2.84 g, 8.73 mmol) and dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (468 mg, 0.87 mmol). The mixture was stirred at 90° C. under N2 atmosphere for 12 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0% to 9% DCM in MeOH) to give tert-butyl N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (429 mg, 18% yield) as a yellow solid. [ka]

[0150] A solution of tert-butyl N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]carbamate (429 mg, 0.94 mmol) in HCl / dioxane (4 M, 4.4 mL) was stirred for 2 h at 20° C. The mixture was concentrated under reduced pressure to give N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(5-fluoropyrimidin-4-yl)thiazol-2-amine (580 mg, crude) as a yellow solid. [ka]

[0151] To a solution of N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(5-fluoropyrimidin-4-yl)thiazol-2-amine (200 mg, 0.56 mmol) and (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (130 mg, 0.56 mmol) in DMF (6 mL) was added HATU (320 mg, 0.84 mmol) and DIEA (725 mg, 5.61 mmol). The mixture was stirred at 20° C. for 1 h under N2 atmosphere. The mixture was analyzed by prep-HPLC (column: Xtimate C18 100 * 30mm * 10 um; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 10 min) to give tert-butyl (2S,4R)-2-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (62 mg, 17% yield) as a yellow solid. [ka]

[0152] A solution of tert-butyl (2S,4R)-2-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (62 mg, 0.1 mmol) in HCl / dioxane (4 M, 3 mL) was stirred for 1 h at 20° C. The mixture was concentrated under reduced pressure to give (2S,4R)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (70 mg, crude) as a yellow solid. [ka]

[0153] To a solution of (2S,4R)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (70 mg, 0.15 mmol) in NMP (1.5 mL) was added prop-2-enoyl chloride (13 mg, 0.15 mmol) and DIEA (193 mg, 1.49 mmol) at 0° C. The mixture was stirred at 20° C. for 1 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 8%-38%, 15 min) to give (2S,4R)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-hydroxy-1-prop-2-enoyl-pyrrolidine-2-carboxamide (10.9 mg, 14% yield) as a yellow solid. LCMS:t R =0.990 min, 10~80AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=524.4[M+H] + . 1H NMR (400MHz, DMSO-d6): δ=8.97-8.88(m, 1H), 8.87-8.82(m, 1H), 8.81-8.76(m, 1H), 8. 29(s, 1H), 8.24-8.20(m, 2H), 8.17(m, J=5.8Hz, 1H), 7.32-7.18(m, 1H), 6.58(m, J=10. 3, 16.8Hz, 1H), 6.21(d, J=2.2, 16.8Hz, 1H), 5.81-5.40(d, 1H), 5.11-4.90(m, 1H), 4.3 5-4.24(m, 4H), 3.66-3.43(m, 4H), 1.97-1.88(m, 1H), 1.70(m, J=4.8, 8.0, 12.9Hz, 1H). Example 22 (3S)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide [ka] Synthesis of (3S)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide [ka] Testing Procedure: [ka]

[0154] To a solution of N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(5-fluoropyrimidin-4-yl)thiazol-2-amine (160 mg, 0.45 mmol) and (3S)-4-tert-butoxycarbonylmorpholine-3-carboxylic acid (104 mg, 0.45 mmol) in DMF (5 mL) was added HATU (256 mg, 0.67 mmol) and DIEA (580 mg, 4.49 mmol). The mixture was stirred at 20° C. for 1 h. Water (10 mL) was added to the mixture, which was then extracted with EtOAc (20 mL, 3 times). The organic layers were combined, washed with water (30 mL, 3 times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 9% DCM in MeOH ether) to give tert-butyl (3S)-3-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morphone-4-carboxylate (78 mg, 29% yield) as a yellow solid. [ka]

[0155] A solution of tert-butyl (3S)-3-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]morpholine-4-carboxylate (75 mg, 0.13 mmol) in HCl / dioxane (4 M, 2 mL) was stirred for 1 h at 20° C. The mixture was concentrated under reduced pressure to give (3S)—N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (110 mg, crude) as a yellow solid. [ka]

[0156] To a solution of (3S)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (35 mg, 0.075 mmol) in NMP (2 mL) was added prop-2-enoyl chloride (8 mg, 0.082 mmol) and DIEA (96 mg, 0.075 mmol) at 0° C. The mixture was stirred at 20° C. for 0.5 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 15 min) to give (3S)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide (4.7 mg, 12% yield) as a yellow solid. LCMS:t R =1.077 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=524.4[M+H] +. 1H NMR (400MHz, DMSO-d6): δ=8.91(d, J=3.6Hz, 1H), 8.85(s, 1H), 8.79(d, J=3.6Hz, 1H), 8.24-8.17(m, 3H), 7.25-6.73(m, 2H), 6.39-5.37(m, 3H), 4.76-4.44(m, 1H), 4.38-4.24(m, 3H), 4.21-4.04(m, 1H), 3.85-3.66(m, 2H), 3.54-3.42(m, 4H). Example 23 (3S)-4-[(E)-4-(Dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide [ka] Synthesis of (3S)-4-[(E)-4-(dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide [ka]

[0157] Testing Procedure: To a solution of (3S)-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (55 mg, 0.12 mmol) in DMF (3 mL) was added (E)-4-(dimethylamino)but-2-enoic acid (27 mg, 0.2 mmol), DIEA (182 mg, 1.41 mmol) and PyBOP (84 mg, 0.16 mmol). The mixture was stirred at 20° C. for 1.5 h. The mixture was purified by prep-HPLC (column: C18-6 100 * 30mm *5um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 15 min) to give (3S)-4-[(E)-4-(dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]morpholine-3-carboxamide (6 mg, 8% yield) as a yellow solid. LCMS:t R =0.977 min, 10~80AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=581.5[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.99-11.52(d, 1H), 8.96-8.89(m, 1H), 8.88-8.82( m, 1H), 8.81-8.74(m, 1H), 8.27-8.03(m, 3H), 7.57-7.55(m, 1H), 7.28-7.14(m, 1H), 6.76-6.09(m, 2H), 4.77-4.43(m, 1H), 4.34-4.27(m, 2H), 4.20-4.04(m, 1H) ), 3.91-3.36(m, 6H), 3.05-2.87(m, 2H), 2.84-2.61(m, 1H), 2.22-1.96(m, 6H). Example 24 (2S,3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Synthesis of (2S,3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-1-prop-2-enoyl-pyrrolidine-2-carboxamide [ka] Testing Procedure: [ka]

[0158] To a solution of (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-2-carboxylic acid (390 mg, 1.69 mmol) in DMF (6 mL) was added HATU (963 mg, 2.53 mmol), DIEA (2 g, 16.88 mmol), and then N-[1-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2-pyridyl)thiazol-2-amine (600 mg, 1.69 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: Xtimate C18 150 * 40mm * 10um; mobile phase: [water (FA)-ACN]; B%: 20%-60%, 10min; flow rate (25ml / min)) to give tert-butyl (2S,3S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-3-hydroxy-pyrrolidine-1-carboxylate (74mg, 7% yield) as a yellow solid. [ka]

[0159] A solution of tert-butyl (2S,3S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethylcarbamoyl]-3-hydroxy-pyrrolidine-1-carboxylate (74 mg, 0.13 mmol) in 4M HCl / dioxane (10 mL) was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to give (2S,3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide (60 mg, crude) as a yellow solid, which was used directly in the next step without further purification. [ka]

[0160] To a solution of (2S,3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide (60 mg, 0.13 mmol) in NMP (2 mL) was added DIEA (165 mg, 1.28 mmol) followed by prop-2-enoyl chloride (14 mg, 0.15 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was analyzed by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 0%-50%, 15 min; flow rate (25 ml / min)) to give (2S,3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-1-prop-2-enoyl-pyrrolidine-2-carboxamide (21.3 mg, 31% yield) as a yellow solid. LCMS:t R =1.076 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=523.4[M+H]+ . 1 H NMR (400MHz, DMSO-d6): δ=11.47, 11.40(s, s, 1H), 8.80(s, 1H), 8.40-7.74(m, 5H), 7.30- 7.16(m, 2H), 6.65-5.97(m, 2H), 5.74-5.26(m, 2H), 4.32-3.58(m, 8H), 1.81-1.63(m, 2H). Example 25 (2S,3S)-1-(2-Fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide [ka] Synthesis of (2S,3S)-1-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide [ka]

[0161] Testing Procedure: To a solution of 2-fluoroprop-2-enoic acid (29 mg, 0.32 mmol) in DMF (2 mL) was added HATU (162 mg, 0.43 mmol) and DIEA (276 mg, 2.13 mmol), followed by (2S,3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide (100 mg, 0.21 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: Phenomenex C18 75 * 30mm *3um; mobile phase: [water (NH3.H2O+NH4HCO3)-ACN]; B%: 13%-43%, 11 min; flow rate (25 ml / min)) to give (2S,3S)-1-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide (12.2 mg, 11% yield) as a yellow solid. LCMS:t R =1.175 minutes, 10~80AB_4 minutes_220&254_Shimadzu.lcm;MS(ESI)m / z=541.2[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.37(s, 1H), 8.80-8.77(m, 1H), 8.40-8.10(m, 3H), 7.96(d, J=2.4Hz, 1H), 7.79- 7.73(m, 1H), 7.30-7.26(m, 1H), 7.18-7.09(m, 1H), 5.55-5.13(m, 3H), 4.38-3.41(m, 8H), 1.81-1.49(m, 2H). Example 26 (2S,3S)-1-[(E)-4-(Dimethylamino)but-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide [ka] Synthesis of (2S,3S)-1-[(E)-4-(dimethylamino)but-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide [ka]

[0162] Testing Procedure: To a solution of (2S,3S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide (100 mg, 0.21 mmol) in DMF (2 mL) and DIEA (276 mg, 2.13 mmol) was added (E)-4-(dimethylamino)but-2-enoic acid (55 mg, 0.43 mmol), followed by PyBOP (222 mg, 0.43 mmol). The mixture was stirred at 25° C. for 1 h. The mixture was analyzed by prep-HPLC (column: Phenomenex C18 75 * 30mm * 3um; mobile phase: [water (NH3.H2O+NH4HCO3)-ACN]; B%: 10%-45%, 11 min; flow rate (25 ml / min)), and then further purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA)-ACN]; B%: 6%-36%, 8 min; flow rate (25 ml / min)) to give (2S,3S)-1-[(E)-4-(dimethylamino)but-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-1-yl]ethyl]-3-hydroxy-pyrrolidine-2-carboxamide (35 mg, 28% yield) as a yellow solid. LCMS:t R =0.888 min, 10~80AB_4 min_220&254_Shimadzu.lcm;MS(ESI)m / z=580.3[M+H] + . 1 H NMR (400MHz, DMSO-d6): δ=11.42(s, 1H), 8.80-8.31(m, 2H), 8.20-8.14(m, 2H), 7.97-7.55(m, 2H), 7.30-7.17(m, 2H), 6.74-5.92(m, 2H), 5.2 4(s, 1H), 4.32-4.23(m, 2H), 4.13(s, 1H), 4.09-3.99(m, 1H), 3.69-3. 55(m, 4H), 3.10-2.93(m, 2H), 2.17, 2.11(s, s, 6H), 1.81-1.59(m, 2H).

[0163] Example 27 Characterization of the Kinase Inhibitory Properties of the Disclosed Compounds Compound inhibition of recombinant kinases (FLT3, KIT) was measured using the Caliper mobility shift assay, which is based on the difference in capillary electrophoretic mobility of fluorescently tagged peptides as a result of phosphorylation by the kinase under study. Reactions were initiated by adding various concentrations of compounds (initially in DMSO solution) to the kinase solution in assay buffer, followed by the addition of a mixture of ATP and fluorescently tagged peptide substrate in assay buffer. Enzyme, ATP and peptide concentrations were pre-optimized to give 15% substrate conversion to ensure initial rate measurements. After 3 hours of incubation at room temperature, kinase reactions were stopped by the addition of a high concentration EDTA solution and then analyzed on a LabChip EZ Reader II to determine percent inhibition by comparison with DMSO controls.

[0164] Table 2 below summarizes the assay conditions for characterizing the kinase inhibitory properties of the disclosed compounds. [Table 2]

[0165] Table 3 below summarizes the kinase inhibitory properties of the disclosed compounds. [Table 3]

[0166] The cell viability assay was performed according to the following simple procedure. Cells were plated at a density of 5K / well with a volume of 180 μL in 96-well white and clear bottom plates. 20 μL of vehicle or compound was added to the wells at the appropriate concentration. The final volume is 200 μL: DMSO final concentration=0.1%, 11 points, triplicate. Then the cells were treated for 72 hours at 37°C in a TC incubator. An equal volume (200 μL) of CellTiter-Glo Reagent (Promega) was added to the wells and protected from light for 15 minutes at room temperature. Chemiluminescence was measured by EnSight (Perkin Elmer). GI50 was calculated using GraphPad Prism nonlinear regression, Log[inhibitor] response with four parameters. Table 4 below shows the results of the cell type assay of FLT3. [Table 4]

[0167] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compositions and procedures described herein which equivalents are considered to be within the scope of this disclosure and covered by the following claims.

Claims

1. The following formula (I): 【Chemistry 1】 A compound of the formula In the above formula, m is an integer selected from 0 to 4; Ar is phenyl, 【Chemistry 2】 selected from the group consisting of: Z is —CO—, —COO—, or —CONR ４ -, -NR ４ -, -(CH ２ ) １～５ -, -O-, -OPO-, -OPO ２ -, -S-, -SO-, or SO ２ - is; Lは、-CONNR ４ (CH) ２ ) １～５ NR ４ -、-NR ４ CO ２ ) １～５ NR ４ -、-(EH ２ ) １～５ NR ４ -、-(EH ２ ) １～５ O-、 -(CH ２ ) １～５ OCO-、-(CH ２ ) １～５ CONR ４ -、 【Transformation 3】 (wherein each of these is R ６ may be substituted by is; A.A. is, 【Chemistry 4】 (In these formulas, R １ is H, -F, -CF ３ , -CN, -NH ２ , —OH, —OCH ３ , —OEt, methyl, ethyl, propyl, isopropyl, cyclopropyl, and the ring is selected from the group consisting of two or more R other than H. １ may have a natural or unnatural amino acid selected from the group consisting of: R ２ is -H, -F, -Br, -Cl, -CF ３ , -CN, -N ３ , -NH ２ , -NO ２ , —OH, —OCH ３ , methyl, ethyl, propyl, isopropyl, 【Transformation 5】 (Each of these can be one, two, three, or four R ６ may be substituted by selected from the group consisting of: R ３ is —CO(CH2)0-5CH3, —CONR4(CH2)0-5CH3, -COO(CH2)0-5CH3, -SO2(CH2)0-5CH3, -CO(CH2)0-5CH=CH2, -CONR4(CH2)0-5 CH=CH2, -COO(CH2)0-5CH=CH2, -SO2(CH2)0-5CH=CH2, -CO(CH2)0-5CH=CHCH3, -COO(CH2)0~5CH=CHCH3、-CONR ４ (CH2)0~5CH=CHCH3、-SO2(CH2)0~5CH=CHCH3、 -CO(CH2)0~5C≡CH, -COO(CH2)0~5C≡CH, -CONR ４ and -SO2(CH2)0-5C≡CH, -CO(CH2)0-5C≡CCH3, -COO(CH2)0-5C≡CCH3, -CONR4(CH2)0-5C≡CCH3, and -SO2(CH2)0-5C≡CCH3, wherein each of the foregoing groups is selected from the group consisting of one, two, three, or four R ６ may be substituted by R ４ is H, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclobutyl; R ５ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2SCH3, -CH2Ph, -CH2PhOH, -CH2OH, -CHOHCH3, -CH2CONH2, -CH2CH2CONH2, -CH2SH, -CH2SeH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2CH2NH2, 【Transformation 6】 selected from the group consisting of: Each R ６ are independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, —F, —Br, —Cl, —CF3, —NO2, —OH, —OCH3, —CN, or an unsubstituted amino group or an amino group substituted with methyl, ethyl, or propyl; The compound, or an optically pure stereoisomer, pharmaceutically acceptable salt or solvate thereof.

2. R ３ but, 【Transformation 7】 10. The compound of claim 1, selected from the group consisting of: or an optically pure stereoisomer, pharmaceutically acceptable salt or solvate thereof.

3. The following formula (II): 【Transformation 8】 (In the formula, R ２ , Ar, Z, L, AA, m, and R ３ each of which is as defined in claim 1.

10. The compound of claim 1, having the formula:

4. The following formula (III): 【Chemistry 9】 and However, in the above formula, A.A. is, 【Chemistry 10】 a natural or unnatural amino acid selected from the group consisting of: R ２ teeth, 【Chemistry 11】 (Each of these can be one, two, three, or four R ６ may be substituted by selected from the group consisting of: R ３ teeth, 【Chemistry 12】 selected from the group consisting of: R ４ is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl; and Each R ６ are independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, —F, —Br, —Cl, —CF3, —NO2, —OH, —OCH3, —CN, or an unsubstituted amino group, or C １～３ an amino group substituted with an alkyl group; 10. The compound of claim 1, or an optically pure stereoisomer, pharmaceutically acceptable salt or solvate thereof.

5. 10. A compound according to claim 1 selected from the table below, or an optically pure stereoisomer, pharmaceutically acceptable salt or solvate thereof. Table 1

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or an optically pure stereoisomer, pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition described in claim 6 for treating cancer in a subject by administering the pharmaceutical composition to the subject.

8. 8. The pharmaceutical composition of claim 7, wherein the cancer is breast cancer, myeloid cancer, lung cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, rhabdomyosarcoma, liver cancer, gastric cancer, or intestinal cancer.

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