IMID AZOPYRIDINE INHIBITORS OF TYROSINE KINASE

FIELD

[0001] The present disclosure relates generally to the field of compounds, pharmaceutical compositions, and methods of using the compounds and compositions containing them. The present disclosure specifically relates to imidazopyridines that are tyrosine kinase inhibitor compounds and compositions containing them, and the use of the compounds and compositions for the treatment of cancer.

BACKGROUND

[0002] In recent years, inhibition of specific cancer-associated tyrosine kinases has emerged as an important approach for cancer therapy. Tyrosine kinases as mediators of cell signaling play a key role in many diverse physiological pathways including cell growth and differentiation. Deregulation of tyrosine kinases activity may result in cellular transformation leading to the development of cancer.

SUMMARY OF THE INVENTION

[0003] Disclosed herein are compounds used as tyrosine kinase inhibitors, pharmaceutical compositions containing the compounds, and method of using the compounds and compositions for the treatment of cancer. Many of the disclosed compounds are capable of covalent inhibition of particular tyrosine kinases, thus they exhibit high potency and outstanding selectivity toward these kinases. In some embodiments, the present disclosure provides a compound of Formula (I)

Formula (I) or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. In some aspects, m may be an integer ranging from 0 to 4.

In Formula (I), Ar is selected from the group consisting of phenyl, each of which may be optionally substituted by R ⁶ .

AA is a natural or unnatural amino acid selected from the group consisting of where R ¹ is selected from the group consisting of H, -F, -CF3, -CN, -NH2, -OH, -OCH3,

-OEt, methyl, ethyl, propyl, isopropyl, cyclopropyl. Rings may have more than 1 non-hydrogen R ¹ .

R ² is selected from the group consisting of H, -F, -Br, -Cl, -CF3, -CN, -N3, -NH2, -NO2,

-OH, -0CH3, methyl, ethyl, propyl, isopropyl, each of which may be substituted by one, two, three, or four R ⁶ . R ³ is selected from the group consisting of -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 preceding groups is optionally substituted by one, two, three, or four R ⁶ .

In some aspects, R ³ may be selected from the group consisting of

R ⁴ may be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.

R ⁵ may be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2SCH3, -CH2Ph, -CH2PhOH, -CH20H, -CH0HCH3, -CH2CONH2, -CH2CH2CONH2, -CH2SH, -CH2SeH, -CH2C00H, -CH2CH2COOH, -CH2CH2CH2CH2NH2, each R ⁶ may be independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, 0CH3, CN, or amino group unsubstituted or substitutedwith methyl, ethyl, or propyl.

[0004] As a preferred embodiment, the compound of Formula (I) as discussed above is shown in Formula (II)

Formula (II).

[0005] In further preferred embodiments, compounds of the invention are specifically as shown in Formula (III):

Formula (III) or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof. AA may be a natural or unnatural amino acid selected from the group consisting of: R ² may be selected from the group consisting of each of which may be substituted by one, two, three, or four R6.

In some aspects, R ³ is selected from the group consisting of and R4 may be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl.

Each R6 may be independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, F, Br, Cl, CF3, NO2, OH, 0CH3, CN, or amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0006] Also disclosed herein is a pharmaceutical composition including a compound according to Formula (I).

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

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

[0009] Other features and advantages may become apparent from the following detailed description.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0010] Below are some acronyms used in the present disclosure. n-BuOK refers to potassium tert-butoxide; DMF refers to dimethylformamide; Boc refers to tert-Butyloxy carbonyl protectinggroup; DMSO refers to dimethyl sulfoxide; HATU refers to 1- [bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4, 5-b]pyridinium 3 -oxide hexafluorophosphate; DIEA refers to N, N- Diisopropylethylamine; DIPEA refers to N,N- Diisopropylethylamine; TFA refers to trifluoroacetic acid; PyBOP refers to benzotriazol- 1- yloxytripyrrolidinophosphonium hexafluorophosphate. [0011] The term “about” will be understood by persons of ordinary skill in the art. Whether the term “about” is used explicitly or not, every quantity given herein refers to the actual given value, and it is also meant to refer to the approximation to such given value that would be reasonably inferred based on the ordinary skill in the art.

[0012] Alkyl groups refer to univalent groups derived from alkanes by removal of a hydrogen atom from any carbon atom, which include straight chain and branched chain with from 1 to 12 carbon atoms, and typically from 1 to about 10 carbons or in some embodiments, from 1 to about 6 carbon atoms, or in other embodiments having 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. Alkyl groups may be substituted or unsubstituted. Representative substituted alkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, di-, or tri-substituted. As used herein, the term alkyl, unless otherwise stated, refers to both cyclic and noncyclic groups.

[0013] The terms “cyclic alkyl” or “cycloalkyl” refer to univalent groups derived from cycloalkanes by removal of a hydrogen atom from a ring carbon atom. Cycloalkyl groups are saturated or partially saturated non-aromatic structures with a single ring or multiple rings including isolated, fused, bridged, and spiro ring systems, having 3 to 14 carbon atoms, or in some embodiments, from 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 more than once, 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 multi-cyclic ring systems include, but are not limited to, bicycle[4.4.0]decane, bicycle[2.2.1]heptane, spiro[2.2]pentane, and the like.

[0014] Alkenyl groups refer to straight and branched chain and cycloalkyl groups as defined above, with 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 2, 3 or 4 carbon atoms in other embodiments. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono- substituted or substituted more than once, 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 and cycloalkyl groups as defined above, with one or more triple bonds between two carbon atoms. Alkynyl 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 2, 3 or 4 carbon atoms in other embodiments. Alkynyl groups may be substituted or unsubstituted. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, 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 that include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups. Aryl groups may contain from 6 to about 18 ring carbons, or in some embodiments, from 6 to 14 ring carbons or even 6 to 10 ring carbons in other embodiments. Aryl group also includes heteroaryl groups, which are aromatic ring compounds containing 5 or more ring members, one or more ring carbon atoms of which are replaced with 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 more than once, 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 with atoms of at least two different elements as members of its rings, of which one or more is a heteroatom such as, but not limited to, N, O, or S. Heterocyclyl groups may include 3 to about 20 ring members, or 3 to 18 in some embodiments, or about 3 to 15, 3 to 12, 3 to 10, or 3 to 6 ring members. The ring systems in heterocyclyl groups 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, but are not limited to, 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, 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, quinolizinyl, cinnolinyl, phthalazinyl, pteridinyl, and benzothiazolyl groups. [0018] Polycyclic or polycyclyl groups refer to two or more rings in which two or more carbons are common to the two adjoining rings, wherein the rings are “fused rings”; if the rings are joined by one common carbon atom, these are “spiro” ring systems. Rings that are joined 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 group refers to -NO2; cyano group refers to -CN; isocyano group refers to -N=C; epoxy groups encompass structures in which an oxygen atom is directly attached to two adjacent or non-adjacent carbon atoms of a carbon chain or ring system, which is essentially a cyclic ether structure. An epoxide is a cyclic ether with a three- atom ring.

[0020] An alkoxy group is a substituted or unsubstituted alkyl group, as defined above, singular bonded to oxygen. Alkoxy groups 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 groups.

[0021] The terms “amine” and “amino” refer to derivatives of ammonia, wherein one of more hydrogen atoms have been replaced by a substituent which include, but are not limited to alkyl, alkenyl, aryl, and heterocyclyl groups. Carbamate groups refers to -O(C=O)NR ⁿ R ¹² , where R ¹¹ and R ¹² are independently hydrogen, aliphatic groups, aryl groups, or heterocyclyl groups. [0022] Pharmaceutically acceptable salts of compounds described herein include conventional nontoxic salts or quaternary ammonium salts of a compound, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxy maleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like. In other cases, described compounds may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. These salts may likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

[0023] Those skilled in the art of organic chemistry will appreciate that many organic compounds may form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” For example, a complex with water is known as a “hydrate”. Solvates of the compound of formula (I) are within the scope of the invention. It will also be appreciated by those skilled in organic chemistry that many organic compounds may exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms of the compound of formula (I) or the pharmaceutically acceptable solvates thereof are within the scope of the present invention.

[0024] Disclosed herein are compounds used as tyrosine kinase inhibitors, pharmaceutical compositions containing the compounds, and method of using the compounds and compositions for the treatment of cancer. The disclosed compounds may afford covalent inhibition of particular tyrosine kinases; thus they exhibit high potency and outstanding selectivity toward these kinases. In some embodiments, the present disclosure provides a compound of Formula (I):

Formula (I)

In Formula (I), Ar is selected from the group consisting of phenyl, Z may be selected from the group consisting of -CO-, -COO-, -CONR ⁴ -, -NR ⁴ -, -(CH ₂ )I-5-, - O-,

-0P0-, -OPO2-, -S-, -SO-, or-SO ₂ -;

L may

-(CH2 each of which may be optionally substituted by R ⁶ .

AA is a natural or unnatural amino acid selected from the group consisting of where R ¹ is selected from the group consisting of H, -F, -CF3, -CN, -NH2, -OH, -0CH3,

-OEt, methyl, ethyl, propyl, isopropyl, cyclopropyl. Rings may have more than 1 non-hydrogen R ¹ .

R ² may be selected from the group consisting of H, -F, -Br, -Cl, -CF3, -CN, -N3, -NH2, -

NO2, each of which may be substituted by one, two, three, or four R ⁶ .

R ³ may be selected from the group consisting of -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 preceding groups is optionally substituted by one, two, three, or four R ⁶ .

In some aspects, R ³ may be selected from the group consisting of

R ⁴ may be H, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl. R ⁵ may be H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2SCH3, -CH2Ph, -CH2PhOH, -CH20H, -CH0HCH3, -CH2CONH2, -CH2CH2CONH2, -CH2SH, -CH2SeH, -CH2COOH, -CH2CH2COOH, -CH2CH2CH2CH2NH2, each R ⁶ may be independently H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, -F, -Br, -Cl, -CF3, -NO2, -OH, -OCH3, -CN, or amino group unsubstituted or substituted with methyl, ethyl, or propyl.

[0025] In certain aspects, compounds of the invention is specifically having Formula (II) Formula (II) or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein each of R ² , Ar, Z, L, AA, m, and R ³ has been defined above.

[0026] In certain aspects, compounds of the invention are specifically as shown in Formula

(III):

Formula (III) or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein each of R ² , AA, and R ³ has been defined above.

[0027] Compounds of the present disclosure are synthesized by an appropriate combination of generally established synthetic methods. Techniques useful in synthesizing the compounds of the disclosure are both readily apparent and accessible to those of skill in the relevant art. The discussion below is offered to illustrate certain of the diverse methods available for use in assembling the compounds of the 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 compounds in the present application are shown in Scheme 1, but are not limited to this scheme, where R and R ¹ may form a ring (such as pyrrolidine, morpholine, piperazine or piperidine, optionally substituted), and R ³ , R ⁴ , and R ⁵ mayall be H, or one or more may independently be Me, F, CH2N(CH3)2 , but are not limited to these substituents. R ² is as defined in the Formula 1.

Table 1. [0028] The term "treatment" is used interchangeably herein with the term "therapeutic method" and refers to both 1) therapeutic treatments or measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic conditions, disease or disorder, and 2) and prophylactic/ preventative measures. Those in need of treatment may include individuals alreadyhaving a particular medical disease or disorder as well as those who may ultimately acquire the disorder (i.e., those needing preventive measures).

[0025] The term “subject” as used herein refers to any individual or patient to which the subject methods are performed. Generally, the subject is human, although as will be appreciated by thosein the art, the subject may be an animal.

[0026] The terms “therapeutically effective amount”, “effective dose”, “therapeutically effective dose”, “effective amount,” or the like refer to the amount of a subject compound 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 amelioration of symptoms in a patient or a desired biological outcome. Such amount should be sufficient to inhibit tyrosine kinase enzymatic activity.

[0027] Also disclosed herein are pharmaceutical compositions including compounds with the structures of Formula (I). The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier that may be administered to a patient, together with a compound of this disclosure, and which does not destroy the pharmacological activity thereof. Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, poly acrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0028] Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, poly acrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat and self-emulsifying drug delivery systems (SEDDS) such as a-tocopherol, polyethyleneglycol 1000 succinate, or other similar polymeric delivery matrices.

[0029] In pharmaceutical composition comprising only the compounds described herein as the active component, methods for administering these compositions may additionally comprise the step of administering to the subject an additional agent or therapy. Such therapies include, but are not limited to, an anemia therapy, a diabetes therapy, a hypertension therapy, a cholesterol therapy, neuropharmacologic drugs, drugs modulating cardiovascular function, drugs modulating inflammation, immune function, production of blood cells; hormones and antagonists, drugs affecting gastrointestinal function, chemotherapeutics of microbial diseases, and/or chemotherapeutics of neoplastic disease. Other pharmacological therapies may include any other drug or biologic found in any drug class. For example, other drug classes may comprise allergy/cold/ENT therapies, analgesics, anesthetics, anti-inflammatories, antimicrobials, antivirals, asthma/pulmonary therapies, cardiovascular therapies, dermatology therapies, endocrine/metabolic therapies, gastrointestinal therapies, cancer therapies, immunology therapies, neurologic therapies, ophthalmic therapies, psychiatric therapies or rheumatologic therapies. Other examples of agents or therapies that may be administered with the compounds described herein include a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.

[0030] The term “therapeutically effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) Preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) Inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) Ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) . [0031] The compounds of this disclosure may be employed in a conventional manner for controlling the disease described herein, including, but not limited to, cancer. Such methods of treatment, their dosage levels and requirements may be selected by those of ordinary skill in the art from available methods and techniques. For example, the compounds of this disclosure maybe combined with a pharmaceutically acceptable adjuvant for administration to a patient suffering from cancer in a pharmaceutically acceptable manner and in an amount effective to treat cancer.

[0032] Alternatively, the compounds of this disclosure may be used in compositions and methods for treating or protecting individuals against the diseases described herein, including butnot limited to a cancer, over extended periods of time. The compounds may be employed in such compositions either alone or together with other compounds of this disclosure in a manner consistent with the conventional utilization of such compounds in pharmaceutical compositions. For example, a compound of this disclosure may be combined with pharmaceutically acceptable adjuvants conventionally employed in vaccines and administered in prophylactically effective amounts to protect individuals over an extended period of time against the diseases described herein, including, but not limited to, cancer.

[0033] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a described compound may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a described compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Two or more agents are typically considered to be administered "in combination" when a patient or individual is simultaneously exposed to both agents. In many embodiments, two or more agents are considered to be administered "in combination" when a patient or individual simultaneously shows therapeutically relevant levels of the agents in a particular target tissue or sample (e.g., in brain, in serum, etc.).

[0034] When the compounds of this disclosure are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient.

Alternatively, pharmaceutical or prophylactic compositions according to this disclosure comprise 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." [0035] The compounds utilized in the compositions and methods of this disclosure may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those, which 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 rate of excretion.

[0036] According to a preferred embodiment, the compositions of this disclosure are formulated for pharmaceutical administration to a subject or patient, e.g., a mammal, preferably a human being. Such pharmaceutical compositions are used to ameliorate, treat or prevent any of the diseases described herein including but not limited to cancer in a subject.

[0037] Agents of the disclosure are often administered as pharmaceutical compositions comprising an active therapeutic agent, i.e., and a variety of other pharmaceutically acceptable components. 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 compositions may also include, depending on the formulation desired, pharmaceutically acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The diluent is selected so as not to affect the biological activity of the combination. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.

[0038] In some embodiments, the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of a described compound, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents for use in treating the diseases described herein, including, but not limited to cancer. While it is possible for a described compound to be administered alone, it is preferable to administer a described compound as a pharmaceutical formulation (composition) as described herein. Described compounds may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.

[0039] As described in detail, pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream or foam; sublingually; ocularly; transdermally; or nasally, pulmonary and to other mucosal surfaces.

[0040] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the compositions.

[0041] Examples of pharmaceutically 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 chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0042] Formulations for use in accordance with 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 presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient, which may be combined with a carrier material, to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration. The amount of active ingredient that may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound, which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of 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%.

[0043] In certain embodiments, a formulation as described herein comprises an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and poly anhydrides; and a compound of the present disclosure. In certain embodiments, an aforementioned formulation renders orally bioavailable a described compound of the present disclosure. [0044] Methods of preparing formulations or compositions comprising described compounds include a step of bringing into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, formulations may be prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0045] The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This 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, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed 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 in their polyoxyethylated versions. These oil solutions or suspensions mayalso contain a long-chain alcohol diluent or dispersant, such as those described in Pharmacopeia Helvetica, or a similar alcohol. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0046] In some cases, in order to prolong the effect of a drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0047] Injectable depot forms are made by forming microencapsule matrices of the described compounds in biodegradable polymers such as polylactide-poly glycolide. Depending on the ratioof drug to polymer, and the nature of the particular polymer employed, the rate of drug release may 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, which are compatible with body tissue.

[0048] The pharmaceutical compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers, which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and solutions and propylene glycol are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

[0049] Formulations described herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure asan active ingredient. Compounds described herein may also be administered as a bolus, electuaryor paste.

[0050] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), an active ingredient is mixed with one or more pharmaceutically- acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodiumlauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0051] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made in a suitable machine in which a mixture of the powdered compound is moistened with an inert liquid diluent. If a solid carrier is used, the preparation may be in tablet form, placed in a hard gelatin capsule in powder or pellet form, or inthe form of a troche or lozenge. The amount of solid carrier will vary, e.g., from about 25 to 800mg, preferably about 25 mg to 400 mg. When a liquid carrier is used, the preparation may be, e.g., in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example, using the aforementioned carriers in a hard gelatin capsule shell.

[0052] Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may alternatively or additionally be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze- dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that may be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0053] Liquid dosage forms for oral administration of compounds of the disclosure include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0054] Besides inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0055] Suspensions, in addition to active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0056] The pharmaceutical compositions of this disclosure may also be administered in the forrnof suppositories for rectal administration. These compositions may be prepared by mixing a compound of this disclosure with a suitable non-irritating excipient, which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[0057] Topical administration of the pharmaceutical compositions of this disclosure is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylenepolyoxypropylene compound, 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 compositions of this disclosure may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-administered transdermal patches are also included in this disclosure. [0058] The pharmaceutical compositions of this disclosure may be administered by nasal aerosolor inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

[0059] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[0060] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present disclosure to the body. Dissolving or dispersing the compound in the proper medium may make such dosage forms. Absorption enhancers may also be used to increasethe flux of the compound across the skin. Either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel may control the rate of such flux.

[0061] Examples of suitable aqueous and nonaqueous carriers, which may be employed in the pharmaceutical compositions of the disclosure, include water, ethanol, polyols (such as 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. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0062] Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Inclusion of one or more antibacterial and/orantifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like, may be desirable incertain embodiments. It may alternatively or additionally be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents, which delay absorption such as aluminum monostearate and gelatin.

[0063] In certain embodiments, a described compound or pharmaceutical preparation is administered orally. In other embodiments, a described compound or pharmaceutical preparation is administered intravenously. Alternative routes of administration include sublingual, intramuscular, and transdermal administrations. [0064] When compounds described herein are administered as pharmaceuticals, to humans and animals, they may be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% of active ingredient in combination with a pharmaceutically acceptable carrier. In some embodiments, 0.5% to 90% of active ingredient may be used. Preparations described herein may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for the relevant administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.

[0065] Such compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.

[0066] Regardless of the route of administration selected, compounds described herein which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutic ally- acceptable dosage forms by conventional methods known to those of skill in the art.

[0067] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the disclosure may be varied so as 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.

[0068] The terms “administration of’ and or “administering” should be understood to mean providing a pharmaceutical composition in a therapeutically effective amount to the subject in need of treatment. Administration routes may be enteral, topical or parenteral. As such, administration routes include but are not limited to intracutaneous, subcutaneous, intravenous, intraperitoneal, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transdermal, transtracheal, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal , oral, sublingual buccal, rectal, vaginal, nasal ocular administrations, as well infusion, inhalation, and nebulization.

[0069] The term “cancer” refers to a group diseases characterized by abnormal and uncontrolled cell proliferation starting at one site (primary site) with the potential to invade and to spread to others sites (secondary sites, metastases) which differentiate cancer (malignant tumor) from benign tumor. Virtually all the organs may be affected, leading to more than 100 types of cancer that may affect humans. Cancers may result from many causes including genetic predisposition, viral infection, exposure to ionizing radiation, exposure environmental pollutant, tobacco and oralcohol use, obesity, poor diet, lack of physical activity or any combination thereof.

[0070] Exemplary cancers include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male;

Bronchial Adenomas/Carcinoids, Childhood: Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood;

Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma. Childhood Brain Stem; Glioma. Childhood Visual Pathway and Hypothalamic; 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; Hypothalamic and Visual Pathway Glioma, 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 Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; 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's, Adult; Lymphoma, Hodgkin's; Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy;

Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplasia Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer;

Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood', Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; 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, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma;

Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (OsteosarcomaVMalignant 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 Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood;

Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood;

Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor.

[0071] In certain aspects, cancer include Lung cancer, Breast cancer, Colorectal cancer, Prostate cancer, Stomach cancer, Liver cancer, cervical cancer, Esophageal cancer, Bladder cancer, NonHodgkin lymphoma, Leukemia, Pancreatic cancer, Kidney cancer, endometrial cancer, Head and neck cancer, Lip cancer, oral cancer, Thyroid cancer, Brain cancer, Ovary cancer, Melanoma, Gallbladder cancer, Laryngeal cancer, Multiple myeloma, Nasopharyngeal cancer, Hodgkin lymphoma, Testis cancer and Kaposi sarcoma.

[0072] In certain aspects, the method further includes administering a chemotherapeutic agent. The compounds of the disclosure may be administered in combination with one or more additional therapeutic agents. The phrases “combination therapy”, “combined with” and the like refer to the use of more than one medication or treatment simultaneously to increase the response. The tyrosine kinase inhibitor of the present disclosure might for example be used in combination with other drugs or treatment in use to treat cancer. In various aspects, the compound is administered prior to, simultaneously with or following the administration of the chemotherapeutic agent.

[0073] The term “anti-cancer therapy” refers to any therapy or treatment that may be used for the treatment of a cancer. Anti-cancer therapies include, but are not limited to, surgery, radiotherapy, chemotherapy, immune therapy and targeted therapies.

[0074] Examples of chemotherapeutic agents or anti-cancer agents include, but are not limited to, Actinomycin, Azacitidine, Azathioprine, Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone, Etoposide, Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Irinotecan, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Teniposide, Tioguanine, Topotecan, Valrubicin, Vinblastine, Vincristine, Vindesine, Vinorelbine, panitumamab, Erbitux (cetuximab), matuzumab, IMC-IIF 8, 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, ProstaScint (Indium-Ill labeled Capromab Pendetide), Bexxar (tositumomab), Zevalin (ibritumomab tiuxetan (IDEC-Y2B8) conjugated to yttrium 90), Xolair (omalizumab), MabThera (Rituximab), ReoPro (abciximab), MabCampath (alemtuzumab), Simulect (basiliximab), LeukoScan (sulesomab), CEA-Scan (arcitumomab), Verluma (nofetumomab), Panorex (Edrecolomab), alemtuzumab, CDP 870, natalizumab Gilotrif (afatinib), Lynparza (olaparib), Perjeta (pertuzumab), Otdivo (nivolumab), Bosulif (bosutinib), Cabometyx (cabozantinib), Ogivri (trastuzumab-dkst), Sutent (sunitinib malate), Adcetris (brentuximab vedotin), Alecensa (alectinib), Calquence (acalabrutinib), Yescarta (ciloleucel), Verzenio (abemaciclib), Keytruda (pembrolizumab), Aliqopa (copanlisib), Nerlynx (neratinib), Imfinzi (durvalumab), Darzalex (daratumumab), Tecentriq (atezolizumab), and Tarceva (erlotinib). [0075] Examples of immunotherapeutic agent include, but are not limited to, interleukins (11-2, 11-7, II- 12), cytokines (Interferons, G-CSF, imiquimod), chemokines (CCL3, CC126, CXCL7), immunomodulatory imide drugs (thalidomide and its analogues).

[0076] In treatment, the dose of agent optionally ranges from about 0.0001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 5 mg/kg, about 0.15 mg/kg to about 3 mg/kg, 0.5 mg/kg to about 2 mg/kg and about 1 mg/kg to about 2 mg/kg of the subject's body weight. In other embodiments the dose ranges from about 100 mg/kg to about 5 g/kg, about 500 mg/kg to about 2 mg/kg and 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 pg/kg to 15 mg/kg (e.g., 0.1-20 mg/kg) of agent is a candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. A typical daily dosage is in the range from about 1 pg/kg to 100 mg/kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. Unit doses may be in the range, for instance of about 5 mg to 500 mg, such as 50 mg, 100 mg, 150 mg, 200 mg, 250 mg and 300 mg. The progress of therapy is monitored by conventional techniques and assays. [0077] In some embodiments, an agent is administered to a human patient at an effective amount (or dose) of less than about 1 pg/kg, for instance, about 0.35 to about 0.75 pg/kg or about 0.40 to about 0.60 pg/kg. In some embodiments, the dose of an agent is about 0.35 pg/kg, or about 0.40 pg/kg, or about 0.45 pg/kg, or about 0.50 pg/kg, or about 0.55 pg/kg, or about 0.60pg/kg, or about 0.65 pg/kg, or about 0.70 pg/kg, or about 0.75 pg/kg, or about 0.80 pg/kg, or about 0.85 pg/kg, or about 0.90 pg/kg, or about 0.95 pg/kg or about 1 pg/kg. In various embodiments, the absolute dose of an agent is about 2 pg/subject to about 45 pg/subject, or about 5 to about 40, or about 10 to about 30, or about 15 to about 25 pg/subject. In some embodiments, the absolute dose of an agent is about 20 pg, or about 30 pg, or about 40 pg.

[0078] In various embodiments, the dose of an agent may be determined by the human patient’s body weight. For example, an absolute dose of an agent of about 2 pg for a pediatric human patient of about 0 to about 5 kg (e.g. about 0, or about 1, or about 2, or about 3, or about 4, or about 5 kg); or about 3 pg for a pediatric human patient of about 6 to about 8 kg (e.g. about 6, or about 7, or about 8 kg), or about 5 pg for a pediatric human patient of about 9 to about 13 kg (e.g. 9, or about 10, or about 11, or about 12, or about 13 kg); or about 8 pg for a pediatric human patient of about 14 to about 20 kg (e.g. about 14, or about 16, or about 18, or about 20 kg), or about 12 pg for a pediatric human patient of about 21 to about 30 kg (e.g. about 21, or about 23, or about 25, or about 27, or about 30 kg), or about 13 pg for a pediatric human patient of about 31 to about 33 kg (e.g. about 31, or about 32, or about 33 kg), or about 20 pg for an adult human patient of about 34 to about 50 kg (e.g. about 34, or about 36, or about 38, or about 40, or about 42, or about 44, or about 46, or about 48, or about 50 kg), or about 30 pg for an adult human patient of about 51 to about 75 kg (e.g. about 51, or about 55, or about 60, or about 65, or about 70, or about 75 kg), or about 45 pg for an adult human patient of greater than about 114 kg (e.g. about 114, or about 120, or about 130, or about 140, or about 150 kg).

[0079] In certain embodiments, an agent in accordance with the methods provided herein is administered subcutaneously (s.c.), intraveneously (i.v.), intramuscularly (i.m.), intranasally or topically. Administration of an agent described herein may, independently, be one to four times daily or one to four times per month or one to six times per year or once every two, three, four or five years. Administration may be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the human patient. The dosage may be administered as a single dose or divided into multiple doses. In some embodiments, an agent is administered about 1 to about 3 times (e.g. 1, or 2 or 3 times). [0080] Presented below are examples discussing the design and evaluation of efficacy of new tyrosine kinase inhibitors contemplated for the discussed applications. The following examples are provided to further illustrate the embodiments of the present disclosure, but are not intended to limit the scope of the disclosure. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.

EXAMPLES

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

Synthesis of (3S)-4-prop-2-enoyl-A-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amin o]imidazo[4,5- c]pyridin-l-yl]ethyl]morpholine-3-carboxamide Experimental Procedure:

[0081] To a solution of 2, 4-dichloro-5 -nitro-pyridine (2 g, 10.36 mmol) in THF (50 mL), El N (1.36 g, 13.47 mmol) and tert-butyl N-(2-aminoethyl)carbamate (1.99 g, 12.44 mmol) were added. The mixture was stirred at 0°C for 2 hours. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to afford tert-butyl A ^, -|2-|(2-chloro-5-nilro-4- pyridyl)amino]ethyl]carbamate (1.6 g, 49% yield) as a yellow solid.

[0082] To a solution of tert-butyl ?/-[2-[(2-chloro-5-nitro-4-pyridyl)amino]ethyl ]carbamate (1.6 g, 5.05 mmol) in THF (5 mL) and H2O (4 mL), NH4C1 (2.70 g, 50.51 mmol) and Fe (2.82 g, 50.51 mmol) was added. The mixture was stirred at 65°C for 3 hours. The solution was filtered with diatomite, and the filtrate was concentrated under reduced pressure to give a residue. The residuewas diluted with water (20 mF) and extracted with DCM (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl jV-[2-[(5-amino- 2-chloro-4- pyridyl)amino]ethyl]carbamate (1.48 g, crude) as a yellow solid.

[0083] To a solution of tert-butyl 7V-[2-[(5-amino-2-chloro-4-pyridyl)amino]ethyl ]carbamate (1.48 g, 5.16 mmol) in toluene (20 mL), CH(OEt)3 (1.15 g, 7.74 mmol) and TsOH (17mg, 0.103 mmol) were added. The mixture was stirred at 110°C for 1 hour. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% Dichloromethane\Methanol @ 60 mL/min) to afford tert-butyl A-[2-(6-chloroimidazo[4,5- c]pyridin-l-yl)ethyl]carbamate (1.2 g, 78% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-76): 5 = 8.73 (s, 1H), 8.36 (s, 1H), 7.76 (s, 1H), 6.96 (t, 7 = 8 Hz, 1H), 4.31-4.26 (m, 2H), 3.31-3.30 (m, 2H), 1.22 (

[0084] A mixture of 5-(4-pyridyl)thiazol-2-amine (119 mg, 0.673 mmol), tert-butyl A-[2-(6- chloroimidazo[4,5-c]pyridin-l-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 for 3 times, and then the mixture was stirred at 100°C forl2 hours under N2 atmosphere. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate/Petroleum ether gradient @ 60 mL/min) to afford tert-butyl A-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyri din-l- yl]ethyl]carbamate (240 mg, 81% yield) as a yellow solid.

[0085] A solution of tert-butyl A-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyri din- l-yl]ethyl]carbamate (20 mg, 0.045 mmol) in HCl/dioxane (2 mL, 4 M) was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to afford A-[l-(2- aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-pyridyl)thiazol- 2-amine (20 mg, crude) as a yellow solid.

[0086] To a solution of A-[l-(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 hours. The mixture was diluted with water (30mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-15% Dichloromethane/Methanol @ 50 mL/min) to afford tert- butyl (3S)-3-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c ]pyridin-l- yl]ethylcarbamoyl]morpholine-4-carboxylate (290 mg, 71% yield) as a yellow solid.

[0087] A solution of tert-butyl (3S)-3-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5- c]pyridin-l-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 hours. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18 150*40mm*10um; Condition: water(0.04% NH3.H2O+10 mM NH4HCO3)- ACN; B% from 10 to 40; Gradient Time: 10 min; Flow rate: 25 mL/min) to afford

(3S)-A-[2-[6- [[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl ]ethyl]morpholine-3- carboxamide (180 mg, 76% yield) as a yellow solid.

[0088] To a solution of (3S)-A-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c ]pyridin-l- yl]ethyl]morpholine-3-carboxamide (50 mg, 0.111 mmol) in NMP (6 mL), DIEA (28 mg, 0.222 mmol) and prop-2-enoyl chloride (10 mg, 0.111 mmol) were added. The mixture was stirred at 0°C for 0.5 hour. The mixture was concentrated under reduced pressure to give the residue.

The residue was purified by preparative HPLC (Phenomenex luna 30*30mm*10um; Condition: water(0.225%FA)-ACN; B% from 0 to 38; Gradient Time: 22 min; Flow rate: 25 mL/min) to afford (3S)-4-prop-2-enoyl-A-[2-[6-[[5-(4-pyridyl)thiazol-2-yl]amin o]imidazo[4,5-c]pyridin-l- yl]ethyl]morpholine-3-carboxamide (11 mg, 18% yield) as a yellow solid. LCMS: / = 0.740 min in 5-95 AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z =505.0 [M+H] ⁺ . *H NMR (400 MHz, DMSCW6): 5 = 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: /R = 3.925 min (Instrument colummChiral MJ-3 100x4.6mm I.D., 3um, Mobile phase: A: CO2, B: ethanol (0.05% DEA); isocratic elution 8 minutes, flow rate: 2.8 mL/min, Column temperature: 40°C, UV detection: 220 nm), ee%= 100%. [ a ] ²⁰ = - 89.0 (c=0.10 g/100 mL, MeOH).

EXAMPLE 2 (2S)-l-[(Z)-but-2-enoyl]-N-[2-[6-[[5-(4-fluorophenyl)thiazol -2- yl]amino]imidazo[4,5-c]pyridin- l-yl]ethyl]pyrrolidine-2-carboxamide

Synthesis of (25)- 1 - [(Z)-but-2-enoyl] -N - [2- [6- [ [5 -(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]pyrrolidine-2-carb oxamide Experimental Procedure:

[0089] To a solution of tert-butyl N-[2-(6-chloroimidazo[4,5-c]pyridin-l-yl)ethyl]carbamate (300 mg, 1.01 mmol) and 5-(4-fluorophenyl)thiazol-2-amine (196 mg, 1.01 mmol) in NMP (8 mL), BrettPhos Pd G3 (92 mg, 0.10 mmol) and Cs2CO3 (659 mg, 2.02 mmol) were added. The mixture was stirred at 100°C for 3 hours by microwave. The mixture was extracted with ethyl acetate (50 mL x 3), washed with water (50 mL x 7). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue, which was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 100%) to afford tert-butyl A-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]carbamate (732 mg, 22% yield) as brown oil.

[0090] A solution of tert-butyl A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5- c]pyridin-l-yl]ethyl]carbamate (732 mg, 1.61 mmol) in HCl/dioxane (4 M, 8 mL) was stirred at 25 °C for 2 hours. The mixture was concentrated and the residue was basified with satd.

NaHCO3 till pH = 8 and then extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and purified by flash column chromatography on silica gel (methanol in dichloromethane from 0% to 100%) to afford A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-fluoroph enyl)thiazol-2-amine (307 mg, 37% yield) as yellow solid. [0091] To a solution of (2S)- l-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (270 mg, 1.26 mmol) in DMF (3 mL), HATU (567 mg, 1.49 mmol), DIEA (805 mg, 6.23 mmol) andA-[l-(2- aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-fluorophenyl)thi azol-2-amine (287 mg, 0.81 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The mixture was purified by prep- HPLC (column: C18-6 100*30mm*5um; mobile phase: water(FA)-ACN; B%: 35- 65%,15min);Flow Rate(25 ml/min)) to afford 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, 26% yield) as yellow solid. [0092] A solution of tert-butyl (2S)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]pyrrolidi ne-l-carboxylate (138 mg, 0.25 mmol) in HCl/dioxane (4 M, 2 mF) was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure to afford (2S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]pyrrolidine-2-carb oxamide (140 mg, crude) as yellow solid.

[0093] To a solution of (Z)-but-2-enoic acid (20 mg, 0.23 mmol) in DMF (1 mL) and NMP (1 mL), HATU (88 mg, 0.23 mmol), DIEA (200 mg, 1.55 mmol) and (2S)-A-[2-[6-[[5- (4- fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]e thyl]pyrrolidine-2-carboxamide (70 mg, 0.16 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The mixture was purified by prep-HPLC (column: C18-6 100*30mm*5um; mobile phase: water(FA)-ACN; B%: 30- 50%,15min); Flow Rate(25 ml/min)) to afford (2S)-l-[(Z)-but-2-enoyl]-N-[2-[6-[[5-(4- fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]e thyl]pyrrolidine-2-carboxamide (21.9 mg, 26% yield) as white solid. LCMS: /R = 1.401 min in 10-80AB_4 ri6):8 = 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-(di methy I ami no )bul-2-enoy 11 -N- [2- [6- [ [5 -(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]pyrrolidine-2-carb oxamide

Synthesis of (2S)-l-[(E)-4-(dimethylamino)but-2-enoyl]-jV-[2-[6-[[5-(4- fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]pyrrolidine-2-carb oxamide

Experimental Procedure:

[0094] To a solution of (2S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[ 4,5- c]pyridin-l-yl]ethyl]pyrrolidine-2-carboxamide (70 mg, 0.16 mmol) in DMF (2 mL), 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) were added. The mixture was stirred at 25 °C for 2 hours. The mixture was purified by prep-HPLC (column: C18-6 100*30mm*5um; mobile phase: water(FA)-ACN; B%: 0-50%, 15min); FlowRate(25 ml/min)) to afford (2S)-l-[(£ ^, )-4-(dimethylamino)but-2-enoyl]-A- [2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]p yridin-l-yl]ethyl]pyrrolidine-2- carboxamide (18.1 mg, 21% yield) as yellow solid. LCMS: /R = 1.172 min in 10-80AB_4 min_220&254_Shimadzu.lcm, MS (ESI) m/z =563.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6) 5 = 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)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imida zo[4,5-c]pyridin-l-yl]ethyl]-l-(2- fluoroprop-2-enoyl)pyrrolidine-2-carboxamide

Synthesis of (2S)-A-[2-[6-[[5-(4-fhiorophenyl)thiazol-2-yl]arnino]imidazo [4,5-c]pyridin-l- yl]ethyl]-l-(2-fluoroprop-2-enoyl)pyrrolidine-2-carboxamide

Experimental Procedure:

[0095] To a solution of 2-fluoroprop-2-enoic acid (21 mg, 0.23 mmol) in DMF (1 mL) and NMP(1 mL), HATU (88 mg, 0.23 mmol), DIEA (200 mg, 1.55 mmol) and (2S)-A-[2-[6-[[5-(4- fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]e thyl]pyrrolidine-2-carboxamide (70 mg, 0.16 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The mixture was purified by prep-HPLC (column: C18-6 100*30mm*5um; mobile phase: water(FA)-ACN; B%: 30- 50%,15min); Flow Rate(25 ml/min)) to afford (2S)-A-[2-[6-[[5-(4-fhiorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-l-(2-fluoroprop-2 -enoyl)pyrrolidine-2-carboxamide (17.5 mg, 20% yield) as white solid. LCMS: / = 1.365 min in 10-80AB_4 min_220&254_Shimadzu.lcm, MS (ESI) m/z =524.3 [M+H] ⁺ . ^J H NMR (400 MHz, DMSO- ri6): 5 = 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, J = 8.8, 5.6 Hz, 2H), 7.35 - 7.09 (m, 3H), 5.53 - 5.07 (m, 2H), 4.49 - 4.17 (m, 3H), 3.71 - 3.52 (m, 3H), 2.25 - 1.11 (m, 5H).

EXAMPLE 5

2S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidaz o[4,5-c]pyridin-l-yl]ethyl]-l-prop-2- enoyl-pyrrolidine-2-carboxamide

Synthesis of (2S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[ 4,5-c]pyridin-l- yl]ethyl]-l-prop-2-enoyl-pyrrolidine-2-carboxamide

Experimental Procedure:

[0096] To a solution of (2S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[ 4,5- c]pyridin-l-yl]ethyl]pyrrolidine-2-carboxamide (77 mg, 0.17 mmol) in DCM (2 mL), DIEA (220 mg, 1.71 mmol) and prop- 2-enoyl chloride (17 mg, 0.19 mmol) were added at 0°C. Then the mixture was stirred at 25 °C for 1 hour. The mixture was filtered and the filtrate was concentrated, purified by prep-HPLC (column: C18-6 100*30mm*5um; mobile phase: water(FA)-ACN; B%: 10-80%, 15min); Flow Rate(25 ml/min)) to afford (2S)-N- [2- [6-[[5-(4- fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]e thyl]-l-prop-2-enoyl-pyrrolidine- 2-carboxamide (4.6 mg, 5% yield) as white solid. LCMS: / = 1.406 min in 10-80AB_4 min_220&254_Shimadzu.lcm, MS (ESI) m/z =506.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- ri6):5 = 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)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imida zo[4,5-c]pyridin-l- yl]ethyl]-4-prop-

2-enoyl-morpholine-3-carboxamide Synthesis of (3S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[ 4,5-c]pyridin-l- yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamide

Experimental Procedure: [0097] 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)thi azol-2-amine (258 mg, 0.73 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The mixture was purified by prep- HPLC (column: C18-6 100*30mm*5um; mobile phase: water(FA)-ACN; B%: 35- 65%,15min);FlowRate(25 ml/min)) to afford tert-butyl (3S)-3-[2-[6-[[5-(4-fluorophenyl)thiazol- 2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]morpholin e-4-carboxylate (246 mg, 57 % yield) as yellow oil.

[0098] A solution of tert-butyl (3S)-3-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]morpholin e-4-carboxylate (246 mg, 0.43 mmol) in HCl/dioxane (4 M, 3 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford (3S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5- c]pyridin-l-yl]ethyl]morpholine-3-carboxamide (249 mg, crude) as yellow solid.

[0099] To a solution of (3S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[ 4,5- c]pyridin-l-yl]ethyl]morpholine-3-carboxamide (149 mg, 0.32 mmol) in NMP (2 mL), DIEA (412 mg, 3.19 mmol) and prop-2-enoyl chloride (32 mg, 0.35 mmol) were added at 0°C. Then the mixture was stirred at 25 °C for 1 hour. 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); FlowRate (25 ml/min)) to afford (3S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-prop-2-enoyl-mo rpholine-3-carboxamide (10.2 mg, 6% yield) as white solid. LCMS: / = 1.356 min in 10-80AB_4 5 = 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, 5.2 Hz, 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 Synthesis of ((2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imi dazo[4,5-c]pyridin-l- yl]ethyl]-l-prop-2-enoyl-azetidine-2-carboxamide Experimental Procedure: PMB-OH PMB //” PPh ₃ , DIAD Boc ^b

7-1 7-2

[0100] To a mixture of tert-butyl A-(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) at 0°C under N2. The resulting mixture was stirred at 25 °C for 2 h underN2 atmosphere. The mixture was concentrated under reduced pressure to give the residue, whichwas purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether from0% to 5%) to afford tert-butyl A-(5-bromothiazol-2-yl)-A-[(4- methoxyphenyl)methyl]carbamate (29.28 g, 77% yield) as an off-white solid.

[0101] A solution of tert-butyl A-(5-bromothiazol-2-yl)-A-[(4- methoxyphenyl)methyl]carbamate(5 g, 12.52 mmol) in dry THF (80 mL) was cooled to -78°C under N2 atmosphere, then n-BuLi (2.5 M, 5.5 mL) was added dropwise. The reaction mixture was stirred at -78°C for 0.5 hour, then 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2 g, 15.70 mmol) was added and stirred at -78 °C for another 0.5 hour. The mixture was warmed to 25 °C and was quenched by satd. aq. NH4C1 (200 mL), extracted with EtOAc (200 mL x 3), then the combined organic layers were dried over Na2SO4, filtered and concentrated, which was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 7%) to afford tert-butyl A-[(4- methoxyphenyl)methyl]-A-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)thiazol-2- yl]carbamate (3.9 g, 68% yield) as an off-white solid.

[0102] A solution of tert-butyl A-[(4-methoxyphenyl)methyl]-A-[5-(4,4,5,5-tetramethyl-l,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)C12 (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 for 1 hour under N2 atmosphere. The mixture was concentratedunder reduced pressure to give the residue. The mixture was diluted with satd. aq. NH4C1 (200 mL), extracted with EtOAc (200 mL x 3), then the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 17%) to afford tertbutyl A-[5-(3- fhioro-2-pyridyl)thiazol-2-yl]-A-[(4-methoxyphenyl)methyl]ca rbamate (874 mg, 19% yield) as a yellow solid.

[0103] A solution of tert-butyl A-[5-(3-fluoro-2-pyridyl)thiazol-2-yl]-A-[(4- methoxyphenyl)methyl]carbamate (873 mg, 2.1 mmol) in TFA (10 mL) was stirred at 75°C for 12 hours. The mixture was concentrated and the residue was adjusted to pH = 8 by addition of satd. aq. NaHCO3, then extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate in petroleum ether from 0% to 58%) to afford 5-(3- fluoro-2-pyridyl)thiazol-2-amine (353 mg, 78% yield) as yellow solid.

[0104] 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-l-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 for 3 times, and then the mixture was stirred at 90°C for 12 h under N2 atmosphere.

The mixture was concentrated under reduced pressure to give the residue, which was purified by flash column chromatography on silica gel (methanol in dichloromethane from 0% to 13%) to afford of tert-butyl A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4 ,5-c]pyridin-l- yl]ethyl]carbamate (359 mg, 36% yield) as a yellow solid. [0105] A solution of tert-butyl A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4 ,5- olpyridin- 1 -yl |ethyl Icarbamale (358 mg, 0.78 mmol) in 4 M HCl/dioxane (5 mL) was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to afford A-[l-(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.

[0106] To a solution of (2S)-l-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, and then A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2 - pyridyl)thiazol- 2-amine (170 mg, 0.47 mmol) was added. The mixture was stirred at 25°C for 1 h. To the mixture, water (10 mL) was added, which was then extracted with ethyl acetate (10 mL x 3). The combined organic layers were concentrated. The residue was purified by flash column chromatography on silica gel (methanol in dichloromethane from 0% to 8%) to afford tert- butyl (2S)-2-[2-[6-[[5-(3-fhioro-2-pyridyl)thiazol-2-yl]arnino]imi dazo[4,5-c]pyridin-l- yl]ethylcarbamoyl]azetidine-l-carboxylate (214 mg, 80% yield) as a yellow solid.

[0107] A solution of tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl |amino|imidazo|4,5-c|pyridin- Lyl lethylcarbamoyl lazelidine- 1 -carboxylate (214 mg, 0.39 mmol) in 4 M HCl/dioxane (5 mL) was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to give (2S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]azetidine-2-carbox amide (170 mg, crude) as a yellow solid which was used directly in the next step without further purification. [0108] To a solution of (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imid azo[4,5- c]pyridin-l-yl]ethyl]azetidine-2-carboxamide (170 mg, 0.38 mmol) in NMP (2 mL) DIEA (1 g, 7.75 mmol) was added and then prop-2-enoyl chloride (56 mg, 0.62 mmol) was added 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, the mixture was stirred at 25 °C for another 0.5 h. The mixture was purified by prep- HPLC (column: C18 - 6 100 * 30 mm * 5 um; mobile phase: [water (FA)-ACN]; B%: 0% - 50%, 15 min); Flow Rate (25 ml/min)) to afford (2S)-N-[2-[6-[[5-(3-fluoro-2- pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-l-prop-2-enoyl-az etidine-2- carboxamide (6.3 mg, 3% yield) as an off-white solid. ECMS: tR = 1.302 min in 5- 95AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 493.1 [M+H]+. ¹ H NMR (400 MHz, DMSO-de): 5 = 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).

EXAMPEE 8

(2S)-A-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]i midazo[4,5-c]pyridin-l-yl]ethyl]-l- prop-2-enoyl-pyrrolidine-2-carboxamide

Synthesis of (2S)-N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imid azo[4,5-c]pyridin-l- yl]ethyl]-l-prop-2-enoyl-pyrrolidine-2-carboxamide Experimental Procedure:

[0109] 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), Pd(dppf)Ch (1.72 g, 2.35 mmol) and K2CO3 (4.33 g, 31.36 mmol) were added. The mixture was stirred at 80°C for 2 h under N2 atmosphere. The mixture was concentrated under reduced pressure. To the mixture was added water (50 mL), and then extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (30 mL x 2), 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 afford tert-butyl N-[5-(3-fluoro-4- pyridyl)thiazol-2-yl]-N-[(4-methoxyphenyl)methyl]carbamate (2.62 g, 32% yield) as white solid. NMR (400 MHz, DMSO-d ₆ ): 5 = 8.64 (d, J = 2.8 Hz, 1H), 8.43 - 8.42 (m, 1H), 8.24 (s, 1H), 7.86 - 7.83 (m, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.22 (s, 2H), 3.71 (s, 3H), 1.52 (s, 9H).

[0110] 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 satd. aq.

NaHCCL, and then extracted with ethyl acetate (150 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue. The residue was purified by flash column chromatography (silica gel, 100 - 200 mesh, 0 - 4% methanol in dichloromethane) to afford 5-(3-fluoro-4-pyridyl)thiazol- 2-amine (1.17 g, 67% yield) as yellow solid. ¹ H NMR (400 MHz, DMSO-<76): 5 = 8.50 (d, J = 3.6Hz, 1H), 8.31 - 8.29 (m, 1H), 7.76 (s, 1H), 7.57 - 7.55 (m, 3H).

[0111] 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-l-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 for 3 times, and then the mixture was stirred at 100°C for 3 h under N2 atmosphere in microwave. To the mixture was added water (5 mL), and then extracted with ethyl acetate (10 mL x 3). The organic phase was separated, and the organic phase was extracted with water (10 mL x 5). The combined organic layer was concentrated and purified by flash column chromatography on silica gel (methanol in dichloromethane from 0% to 9%) to afford of tert- butyl N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4 ,5-c]pyridin-l- yl]ethyl]carbamate (172 mg, 7% yield) as yellow solid.

[0112] A solution of tert-butyl N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imidazo[4 ,5- c]pyridin-l-yl]ethyl]carbamate (170 mg, 0.37 mmol) in 4 M HCl/dioxane (5 mL) was stirred at 25 °C for 1 h. The mixture was concentrated and to the residue water (10 mL) was added, the mixture was adjusted to pH = 8 by addition of saturated aqueous NaHCCL. The mixture was concentrated in vacuo to give a residue, then diluted with MeOH (10 mL) and washed with MeOH (10 mL x 3). The mixture was filtered and the filtrate was evaporated to afford N-[l-(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.

[0113] To a solution of (2S)-l-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (122 mg, 0.57 mmol) in DMF (2 mL), HATU (208 mg, 0.55 mmol), DIEA (472 mg, 3.66 mmol) and N-[l-(2- aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-4-pyridyl )thiazol-2-amine (130 mg, 0.366 mmol) were added. The mixture was stirred at 25 °C for 1 h. To the mixture was added water (10 mL),and then extracted with ethyl acetate (10 mL x 3). The organic phase was separated, and then was washed with brine (30 mL x 5), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue, which was purified by flash column chromatography on silica gel (methanol in dichloromethane from 0% to 8%) to afford of tert-butyl (2S)-2-[2-[6- [[5-(3-fhioro-4-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyr idin-l- yl]ethylcarbamoyl]pyrrolidine-l -carboxylate (176 mg, 84% yield) as a yellow solid.

[0114] A solution of tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]pyrrolidi ne-l-carboxylate (176 mg, 0.32 mmol) in 4 M 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-l-yl]ethyl]pyrrolidine-2-carb oxamide (144 mg, 88% yield) as yellow solid which was used directly in the next step without further purification.

[0115] To a solution of (2S)-N-[2-[6-[[5-(3-fluoro-4-pyridyl)thiazol-2-yl]amino]imid azo[4,5- c]pyridin-l-yl]ethyl]pyrrolidine-2-carboxamide (144 mg, 0.32 mmol) in DCM (3 mL), DIEA (411 mg, 3.18 mmol) was added and then prop-2-enoyl chloride (31 mg, 0.35 mmol) was added at 0°C. The mixture was stirred at 25°C for 0.5 h. The mixture was concentrated under reduced pressure to give the residue, which was purified by prep-HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 um; mobile phase: water (0.05% HC1) - ACN; B%: 20 - 50%, 9 min); Flow Rate (25 ml/min)) and lyophilized to afford (2S)-N-[2-[6-[[5-(3-fluoro-4- pyridyl)thiazol- 2-yl]amino]imidazo[4,5-c]pyridin- 1 -yljethyl]- l-prop-2-enoyl-pyrrolidine-2- carboxamide (37.9 mg, 23% yield) as a yellow solid. LCMS: tR = 0.913 min in 10- 80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 507.4 [ DMSO-d ₆ ): 5 = 11.62, 11.53 (s, 1H), 8.77 (s, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 4.8 Hz, 1H), 8.24 - 8.09 (m, 3H), 7.75 (t, J = 6.0 Hz, 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: /R = 2.166 min (Instrument column: Chiralpak AS-3 50x4.6mm I.D., 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 2.5 min and hold 40% of 0.5 min, then 5% of B for 1 min Flow rate: 4ml/min Column temp.: 35°C, AB PR: 1500psi), ee % = 99.04 %; [ a ] ²⁰ = +39.0 (c=0.1 g/100 mL, MeOH).

EXAMPLE 9

(2S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]i midazo[4,5-c]pyridin-l- yljethylj-l- prop-2-enoyl-pyrrolidine-2-carboxamide

Synthesis of (2S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl |amino|imidazo|4,5-c|pyridin- 1- yl]ethyl]-l-prop-2-enoyl-pyrrolidine-2-carboxamide [0116] To a solution of (2S)-l-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (103 mg, 0.47 mmol) in DMF (7 mL), HATU (217 mg, 0.57 mmol) and DIEA (308 mg, 2.38 mmol) were added, and, then to it N-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2 - pyridyl)thiazol-2-amine (169 mg, 0.31 mmol) was added. The mixture was stirred at 25 °C for 1 h. To the mixture water (10 mL) was added, and then extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 5), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue, which was purified by flash column chromatography on silica gel (methanol in dichloromethane from 0% to 7%) to afford tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imid azo[4,5-c]pyridin-l- yl]ethylcarbamoyl]pyrrolidine-l -carboxylate (125 mg, 65% yield) as a yellow solid.

[0117] A solution of tert-butyl (2S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]pyrrolidi ne-l-carboxylate (125 mg, 0.22 mmol) in 4 M 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-l-yl]ethyl]pyrrolidine-2-carb oxamide (100 mg, crude) as a yellow solid which was used directly in the next step without further purification.

[0118] To a solution of (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imid azo[4,5- c]pyridin-l-yl]ethyl]pyrrolidine-2-carboxamide (100 mg, 0.22 mmol) in DCM (4 mL), DIEA (287 mg, 2.22 mmol) was added and then prop-2-enoyl chloride (21 mg, 0.23 mmol) was added at 0°C. The mixture was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to give the residue, which was purified by prep-HPLC (column: Xtimate C18 100 * 30 mm * 10 um; mobile phase: [water (FA) - ACN]; B%: 20% - 50%, 10 min); FlowRate (25 ml/min)) to afford and lyophilized to afford of (2S)-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-l-prop-2-enoyl-py rrolidine-2-carboxamide (37.7 mg, 32% yield) as yellow solid. LCMS: tR = 0.972 min in 10- 80AB_4min_220&254_Shimadzu.l cm, MS (ESI) m/z = 507.0 [ DMSO-de): 5 = 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), 4.34 - 4.22 (m, 3H), 3.63 - 3.45 (m, 4H), 2.07 - 1.90 (m, 1H), 1.80 - 1.53 (m, 3H). Chiral SFC: tR = 1.660 min (Instrument column: Chiralpak OJ-3 50x4.6mm I.D., 3 pm. Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 2.5 min and hold 40% of 0.5 min, then 5% of B for 1 min Flow rate: 4ml/min Column temp.: 35°C, ABPR: 1500psi), ee % = 100 %; [a] 20= +29.0 (c=0.10 g/100 mL, MeOH).

EXAMPLE 10

(2S)-l-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyr idyl)thiazol-2- yl]amino]imidazo

|4,5-c|pyridin- 1 -yl lethyl |pyrrolidine-2-carboxamide

Synthesis of (2S)-l-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridy l)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]pyrrolidine-2-carb oxamide

Experimental Procedure:

[0119] To a solution of 2-fluoroprop-2-enoic acid (15 mg, 0.17 mmol) in DMF (2 mL), HATU (64 mg, 0.17 mmol) and DIEA (146 mg, 1.13 mmol) were added and then was added (2S)-A- [2- [6- [ [5 -(3 -fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo [ 4,5-c Jpyridi n- 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 * 30 mm * 5 um; mobile phase: [water (FA) - ACN];B%: 28% - 42%, 8 min); FlowRate (25 ml/min)) to afford (2S)-l-(2-fhioroprop-2-enoyl)- A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4 ,5-c]pyridin-l-yl]ethyl]pyrrolidine- 2-carboxamide (10.8 mg, 18% yield) as yellow solid. LCMS: /R = 1.316 min in 10- 80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 525.1 DMSO- 6): 5 = 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: /R = 1.640 min (Instrument column: Chiralpak OJ-3 50x4.6mm I.D., 3 pm. Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 2.5 min and hold 40% of 0.5 min, then 5% of Bfor 1 min Flow rate: 4ml/min Column temp.: 35°C, ABPR: 1500psi), ee % = 100%;

[ a ] ²⁰ = +11.0 (c=0.10 g/100 mL, MeOH).

EXAMPLE 11

(2S)- 1 - [(Z)-but-2-enoyl] -N- [2- [6- [[5 -(3-fhioro-2-pyridyl)thiazol-2-yl] amino]imidazo [4,5 -

<-• Ipyridi n- 1 -yl]ethyl]pyrrolidine-2-carboxamide

Synthesis (2S)-l-[(Z)-but-2-enoyl]-N-[2-[6-[[5-(3-fluoro-2-pyridyl)thi azol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]pyrrolidine-2-carb oxamide

Experimental Procedure:

[0120] To a solution of (Z)-but-2-enoic acid (7 mg, 0.08 mmol) in DMF (2 mL) HATU (32 mg, 0.08 mmol) and DIEA (71 mg, 0.55 mmol) were added and then (2S)-A-[2-[6-[[5-(3-fluoro-2- pyridyl )lhiazol-2-yl |amino |imidazo| 4,5-c Ipyridin- l-yl]ethyl]pyrrolidine-2- carboxamide (25 mg, 0.05 mmol) was added. The mixture was stirred at 25 °C for 1 h. The mixture was purified by prep-HPLC (column: Phenomenex C18 75 * 30 mm * 3 um; mobile phase: [water (NH3.H2O+ NH4HCO3) - ACN]; B%: 23% - 49%, 9 min); Flow Rate (25 ml/min)) to afford (2S)- 1 - f(Z)-but-2-enoyl] -N- [2- [6- [[5 -(3-fluoro-2-pyridyl)thiazol-2-yl] amino]imidazo [4,5- r Ipyridin- 1 -yl |elhyl |pyrrolidine-2-carboxamide (11.6 mg, 40% yield) as a white solid. LCMS: /R = 1.545 min in 10-80CD_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 521.4 [M+H] ⁺ . H NMR (400 MHz, DMSO-^6): 5 = 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, 1H), 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: /R = 1.987 min (Instrument column: Chiralpak OD-3 50x4.6mm I.D., 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA)Gradient: 40% EtOH (0.05% DEA) Flow rate: 4ml/min Column temp.: 35°C, ABPR: 1500psi),ee % = 98.46%; [ a ] ²⁰ = +14.0 (c=0.067 g/100 mL, MeOH).

EXAMPLE 12

(3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]i midazo[4,5-c]pyridin-l-yl]ethyl]-4- prop-2-enoyl-morpholine-3-carboxamide Synthesis of (3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imid azo[4,5- c]pyridin-l-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamid e Experimental Procedure:

[0121] To a solution of A-[l-(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) HATU (696 mg, 1.83mmol) and DIEA (1.5 g, 11.82 mmol) were added and then (3S)-4-tert- butoxycarbonylmorpholine-3- carboxylic acid (410 mg, 1.77 mmol) was added. The mixture was stirred at 25°C for 1 h. To the mixture, water (10 mL) was added, and then extracted with ethyl acetate (lOmL x 3). The combined organic phase was washed with brine (10 mL x 5), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (methanol in dichloromethane from 0% to 8%) to afford tert-butyl(3S)-3-[2-[6-[[5-(3- fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l- yl]ethylcarbamoyl]morpholine-4- carboxylate (28 mg, 4% yield) as white solid.

[0122] A solution of tert-butyl (3S)-3-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]morpholin e-4-carboxylate (28 mg, 0.05 mmol) in 4 M HCl/dioxane (2 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give (3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morpholine-3-carbo xamide (23 mg, 99% yield) as a yellow solid which was used directly in the next step without further purification.

[0123] To a solution of (3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imid azo[4,5- c]pyridin-l-yl]ethyl]morpholine-3-carboxamide (23 mg, 0.05 mmol) in DCM (2 mL), DIEA (63 mg, 0.49 mmol) was added and then prop-2-enoyl chloride (5 mg, 0.06 mmol) was added at 0°C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give the residue, which was purified by prep-HPLC (column: C18 - 6 100 * 30 mm * 5 um; mobile phase: [water (FA) - ACN]; B%: 108% - 80%, 15 min); Flow Rate (25 ml/min)) and lyophilized to afford the product (3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-prop-2-enoyl-mo rpholine-3-carboxamide (1.9 mg, 7% yield) as an off-white solid. LCMS: / = 1.212 min in 10- 80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 523.1 DMSO-76): 5 = 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, 7 = 2.0 Hz, 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: /R = 1.813 min (Instrument column: Chiralpak OJ-3 50x4.6mm I.D., 3um Mobile phase: A: CO2 B: Ethanol (0.05% DEA) Gradient:from 5% to 40% of B in 2.5 min and hold 40% of 0.35 min, then 5% of B for 0.15 min Flow rate: 4ml/min Column temp.: 35°C, ABPR: 1500psi), ee % = 99.12 %.

EXAMPLE 13

(2S, 4R)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4 ,5-c]pyridin-l-yl]ethyl]-4- hydroxy- l-prop-2-enoylpyrrolidine-2-carboxamide Synthesis of (2S, 47?)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[ 4,5-c]pyridin-l- yl]ethyl]-4-hydroxy- 1 -prop-2-enoylpyrrolidine-2-carboxamide [0124] To a solution of (2S, 47?)- 1 -tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid

(233 mg, 1.01 mmol) in DMF (2 mL), HATU (454 mg, 1.19 mmol), DIEA (645 mg, 4.99 mmol) and A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4-fluoroph enyl)thiazol-2- amine (230 mg, 0.65 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue, which 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 afford tert-butyl (2S, 4R)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4 ,5-c]pyridin- l-yl]ethylcarbamoyl]-4-hydroxypyrrolidine-l-carboxylate (50 mg, 13% yield) as colorless oil.

[0125] A solution of tert-butyl (2S, 4R)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]- 4-hydroxy-pyrrolidine- 1 -carboxylate (50 mg, 0.088 mmol) in HCl/dioxane (4 M, 1 mL) was stirred at 25°C for 2 hours. The mixture was concentrated in vacuo to give (2S, 4R)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hydroxy-pyrroli dine-2-carboxamide (50 mg, crude) as white solid.

[0126] To a solution of (2S, 4R)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4 ,5- c]pyridin-l-yl]ethyl]-4-hydroxypyrrolidine-2-carboxamide (50 mg, 0.18 mmol) in NMP (2 mL), DIEA (138 mg, 1.07 mmol) and prop-2-enoyl chloride (11 mg, 0.12 mmol) were added at 0°C. The mixture was stirred at 25 °C for 1 hour. The mixture was purified by prep-HPLC (column: C18-6 100*30mm*5um; mobile phase: water(FA)-ACN; B%: 10-40%, 15min); FlowRate(25 ml/min)) to afford (2S, 4R)-A-[2-[6-[[5-(4-fhiorophenyl)thiazol-2-yl]amino]imidazo[4 ,5- c]pyridin-l-yl]ethyl]-4-hydroxy-l-prop-2-enoylpyrrolidine-2- carboxamide (3.2 mg, 5% yield) as white solid. LCMS: / = 1.150 min in 10-80AB_4 min_220&254_Shimadzu.lcm, MS (ESI) m/z =522.3 [M+H] ⁺ . 'H NMR (400 MHz, DMSO- 6): 5 = 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)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4 ,5-c]pyridin-l-yl]ethyl]-4- hydroxy- l-prop-2-enoylpyrrolidine-2-carboxamide Synthesis of (2S, 4S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]irnidazo[ 4,5-c]pyridin-l- yl]ethyl]-4-hydroxy- 1 -prop-2-enoylpyrrolidine-2-carboxamide

Experimental Procedure: [0127] To a solution of (2S, 45)- 1 -tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (243 mg, 1.05 mmol) in DMF (2 mL) HATU (474 mg, 1.25 mmol) and DIEA (673 mg, 5.21 mmol) were added, A-[l-(2-aminoethyl)imidazo[4,5-c]70yridine-6-yl]-5-(4- fluorophenyl)thiazol-2-amine (240 mg, 0.68 mmol). The mixture was stirred at 25°C for 1 hours. The mixture was purified by prep-HPLC (column: C18-6 100*30mm*5um; mobile phase: water(FA)-CAN; B%: 24-54%, 15 min); FlowRate (25 ml/min)) to afford tert-butyl (25, 45)-2-[2-[6-[[5-(4- fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]70yridine-l- yl]ethylcarbamoyl]-4- hydroxypyrrolidine- 1 -carboxylate (200 mg, 39% yield) as white solid.

[0128] A solution of tert-butyl (25, 45)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]7 lyridine- l-yl]ethylcarbamoyl]-4-hydroxy -pyrrolidine- 1-carboxylate (200 mg, 0.35 mmol) in HCl/dioxane (4 M, 2 mL) was stirred at 25°C for 2 hours. The mixture was concentrated in vacuo to give (2S, 4S)-N-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]7 lyridine- l-yl]ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (190 mg, crude) as white solid.

[0129] To a solution of (25, 45)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4 ,5- c]71yridine-l-yl]ethyl]-4-hydroxypyrrolidine-2-carboxamide (100 mg, 0.21 mmol) in NMP (2 mL), DIEA (276 mg, 2.14 mmol) and prop-2-enoyl chloride (21 mg, 0.24 mmol) were added at 0°C. The mixture was stirred at 25 °C for 1 hours. The mixture was purified 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 afford (25, 45)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]7 lyridine- l-yl]ethyl]-4-hydroxy- l-prop-2-enoylpyrrolidine-2- carboxamide (6.2 mg, 6% yield) as white solid. LCMS: / = 1.311 min in 10-80AB_4 5 = 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)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4 ,5-c]72yridine-l-yl]ethyl]-3- hydroxy- l-prop-2-enoylpyrrolidine-2-carboxamide Synthesis of (2S, 3S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]irnidazo[ 4,5-c]72yridine- l-yl]ethyl]-3-hydroxy-l-prop-2-enoylpyrrolidine-2-carboxamid e

Experimental Procedure:

[0130] To a solution of (2S, 3S)-1 -tert-butoxycarbonyl-3 -hydroxy-pyrrolidine-2-carboxy lie acid (150 mg, 0.65 mmol, 1.55 eq) in DMF (2 mL), HATU (293 mg, 0.77 mmol), DIEA (416 mg, 3.22 mmol), and A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(4- fluorophenyl)thiazol-2- amine (148 mg, 0.42 mmol) were added. The mixture was stirred at 25 °C for 1 hour. The mixture was purified by prep-HPLC (column: Cl 8-6 100*30mm*5um; mobile phase: water(FA)-ACN; B%: 24-54%, 15min); FlowRate (25 ml/min)) to afford tert-butyl (2S, 3S)-2- [2-[6-[[5-(4-fluorophenyl)thiazol-2-yl]amino]imidazo[4,5-c]p yridin-l-yl]ethylcarbamoyl]-3- hydroxypyrrolidine- 1 -carboxylate (59 mg, 24% yield) as yellow solid.

[0131] A solution of tert-butyl (2S, 3S)-2-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]-3-hydrox y-pyrrolidine-l-carboxylate (59 mg, 0.10 mmol) in HCl/dioxane (4 M, 1 mL) was stirred at 25°C for 2 hours. The mixture was concentrated in vacuo to give (2S, 3S)-A-[2-[6-[[5-(4-fluorophenyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-3-hydroxy-pyrroli dine-2-carboxamide (70 mg, crude) as yellow solid.

[0132] To a solution of (2S, 3S)-A-[2-[6-[[5-(4-fhiorophenyl)thiazol-2-yl]amino]imidazo[4 ,5- c]pyridin-l-yl]ethyl]-3-hydroxypyrrolidine-2-carboxamide (70 mg, 0.15 mmol) in NMP (2 mL) DIEA (194 mg, 1.50 mmol) and prop-2-enoyl chloride (15 mg, 0.16 mmol) were added at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was purified by prep-HPLC (column: C18-6 100*30mm*5um; mobile phase: water(FA)-ACN; B%: 16-46%, 15 min); FlowRate (25 ml/min)) to afford (2S, 3S)-A-[2-[6-[[5-(4-fhiorophenyl)thiazol-2-yl]amino]imidazo[4 ,5- c]pyridin-l-yl]ethyl]-3-hydroxy-l-prop-2-enoylpyrrolidine-2- carboxamide (17.7 mg, 22% yield)as white solid. LCMS: / = 1.291 min in 10-80AB_4 min_220&254_Shimadzu.lcm, MS 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), 7.27 - 7.13 (m, 3H), 6.62

(dd, 7 = 16.4, 10.4 Hz, 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)-A-[2-[6-[[5-(3-fluoro-2-pyr idyl)thiazol-2- yl]amino]imidazo[4,5- c]pyridin-l-yl]ethyl]morpholine-3-carboxamide

Synthesis of (3S)-4-(2-fluoroprop-2-enoyl)-A-[2-[6-[[5-(3-fluoro-2-pyridy l)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morpholine-3-carbo xamide

Experimental Procedure:

[0133] To a solution of (3S)-4-tert-butoxycarbonylmorpholine-3-carboxylic acid (93 mg, 0.4 mmol) in DMF (25 mL), HATU (157 mg, 0.4 mmol) and DIEA (691 mg, 5.3 mmol) were added and then A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2 - pyridyl)thiazol- 2-amine (95 mg, 0.3 mmol) was added. The mixture was stirred at 25 °C for 1 h. To the reaction mixture, water (10 mL) was added, and then extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL x 5), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue, which was purified by flash column chromatography on silica gel (methanol in dichloromethane from 0% to 8%) to afford tert-butyl (3S)-3-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imid azo[4,5-c]pyridin-l- yl]ethylcarbamoyl]morpholine-4-carboxylate (84 mg, 51% yield) as a yellow solid.

16-2 16-3

[0134] A solution of tert-butyl (3S)-3-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]morpholin e-4-carboxylate (84 mg, 0.14 mmol) in 4 M HCl/dioxane (2 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give (3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morpholine-3-carbo xamide (158 mg, HC1 salt) as a yellow solid which was used directly in the next step without further purification.

[0135] To a solution of 2-fluoroprop-2-enoic acid (17 mg, 0.18 mmol) in DMF (2 mL) HATU (96 mg, 0.25 mmol) and DIEA (435 mg, 3.36 mmol) were added and then (3S)-N- [2- [6-[[5-(3- fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l- yl]ethyl]morpholine-3- carboxamide (79 mg, 0.17 mmol) was added. The mixture was stirred at 25 °C for 1 h, and 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, the mixture was stirred at 25 °C for another 1 h. The mixture was purified by prep-HPLC (column: C18 - 6 100 * 30 mm * 5 um; mobile phase: [water (FA)-ACN]; B%: 0% - 50%, 15 min); Flow Rate (25 ml/min)) to afford (3S)-4-(2-fluoroprop-2-enoyl)-N-[2-[6-[[5-(3-fluoro-2-pyridy l)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morpholine-3-carbo xamide (4.7 mg, 5% yield) as an off-white solid. ECMS: tR = 1.336 min in 5-5AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 541.2 [M+H]+. MHz, DMSO-d ₆ ): 5 = 11.43 - 11.37 (m, 1H), 8.81 - 8.79 (m, 1H), 8.41 - 8.40 (m, 1H), 8.31 - 8.20 (m, 1H), 8.13 (s, 1H), 7.97 (d, J = 2.4 Hz, 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 = 5.6 Hz, 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- [(£')-4-(dimethylamino)but-2-enoyl] -N- [2- [6- [ [5 -(3 -fluoro-2- pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morpholine-3-carbo xamide

Synthesis of (3S)-4-[(E)-4-(dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(3-flu oro-2- pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl] morpholine-3-carboxamide

Experimental Procedure:

[0136] To a solution of (3S)-N-[2-[6-[[5-(3-fhioro-2-pyridyl)thiazol-2-yl]amino]imid azo[4,5- c]pyridin-l-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, and then (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 another 1 h. The mixture was purified by prep-HPLC (column: C18 - 6 100 * 30 mm * 5 um; mobile phase: [water (FA) - ACN]; B%: 0% - 45%, 15 min); Flow Rate (25 ml/min)) to afford (3S)-4-[(E)-4-(dimethylamino)but-2-enoyl]-A-[2-[6-[[5-(3-flu oro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morpholine-3-carbo xamide (8.2 mg, 8% yield) as an off-white solid. LCMS: / = 0.972 min in 10-80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 580.4 [ 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,lH), 3.80 - 3.71 (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)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imida zo[4,5-c]pyridin-l-yl]ethyl]-

4-hydroxy-l-prop-2-enoyl-pyrrolidine-2-carboxamide

Synthesis of (2S, 4R)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5- c]pyridin-l-yl]ethyl]-4-hydroxy-l-prop-2-enoyl-pyrrolidine-2 - carboxamide

Experimental Procedure:

[0137] To a solution of (2S, 4R)-l-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (222 mg, 0.96 mmol) in DMF (10 mL), HATU (497 mg, 1.31 mmol) and DIEA (2.25 g, 17.45 mmol) were added, and then A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3- fluoro-2- pyridyl)thiazol-2-amine (310 mg, 0.872 mmol) was added. The mixture was stirred at 25°C for 2 h. The mixture was purified by prep-HPLC (column: Xtimate C18 150 * 40 mm * 10 um; mobile phase: [water (FA) - ACN]; B%: 20% - 50%, 10 min); Flow Rate (25 ml/min)) to afford tert- butyl (2S, 4R)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imida zo[4,5-c]pyridin-l- yl]ethylcarbamoyl]-4-hydroxy-pyrrolidine-l-carboxylate (300 mg, 59% yield) as a brown solid.

[0138] A solution of tert-butyl (2S, 4R)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- y I |ami no | i midazo| 4,5-<-- Ipyridi n- 1 -yl]ethylcarbamoyl]-4-hydroxy -pyrrolidine- 1 -carboxylate

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

[0139] To a solution of (2S, 4R)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hydroxy-pyrroli dine-2-carboxamide (80 mg, 0.17 mmol) in NMP (2 mL) DIEA (278 mg, 2.15 mmol) and prop-2-enoyl chloride (22 mg, 0.24 mmol) were added 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 afford (2S, 47?)-A-[2-[6-[[5-(3-fluoro-2- pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl] -4-hydroxy-l-prop-2-enoyl- pyrrolidine-2- carboxamide (6.2 mg, 7% yield) as a yellow solid. LCMS: /R = 1.220 min in 5- 95AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 523.2 [ DMSO-<76): 5 = 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 - 7.17 (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, 47?)- 1 -(2-fluoroprop-2-enoyl)- N- [2- [6- [ [5 -(3 -fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hydroxy-pyrroli dine-2-carboxamide

Synthesis of (2S, 47?)-l-(2-fluoroprop-2-enoyl)-A-[2-[6-[[5-(3-fluoro-2-pyridy l)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hydroxy-pyrroli dine-2-carboxamide

Experimental Procedure:

[0140] To a solution of 2-fluoroprop-2-enoic acid (23 mg, 0.25 mmol) in DMF (2 mL), HATU (122 mg, 0.32 mmol), DIEA (278 mg, 2.15 mmol) and (2S, 47?)-A-[2-[6-[[5-(3- fhioro-2-pyridyl)thiazol-2-yl]arnino]imidazo[4,5-c]pyridin-l -yl]ethyl]-4-hydroxy-pyrrolidine-2- carboxamide (80 mg, 0.17 mmol) were added. The mixture was stirred at 25C for 1 h. The mixture was purified by prep-HPLC (column: C18 - 6 100 * 30 mm * 5 um; mobile phase: [water (FA) - ACN]; B%: 0% - 50%, 15 min); FlowRate(25 ml/min)) and lyophilized to afford the crude product, and then was purified by prep-HPLC (column: Phenomenex Cl 8 75 * 30 mm * 3um; mobile phase: [water (NH3.H2O + NH4HCO3) - ACN]; B%: 10% - 40%, 14 min); FlowRate (25 ml/min)) to afford (2S, 47?)-l-(2-fluoroprop-2-enoyl)-A-[2-[6-[[5-(3-fluoro-2- pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl] -4-hydroxy -pyrrolidine-2- carboxamide (5.5 mg, 6%yield) as an off-white solid. LCMS: / = 1.059 min in 5- 95AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 541.0 [M+H] ⁺ . DMSO-76): 5 = 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, 7= 2.0 Hz, 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, 47?)- 1 - [(£')-4-(dimethylamino)but-2-enoyl] -N- [2- [6- [ [5 -(3 -fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hydroxy-pyrroli dine-2-carboxamide

Synthesis of (2S, 47?)-l-[(£ ^, )-4-(dimethylamino)but-2-enoyl]-A-[2-[6-[[5-(3-fluoro- 2- pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl] -4-hydroxy -pyrrolidine-2- carboxamide

Experimental Procedure:

[0141] To a solution of (2S, 47?)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hydroxy-pyrroli dine-2-carboxamide (80 mg, 0.17 mmol) and (£)-4-(dimethylamino)but-2-enoic acid (39 mg, 0.30 mmol) in DMF (2 mL), (276 mg, 2.14 mmol) and PyBOP (123 mg, 0.23 mmol) were added. 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%,15min); Flow Rate (25 ml/min)) to afford (2S, 4R)-1- [(£)-4-(dimethylamino)but-2-enoyl]-A-[2-[6-[[5-(3-fluoro-2- pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hydroxy-pyrroli dine-2-carboxamide (28.9 mg, 29% yield) as a yellow solid. LCMS: / = 1.127 min in 5-

95AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 580.3 DMSO-76): 5 = 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, 7 = 6.0 Hz, 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)-A-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]i midazo[4,5-c]pyridin-l- yl]ethyl]-4-hydroxy- 1 -prop-2-enoyl-pyrrolidine-2-carboxamide Synthesis of (2S, 4R)-A-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2- yl]amino]imidazo[4,5- c]pyridin-l-yl]ethyl]-4-hydroxy-l-prop-2-enoyl-pyrrolidine-2 - carboxamide

Experimental Procedure:

[0142] To a solution of tert-butyl ?/-[(4-methoxyphenyl)methyl]-?/-[5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)thiazol-2-yl]carbamate (5.6 g, 12.55 mmol) and 4-chloro-5-fluoro- pyrimidine (2.49 g, 18.82 mmol) in dioxane (100 mL) and H2O (20 mL), Pd(dppf)C12 (918 mg, 1.25 mmol) and K2CO3 (5.20 g, 37.64 mmol) were added. The mixture was stirred at 80°C for

1 h at N2 atmosphere. The mixture was concentrated and the residue was diluted with H2O (30 mL), andthen extracted with ethyl acetate (60 mL x 3). Then the combined organic layers were washed with satd. aq. NaCl (20 mL x 2), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc in PE from 0% to 15%) to afford tert-butyl A-[5-(5-fhioropyrimidin-4-yl)thiazol-2-yl]-iV-[(4- methoxyphenyl)methyl]carbamate (2.8 g, 51% yield) as yellow solid.

21-5

21-6

[0143] A solution of tert-butyl A-[5-(5-fhioropyrimidin-4-yl)thiazol-2-yl]-A-[(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 and the residue was basified with aq. satd.Na2CO3 until pH = 9 and then extracted with ethyl acetate (60 mL x 3), then the combined organic layers washed with satd. aq. NaCl (20 mL x 2), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (DCM in MeOH ether from 0% to 7%) to afford 5-(5-fluoropyrimidin-4-yl)thiazol-2-amine (856 mg,

58% yield) as yellow solid.

21-6

[0144] To a solution of 5-(5-fluoropyrimidin-4-yl)thiazol-2-amine (856 mg, 4.36 mmol) and tert-butyl A-[2-(6-chloroimidazo[4,5-c]pyridin-l-yl)ethyl]carbamate (1.29 g, 4.36 mmol) in dioxane (50 mL), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicycl ohexyl-[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)phen yl]phosphane (468 mg, 0.87 mmol) were added. The mixture was stirred at 90°C for 12 h under N2 atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (DCM in MeOH from 0% to 9%) to afford tert-butyl A-[2-[6-[[5-(5-fhioropyrimidin-4-yl)thiazol-2-yl]amino]imida zo[4,5-c]pyridin- l-yl]ethyl]carbamate (429 mg, 18% yield) as yellow solid.

[0145] A solution of tert-butyl A-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]carbamate (429 mg, 0.94 mmol) in HCl/dioxane (4 M, 4.4 mL) was stirred at 20°C for 2 h. The mixture was concentrated under reduced pressure to give A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(5-fluoropy rimidin-4-yl)thiazol-2- amine(580 mg, crude) as yellow solid.

[0146] To a solution of A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(5-fluoropy rimidin- 4-yl)thiazol-2-amine (200 mg, 0.56 mmol) and (2S, 47?)-l-tert-butoxycarbonyl-4-hydroxy- pyrrolidine-2-carboxylic acid (130 mg, 0.56 mmol) in DMF (6 mL), HATU (320 mg, 0.84 mmol) and DIEA (725 mg, 5.61 mmol) were added. The mixture was stirred at 20°C for 1 h at N2 atmosphere. The mixture was purified by prep - HPLC (column: Xtimate Cl 8 100 * 30mm * lOum; mobile phase: [water (FA)-ACN]; B%: 15% - 45%, 10 min) to afford tert-butyl (2S, 47?)-2-[2-[6-[[5-(5-fhioropyrimidin-4-yl)thiazol-2-yl]amino] imidazo[4,5-c]pyridin-l- yl]ethylcarbamoyl]-4-hydroxy-pyrrolidine-l-carboxylate (62 mg, 17% yield) as yellow solid.

[0147] A solution of tert-butyl (2S, 47?)-2-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]-4-hydrox y-pyrrolidine-l-carboxylate (62 mg, 0.1 mmol) in HCl/dioxane (4 M, 3 mL) was stirred at 20°C for 1 h. The mixture was concentrated under reduced pressure to give (2S, 47?)-A-[2-[6-[[5-(5-fhioropyrimidin-4- yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hy droxy-pyrrolidine-2-carboxamide (70 mg, crude) as yellow solid.

[0148] To a solution of (2S, 47?)-A-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hydroxy-pyrroli dine-2-carboxamide (70 mg, 0.15 mmol) in NMP (1.5 mL), prop-2-enoyl chloride (13 mg, 0.15 mmol) and DIEA (193 mg, 1.49 mmol) were added at 0°C. The mixture was stirred at 20°C for 1 h. The mixture was purified by prep-HPLC (column: C18 - 6 100 * 30 mm * 5 um; mobile phase: [water(FA) - ACN];B%: 8% -38%, 15 min) to afford (2S, 47?)-A-[2-[6-[[5-(5-fhioropyrimidin-4-yl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-4-hydroxy-l-prop- 2-enoyl-pyrrolidine-2- carboxamide (10.9 mg, 14% yield) as yellow solid. LCMS: / = 0.990 min in: 10-80 AB_4 min_220 &2 54_Shimadzu.lcm, MS (ESI) m/z = 524.4 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- d6 5 = 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 = 5.8 Hz, 1H), 7.32 - 7.18 (m, 1H), 6.58 (m, J = 10.3, 16.8 Hz, 1H), 6.21 (d, J = 2.2, 16.8 Hz, 1H), 5.81 - 5.40 (d, 1H), 5.11 - 4.90 (m, 1H), 4.35 - 4.24 (m, 4H), 3.66 - 3.43 (m, 4H), 1.97 - 1.88 (m, 1H), 1.70 (m, J = 4.8, 8.0, 12.9 Hz, 1H).

EXAMPLE 22

(3S)-A-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]ami no]imidazo[4,5-c]pyridin-l-yl]ethyl]-

4-prop-2-enoyl-morpholine-3-carboxamide

Synthesis of (3S)-A-[2-[6-[[5-(5-fhioropyrimidin-4-yl)thiazol-2-yl]amino] imidazo[4,5- c]pyridin-l-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamid e

Experimental Procedure:

[0149] To a solution of A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(5-fluoropy rimidin- 4- yl)thiazol-2-amine (160 mg, 0.45 mmol) and (3S)-4-tert-butoxycarbonylmorpholine-3- carboxylicacid (104 mg, 0.45 mmol) in DMF (5 mL), HATU (256 mg, 0.67 mmol) and DIEA (580 mg, 4.49 mmol) were added. The mixture was stirred at 20°C for 1 h. The mixture was added water (10 mL), then extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with water (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM in MeOH etherfrom 0% to 9%) to afford tert-butyl (3S)-3-[2-[6-[ [5-(5-fhioropyrimidin- 4-yl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]morpholin e-4-carboxylate (78 mg, 29%yield) as yellow solid. [0150] A solution of tert-butyl (3S)-3-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethylcarbamoyl]morpholin e-4-carboxylate (75 mg, 0.13 mmol) in HCl/dioxane (4 M, 2 mL) was stirred at 20°C for 1 h. The mixture was concentrated under reduced pressure to give (3S)-A-[2-[6-[[5-(5-fhioropyrimidin-4-yl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morpholine-3-carbo xamide (110 mg, crude) as yellow solid.

[0151] To a solution of (3S)JV-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morpholine-3-carbo xamide (35 mg, 0.075 mmol) in NMP (2 mL), prop-2-enoyl chloride (8 mg, 0.082 mmol) and DIEA (96 mg, 0.075 mmol) were added 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%,15min) to afford (3S)-A-[2-[6-[[5-(5-fhioropyrimidin-4-yl)thiazol-2-yl ]amino]imidazo[4,5- c]pyridin-l-yl]ethyl]-4-prop-2-enoyl-morpholine-3-carboxamid e (4.7 mg, 12% yield) as yellow solid. LCMS: /R = 1.077 min in: 10-80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z =

524.4 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-76): 5 = 8.91 (d, J= 3.6 Hz, 1H), 8.85 (s, 1H), 8.79 (d, 7 = 3.6 Hz, 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-l-yl]ethyl]morpholine-3-carbo xamide Synthesis of (3S)-4-[(E)-4-(dimethylamino)but-2-enoyl]-A-[2-[6-[[5-(5- fluoropyrimidin-4- yl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morph oline-3-carboxamide

Experimental Procedure:

[0152] To a solution of (3S)-A-[2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]morpholine-3-carbo xamide (55 mg, 0.12 mmol) in DMF (3 mL), (£’)-4-(dimethylamino)but-2-enoic acid (27 mg, 0.2 mmol), DIEA (182 mg, 1.41 mmol) and PyBOP (84 mg, 0.16 mmol) were added. The mixture was stirred at 20°C for 1.5 h. Themixture was purified by prep-HPLC (column: C18-6 100 * 30mm * 5um; mobile phase: [water (FA) - ACN];B%: 10% - 40%, 15 min) to afford (3S)-4-[(E)-4-(dimethylamino)but-2- enoyl]-A- [2-[6-[[5-(5-fluoropyrimidin-4-yl)thiazol-2-yl]amino]imidazo [4,5-c]pyridin-l- yl]ethyl]morpholine-3-carboxamide (6 mg, 8% yield) as yellow solid. LCMS: / = 0.977 min in: 10-80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 581.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-<76): 5 = 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)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imida zo[4,5-c]pyridin-l-yl]ethyl]-

3 -hydroxy- l-prop-2-enoyl-pyrrolidine-2-carboxamide Synthesis of (2S, 3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin- l-yl]ethyl]-3-hydroxy-l-prop-2-enoyl-pyrrolidine-2- carboxamide

Experimental Procedure:

[0153] To a solution of (2S, 3S)-l-tert-butoxycarbonyl-3-hydroxy-pyrrolidine-2-carboxylic acid

(390 mg, 1.69 mmol) in DMF (6 mL), HATU (963 mg, 2.53 mmol), DIEA (2 g, 16.88mmol) and then A-[l-(2-aminoethyl)imidazo[4,5-c]pyridin-6-yl]-5-(3-fluoro-2 - pyridyl)thiazol-2- amine (600 mg, 1.69 mmol) were added. The mixture was stirred at 25 °C for 1 h. The mixture was purified by prep-HPLC (column: Xtimate Cl 8 150 * 40 mm * 10 um; mobile phase: [water (FA)-ACN]; B%: 20% - 60%, 10 min); Flow Rate (25 ml/min)) to afford tert-butyl (2S, 3S)-2- [2-[6-[[5-(3-fhioro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5 -c]pyridin-l- yl]ethylcarbamoyl]- 3 -hydroxy-pyrrolidine- 1 -carboxylate (74 mg, 7% yield) as a yellow solid. [0154] A solution of tert-butyl (2S, 3S)-2-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl |amino |imidazo| 4,5-c Ipyridin- l-yl]ethylcarbamoyl]-3-hydroxy-pyrrolidine- 1-carboxylate (74 mg, 0.13 mmol) in 4 M HCl/dioxane (10 mL) was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure to give (2S, 3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-3-hydroxy-pyrroli dine-2-carboxamide (60 mg, crude) as a yellow solid which was used directly in the next step without further purification.

[0155] To a solution of (2S, 3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-3-hydroxy-pyrroli dine-2-carboxamide (60 mg, 0.13 mmol) in NMP (2 mL), DIEA (165 mg, 1.28 mmol) was added and then prop-2-enoyl chloride (14 mg, 0.15 mmol) was added 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 * 30 mm * 5 um; mobile phase: [water (FA) - ACN]; B%: 0% - 50%, 15 min); Flow Rate (25 ml/min)) to afford (2S, 3S)-A-[2-[6-[[5-(3- fluoro-2-pyridyl)thiazol- 2-yl]amino]imidazo 14,5 -c Ipyridi n- 1 -yl] ethyl] -3 -hydroxy- 1 -prop-2- enoyl-pyrrolidine-2- carboxamide (21.3 mg, 31% yield) as a yellow solid. LCMS: / = 1.076 min in 10- 80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 523.4 [ (400 MHz, DMSO-<76): 5 = 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-l-yl]ethyl]-3-hydroxy-pyrroli dine-2-carboxamide Synthesis of (2S, 3S)-l-(2-fluoroprop-2-enoyl)-jV-[2-[6-[[5-(3-fluoro-2- pyridyl)thiazol-2-

Experimental Procedure:

[0156] To a solution of 2-fluoroprop-2-enoic acid (29 mg, 0.32 mmol) in DMF (2 mL), HATU (162 mg, 0.43 mmol) and DIEA (276 mg, 2.13 mmol) were added, and then (2S, 3S)-A-[2-[6- [[5-(3-fluoro-2-pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyr idin-l-yl]ethyl]-3- hydroxy - pyrrolidine-2-carboxamide (100 mg, 0.21 mmol) was added. The mixture was stirred at 25 °C for Ih. The mixture was purified by prep-HPLC (column: Phenomenex Cl 8 75 * 30 mm * 3 urn; mobile phase: [water (NH3.H2O + NH4HCO3) - ACN]; B%: 13% - 43%, 11 min); Flow Rate (25 ml/min)) to afford (2S, 3S)-l-(2-fhioroprop-2-enoyl)-A-[2-[6-[[5-(3-fluoro-2- pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-3-hydroxy-pyrroli dine-2- carboxamide (12.2 mg, 11% yield) as a yellow solid. LCMS: / = 1.175 min in 10- 80AB_4min_220&254_Shimadzu.lcm, MS (ESI) m/z = 541.2 [ DMSO-76): 5 = 11.37 (s, IH), 8.80 - 8.77 (m, IH), 8.40 - 8.10 (m, 3H), 7.96 (d, 7 = 2.4 Hz, IH), 7.79 - 7.73 (m, IH), 7.30 - 7.26 (m, IH), 7.18 - 7.09 (m, IH), 5.55 - 5.13 (m, 3H), 4.38 - 3.41 (m,8H), 1.81 - 1.49 (m, 2H).

EXAMPLE 26

(2S, 3S)- 1 - [(£')-4-(dimethylamino)but-2-enoyl] -N- [2- [6- [ [5 -(3 -fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-3-hydroxy-pyrroli dine-2-carboxamide Synthesis of (2S, 3S)-l-[(E)-4-(dimethylamino)but-2-enoyl]-N-[2-[6-[[5-(3-fluo ro-2- pyridyl)thiazol-2-yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl] -3-hydroxy -pyrrolidine-2- carboxamide

Experimental Procedure:

[0157] To a solution of (2S, 3S)-A-[2-[6-[[5-(3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-3-hydroxy-pyrroli dine-2-carboxamide (100 mg, 0.21 mmol) in DMF (2mL) and DIEA (276 mg, 2.13 mmol), (£)-4-(dimethylamino)but-2-enoic acid (55 mg, 0.43 mmol) was added and then PyBOP (222 mg, 0.43 mmol) was added. The mixture was stirred at 25 °C for Ih. The mixture was purified by prep-HPLC (column: Phenomenex C18 75 * 30 mm * 3 um; mobile phase: [water (NH3.H2O + NH4HCO3) - ACN]; B%: 10% -45 %, 11 min); Flow Rate (25 ml/min)) then further purified by prep-HPLC (column: C18-6 100 * 30 mm * 5 um; mobile phase: [water (FA) - ACN]; B%: 6% - 36%, 8 min); FlowRate (25 ml/min)) to afford (2S, 3S)-1- [(£)-4-(dimethylamino)but-2-enoyl ]-7V-[2- [6-[ [5- (3-fluoro-2-pyridyl)thiazol-2- yl]amino]imidazo[4,5-c]pyridin-l-yl]ethyl]-3-hydroxy- pyrrolidine-2-carboxamide (35 mg, 28% yield) as a yellow solid. LCMS: / = 0.888 min in 10- 80AB_4min_220&254_Shimadzu.lcm, MS(ESI) m/z = 580.3 [ DMSO-<76): 5 = 11.42 (s, IH), 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), 5.24 (s, IH), 4.32 - 4.23 (m, 2H), 4.13 (s, IH), 4.09 - 3.99 (m, IH), 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).

EXAMPLE 27

Characterization of the Kinase Inhibition Properties of the Disclosed Compounds

[0158] Compounds’ inhibition of recombinant kinases (FLT3, KIT) was measured using Caliper mobility shift assay, which is based on the difference in capillary electrophoresis mobility of a fluorescent-tagged peptide as a result of a phosphorylation by the kinase under study. Reactions were started by the addition of various concentrations of a compound (originally in DMSO solution) to a kinase solution in assay buffer followed by addition of a mixture of ATP and a fluorescent-tagged peptide substrate in assay buffer. Concentrations of the enzyme, ATP and thepeptide were pre-optimized so that 15% substrate conversion to ensure initial velocity measurements. After incubation for 3 hours at room temperature, the kinase reaction was quenched by the addition of a concentrated EDTA solution before analysis on a LabChip EZ Reader II to yield percentage inhibition by comparing to the DMSO control.

[0159] Table 2 below summarizes the assay conditions for the characterization of the kinase inhibition properties of the disclosed compounds.

Table 2. Assay conditions to characterization difference kinase inhibition properties.

[0160] Table 3 below summarizes the kinase inhibition properties of the disclosed compounds.

++++ less than 1 nmol/L

+++: more than or equal to 1 nmol/L and less than 10 nmol/L ++: more than or equal to 10 nmol/L and less than 100 nmol/L

+: more than or equal to 100 nmol/L and less than 1000 nmol/L more than or equal to 1000 nmol/L

N/A: not available [0161] Cell viability assay was performed based on the following brief procedures. Cells were plated at the density of 5K/well with volume of 180 |1L in 96-well white plate and clear bottom plates. 20 |1L of veh. or compound was added at proper concentration to the well. The final volume is 200 p.L, with final cone, of DMSO=0.1%, 11 points, triplicates. The cells were then treated at 37 °C in the TC incubator for 72 hr. Equal volume (200 |1L) of CellTiter-Glo reagent (Promega) was added to the well and protect from light at room temperature for 15 min. The chemiluminescence was measured with EnSight (Perkin Elmer). GraphPad Prism non-linear regression, Log [inhibitor] response with four parameters were used to calculate GI50- Table 4 below shows the FLT3 cell-based assay results.

Table 4. The tyrosine kinase inhibitor compounds in cell viability assays in the present disclosure.

+++: less than 10 nmol/L

++: more than or equal to 10 nmol/L and less than 100 nmol/L

+: more than or equal to 100 nmol/L and less than 1000 nmol/L -: more than or equal to 1000 nmol/L

[0162] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific composition and procedures described herein. Such equivalents are considered to be within the scope of this disclosure and are covered by the following claims.