6-aryl imidazo[2,1-b]thi / oxazole-2-carboxilic acid derivative and pharmaceutical composition for treating alzheimer's disease containing same as active ingredient

Abstract

The present invention relates to a 6-aryl imidazo(2,1-b)thi / oxazole-2-carboxilic acid derivative. The compound according to the present invention acts as a JNK3 inhibitor capable of acting specifically on JNK3. The compound according to the present invention has a relatively high inhibitory activity against JNK3 compared to inhibitory activities against JNK1 and JNK2, and thus can be used as a therapeutic agent for Alzheimer's disease with low risk of side effects.

Description

6-ARYL IMIDAZO[2,1-B]THI / OXAZOLE-2-CARBOXILIC ACID derivative and pharmaceutical composition for treating Alzheimer's disease containing the same as an active ingredient

[0001] The present invention relates to a 6-Aryl imidazo[2,1-b]thi / oxazole-2-carboxilic acid derivative and a pharmaceutical composition for treating Alzheimer's disease containing the same as an active ingredient.

[0002]

[0003] Among the MAPK pathway, a representative cell signaling system that regulates cell death, the c-Jun N-terminal kinase 3 (JNK3) isoform is concentrated in brain tissue, unlike the dozen or so isozymes of the same type, and is deeply related to neuronal apoptosis. It is distributed in pyramidal neurons located in the CA1 and CA2 regions of the hippocampus of the cerebral cortex, and is known to cause apoptosis due to overexpression of c-Jun, one of the intraneuronal substrates, the degree of phosphorylation by JNK3, and overactivation of JNK3.

[0004] First, JNK3 phosphorylates and activates amyloid precursor protein (APP), a precursor of Aβ, the main cause of Alzheimer's disease, to localize it to the cell membrane and promote its conversion to Aβ. In particular, endocytosis of phosphorylated APP during this process is known to be a crucial step in the production of Aβ. Secondly, it is noteworthy that Tau, the main component of NFTs found in the brain cells of Alzheimer's patients, is also phosphorylated by JNK. In addition, it was reported that APP / Aβ-induced neurodegeneration was attenuated and neuroprotective action was activated in an animal model in which the JNK3 gene was deleted (Tg2576 / PSM146L transgenic mice). This demonstrated that JNK3 mediates the production and toxicity of Aβ, and revealed that JNK3 inhibitors could be useful as therapeutic agents for AD.

[0005]

[0006] The present invention aims to provide a 6-Aryl imidazo[2,1-b]thi / oxazole-2-carboxilic acid derivative having a specific inhibitory activity against JNK3.

[0007]

[0008] The present invention aims to provide a 6-Aryl imidazo[2,1-b]thi / oxazole-2-carboxilic acid derivative and a composition for treating Alzheimer's disease comprising the same.

[0009] More specifically, the present invention provides a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0010] [Chemical Formula 1]

[0011]

[0012] In the above chemical formula 1,

[0013] X is O, or S,

[0014] R4 is -(CH2) l O(CH2) m CH3, , , , , or ,

[0015] l is an integer from 1 to 3,

[0016] m is an integer from 0 to 2,

[0017] n is an integer from 1 to 3,

[0018] R1 is a C3 to C5 cycloalkyl, or an amine which is optionally substituted with one or two C1 to C3 alkyls,

[0019] R5 is , , , , or ,

[0020] wherein R2 is -OMe, -OEt, an amine which is unsubstituted or substituted with one or two C1 to C3 alkyl groups,

[0021] The above Ar is phenyl substituted with methyl, which is optionally substituted with F; phenyl substituted with a halogen group element at one or more positions; phenyl substituted with methyl, which is optionally substituted with F, and phenyl substituted with a halogen group element; phenyl substituted with a cyclized -OCH2O-, or -OCH2CH2O-; or substituted or unsubstituted naphthyl.

[0022] In one embodiment of the present invention, in the chemical formula 1

[0023] R4 is , , , , or ,

[0024] n is an integer from 1 to 3,

[0025] R1 is , or And,

[0026] R5 is , , , , or ,

[0027] wherein R2 is -OEt, -NH2, or -NHMe,

[0028] The above Ar is , , , or am.

[0029] In one embodiment of the present invention, the compound of formula 1 provides a compound having a structure of any one of the following formulae 2 to 7:

[0030] [Chemical Formula 2]

[0031]

[0032] In the above chemical formula 2,

[0033] The above R1 is , or And,

[0034] wherein R2 is -OEt, -NH2, or -NHMe,

[0035] Above silver , , , or am;

[0036]

[0037] [Chemical Formula 3]

[0038]

[0039] In the above chemical formula 3,

[0040] The above R3 is , , , or And,

[0041] wherein R2 is -OEt, -NH2, or -NHMe,

[0042] Above silver , , , or am;

[0043]

[0044] [Chemical Formula 4]

[0045]

[0046] In the above chemical formula 4,

[0047] The above R1 is , or And,

[0048] wherein R2 is -OEt, -NH2, or -NHMe,

[0049] Above silver , , , or And,

[0050] n is 1 or 2;

[0051]

[0052] [Chemical Formula 5]

[0053]

[0054] In the above chemical formula 5,

[0055] The above R3 is , or And,

[0056] wherein R2 is -OEt, -NH2, or -NHMe,

[0057] Above silver , , , or am;

[0058] [Chemical Formula 6]

[0059]

[0060] In the above chemical formula 6,

[0061] The above R is , or And,

[0062] The above X is , , , or And,

[0063] Above silver , , or am;

[0064]

[0065] [Chemical Formula 7]

[0066]

[0067] In the above chemical formula 7,

[0068] The above R is , or And,

[0069] The above X is , , , or And,

[0070] Above silver , , or am.

[0071]

[0072] In one embodiment of the present invention, the compound of formula 1 provides a compound that is one of the compounds shown in Tables 9 to 14 below.

[0073] [Table 9]

[0074]

[0075] [Table 10]

[0076]

[0077] [Table 11]

[0078]

[0079] [Table 12]

[0080]

[0081] [Table 13]

[0082]

[0083] [Table 14]

[0084]

[0085] In one embodiment of the present invention, a pharmaceutical composition for preventing or treating a degenerative brain disease is provided, comprising the compound, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. In one embodiment of the present invention, the degenerative brain disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, Lou Gehrig's disease, or stroke, and in another embodiment of the present invention, the compound, a derivative thereof, or a pharmaceutically acceptable salt thereof inhibits the activity of JNK3 (c-Jun N-terminal kinase 3).

[0086]

[0087] The present invention discloses a method for preventing or treating a degenerative brain disease, comprising administering to a subject a compound, a derivative thereof, a pharmaceutically acceptable salt thereof, or a composition comprising the same. In one embodiment of the present invention, the subject refers to a person diagnosed with a degenerative brain disease, such as Alzheimer's disease, or at risk of developing Alzheimer's disease.

[0088]

[0089] The compound according to the present invention has a selective inhibitory activity against JNK3 compared to JNK1 and / or JNK2, and therefore can be used as a treatment for degenerative brain diseases, particularly Alzheimer's disease, with reduced or lower side effects.

[0090]

[0091] Hereinafter, the present invention will be described in detail with reference to the attached drawings and embodiments thereof. However, the following embodiments are provided as examples of the present invention. If a detailed description of a technology or configuration well known to those skilled in the art is judged to unnecessarily obscure the gist of the present invention, such detailed description may be omitted, and the present invention is not limited thereby. The present invention is capable of various modifications and applications within the scope of the following claims and equivalents interpreted therefrom.

[0092] Additionally, the terminology used in this specification is intended to appropriately express preferred embodiments of the present invention, and may vary depending on the intent of the user or operator, or the customs of the field to which the present invention pertains. Therefore, the definitions of these terms should be determined based on the contents throughout this specification. Throughout this specification, when a part is said to "include" a certain component, unless specifically stated otherwise, this does not mean that other components are excluded, but rather that other components may be included.

[0093] Unless otherwise defined, all technical terms used in this invention have the same meaning as commonly understood by those skilled in the art. While preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. The contents of all publications cited herein as references are incorporated herein by reference.

[0094]

[0095] The present invention provides a compound of any one of chemical formulas 1 to 7.

[0096] [Chemical Formula 1]

[0097]

[0098] In the above chemical formula 1,

[0099] X is O, or S,

[0100] R4 is -(CH2) l O(CH2) m CH3, , , , , or ,

[0101] l is an integer from 1 to 3,

[0102] m is an integer from 0 to 2,

[0103] n is an integer from 1 to 3,

[0104] R1 is a C3 to C5 cycloalkyl, or an amine which is optionally substituted with one or two C1 to C3 alkyls,

[0105] R5 is , , , , or ,

[0106] wherein R2 is -OMe, -OEt, an amine which is unsubstituted or substituted with one or two C1 to C3 alkyl groups,

[0107] The above Ar is phenyl substituted with methyl, which is optionally substituted with F; phenyl substituted with a halogen group element at one or more positions; phenyl substituted with methyl, which is optionally substituted with F, and phenyl substituted with a halogen group element; phenyl substituted with a cyclized -OCH2O-, or -OCH2CH2O-; or substituted or unsubstituted naphthyl.

[0108] [Chemical Formula 2]

[0109]

[0110] In the above chemical formula 2,

[0111] The above R1 is , or And,

[0112] wherein R2 is -OEt, -NH2, or -NHMe,

[0113] Above silver , , , or am;

[0114]

[0115] [Chemical Formula 3]

[0116]

[0117] In the above chemical formula 3,

[0118] The above R3 is , , , or And,

[0119] wherein R2 is -OEt, -NH2, or -NHMe,

[0120] Above silver , , , or am;

[0121]

[0122] [Chemical Formula 4]

[0123]

[0124] In the above chemical formula 4,

[0125] The above R1 is , or And,

[0126] wherein R2 is -OEt, -NH2, or -NHMe,

[0127] Above silver , , , or And,

[0128] n is 1 or 2;

[0129]

[0130] [Chemical Formula 5]

[0131]

[0132] In the above chemical formula 5,

[0133] The above R3 is , or And,

[0134] wherein R2 is -OEt, -NH2, or -NHMe,

[0135] Above silver , , , or am;

[0136]

[0137] [Chemical Formula 6]

[0138]

[0139] In the above chemical formula 6,

[0140] The above R is , or And,

[0141] The above X is , , , or And,

[0142] Above silver , , or am;

[0143]

[0144] [Chemical Formula 7]

[0145]

[0146] In the above chemical formula 7,

[0147] The above R is , or And,

[0148] The above X is , , , or And,

[0149] Above silver , , or am.

[0150]

[0151] In one embodiment of the present invention, the compound of formula 1 provides a compound that is one of the compounds shown in Tables 9 to 14 below.

[0152] [Table 9]

[0153]

[0154] [Table 10]

[0155]

[0156] [Table 11]

[0157]

[0158] [Table 12]

[0159]

[0160] [Table 13]

[0161]

[0162] [Table 14]

[0163]

[0164] The term “alkyl” used in the present invention means a straight or branched carbon chain. The term Cm to Cn alkyl used in the present invention means a chain having m to n carbon atoms. For example, if C1 to C4 are terminals in a molecule, they can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and if they are located in the middle, they can be -CH2-, -CH2-CH2-, -CH(CH3)-, -C(CH2)-, -CH2-CH2-CH2-, -CH(C2H5)-, -CH(CH3)2-.

[0165] The term “cycloalkyl” used in the present invention means a cyclic alkyl chain.

[0166] The term “halogen” used in the present invention means fluoro (F), chloro (Cl), bromo (Br), or iodine (I). In the present invention, the halogen is preferably F or Cl.

[0167] The term “aryl” or “Ar” as used herein refers to an aromatic moiety having at least one aromatic ring, which may be substituted or unsubstituted. The aromatic ring may include a heteroatom and may be fused or unfused. Preferred “aryl” moieties are phenyl, naphthyl, a heterocycle (“heteroaryl”) containing at least one aromatic ring, and a heterobicycle (“heterobiaryl”) containing at least one aromatic ring.

[0168] Below, pharmaceutically acceptable salts of the present compound are described as examples. However, the description below is not intended to limit the invention.

[0169] One or more acidic groups in the compounds of the present invention may be used, for example, as an alkali metal salt, an alkaline earth metal salt, or an ammonium salt. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or ammonia salts, or organic amine salts such as ethylamine, ethanolamine, triethanolamine, or amino acids.

[0170] The compound according to the present invention can form different salts simultaneously.

[0171] One or more basic groups in the compound of the present invention may have the form of an inorganic or organic acid salt.

[0172] Examples of suitable salts include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to those skilled in the art.

[0173] The term “pharmaceutically acceptable” as used in the present invention means approved for use in animals, preferably humans, by the KFDA (Korea), FDA (USA), EMEA (Europe) and / or other national regulatory agencies.

[0174] The compound of the present invention containing a basic group can form different salts simultaneously.

[0175] When the compound according to the present invention contains both acidic and basic groups, the present invention also includes inner salts or betaines in addition to the mentioned salt forms.

[0176] Each salt of the compound according to the present invention can be obtained by conventional methods known to those skilled in the art, such as, for example, contacting them with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with another salt.

[0177] The present invention also encompasses all salts of the compounds according to the invention which are not suitable for direct use in medicine due to low physiological compatibility, but which may be suitable for use, for example, as intermediates in chemical reactions or for use in preparing pharmaceutically acceptable salts, or for studying the JNK3 inhibitory activity of the compounds according to the invention in an appropriate manner (e.g., in an appropriate in vitro assay).

[0178] The present invention also includes all solvates of the compounds according to the present invention.

[0179] The present invention also encompasses derivatives / prodrugs (including salts thereof) of the compounds according to the present invention, which contain a physiologically acceptable and cleavable group and are metabolized to the compounds according to the present invention in an animal, preferably a mammal, most preferably a human.

[0180] The present invention also includes metabolites of the compounds according to the present invention.

[0181] The term "metabolite" as used herein refers to any molecule derived from one of the compounds of the present invention in a cell or organism, preferably a mammal. Preferably, the term relates to a molecule distinct from any molecule present in the cell or organism under physiological conditions. The chemical structure of a metabolite of a compound of the present invention can be readily designed by a skilled artisan using a variety of appropriate methods.

[0182] Compounds according to formulae 1 to 7 can be prepared according to the methods described in the present invention or by similar methods, respectively. Methods for synthesizing the compounds are described, for example, in Houben-Weyl, Methoden der Organischen Chemie (Method of Organic Chemistry), Thieme-Verlag, Stuttgart, or Organic Reactions, John Wiley & Sons, New York.

[0183] Depending on the circumstances of each individual case, it may be necessary or advantageous to introduce a protecting group to temporarily block the functional group during the synthesis of compounds of formulae 1 to 7 to avoid side reactions and then release the protecting group at a later stage of the synthesis, or to introduce the functional group in the form of a precursor group and convert it to the desired functional group at a later stage. Such synthetic strategies, protecting groups, and precursor groups suitable for each individual case are well known to those skilled in the art.

[0184] If desired, compounds of formulae 1 to 7 can be purified by conventional purification procedures such as recrystallization or chromatography. Starting compounds for preparing compounds of formulae 1 to 7 are commercially available or can be prepared according to or similar to literature procedures.

[0185] Another aspect of the present invention is a pharmaceutical composition comprising a compound according to the present invention or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. In another aspect of the present invention, a pharmaceutical composition is provided comprising one or more compounds disclosed herein or a pharmaceutically acceptable salt thereof, together with a compound or therapeutic agent capable of treating or preventing Alzheimer's disease or inhibiting the activity of JNK3.

[0186] The term "treatment" as used herein refers to any process that can slow, hinder, stop or halt the progression of a disease, but does not necessarily mean complete disappearance of all symptoms.

[0187] The term "inhibition of JNK3 activity" as used herein refers to a state in which the phosphorylation catalytic activity of JNK3 is reduced, or preferably, a state in which the activity of JNK3 to phosphorylate Ser63 and / or Ser73 of c-jun is reduced compared to the wild-type / non-pathological situation.

[0188] The present invention also discloses a mixture comprising a compound according to the present invention and an inert carrier.

[0189] In one embodiment of the present invention, the present invention relates to a composition comprising a compound according to the present invention mixed with an inert carrier, wherein the inert carrier is a pharmaceutical carrier.

[0190] The term "carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle through which a therapeutic agent is administered. Such pharmaceutical carriers may be sterile liquids such as water and oils, including but not limited to those of petroleum, animal, vegetable, or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, and sesame oil. In one embodiment of the present invention, water may be used as a carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose may be used when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may be used as liquid carriers for injection solutions.

[0191] Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, glycol, water, and ethanol. If desired, the composition may also contain minor amounts of wetting or emulsifying agents or pH buffering agents. The composition may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. The composition may be formulated as a suppository with traditional binders and carriers such as triglycerides. Oral formulations may include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic agent, preferably in purified form, together with an appropriate amount of carrier to provide a form suitable for administration to the patient. The formulation should be suitable for the intended route of administration.

[0192] When the compound according to the present invention is synthesized as a racemate, the racemate can be separated using a standard method well known to those skilled in the art to obtain the enantiomer.

[0193] The compounds according to the present invention and their pharmaceutically acceptable salts can be used to treat or prevent degenerative brain diseases. The degenerative brain diseases include, but are not limited to, one or more diseases selected from the group consisting of stroke, amnesia, amnesia, memory impairment, dementia, amnesia, cognitive dysfunction, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeldt-Karkob disease, Huntington's disease, and Lou Gehrig's disease. In one embodiment of the present invention, the degenerative brain disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, Lou Gehrig's disease, or stroke. In one embodiment of the present invention, the degenerative brain disease is Alzheimer's disease.

[0194] The compounds according to the present invention and their pharmaceutically acceptable salts may be administered as a pharmaceutical substance, either by itself or in admixture with other drugs or in the form of a pharmaceutical preparation, to an animal, in one embodiment a mammal, and in another embodiment a human, optionally in combination with other pharmaceutically active compounds suitable for treating or preventing Alzheimer's disease, such as Aricept (Eisai), Donepezil (Pfizer), Cognex (Warner-Lambert), Tacrine (Warner-Lambert), Axura (Merz), Memantine (Merz) or other drugs known to those skilled in the art suitable for treating or preventing Alzheimer's disease.

[0195] Various delivery systems are known and can be used to administer the compounds of the invention for the treatment of Alzheimer's disease and / or inhibition of JNK3 activity, including, but not limited to, encapsulation in coatings, liposomes, microparticles, and microcapsules. When the compound of the present invention or a pharmaceutical composition comprising the same is not directly delivered to the central nervous system or the brain, it is advantageous to select and / or modify the administration method so that the compound of the present invention can cross the blood-brain barrier. Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, or intraendothelial, nasal, epidural, and oral.

[0196] The compound may be administered by any convenient route, such as injection, bolus injection, or absorption through the epithelial or mucosal skin lining, and may be administered together with other biologically active agents.

[0197] Administration may be systemic or local. Furthermore, the pharmaceutical composition of the present invention may be introduced into the central nervous system by any suitable route, including intracerebroventricular and intrathecal injection. Intracerebroventricular injection may be facilitated by an intracerebroventricular catheter attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration may also be achieved, for example, by using an inhaler or nebulizer, or by formulating the composition with an aerosolizing agent.

[0198] In another embodiment, the therapeutic agent may be delivered in a vesicle, particularly a liposome (Langer, 1990, Science 249:1527-1533; Treat et al., 1989, In: Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler, eds., Liss, New York, 353-365; Lopez-Berestein, ibid., 317-327; see generally ibid). In another embodiment, the therapeutic agent may be delivered via a controlled release system. In one embodiment, a pump may be used (Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201-240; Buchwald et al., 1980, Surgery 88:507-516; Saudek et al., 1989, N. Engl. J. Med. 321:574-579). In other embodiments, polymeric materials may be used (Medical Applications of Controlled Release, Langer and Wise, eds., CRC Press, Boca Raton, Florida, 1974; Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball, eds., Wiley, New York, 1984; Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61; Levy et al., 1985, Science 228:190-192; During et al., 1989, Ann. Neurol. 25:351-356; Howard et al., 1989, J. Neurosurg. 71:858-863).In another embodiment, the controlled release system can be placed near the target of treatment, i.e., the brain, so that only a portion of the systemic dose can be administered (e.g., Goodson, 1984, In: Medical Applications of Controlled Release, supra, Vol. 2, 115-138).

[0199] To select the appropriate route of administration, the skilled practitioner will also consider the route of administration selected for other known anti-Alzheimer's drugs. For example, Aricept / Donepezil and Cognex / Tacrine (both acetylcholinesterase inhibitors) are administered orally, while Axura / Memantine (an NMDA receptor antagonist) is available as tablets / liquid and intravenous solution.

[0200] To select an appropriate dosage, a skilled practitioner would select a dose that has been shown to be non-toxic in preclinical and / or clinical studies and that may be consistent with or different from the previously provided values.

[0201] The exact dosage used in a formulation will vary depending on the route of administration, the severity of the disease or disorder, and will be determined by the physician's judgment and the individual patient's circumstances. However, an appropriate dosage range for intravenous administration is generally approximately 20-500 μg of active compound per kilogram of body weight. An appropriate dosage range for intranasal administration is generally approximately 0.01 mg to 1 mg per kilogram of body weight. The effective dose can be inferred from a dose-response curve obtained in vitro or in an animal model test system.

[0202] A representative animal model is the transgenic mouse strain "Tg2576" containing an APP695 form with the double mutation KM670 / 671NL. For example, patents US5877399 and Hsiao, K, et al. (1996), Science 274: 99-102, Kawarabayahsi T (2001), J. Neurosci 21: 372-81; Frautschy, et al. (1998), Am J Pathol 152: 307-17, Irizarry, et al. (1997) J Neuropathol Exp Neurol 56: 965-73; Lehman, et al. (2003) Neurobiol Aging 24: 645-653 are incorporated herein by reference.

[0203] The practitioner has access to substantial data from several studies that can assist the practitioner in selecting an appropriate dosage for the chosen treatment regimen.

[0204]

[0205] The present invention provides a food composition or health functional food composition for preventing or improving degenerative brain diseases, comprising a compound represented by chemical formulas 1 to 7 or a pharmaceutically acceptable salt thereof.

[0206] In the present invention, the composition can inhibit the activity of JNK3.

[0207] In the present invention, the degenerative brain disease includes, but is not limited to, one or more diseases selected from the group consisting of stroke, amnesia, memory loss, memory impairment, dementia, amnesia, cognitive dysfunction, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeldt-Karkob disease, Huntington's disease, and Lou Gehrig's disease. In one embodiment of the present invention, the degenerative brain disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, Lou Gehrig's disease, or stroke.

[0208] The type of food is not particularly limited. Examples of foods to which the active substance of the present invention can be added include beverages, meat, sausages, bread, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, instant ramen, other noodles, gum, dairy products including ice cream, various soups, drinking water, alcoholic beverages, vitamin complexes, dairy products, dairy products, etc., and include all health foods and health functional foods in the conventional sense.

[0209] The health food and health functional food compositions containing the compounds according to the present invention can be added directly to food or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The amount of active ingredient mixed can be appropriately determined depending on the purpose of use (prevention or alleviation). Generally, the amount of the composition in health foods and health functional foods can be 0.1 to 90 parts by weight of the total food weight. However, if consumed for a long period of time for the purpose of maintaining or managing health, the amount may be below the above range, and since there is no problem with safety, the active ingredient can be used above the above range.

[0210] The health food and health functional food compositions of the present invention contain the active substance of the present invention as an essential ingredient in a predetermined proportion, and the health food and health functional food compositions of the present invention may contain various flavoring agents, natural carbohydrates, etc., similar to those of conventional beverages, as additional ingredients, but are not particularly limited thereto. Examples of the natural carbohydrates include monosaccharides such as glucose, fructose, etc.; disaccharides such as maltose, sucrose, etc.; and polysaccharides such as dextrin, cyclodextrin, etc.; and sugar alcohols such as xylitol, sorbitol, and erythritol. In addition to those described above, natural flavoring agents (thaumatin), stevia extracts (such as rebaudioside A, glycyrrhizin, etc.), and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used as flavoring agents. The proportion of natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 g of the health functional food composition of the present invention.

[0211] The health food and health functional food compositions containing the active substance of the present invention may contain, in addition to additives, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, colorants and thickeners (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the health food and health functional food compositions of the present invention may contain fruit pulp for producing natural fruit juice, fruit juice drinks, and vegetable drinks.

[0212] These ingredients may be used alone or in combination. The proportion of these additives is not particularly critical, but is generally selected within the range of 0.1 to 20 parts by weight per 100 parts by weight of the health food and health functional food composition of the present invention containing the active substance of the present invention.

[0213] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended only to illustrate the present invention, and the scope of the present invention is not limited by the following examples.

[0214] 1. 6-Aryl imidazo[2,1-b]thiazole-2-carboxilic acid derivative

[0215] 1.1 Synthesis method

[0216] Ethyl 2-aminothiazole-5-carboxylate and 2-bromo-1-(naphthalen-1-yl)ethan-1-one were refluxed in ethanol to prepare imidazo[2,1-b]thiazole rings (3a-f) as a core scaffold. 4-chloro-2-(methylthio)pyrimidine was introduced at the C-5 position (4a-f). Subsequently, methyl sulfide was oxidized using potassium peroxymonosulfate to generate methyl sulfone (5a-f) and (R / S) 1-Boc-3-aminopiperidine (6a-6d, 7a-7d) (S N (AR) is prepared. The terminal N-Boc group is removed from (R / S) amino piperidine to form an amide and a urea to prepare the products (8-11). Finally, the ethyl esters are converted to carboxamide (12-15) or N-methyl amide (18-19), respectively, using 7N ammonia or 33% N-methylamine ethanol solution in methanol solvent.

[0217] Methyl sulfide is oxidized with potassium peroxymonosulfate (5a, 5b, 5d, 5e) to generate methyl sulfone for introduction of alkylamine (20). The ethyl ester is converted to carboxamide (21) or N-methyl amide (22) using 7N ammonia or 33% N-methylamine ethanol solution in methanol solvent, respectively.

[0218] [Reaction Formula 1]

[0219]

[0220] In the above reaction scheme 1, the reagents and reaction conditions are as follows:

[0221] (i) 2, EtOH, Reflux, 16 h;

[0222] (ii) 4-chloro-2-(methylthio)pyrimidine, Pd(OAC)2, Cs2CO3, PPh3, DMF, 80 °C, 18 h;

[0223] (iii) Oxone, H2O, MeOH 2 h

[0224] (iv) (R / S) 1-Boc-3-aminopiperidine, DIPEA, THF, 60 °C 18 h;

[0225] (v) Alkyl amine (R3NH2), DIPEA, DMSO, 100 °C, 18 h;

[0226] (vi) 20% TFA, MC, 10 min;

[0227] (vii) R1COCl, DIPEA, THF, rt;

[0228] (viii) 7 N NH3 in MeOH, rt or 33% N-methylamine in EtOH, rt.

[0229]

[0230] 1.2 In vitro JNK3 inhibitory activity assay

[0231] The inhibitory activity (IC50) against JNK3 of the compound synthesized in 1.1 above was measured, and the results are shown in Tables 1 and 2 below.

[0232] JNK3 inhibitory activity (IC) of 6-aryl-5-pyrimydyl-imidazo[2,1-b]thiazole derivatives 50 ) NoArR1*R2IC 50 (nM)8 af fR-OEt+++12 af -NH2+++16 af -NHMe+++9 af fS-OEt++13 af -NH2++16 af -NHMe++10 ag gR-OEt+++14 ag -NH2+++18 ag -NHMe+++11 ag gS-OEt++15 ag -NH2++19 ag -NHMe++8 bf fR-OEt+++12 af -NH2+++16 af -NHMe+++9 bf fS-OEt++13 bf -NH2++17 bf -NHMe++10 bg gR-OEt++++14 bg -NH2++++18 bg -NHMe++++11 bg gS-OEt++15 bg -NH2++19 bg -NHMe++8 cf fR-OEt+++12 cf -NH2+++16 cf -NHMe+++9 cf fS-OEt++13 cf -NH2++17 cf -MeNH++10 cggR-OEt+++14 cg -NH2+++18 cg -NHMe+++11 cg gS-OEt++15 cg -NH2++19 cg -NHMe++8 df fR-OEt+++12 df -NH2+++16 df -NHMe+++9 df fS-OEt++13 df -NH2++17 df -NHMe++10 dg gR-OEt++++14 dg -NH2++++18 dg -NHMe++++11 dg gS-OEt++15 dg -NH2++19 dg -NHMe++JNKi VIII14.15±4.25

[0233]

[0234] −: >10 μM

[0235] + : 1~10 μM

[0236] ++ : 30 nM ~1 μM

[0237] +++ : 1~ 30 nM

[0238] ++++ : < 1 nM

[0239]

[0240] 6-aryl-5-pyrimydyl-imidazo[2,1-b]thiazole 유도체의 JNK3 억제 활성(IC 50 ) NoArR3R2IC 50 (nM)20 ah h-OEt++21 ah -NH2++22 ah -NHMe+++20 ai OEt+++21 ai -NH2++22 ai -NHMe+++20 bi OEt++21bi -NH2+++22 bi -NHMe+++20 bj j-OEt++++21 bj -NH2+++22 bj -NHMe+++20 ei i-OEt+++21 ei -NH2+++22 ei -NHMe+++20 aj j-OEt++++21 aj -NH2++22 aj -NHMe+++20 ak k-OEt++21 ak -NH2-22 ak -NHMe+20 di i-OEt++21 di -NH2+++22 di -NHMe++20 dj j-OEt+++21 dj -NH2++22 dj -NHMe+++20ej j-OMe / -OEt++++ / ++++21ej-NH2++++22ej-NHMe+++JNKi VIII14.15±4.25

[0241]

[0242] -: >10 μM +: 1~10 μM

[0243] ++ : 30 nM ~1 μM

[0244] +++ : 1~ 30 nM

[0245] ++++ : < 1 nM

[0246]

[0247] 2. 6-Aryl imidazo[2,1-b]oxazole-2-carboxilic acid derivatives

[0248] 2.1 Synthesis method

[0249] [Reaction Formula 2]

[0250]

[0251] In the above reaction scheme 2, the reagents and reaction conditions are as follows:

[0252] (i) 2, t-BuOK, THF, -78 °C →0 °C, 5 h;

[0253] (ii) urea, H2O, 100°C, 2 h;

[0254] (iii) 5, anhyd. THF, CH3CN, 50°C, 3 overnight;

[0255] (iv) TiCl4, toluene, 0 °C→°C, 18 h;

[0256] (v) 4-chloro-2-(methylthio)pyrimidine, Pd(OAC)2, Cs2CO3, PPh3, DMF, 80 °C, 3 h;

[0257] (vi) Oxone, H2O, MeOH 12 h ;

[0258] (vii) (R / S) 1-Boc-3-aminopyrrolidine or (R / S) 1-Boc-3-aminopiperidine, DIPEA, DMSO, 100 °C, 2 h

[0259] (viii) 20% TFA, MC, 10 min; R1COCl, DIPEA, THF, rt 15 min;

[0260] (ix) 7 N NH3 in MeOH, rt, or 33% N-methylamine in EtOH, rt;

[0261] (x) 1-Boc-4-aminopiperidine, DIPEA, DMSO, 100 °C 2 h;

[0262] (xi) Alkyl amine (R3NH2), DIPEA, DMSO, 100 °C, 2 h;

[0263] JNK3 inhibitory activity (IC) of 6-aryl-5-pyrimydyl-imidazo[2,1-b]oxazole derivatives 50 ) NoArR1n*R2IC 50 (nM)44 ae e1R-OEt-50 ae -NH2+56 ae -NHMe-45 ae e1S-OEt-51 ae -NH2+57 ae -NHMe+46 ae e2R-OEt+++52 ae -NH2++++58 ae -NHMe++++47 ae e2S-OEt+++53 ae -NH2++++59 ae -NHMe++++48 af f2R-OEt++++54 af -NH2++++60 af -NHMe++++49 af f2S-OEt++55 af -NH2++++61 af -NHMe+++46 be e2R-OEt++++52 be -NH2++++58 be -NHMe++++47 be e2S-OEt-53 be -NH2+59 be -NHMe-48 b ff2R-OEt-54 bf -NH2+60 bf -NHMe+49 bf f2S-OEt+++55 bf -NH2++++61 bf -NHMe++++46 ce e2R-OEt+++52 ce -NH2++++58 ce -NHMe++++47 ce e2S-OEt++++53 ce -NH2++++59 ce -NHMe++++46 de e2R-OEt++52 de -NH2++++58 de-NHMe+++47 de e2S-OEt++++53 de -NH2++++59 de -NHMe++++JNKi VIII14.15±4.25

[0264] -: >10 μM +: 1~10 μM

[0265] ++ : 30 nM ~1 μM

[0266] +++ : 1~ 30 nM

[0267] ++++ : < 1 nM

[0268]

[0269] JNK3 inhibitory activity (IC) of 6-aryl-5-pyrimydyl-imidazo[2,1-b]oxazole derivatives 50 ) NoR2IC 50 (nM)64 ae -OEt+++65 ae -NH2++++66 ae -NHMe+++

[0270] -: >10 μM +: 1~10 μM

[0271] ++ : 30 nM ~1 μM

[0272] +++ : 1~ 30 nM

[0273] ++++ : < 1 nM

[0274]

[0275] JNK3 inhibitory activity (IC) of 6-aryl-5-pyrimydyl-imidazo[2,1-b]oxazole derivatives 50 ) NoArR1R2IC 50 (nM)67 ag g-OEt++++68 ag -NH2++69 ag -NHMe++++67 ah h-OEt++++68 ah -NH2++++69 ah -NHMe+++67 bg g-OEt++++68 bg -NH2++++69 bg -NHMe++++67 bh h-OEt++++68 bh -NH2++++69 bh -NHMe++++67 cg g-OEt++++68 cg -NH2++++69 cg -NHMe++++67 ch h-OEt++++68 ch -NH2+++69 ch -NHMe++++67 dg g-OEt+++68 dg -NH2+++69 dg -NHMe+++67 dh h-OEt+++68 dh -NH2+++69 dh -NHMe+++JNKi VIII14.15±4.25

[0276]

[0277] -: >10 μM +: 1~10 μM

[0278] ++ : 30 nM ~1 μM

[0279] +++ : 1~ 30 nM

[0280] ++++ : < 1 nM

[0281]

[0282] 3. Synthesis method of imidazo[2,1-b]thiazole-based covalent inhibitors

[0283] Although 518 different protein kinases exist, the active site-ATP binding region is conserved, limiting the selectivity of protein kinase inhibitors (PKIs). One strategy for achieving high selectivity in PKIs is to form covalent bonds with specific protein kinases, such as covalent kinase inhibitors (CKIs). Covalent kinase inhibitors typically have the advantage of long duration of activity and increased selectivity for their target proteins, which can reduce side effects due to interactions with non-targets. Several covalent inhibitors have been approved by the FDA and are in use as drugs.

[0284] When designing highly selective CKIs, it is important to determine whether Cys residues surrounding the ATP-binding site are covalently linked. Accessible Cys residues in protein kinases can be categorized into seven major locations: the front region, P-loop, hinge region, DFG region, A-loop, C-loop, and remote loop. Among these, CYS residues in the front region and P-loop account for the majority of covalently bound kinase inhibitors. In the case of JNK3, the Cys154 residue in the ATP-binding site is located in the front region, indicating that the JNK3 inhibitor of the present invention is a suitable location for forming a covalent bond.

[0285] 3.1 Imidazo[2,1-b]thiazole-based covalent JNK3 inhibitors

[0286] 3.1.1 Synthesis method

[0287] [Reaction Formula 3]

[0288]

[0289] In Scheme 3, the reagents and reaction conditions are as follows:

[0290] (v) NaOH, EtOH, 45 °C;

[0291] (vi) DPPA, TEA, t-BuOH, 80 °C;

[0292] (vii) 15% TFA, MC;

[0293] (viii) Acryloyl chloride, TEA, THF, rt;

[0294] (ix) Oxalyl chloride, DMF, MC, 0 °C→rt;

[0295] (x) N,O-Dimethylhydroxylamine, DIPEA, THF anhydrous

[0296] (xi) 3.1 M CH3Li in ethoxymethane, THF, -78 °C→rt;

[0297] (xii) N,N-Dimethylformamide dimethyl acetal, DMF, μW

[0298] (xiii) 1.0 M Vinylmagnesium bromide in THF, -78 °C→rt.

[0299]

[0300] Ethyl 2-aminothiazole-5-carboxylate and 2-bromo-1-(naphthalen-1-yl) ethan-1-one were refluxed in ethanol to prepare an imidazo[2,1]thiazole ring as a core scaffold (3a-c). 4-chloro-2-(methylthio) pyrimidine was introduced at the C-5 position (4a-c). Then, methyl sulfide was oxidized using potassium peroxymonosulfate to produce methyl sulfone (5a-c), which was then converted to an alkyl amine (6 ad -6 ce ) (S N AR) is manufactured. After hydrating the ester to manufacture a carboxylic acid (7ad -7 ce ), N-Boc(8) was prepared by performing Curtius rearrangement reaction using DPPA. ad -8 ce ) is formed. After that, BOC protecting group removal is performed (9 ad -9 ce ) introduces an acryloyl group as a covalent warhead (10 ad -10 ce ).

[0301] Carboxylic acid was converted to acid chloride(11) using oxalyl chloride ad -11 ce ) and forms Weinreb amide (12 ad -12 ce ) Then, a methyl group was introduced using an alkyl lithium reagent (13 ad -13 ce ), dimethylformamide dimethyl acetal is reacted to synthesize a covalent warhead product (14 ad -14 ce ).

[0302] Weinreb amide (12 ad , 12 ae ) is reacted with vinyl magnesium bromide to synthesize a covalent warhead product (15 ad , 15 ae ).

[0303]

[0304] 3.1.2 In vitro JNK3 inhibition assay

[0305] JNK3 inhibitory activity (IC50) of 6-aryl-5-pyrimydyl-imidazo[2,1-b]thiazole derivatives NoArR3XIC 50 (nM)80 ad di++++84 ad ii+++85 adiii+++86 ad iv+++80 bd di++++84 bd ii++86 bd iv+++80 be ei++++84 be ii++++86 be iv+++80 ae ei++++84 ae ii+++85 ae iii+++86 ae iv+++80 cd di+++84 cd ii+++86 cd iv+++80 ce ei+++84 ce ii++++86 ce iv++++JNKi VIII14.15±4.25

[0306] -: >10 μM +: 1~10 μM

[0307] ++ : 30 nM ~1 μM

[0308] +++ : 1~ 30 nM

[0309] ++++ : < 1 nM

[0310]

[0311] 3.2 Imidazo[2,1-b]oxazole-based covalent JNK3 inhibitors

[0312] 3.2.1 Synthesis method

[0313] [Reaction Formula 4]

[0314]

[0315] In Scheme 4, the reagents and reaction conditions are as follows:

[0316] (vii) NaOH, EtOH, 45 °C;

[0317] (ix) DPPA,TEA, Anhyd ACN, 70 °C;

[0318] (x) water, toluene, 90 °C;

[0319] (xi) Acryloyl chloride, TEA, THF, rt;

[0320] (xii) Oxalyl chloride, DMF, MC, 0°C->rt;

[0321] (xiii) N,O-Dimethylhydroxylamine, DIPEA, anhydrous THF

[0322] (xiv) 3.1 M MeLi in ethoxymethane, THF, -78 °C;

[0323] (xv) N,N-Dimethylformamide dimethyl acetal, DMF, 80 °C

[0324] (xvi) 1.0 M Vinylmagnesium bromide in THF, 0 °C →rt

[0325] (xvii) propargyl amine, EDC·HCl, HOBt, TEA, ACN

[0326]

[0327] 3.2.2 In vitro JNK3 activation

[0328] 6-aryl-5-pyrimydyl-imidazo[2,1-b]oxazole activator JNK3 activator (IC). 50 ) NoArRXIC 50 (nM)103 ad the++++1 ad ii+++108 ad iii+++109 ad iv+++103 bd i++++107 bd ii++109 bd iv+++++++103 cd i++++107 cd ii+++109 cd iv+++++++103ae ei++++107 ae ii+++108 ae iii+++109 ae iv+++103 be i+++107 be ii+++109 be iv++++++103 ce i++++107 ce ii++++109 cd iv++++++++JNKi VIII14.15±4.25

[0329]

[0330] -: >10 μM +: 1~10 μM

[0331] ++ : 30 nM ~1 μM

[0332] +++ : 1~ 30 nM

[0333] ++++ : < 1 nM

[0334]

[0335] 4. Activity of major compounds against JNK1 / 2 / p38α

[0336] Compound NoStructureSelectivity (IC 50 fold )JNK1 / JNK3JNK2 / JNK3p38α / JNK3JNK38af 10010ND+++10ag 292ND+++12af 203ND+++14ag 102ND+++16af 647ND+++18ag 11241+++18dg 1091319+++10bg 63879164++++20aj 174177916++++20bj 124122++++80ad 1809238++++80ae 94760++++80bd 503172++++80be 16229++++69ag 52121063++++52be 557561316++++58be 389281245++++48bf 11318246++++60bf 9667964++++

[0337] -: >10 μM +: 1~10 μM

[0338] ++ : 30 nM ~1 μM

[0339] +++ : 1~ 30 nM

[0340] ++++ : < 1 nM

[0341]

[0342] 5. Manufacturing example

[0343] 5.1. 6-Aryl imidazo[2,1-b]thiazole-2-carboxilic acid derivative (Scheme 1)

[0344] Ethyl 6-aryl-imidazo[2,1-b]thiazole-2-carboxylate (3a~3e)

[0345]

[0346]

[0347] Compound 1 (859 mg, 4.99 mmol) and compound 2a (1245 mg, 4.99 mmol) were dissolved in EtOH (17 ml), refluxed, and stirred for 18 hours. After confirming the completion of the reaction, the white solid was filtered to obtain compound 3a (1250 mg, 78%).

[0348]

[0349] 3a (1.3 g, 78%) 1H NMR (400 MHz, CDCl3) δ8.42 (s, 1H), 8.28 (s, 1H), 8.02 - 7.93 (m, 3H), 7.88 - 7.84 (m, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 18 H 14 N2O2S [M+H]+: 323.0849, found: 323.18

[0350]

[0351] 3b (2.6 g, 66 %) 1 H NMR (400 MHz, CDCl3) δ8.16 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.76 (s, 1H), 7.65 (dd, J = 8.4, 2.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H).

[0352] LRMS (ESI+) calculated C 14 H 10 Cl2N2O2S [M+H]+: 340.9913, found: 340.15

[0353] 3c (2.4 g, 61 %) 1 H NMR (400 MHz, CDCl3) δ8.15 (s, 1H), 8.07 - 8.04 (m, 1H), 8.00 - 7.94 (m, 1H), 7.76 (s, 1H), 7.23 (ddd, J = 10.2, 8.7, 0.8 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H).

[0354] LRMS (ESI+) calculated C 15 H 10F4N2O2S [M+H]+: 359.0472, found: 359.10

[0355] 3d (2.5 g, 99 %) 1 H NMR (400 MHz, DMSO) δ8.98 (s, 1H), 8.40 (s, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.46 (dd, J = 8.3, 2.1 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.43 (m, 4H), 1.48 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 16 H 14 N2O4S [M+H]+: 331.0747, found: 331.16

[0356]

[0357] 3e (2.5 g, 65 %) 1 H NMR (400 MHz, CDCl3) δ8.26 (s, 1H), 7.86 (dd, J = 6.9, 2.3 Hz, 1H), 7.83 (s, 1H), 7.74 (ddd, J = 8.6, 4.4, 2.2 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 14 H 10 ClFN2O2S [M+H]+: 325.0209, found: 325.10

[0358]

[0359] Ethyl 5-(2-(methylthio)pyrimidin-4-yl)-6-Aryl imidazo[2,1-b]thiazole-2-carboxylate (4a~4f)

[0360]

[0361] Compound 3a (500 mg, 1.63 mmol) was dissolved in DMF (5.43 ml), Pd(OAC)2 (73 mg, 0.33 mmol), Cs2CO3 (796 mg, 2.45 mmol), PPh3 (171 mg, 0.65 mmol), 4-chloro-2-(methylthio)pyrimidine (291 μl, 2.44 mmol) was added, refluxed at 80 °C, and stirred for 18 h. After completion of the reaction, the reaction mixture was extracted with EA, washed with DW and Brine, and concentrated after removing the remaining moisture with Na2SO4. The residue was purified by column chromatography with an EA:HEX = 1:8 mobile phase to obtain compound 4a (336 mg, 48%).

[0362]

[0363] 4a (336 mg, 48%) 1 H NMR (400 MHz, CDCl3) δ9.28 (s, 1H), 8.19 (d, J = 5.4 Hz, 1H), 8.13 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.84 (dd, J = 11.0, 4.0 Hz, 2H), 7.67 (dd, J = 8.5, 1.5 Hz, 1H), 7.56 - 7.48 (m, 2H), 6.90 (d, J = 5.4 Hz, 1H), 4.41 (d, J = 7.1 Hz, 2H), 2.65 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 23 H 18 N4O2S2[M+H]+: 447.0944, found: 447.15

[0364]

[0365] 4b (165 mg, 24%) 1H NMR (400 MHz, CDCl3) δ9.25 (s, 1H), 8.38 (d, J = 5.4 Hz, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.50 (dd, J = 8.3, 2.0 Hz, 1H), 6.94 (s, 1H), 4.46 (d, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 19 H 14 Cl2N4O2S2[M+H]+: 465.0008, found: 465.28

[0366]

[0367] 4c (282 mg, 21 %)

[0368] 1 H NMR (400 MHz, CDCl3) δ9.24 (s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 7.98 (dd, J = 6.8, 2.3 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.32 (t, J = 9.4 Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). LRMS (ESI+) calculated C 20 H 14 F4N4O2S2[M+H]+: 483.0567, found: 483.22

[0369]

[0370] 4d (879 mg, 62 %) 1H NMR (400 MHz, CDCl3) δ9.26 (s, 1H), 8.26 (d, J = 5.4 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.3, 2.1 Hz, 1H), 6.99 (d, J = 5.5 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.40 (t, J = 7.1 Hz, 2H), 4.29 (tdd, J = 6.7, 3.7, 1.8 Hz, 4H), 2.64 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 21 H 18 N4O4S2[M+H]+: 455.0842, found: 455.18

[0371]

[0372] 4e (478 mg, 30 %) 1 H NMR (400 MHz, CDCl3) δ9.26 (s, 1H), 8.37 (d, J = 5.4 Hz, 1H), 7.82-7.80 (m, 1H), 7.57-7.55 (m, 1H), 7.2 (t, J = 8.6, 2.0 Hz, 1H), 6.54 (d, J = 1H), 4.46 (d, J = 7.1 Hz, 2H), 2.69 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 20 H 14 F4N4O2S2[M+H]+: 483.0567, found: 483.19

[0373]

[0374] Ethyl 5-(2-((1-(tert-butoxycarbonyl)-3l3-piperidin-3-yl)amino)pyrimidin-4-yl)-6-Aryl imidazo [2,1-b]thiazole-2-carboxylate (6a~6d, 7a~7f)

[0375]

[0376] Compound 4a (174 mg, 0.39 mmol) was dissolved in H2O (0.78 ml) and MeOH (3.9 ml), and then Oxone (718 mg, 1.17 mmol) was added and stirred at room temperature for 2 hours. After evaporating the reaction solvent on a rotary evaporator, the reaction mixture was extracted with MC, quenched with a supersaturated NaHCO3 solution, and washed with H2O and Brine. Drying was done with anhydrous magnesium sulfate (MgSO4), and mixture 5a (100 mg) was dissolved in DMSO (2 ml), tert-butyl (R)-3-aminopiperidine-1-carboxylate (80 mg, 0.4 mmol), DIPEA (104 μl, 0.6 mmol) were added, and stirred for 12 hours. After completion of the reaction, the reaction mixture was extracted with EA and washed with H2O and Brine. The remaining moisture was removed with anhydrous magnesium sulfate (MgSO4), and the product was purified by column chromatography with a mobile phase composition of EA:HEX = 1:2 to obtain compound 6a (84 mg, 70%).

[0377]

[0378] 6a (84 mg, 70%) 1H NMR (400 MHz, CDCl3) δ9.23 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.06 - 7.96 (m, 2H), 7.91 - 7.83 (m, 3H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.54 - 7.47 (m, 2H), 6.54 (d, J = 5.4 Hz, 1H), 4.42 (qd, J = 7.1, 1.9 Hz, 2H), 4.30 - 4.23 (m, 1H), 4.13 - 4.07 (m, 1H), 4.06 - 4.00 (m, 1H), 3.92 - 3.82 (m, 1H), 3.72 - 3.63 (m, 1H), 1.89 - 1.82 (m, 2H), 1.82 - 1.77 (m, 1H), 1.75 - 1.68 (m, 1H), 1.45 (s, 9H), 1.41 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 32 H 34 N6O4S [M+H]+: 599.2435, found: 599.34

[0379]

[0380] 6b (143 mg, 68 %) 1 H NMR (400 MHz, CDCl3) δ9.14 (s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.78 (dd, J = 1.7, 0.8 Hz, 1H), 7.48 (d, J = 1.7 Hz, 2H), 6.52 (d, J = 5.3 Hz, 1H), 5.45 (s, 1H), 4.41 (qd, J = 7.1, 1.4 Hz, 2H), 4.14 - 4.08 (m, 1H), 4.02 (s, 1H), 3.83 (s, 1H), 3.49 (s, 2H), 2.10 - 2.04 (m, 1H), 1.84 - 1.76 (m, 1H), 1.74 - 1.70 (m, 1H), 1.69 - 1.59 (m, 1H), 1.40 (s, 9H), 1.24 (t, J = 7.1 Hz, 2H).LRMS (ESI+) calculated C28 H 30 Cl2N6O4S [M+H]+: 617.1499, found: 617.23

[0381]

[0382] 6c 1 H NMR (400 MHz, CDCl3) δ9.15 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.95 (dd, J = 6.9, 2.2 Hz, 1H), 7.82 (ddd, J = 8.7, 4.8, 2.3 Hz, 1H), 7.24 (t, J = 9.3 Hz, 1H), 6.45 (d, J = 5.3 Hz, 1H), 5.55 - 5.40 (m, 1H), 4.41 (qd, J = 7.1, 1.6 Hz, 2H), 4.09 - 3.99 (m, 1H), 3.89 - 3.81 (m, 1H), 3.56 - 3.44 (m, 1H), 3.40 - 3.25 (m, 1H), 2.09 - 2.03 (m, 1H), 1.86 - 1.78 (m, 1H), 1.77 - 1.71 (m, 1H), 1.68 - 1.59 (m, 1H), 1.40 (t, 12H). LRMS (ESI+) calculated C 29 H 30 F4N6O4S [M+H]+: 635.2058, found: 635.28

[0383]

[0384] 6d (241 mg, 65 %) 1H NMR (400 MHz, CDCl3) δ9.20 (s, 1H), 8.08 (d, J = 5.4 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.3, 2.1 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 5.3 Hz, 1H), 5.38 (s, 1H), 4.39 (qd, J = 7.1, 2.0 Hz, 2H), 4.29 (dddt, J = 6.7, 5.4, 3.7, 1.7 Hz, 4H), 4.06 - 3.97 (m, 1H), 3.89 - 3.77 (m, 1H), 3.57 - 3.45 (m, 1H), 3.44 - 3.19 (m, 1H), 2.09 - 2.04 (m, 1H), 1.84 - 1.76 (m, 1H), 1.74 - 1.69 (m, 1H), 1.67 - 1.60 (m, 1H), 1.39 (t, J = 7.2 Hz, 12H). LRMS (ESI+) calculated C 30 H 34 N6O6S [M+H]+: 607.2334, found: 607.29

[0385]

[0386] 7a (91 mg, 80 %) 1H NMR (400 MHz, CDCl3) δ9.24 (s, 1H), 8.16 (d, J = 1.7 Hz, 1H), 8.07 - 7.97 (m, 2H), 7.92 - 7.84 (m, 3H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.56 - 7.49 (m, 2H), 6.54 (d, J = 5.4 Hz, 1H), 4.42 (qd, J = 7.1, 1.9 Hz, 2H), 4.31 - 4.24 (m, 1H), 4.14 - 4.08 (m, 1H), 4.07 - 4.00 (m, 1H), 3.93 - 3.82 (m, 1H), 3.73 - 3.64 (m, 1H), 1.90 - 1.82 (m, 2H), 1.82 - 1.77 (m, 1H), 1.76 - 1.69 (m, 1H), 1.45 (s, 9H), 1.42 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 32 H 34 N6O4S [M+H]+: 599.2435, found: 599.34

[0387]

[0388] 7b 1 H NMR (400 MHz, CDCl3) δ9.13 (s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.77 (dd, J = 1.7, 0.8 Hz, 1H), 7.47 (d, J = 1.7 Hz, 2H), 6.52 (d, J = 5.3 Hz, 1H), 5.44 (s, 1H), 4.41 (qd, J = 7.1, 1.4 Hz, 2H), 4.13 - 4.07 (m, 1H), 4.01 (s, 1H), 3.83 (s, 1H), 3.48 (s, 2H), 2.09 - 2.04 (m, 1H), 1.83 - 1.75 (m, 1H), 1.73 - 1.70 (m, 1H), 1.69 - 1.60 (m, 1H), 1.40 (s, 9H), 1.23 (t, J = 7.1 Hz, 2H). LRMS (ESI+) calculated C 28 H30 Cl2N6O4S [M+H]+: 617.1499, found: 617.28

[0389]

[0390] 7c 1 H NMR (400 MHz, CDCl3) δ9.19 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.99 (dd, J = 6.9, 2.2 Hz, 1H), 7.86 (ddd, J = 8.6, 4.7, 2.2 Hz, 1H), 7.29 (t, J = 9.3 Hz, 1H), 6.49 (d, J = 5.3 Hz, 1H), 5.59 - 5.44 (m, 1H), 4.45 (qd, J = 7.1, 1.6 Hz, 2H), 4.13 - 4.01 (m, 1H), 3.98 - 3.80 (m, 1H), 3.63 - 3.48 (m, 1H), 3.46 - 3.29 (m, 1H), 2.15 - 2.05 (m, 1H), 1.87 - 1.80 (m, 1H), 1.79 - 1.72 (m, 1H), 1.72 - 1.62 (m, 1H), 1.45 (t, 12H). LRMS (ESI+) calculated C 29 H 30 F4N6O4S [M+H]+: 635.2058, found: 635.29

[0391]

[0392] 7d (260 mg, 70 %) 1H NMR (400 MHz, CDCl3) δ9.20 (s, 1H), 8.09 (d, J = 5.4 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.3, 2.1 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 5.4 Hz, 1H), 5.36 (s, 1H), 4.40 (qd, J = 7.1, 1.9 Hz, 2H), 4.29 (ttd, J = 7.1, 3.4, 1.6 Hz, 4H), 4.07 - 4.01 (m, 1H), 3.90 - 3.76 (m, 1H), 3.55 - 3.44 (m, 1H), 3.43 - 3.29 (m, 1H), 2.10 - 2.04 (m, 1H), 1.84 - 1.75 (m, 1H), 1.75 - 1.69 (m, 1H), 1.70 - 1.57 (m, 1H), 1.40 (t, J = 7.1 Hz, 12H).LRMS (ESI+) calculated C 30 H 34 N6O6S [M+H]+: 607.2334, found: 607.33

[0393]

[0394] Ethyl 5-(2-((1-(cyclopropanecarbonyl)-3l3-piperidin-3-yl)amino)pyrimidin-4-yl)-6-Aryl imidazo[2,1-b]thiazole-2-carboxylate (8af, 8bf, 8cf, 8df, 9af, 9bf,9cf, 9df, 10ag, 10bg, 10cg, 10dg, 11ag, 11bg, 11cg, 11dg)

[0395]

[0396] Compound 6a (67 mg, 0.11 mmol) was dissolved in MC (0.87 ml), and TFA (0.22 ml) was added dropwise at 0 °C, slowly warmed to room temperature, and stirred for 1 hour. After completion of the reaction, the solvent was evaporated using a rotary evaporator, and the next reaction was carried out without purification. After dissolving the reaction mixture in THF (1.16 ml), DIPEA (40 μl, 0.23 mmol) was added, and cyclopropanecarbonyl chloride (9.5 μl, 0.10 mmol) was added, and the mixture was stirred at room temperature for 1 hour and 30 minutes. After completion of the reaction, the solvent in the reaction mixture was evaporated, extracted with EA, and washed with H2O and Brine. The remaining moisture was removed with anhydrous magnesium sulfate (MgSO4), and column chromatography was performed with a mobile phase composition of EA:HEX = 1:2 to obtain compound 8af (50 mg, 80%).

[0397] 8af (50 mg, 80%) 1 H NMR (400 MHz, DMSO) δ9.34 - 9.12 (m, 1H), 8.19 (s, 1H), 8.09 (s, 1H), 7.97 (q, J = 7.6 Hz, 3H), 7.70 (d, J = 8.6 Hz, 1H), 7.57 (q, J = 6.2) Hz, 2H), 6.39 (s, 1H), 4.57 - 4.22 (m, 3H), 4.18 - 4.01 (m, 1H), 3.87 - 3.69 (m, 1H), 3.27 - 3.06 (m, 2H), 2.93 - 2.75 (m, 1H), 2.13 - 2.01 (m, 1H), 2.01 - 1.92 (m, 1H), 1.88 - 1.74 (m, 1H), 1.67 - 1.53 (m, 1H), 1.38 - 1.28 (m, 3H), 0.77 - 0.52 (m, 4H). LRMS (ESI+) calculated for C 31 H 30 N6O3S [M+H]+: 567.2173, found: 567.28

[0398]

[0399] 8bf (53 mg, 75 %) 1 H NMR (400 MHz, DMSO-d6) δ9.22 - 8.93 (m, 1H), 8.18 (s, 1H), 7.81 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.60 - 7.37 (m, 2H), 6.41 (s, 1H), 4.43 - 4.28 (m, 2H), 4.27 - 4.19 (m, 1H), 4.15 - 4.07 (m, 1H), 3.77 (s, 1H), 3.23 - 3.04 (m, 1H), 2.95 - 2.61 (m, 1H), 2.12 - 2.01 (m, 1H), 1.99 - 1.92 (m, 1H), 1.88 - 1.74 (m, 1H), 1.72 - 1.51 (m, 2H), 1.32 (t, J = 6.1 Hz, 3H), 0.78 - 0.51 (m, 4H). LRMS (ESI+) calculated for C 27 H 26 Cl2N6O3S [M+H]+: 585.1237, found: 585.22

[0400]

[0401] 8cf (19 mg, 80 %) 1 H NMR (400 MHz, DMSO-d6) δ9.25 - 9.02 (m, 1H), 8.19 (s, 1H), 8.04 - 7.92 (m, 2H), 7.60 (t, J = 9.8 Hz, 2H), 6.41 (s, 1H), 4.42 - 4.32 (m, 2H), 4.29 - 4.22 (m, 1H), 4.17 - 4.07 (m, 1H), 3.89 - 3.66 (m, 1H), 3.25 - 3.09 (m, 1H), 2.96 - 2.57 (m, 1H), 2.11 - 2.03 (m, 1H), 1.89 - 1.76 (m, 1H), 1.73 - 1.52 (m, 2H), 1.32 (d, J = 4.7 Hz, 3H), 1.21 (s, 1H), 0.77 - 0.52 (m, 4H).

[0402] LRMS (ESI+) calculated for C 28 H 26 F4N6O3S [M+H]+: 603.1796, found: 603.26

[0403]

[0404] 8df (43 mg, 36 %) 1 H NMR (400 MHz, DMSO-d6) δ9.27 - 9.07 (m, 1H), 8.15 (s, 1H), 7.45 (s, 1H), 7.08 - 7.01 (m, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.46 (s, 1H), 4.50 - 4.34 (m, 2H), 4.29 (q, J = 4.7 Hz, 4H), 4.11 (s, 1H), 3.87 - 3.67 (m, 1H), 3.27 - 3.18 (m, 1H), 2.98 - 2.80 (m, 1H), 2.76 - 2.56 (m, 1H), 2.14 - 2.04 (m, 1H), 1.99 - 1.90 (m, 1H), 1.76 (ddt, J = 9.9, 5.1, 2.5 Hz, 1H), 1.69 - 1.57 (m, 1H), 1.50 - 1.39 (m, 1H), 1.36 - 1.29 (m, 3H), 1.23 - 1.15 (m, 2H), 0.71 - 0.63 (m, 2H). LRMS (ESI+) calculated for C 29 H 30 N6O5S [M+H]+:575.2071, found: 575.28

[0405]

[0406] 9af (29 mg, 68 %) 1H NMR (400 MHz, DMSO-d6) δ9.27 (s, 1H), 8.24 - 8.20 (m, 1H), 8.11 (s, 1H), 8.03 - 7.95 (m, 3H), 7.72 (d, J = 8.3 Hz, 1H), 7.62 - 7.54 (m, 2H), 6.40 (s, 1H), 4.43 - 4.27 (m, 3H), 4.19 - 4.07 (m, 1H), 3.91 - 3.70 (m, 1H), 3.26 - 3.05 (m, 1H), 2.97 - 2.80 (m, 1H), 2.15 - 2.03 (m, 1H), 2.02 - 1.92 (m, 1H), 1.88 - 1.77 (m, 1H), 1.70 - 1.58 (m, 1H), 1.35 (t, J = 5.0 Hz, 3H), 1.23 (s, 1H), 0.75 - 0.60 (m, 4H). LRMS (ESI+) calculated for C 31 H 30 N6O3S [M+H]+: 567.2173, found: 567.31

[0407]

[0408] 9bf (83 mg, 88 %) 1H NMR (400 MHz, DMSO-d6) δ9.23 - 8.90 (m, 1H), 8.15 (s, 1H), 7.79 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.54 (dd, J = 8.3, 2.0 Hz, 2H), 6.40 (s, 1H), 4.40 - 4.29 (m, 2H), 4.30 - 4.20 (m, 1H), 4.17 - 4.06 (m, 1H), 3.85 - 3.66 (m, 1H), 3.24 - 3.05 (m, 1H), 2.96 - 2.78 (m, 1H), 2.09 - 2.01 (m, 1H), 1.84 - 1.76 (m, 1H), 1.72 - 1.50 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.19 (d, J = 7.6 Hz, 1H), 0.77 - 0.53 (m, 4H). LRMS (ESI+) calculated for C 27 H 26 Cl2N6O3S [M+H]+: 585.1237, found: 585.22

[0409]

[0410] 9cf (21 mg, 94 %) 1 H NMR (400 MHz, DMSO-d6) δ9.23 - 9.03 (m, 1H), 8.19 (s, 1H), 8.04 - 7.95 (m, 2H), 7.60 (t, J = 9.8 Hz, 2H), 6.41 (s, 1H), 4.42 - 4.32 (m, 2H), 4.24 (d, J = 12.4 Hz, 1H), 4.11 (s, 1H), 3.87 - 3.62 (m, 1H), 3.27 - 3.08 (m, 1H), 3.00 - 2.80 (m, 1H), 2.00 - 1.94 (m, 1H), 1.82 (s, 1H), 1.74 - 1.57 (m, 1H), 1.32 (t, J = 7.7 Hz, 3H), 0.77 - 0.48 (m, 4H). LRMS (ESI+) calculated for C 28 H 26F4N6O3S [M+H]+: 603.1796, found: 603.25

[0411]

[0412] 9df (36 mg, 75 %) 1 H NMR (400 MHz, DMSO-d6) δ9.30 - 9.00 (m, 1H), 8.14 (s, 1H), 7.46 (s, 1H), 7.10 - 6.99 (m, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.46 (s, 1H), 4.42 - 4.34 (m, 2H), 4.32 - 4.26 (m, 4H), 4.16 - 4.06 (m, 1H), 4.02 (q, J = 7.1 Hz, 1H), 3.87 - 3.66 (m, 1H), 3.28 - 3.11 (m, 1H), 2.86 (s, 1H), 2.06 (d, J = 14.7 Hz, 1H), 1.88 - 1.72 (m, 1H), 1.61 (s, 1H), 1.31 (dt, J = 10.9, 6.3 Hz, 3H), 1.22 - 1.11 (m, 2H), 0.81 - 0.50 (m, 4H). LRMS (ESI+) calculated for C 29 H 30 N6O5S [M+H]+ 575.2071:, found: 575.28

[0413]

[0414] 10ag (23 mg, 61 %) 1H NMR (400 MHz, DMSO-d6) δ9.38 - 9.08 (m, 1H), 8.21 (s, 1H), 8.09 (d, J = 5.3 Hz, 1H), 8.03 - 7.94 (m, 3H), 7.75 - 7.69 (m, 1H), 7.63 - 7.51 (m, 2H), 7.44 (s, 1H), 6.38 (s, 1H), 4.38 (t, J = 7.3 Hz, 2H), 3.95 - 3.79 (m, 1H), 3.76 - 3.53 (m, 1H), 2.70 (s, 6H), 2.12 - 1.93 (m, 2H), 1.81 - 1.70 (m, 1H), 1.64 - 1.52 (m, 2H), 1.34 (d, J = 3.4 Hz, 3H). LRMS (ESI+) calculated for C 30 H 31 N7O3S [M+H]+: 570.2282, found: 570.32

[0415]

[0416] 10bg (76 mg, 86 %) 1 H NMR (400 MHz, DMSO-d6) δ9.04 (d, J = 66.0 Hz, 1H), 8.16 (d, J = 5.1 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.55 (dd, J = 8.3, 1.9 Hz, 1H), 6.40 (d, J = 16.7 Hz, 1H), 4.34 (d, J = 6.8 Hz, 2H), 3.82 (s, 1H), 3.71 - 3.50 (m, 1H), 3.46 - 3.24 (m, 3H), 2.83 - 2.64 (m, 6H), 1.74 (s, 1H), 1.59 - 1.45 (m, 2H), 1.32 (t, J = 6.7 Hz, 3H), 0.85 - 0.75 (m, 1H). LRMS (ESI+) calculated for C 26 H 27 Cl2N7O3S [M+H]+ 588.1346:, found: 588.22

[0417]

[0418] 10cg (25 mg, 89 %) 1 H NMR (400 MHz, DMSO-d6) δ9.26 - 9.02 (m, 1H), 8.19 (d, J = 5.2 Hz, 1H), 8.00 (dd, J = 7.3, 5.1 Hz, 2H), 7.72 - 7.64 (m, 2H), 6.49 - 6.34 (m, 1H), 4.37 (d, J = 7.2 Hz, 2H), 4.28 - 4.16 (m, 2H), 3.84 (s, 1H), 3.72 - 3.39 (m, 2H), 2.79 - 2.63 (m, 6H), 2.02 (d, J = 17.4 Hz, 1H), 1.75 (s, 1H), 1.52 (d, J = 7.0 Hz, 2H), 1.33 (d, J = 7.2 Hz, 3H). LRMS (ESI+) calculated C 27 H 27 F4N7O3S [M+H]+: 606.1905, found: 606.26

[0419]

[0420] 10dg (42 mg, 36 %) 1 H NMR (400 MHz, DMSO-d6) δ9.30 - 9.05 (m, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.62 - 7.32 (m, 1H), 7.09 - 7.01 (m, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.45 (s, 1H), 4.35 (q, J = 6.9 Hz, 2H), 4.29 (q, J = 4.8 Hz, 4H), 3.90 - 3.80 (m, 1H), 3.71 - 3.53 (m, 1H), 3.46 - 3.36 (m, 1H), 2.86 - 2.57 (m, 8H), 2.07 - 1.93 (m, 1H), 1.82 - 1.69 (m, 1H), 1.61 - 1.47 (m, 2H), 1.37 - 1.30 (m, 3H). LRMS (ESI+) calculated for C28 H 31 N7O5S [M+H]+: 578.2180, found: 578.39

[0421]

[0422] 11ag (27 mg, 63 %) 1 H NMR (400 MHz, DMSO-d6) δ9.38 - 9.13 (m, 1H), 8.24 - 8.21 (m, 1H), 8.10 (d, J = 5.3 Hz, 1H), 8.02 - 7.95 (m, 3H), 7.72 (dd, J = 8.5, 1.8 Hz, 1H), 7.62 - 7.54 (m, 2H), 6.39 (s, 1H), 4.39 (d, J = 7.3 Hz, 2H), 3.88 (s, 1H), 3.66 (s, 1H), 3.41 (s, 1H), 3.30 (s, 1H), 2.71 (s, 6H), 2.03 (s, 1H), 1.77 (s, 1H), 1.55 (s, 2H), 1.39 - 1.30 (m, 3H), 1.23 (s, 1H). LRMS (ESI+) calculated for C 30 H 31 N7O3S [M+H]+: 570.0073, found: 570.11

[0423]

[0424] 11bg (90 mg, 90 %) 1H NMR (400 MHz, DMSO-d6) δ9.18 - 8.89 (m, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.3, 2.1 Hz, 2H), 6.46 - 6.29 (m, 1H), 4.33 (q, J = 7.0 Hz, 2H), 3.89 - 3.76 (m, 1H), 3.72 - 3.38 (m, 2H), 2.83 - 2.60 (m, 8H), 1.79 - 1.67 (m, 1H), 1.59 - 1.47 (m, 2H), 1.31 (t, J = 6.1 Hz, 4H), 1.25 - 1.18 (m, 1H). LRMS (ESI+) calculated for C 26 H 27 Cl2N7O3S [M+H]+: 588.1346, found: 588.21

[0425]

[0426] 11cg (23 mg, 88 %) 1 H NMR (400 MHz, DMSO-d6) δ9.24 - 9.00 (m, 1H), 8.18 (d, J = 5.2 Hz, 1H), 8.00 (dd, J = 7.4, 4.9 Hz, 2H), 7.65 - 7.42 (m, 2H), 6.54 - 6.32 (m, 1H), 4.36 (d, J = 6.9 Hz, 2H), 3.83 (s, 1H), 3.74 - 3.53 (m, 1H), 3.40 (s, 1H), 2.83 - 2.62 (m, 8H), 2.00 (d, J = 10.4 Hz, 1H), 1.74 (d, J = 10.5 Hz, 1H), 1.52 (d, J = 7.8 Hz, 2H), 1.35 (d, J = 6.4 Hz, 3H). LRMS (ESI+) calculated for C 27 H 27 F4N7O3S [M+H]+: 606.1905, found: 606.28

[0427]

[0428] 11dg (42 mg, 81 %) 1 H NMR (400 MHz, DMSO-d6) δ9.29 - 9.05 (m, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.59 - 7.32 (m, 1H), 7.10 - 7.00 (m, 2H), 6.91 (d, J = 8.3 Hz, 1H), 6.45 (s, 1H), 4.40 - 4.32 (m, 2H), 4.29 (h, J = 3.8 Hz, 5H), 4.02 (q, J = 7.1 Hz, 1H), 3.91 - 3.80 (m, 1H), 3.72 - 3.52 (m, 1H), 3.40 (s, 1H), 2.84 - 2.61 (m, 7H), 1.75 (s, 1H), 1.55 (d, J = 11.1 Hz, 2H), 1.38 - 1.26 (m, 3H), 1.26 - 1.16 (m, 2H). LRMS (ESI+) calculated for C 28 H 31 N7O5S [M+H]+: 578.2180, found: 578.31

[0429]

[0430] 5-(2-((1-(cyclopropanecarbonyl)-3l3-piperidin-3-yl)amino)pyrimidin-4-yl)-N-6-Arylimidazo [2,1-b]thiazole-2-carboxamide (12af-df, 13af-df, 16af-df, 17af-df, 14ag-dg, 15ag-dg, 18ag-dg, 19ag-dg)

[0431]

[0432] Compound 8af (13 mg, 0.022 mmol) was dissolved in MeOH (0.5 ml), 7 N NH3 in MeOH (47 μl, 2.2 mmol) was added, and the mixture was stirred at room temperature for 48 h. After completion of the reaction, the reaction mixture was extracted with EA and washed with H2O and Brine. The extracted reaction mixture was purified by removing residual moisture with anhydrous magnesium sulfate (MgSO4) and separated using a PreP TLC mobile phase composition of MC:MeOH = 20:1 to obtain compound 12af (6 mg, 51%).

[0433] 12af (6 mg, 51%) 1 H NMR (400 MHz, DMSO-d6) δ9.49 (s, 1H), 8.26 - 8.18 (m, 2H), 8.14 (s, 1H), 7.98 (s, 3H), 7.71 (d, J = 8.5 Hz, 1H), 7.57 (s, 2H), 7.08 (s, 1H), 6.43 (s, 1H), 4.45 (s, 1H), 4.28 (d, J = 12.7 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.93 - 3.74 (m, 1H), 3.16 (s, 1H), 2.14 - 2.03 (m, 1H), 1.87 - 1.42 (m, 4H), 1.27 - 1.09 (m, 2H), 0.75 - 0.65 (m, 2H). LRMS (ESI+) calculated C 29 H 27 N7O2S [M+H]+: 538.2020, found: 538.38

[0434]

[0435] 12bf (18mg, 63%) 1H NMR (400 MHz, DMSO-d6) δ9.38 (s, 1H), 8.37 - 8.18 (m, 2H), 7.88 (d, J = 2.1 Hz, 1H), 7.71 (s, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.21 - 7.04 (m, 1H), 6.66 - 6.45 (m, 1H), 4.49 - 4.28 (m, 1H), 4.18 - 4.00 (m, 1H), 3.91 - 3.74 (m, 1H), 3.21 - 2.87 (m, 1H), 2.83 - 2.60 (m, 1H), 2.17 - 1.92 (m, 1H), 1.88 - 1.73 (m, 1H), 1.69 - 1.53 (m, 1H), 1.52 - 1.37 (m, 1H), 0.81 - 0.51 (m, 4H). LRMS (ESI+) calculated C 25 H 23 Cl2N7O2S [M+H]+: 556.1084, found: 556.28

[0436]

[0437] 12cf (7.4 mg, 71 %) 1 H NMR (400 MHz, DMSO-d6) δ9.38 (s, 1H), 8.24 (s, 2H), 8.00 (s, 3H), 7.60 (s, 1H), 7.13 (s, 1H), 6.54 (s, 1H), 4.54 - 4.44 (m, 1H), 4.32 - 4.22 (m, 1H), 4.17 - 4.03 (m, 1H), 3.89 - 3.71 (m, 1H), 3.20 - 3.08 (m, 1H), 2.11 - 1.93 (m, 2H), 1.87 - 1.75 (m, 1H), 1.71 - 1.60 (m, 1H), 1.53 - 1.41 (m, 1H), 0.80 - 0.53 (m, 4H). LRMS (ESI+) calculated C 26 H 23 F4N7O2S [M+H]+:574.1643, found: 574.20

[0438]

[0439] 12df (21 mg, 61 %) 1 H NMR (400 MHz, DMSO-d6) δ9.44 (s, 1H), 8.18 (s, 2H), 7.95 (s, 1H), 7.15 - 7.02 (m, 2H), 6.92 (s, 1H), 6.50 (s, 1H), 4.36 - 4.19 (m, 4H), 4.10 (s, 1H), 3.85 (s, 1H), 3.15 (s, 1H), 2.99 - 2.58 (m, 1H), 2.11 - 1.90 (m, 1H), 1.88 - 1.70 (m, 1H), 1.20 (d, J = 12.0 Hz, 1H), 0.78 - 0.51 (m, 4H). LRMS (ESI+) calculated C 27 H 27 N7O4S [M+H]+: 546.1918, found: 546.17

[0440]

[0441] 13af (6 mg, 59 %) 1 H NMR (400 MHz, DMSO-d6) δ9.49 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.98 (s, 3H), 7.72 (d, J = 8.4 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.08 (s, 1H), 6.43 (s, 1H), 4.57 - 4.38 (m, 1H), 4.28 (d, J = 12.9 Hz, 1H), 4.17 - 3.98 (m, 1H), 3.93 - 3.75 (m, 1H), 3.24 - 3.05 (m, 1H), 2.11 - 1.73 (m, 4H), 1.50 - 1.40 (m, 1H), 0.93 - 0.78 (m, 2H), 0.75 - 0.65 (m, 2H). LRMS (ESI+) calculated C 29 H 27 N7O2S [M+H]+: 538.2020, found: 538.28

[0442]

[0443] 13bf (23 mg, 48 %) 1 H NMR (400 MHz, DMSO-d6) δ9.46 - 8.82 (m, 1H), 8.24 (s, 2H), 7.97 (s, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 7.60 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 - 7.01 (m, 1H), 6.48 (s, 1H), 4.35 - 4.24 (m, 1H), 4.15 - 3.97 (m, 1H), 3.86 - 3.68 (m, 1H), 3.28 - 3.11 (m, 1H), 3.00 - 2.75 (m, 1H), 2.75 - 2.59 (m, 1H), 2.13 - 1.91 (m, 1H), 1.87 - 1.74 (m, 1H), 1.72 - 1.55 (m, 1H), 1.54 - 1.31 (m, 1H), 0.80 - 0.40 (m, 4H). LRMS (ESI+) calculated C 25 H 23 Cl2N7O2S [M+H]+: 556.1084, found: 556.22

[0444]

[0445] 13cf (6 mg, 70 %) 1H NMR (400 MHz, DMSO-d6) δ9.38 (s, 1H), 9.07 - 8.86 (m, 1H), 8.38 - 8.19 (m, 2H), 8.01 (d, J = 6.6 Hz, 2H), 7.70 - 7.49 (m, 1H), 7.15 (s, 1H), 6.46 (s, 1H), 4.49 - 4.45 (m, 1H), 4.38 - 4.24 (m, 1H), 4.19 - 3.99 (m, 1H), 3.98 - 3.72 (m, 1H), 3.23 - 3.09 (m, 1H), 2.13 - 1.93 (m, 2H), 1.87 - 1.72 (m, 1H), 1.74 - 1.56 (m, 1H), 1.55 - 1.37 (m, 1H), 0.80 - 0.50 (m, 4H). LRMS (ESI+) calculated C 26 H 23 F4N7O2S [M+H]+: 574.1643, found: 574.34

[0446]

[0447] 13df (9 mg, 43 %) 1 H NMR (400 MHz, DMSO-d6) δ9.37 (s, 1H), 8.98 (s, 1H), 8.71 (s, 1H), 8.26 - 8.17 (m, 1H), 7.07 (d, J = 13.2 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.50 (s, 1H), 4.33 - 4.20 (m, 4H), 3.99 - 3.82 (m, 1H), 3.78 - 3.65 (m, 1H), 3.46 - 3.37 (m, 1H), 2.87 - 2.81 (m, 3H), 2.74 (s, 6H), 2.67 - 2.60 (m, 2H), 2.10 - 1.95 (m, 1H), 1.82 - 1.69 (m, 1H), 1.59 - 1.46 (m, 2H). LRMS (ESI+) calculated C 27 H 27 N7O4S [M+H]+: 546.1918, found: 546.29

[0448]

[0449] 14ag (5 mg, 66 %) 1 H NMR (400 MHz, DMSO-d6) δ9.49 (s, 1H), 8.22 (d, J = 1.7 Hz, 1H), 8.13 (s, 1H), 7.98 (d, J = 7.7 Hz, 3H), 7.72 (dd, J = 8.5, 1.8 Hz, 1H), 7.57 (s, 2H), 7.02 (s, 1H), 6.42 (s, 1H), 4.01 - 3.81 (m, 1H), 3.77 - 3.62 (m, 1H), 3.42 (d, J = 8.0 Hz, 1H), 2.82 - 2.66 (m, 6H), 2.61 (d, J = 10.5 Hz, 2H), 2.08 - 1.92 (m, 1H), 1.81 - 1.68 (m, 1H), 1.59 - 1.46 (m, 2H). LRMS (ESI+) calculated C 28 H 28 N8O2S [M+H]+:541.2129, found: 541.29

[0450]

[0451] 14bg (23 mg, 52 %) 1 H NMR (400 MHz, DMSO-d6) δ9.38 (s, 1H), 8.24 (s, 2H), 7.89 (s, 1H), 7.72 (d, J = 9.8 Hz, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 5.0 Hz, 1H), 6.64 - 6.46 (m, 1H), 3.89 (dp, J = 14.0, 4.9 Hz, 1H), 3.76 - 3.61 (m, 1H), 3.51 - 3.36 (m, 1H), 2.80 - 2.71 (m, 4H), 2.61 (s, 3H), 2.08 - 1.90 (m, 1H), 1.83 - 1.63 (m, 1H), 1.60 - 1.40 (m, 2H). LRMS (ESI+) calculated C 24 H 24Cl2N8O2S [M+H]+: 559.1193, found: 559.23

[0452]

[0453] 14cg (4.2 mg, 29 %) 1 H NMR (400 MHz, DMSO-d6) δ9.38 (s, 1H), 8.24 (s, 2H), 8.02 (d, J = 6.3 Hz, 3H), 7.61 (s, 1H), 7.08 (s, 1H), 6.64 - 6.43 (m, 1H), 3.93 - 3.83 (m, 1H), 3.80 - 3.69 (m, 1H), 3.67 - 3.36 (m, 2H), 2.80 - 2.69 (m, 4H), 2.60 (s, 3H), 2.08 - 1.89 (m, 1H), 1.82 - 1.68 (m, 1H), 1.62 - 1.38 (m, 2H). LRMS (ESI+) calculated C 25 H 24 F4N8O2S [M+H]+: 577.1752, found: 577.25

[0454]

[0455] 14dg (20 mg, 62 %) 1 H NMR (400 MHz, DMSO-d6) δ9.44 (s, 1H), 8.17 (d, J = 5.3 Hz, 2H), 7.95 (s, 1H), 7.12 - 7.02 (m, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.49 (d, J = 4.9 Hz, 1H), 4.36 - 4.22 (m, 4H), 3.98 - 3.81 (m, 1H), 3.75 - 3.62 (m, 1H), 3.46 - 3.38 (m, 1H), 2.74 (s, 6H), 2.65 - 2.59 (m, 2H), 2.00 (d, J = 16.7 Hz, 1H), 1.81 - 1.67 (m, 1H), 1.56 - 1.44 (m, 2H) LRMS (ESI+) calculated C 26 H 28N8O4S [M+H]+: 549.2027, found: 549.32

[0456]

[0457] 15ag (6 mg, 65 %) 1 H NMR (400 MHz, DMSO-d6) δ9.49 (s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 8.13 (s, 1H), 7.98 (d, J = 7.7 Hz, 3H), 7.72 (dd, J = 8.4, 1.8 Hz, 1H), 7.57 (s, 2H), 7.02 (s, 1H), 6.42 (s, 1H), 4.02 - 3.86 (m, 1H), 3.78 - 3.66 (m, 1H), 3.48 - 3.40 (m, 1H), 2.76 (d, J = 17.7 Hz, 6H), 2.63 - 2.59 (m, 2H), 2.10 - 1.92 (m, 1H), 1.81 - 1.68 (m, 1H), 1.60 - 1.46 (m, 2H). LRMS (ESI+) calculated C 28 H 28 N8O2S [M+H]+: 541.2129, found: 541.29

[0458]

[0459] 15bg (11 mg, 21 %) 1H NMR (400 MHz, DMSO-d6) δ9.37 (s, 1H), 8.98 (s, 1H), 8.24 (s, 2H), 7.89 (d, J = 2.0 Hz, 1H), 7.72 (s, 1H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.06 (s, 1H), 6.64 - 6.41 (m, 1H), 3.93 - 3.83 (m, 1H), 3.75 - 3.60 (m, 1H), 3.52 - 3.33 (m, 2H), 2.85 - 2.69 (m, 4H), 2.59 (s, 3H), 2.09 - 1.93 (m, 1H), 1.82 - 1.68 (m, 1H), 1.60 - 1.42 (m, 2H). LRMS (ESI+) calculated C 24 H 24 Cl2N8O2S [M+H]+: 559.1193, found: 559.24

[0460]

[0461] 15cg (10 mg, 86 %) 1 H NMR (400 MHz, DMSO-d6) δ9.37 (s, 1H), 8.98 (s, 1H), 8.23 (s, 2H), 8.04 - 7.90 (m, 2H), 7.69 - 7.55 (m, 1H), 7.11 - 7.03 (m, 1H), 6.63 - 6.41 (m, 1H), 3.93 - 3.81 (m, 1H), 3.73 - 3.60 (m, 1H), 3.49 - 3.39 (m, 1H), 2.81 - 2.71 (m, 4H), 2.59 (s, 3H), 2.11 - 1.89 (m, 1H), 1.83 - 1.68 (m, 1H), 1.60 - 1.35 (m, 2H). LRMS (ESI+) calculated C 25 H 24 F4N8O2S [M+H]+: 577.1752, found: 577.21

[0462] 15dg (9.3 mg, 34 %) 1H NMR (400 MHz, DMSO-d6) δ9.45 (s, 1H), 9.01 (s, 1H), 8.25 - 8.11 (m, 2H), 7.96 (s, 1H), 7.14 - 7.03 (m, 2H), 6.95 (t, J = 9.8 Hz, 1H), 6.50 (d, J = 5.2 Hz, 1H), 4.31 (p, J = 4.8 Hz, 4H), 3.96 - 3.82 (m, 1H), 3.78 - 3.65 (m, 1H), 2.79 - 2.68 (m, 6H), 2.63 (dd, J = 12.4, 9.5 Hz, 2H), 2.09 - 1.98 (m, 1H), 1.84 - 1.63 (m, 1H), 1.61 - 1.45 (m, 2H). LRMS (ESI+) calculated C 26 H 28 N8O4S [M+H]+: 549.2027, found: 549.32

[0463]

[0464] 16af (5.5 mg, 43 %) 1 H NMR (400 MHz, DMSO-d6) δ9.41 (s, 1H), 8.74 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 12.0 Hz, 1H), 7.97 (d, J = 7.9 Hz, 3H), 7.71 (dd, J = 8.6, 1.7 Hz, 1H), 7.56 (dt, J = 5.9, 2.1 Hz, 2H), 7.11 (s, 1H), 6.43 (s, 1H), 4.48 (d, J = 12.2 Hz, 1H), 4.28 (d, J = 12.9 Hz, 1H), 3.20 - 3.07 (m, 1H), 2.85 (s, 3H), 2.07 (s, 1H), 1.80 - 1.39 (m, 4H), 0.80 - 0.53 (m, 4H). LRMS (ESI+) calculated C 30 H 29 N7O2S [M+H]+: 552.2176, found: 552.31

[0465]

[0466] 16bf (10 mg, 38 %) 1 H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.70 (s, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 (s, 1H), 6.71 - 6.45 (m, 1H), 4.48 - 4.40 (m, 1H), 4.37 - 4.23 (m, 1H), 4.16 - 3.98 (m, 1H), 3.92 - 3.73 (m, 1H), 3.21 - 3.09 (m, 1H), 2.83 (s, 3H), 2.18 - 1.92 (m, 2H), 1.90 - 1.73 (m, 1H), 1.68 - 1.54 (m, 1H), 1.54 - 1.36 (m, 1H), 0.83 - 0.46 (m, 4H).LRMS (ESI+) calculated C 26 H 25 Cl2N7O2S [M+H]+: 570.124, found: 570.18

[0467]

[0468] 16cf (3 mg, 34 %) 1H NMR (400 MHz, DMSO-d6) δ9.31 (s, 1H), 8.98 (s, 1H), 8.78 (d, J = 5.1 Hz, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.21 (s, 1H), 6.68 - 6.39 (m, 1H), 4.54 - 4.42 (m, 1H), 4.30 - 4.19 (m, 1H), 4.20 - 3.94 (m, 1H), 3.88 - 3.69 (m, 1H), 3.22 - 3.08 (m, 1H), 2.84 (s, 3H), 2.16 - 1.94 (m, 2H), 1.92 - 1.72 (m, 1H), 1.70 - 1.58 (m, 1H), 1.54 - 1.33 (m, 1H), 0.85 - 0.40 (m, 4H).LRMS (ESI+) calculated C 27 H 25 F4N7O2S [M+H]+: 588.18, found: 588.27

[0469]

[0470] 16df (13 mg, 31 %) 1 H NMR (400 MHz, DMSO-d6) δ9.36 (s, 1H), 8.98 (s, 1H), 8.70 (d, J = 5.0 Hz, 1H), 8.19 (s, 1H), 7.11 - 7.03 (m, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.50 (s, 1H), 4.47 (d, J = 12.3 Hz, 1H), 4.29 (q, J = 5.4 Hz, 4H), 4.10 (s, 1H), 3.21 - 3.06 (m, 1H), 2.83 (s, 3H), 2.69 - 2.60 (m, 1H), 2.07 (d, J = 10.7 Hz, 1H), 1.87 - 1.72 (m, 1H), 1.70 - 1.53 (m, 2H), 1.47 - 1.37 (m, 1H), 1.32 - 1.15 (m, 1H), 0.69 (s, 4H). LRMS (ESI+) calculated C 28 H29 N7O4S [M+H]+: 560.2075, found: 260.32

[0471]

[0472] 17af (6 mg, 65 %) 1 H NMR (400 MHz, DMSO-d6) δ9.41 (s, 1H), 8.75 (s, 1H), 8.21 (d, J = 1.7 Hz, 2H), 8.15 (s, 1H), 7.98 (s, 3H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.56 (dd, J = 6.9, 3.2 Hz, 2H), 7.12 (s, 1H), 6.43 (s, 1H), 4.48 (d, J = 12.3 Hz, 1H), 4.28 (d, J = 13.0 Hz, 1H), 4.06 (q, J = 7.1 Hz, 1H), 3.92 - 3.76 (m, 1H), 3.14 (s, 1H), 2.85 (s, 4H), 2.07 (s, 1H), 1.86 - 1.56 (m, 4H), 1.19 - 1.07 (m, 2H), 0.91 - 0.80 (m, 2H). LRMS (ESI+) calculated C 30 H 29 N7O2S [M+H]+: 552.2176, found: 552.36

[0473]

[0474] 17bf (13 mg, 31 %) 1H NMR (400 MHz, DMSO-d6) δ9.28 (s, 1H), 8.74 (d, J = 6.4 Hz, 1H), 8.25 (d, J = 5.1 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.69 (s, 1H), 7.61 (dd, J = 8.3, 2.0 Hz, 1H), 7.16 (s, 1H), 6.68 - 6.44 (m, 1H), 4.47 - 4.43 (m, 1H), 4.32 - 4.23 (m, 1H), 4.18 - 4.00 (m, 1H), 3.90 - 3.70 (m, 1H), 3.19 - 3.09 (m, 1H), 2.82 (s, 4H), 2.08 - 1.94 (m, 1H), 1.79 - 1.73 (m, 2H), 1.69 - 1.53 (m, 1H), 1.52 - 1.41 (m, 1H), 0.77 - 0.52 (m, 4H). LRMS (ESI+) calculated C 26 H 25 Cl2N7O2S [M+H]+: 570.124, found: 570.16

[0475]

[0476] 17cf (3.7 mg, 35 %) 1 H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 8.76 (d, J = 5.0 Hz, 1H), 8.27 (s, 1H), 8.00 (d, J = 7.2 Hz, 2H), 7.60 (s, 1H), 7.13 (s, 1H), 6.48 (s, 1H), 4.55 - 4.38 (m, 1H), 4.34 - 4.22 (m, 1H), 4.19 - 4.00 (m, 1H), 3.89 - 3.68 (m, 0H), 3.20 - 3.10 (m, 1H), 2.83 (s, 3H), 2.13 - 1.94 (m, 2H), 1.88 - 1.71 (m, 1H), 1.73 - 1.60 (m, 1H), 1.51 - 1.38 (m, 1H), 0.80 - 0.50 (m, 4H). LRMS (ESI+) calculated C27 H 25 F4N7O2S [M+H]+: 588.1800, found: 588.24

[0477]

[0478] 17df (3. 5 mg, 16 %) 1 H NMR (400 MHz, DMSO-d6) δ9.36 (s, 1H), 8.99 (s, 1H), 8.70 (d, J = 5.1 Hz, 1H), 8.28 - 8.11 (m, 1H), 7.10 - 7.06 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.50 (s, 1H), 4.36 - 4.21 (m, 4H), 4.14 - 4.05 (m, 1H), 3.94 - 3.74 (m, 1H), 3.22 - 3.03 (m, 1H), 2.83 (s, 3H), 2.12 - 2.04 (m, 1H), 1.89 - 1.38 (m, 4H), 0.83 - 0.43 (m, 4H). LRMS (ESI+) calculated C 28 H 29 N7O4S [M+H]+: 560.2075, found: 560.28

[0479]

[0480] 18ag (2 mg, 26 %) 1H NMR (400 MHz, DMSO-d6) δ9.44 (s, 1H), 8.88 - 8.74 (m, 1H), 8.25 (s, 1H), 8.19 (d, J = 10.7 Hz, 1H), 8.01 (s, 3H), 7.75 (dd, J = 8.4, 1.8 Hz, 1H), 7.59 (d, J = 5.5 Hz, 2H), 6.46 (s, 1H), 4.00 - 3.87 (m, 1H), 3.79 - 3.67 (m, 1H), 3.52 - 3.39 (m, 2H), 2.87 (s, 3H), 2.81 - 2.73 (m, 4H), 2.70 - 2.59 (m, 3H), 2.10 - 1.98 (m, 1H), 1.84 - 1.70 (m, 1H), 1.59 - 1.49 (m, 2H). LRMS (ESI+) calculated C 29 H 30 N8O2S [M+H]+: 555.2285, found: 555.37

[0481]

[0482] 18bg (10 mg, 25 %) 1 H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 8.75 (s, 1H), 8.26 (s, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.70 (s, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.09 (s, 1H), 6.67 - 6.41 (m, 1H), 3.93 - 3.81 (m, 1H), 3.75 - 3.59 (m, 1H), 3.50 - 3.34 (m, 2H), 2.83 (s, 3H), 2.77 - 2.70 (m, 4H), 2.59 (s, 3H), 2.09 - 1.91 (m, 1H), 1.82 - 1.66 (m, 1H), 1.60 - 1.38 (m, 2H). LRMS (ESI+) calculated C 25 H 26 Cl2N8O2S [M+H]+: 573.1349, found: 573.28

[0483]

[0484] 18cg (3.7 mg, 31 %)

[0485] 1 H NMR (400 MHz, DMSO-d6) δ9.30 (s, 1H), 8.77 (s, 1H), 8.26 (s, 1H), 8.02 (dd, J = 7.5, 4.9 Hz, 2H), 7.60 (s, 1H), 7.11 (s, 1H), 6.63 - 6.43 (m, 1H), 3.98 - 3.79 (m, 1H), 3.75 - 3.40 (m, 2H), 2.86 - 2.78 (m, 3H), 2.77 - 2.71 (m, 3H), 2.59 (s, 3H), 2.07 - 1.89 (m, 1H), 1.82 - 1.65 (m, 1H), 1.56 - 1.38 (m, 2H). LRMS (ESI+) calculated C 26 H 26 F4N8O2S [M+H]+: 591.1909, found: 591.28

[0486]

[0487] 18dg (11 mg, 33 %) 1 H NMR (400 MHz, DMSO-d6) δ9.37 (s, 1H), 8.99 (s, 1H), 8.69 (s, 1H), 8.19 (d, J = 5.3 Hz, 1H), 7.07 (d, J = 14.1 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.50 (s, 1H), 4.37 - 4.23 (m, 4H), 3.98 - 3.84 (m, 1H), 3.77 - 3.62 (m, 1H), 3.47 - 3.38 (m, 1H), 2.83 (s, 3H), 2.77 - 2.69 (m, 6H), 2.64 (dd, J = 12.4, 9.5 Hz, 2H), 2.07 - 1.97 (m, 1H), 1.81 - 1.69 (m, 1H), 1.58 - 1.45 (m, 2H). LRMS (ESI+) calculated C 27 H30 N8O4S [M+H]+: 563.2184, found: 563.30

[0488]

[0489] 19ag (5 mg, 53 %) 1 H NMR (400 MHz, DMSO-d6) δ9.41 (s, 1H), 8.74 (s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 8.15 (s, 1H), 7.97 (d, J = 8.3 Hz, 3H), 7.73 (dd, J = 8.4, 1.7 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.03 (s, 1H), 6.43 (s, 1H), 3.91 (s, 1H), 3.71 (s, 1H), 3.40 (s, 1H), 2.85 (s, 2H), 2.73 (d, J = 15.3 Hz, 4H), 2.62 (t, J = 11.2 Hz, 3H), 2.02 (s, 1H), 1.76 (s, 1H), 1.53 (s, 2H). LRMS (ESI+) calculated C 29 H 30 N8O2S [M+H]+: 555.2285, found: 555.32

[0490]

[0491] 19bg (12 mg, 24 %) 1H NMR (400 MHz, DMSO-d6) δ9.38 (s, 1H), 8.24 (s, 2H), 7.89 (s, 1H), 7.72 (d, J = 9.8 Hz, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 5.0 Hz, 1H), 6.64 - 6.46 (m, 1H), 3.89 (dp, J = 14.0, 4.9 Hz, 1H), 3.76 - 3.61 (m, 1H), 3.51 - 3.36 (m, 1H), 2.80 - 2.71 (m, 4H), 2.61 (s, 3H), 2.08 - 1.90 (m, 1H), 1.83 - 1.63 (m, 1H), 1.60 - 1.40 (m, 2H). LRMS (ESI+) calculated C 25 H 26 Cl2N8O2S [M+H]+: 573.1349, found: 573.21

[0492]

[0493] 19cg (3 mg, 29 %) 1 H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 8.75 (s, 1H), 8.25 (s, 1H), 8.04 - 7.96 (m, 2H), 7.60 (s, 1H), 7.10 (s, 1H), 6.64 - 6.38 (m, 1H), 3.92 - 3.77 (m, 1H), 3.77 - 3.39 (m, 2H), 2.83 (s, 3H), 2.74 (tt, J = 8.6, 4.2 Hz, 5H), 2.59 (s, 3H), 2.08 - 1.84 (m, 1H), 1.84 - 1.67 (m, 1H), 1.65 - 1.33 (m, 2H). LRMS (ESI+) calculated C 26 H 26 F4N8O2S [M+H]+: 591.1909, found: 591.28

[0494]

[0495] 19dg (5.4 mg, 15 %) 1H NMR (400 MHz, DMSO-d6) δ9.37 (s, 1H), 8.98 (s, 1H), 8.71 (s, 1H), 8.26 - 8.17 (m, 1H), 7.07 (d, J = 13.2 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.50 (s, 1H), 4.33 - 4.20 (m, 4H), 3.99 - 3.82 (m, 1H), 3.78 - 3.65 (m, 1H), 3.46 - 3.37 (m, 1H), 2.87 - 2.81 (m, 3H), 2.74 (s, 6H), 2.67 - 2.60 (m, 2H), 2.10 - 1.95 (m, 1H), 1.82 - 1.69 (m, 1H), 1.59 - 1.46 (m, 2H). LRMS (ESI+) calculated C 27 H 30 N8O4S [M+H]+: 563.2184, found: 563.29

[0496]

[0497]

[0498] Compound 5a (130 mg, 0.27 mmol) was dissolved in DMSO (1.35 ml), 2-methoxyethylamine (47 μl, 0.54 mmol) and DIPEA (141 μl, 0.81 mmol) were added, and the mixture was stirred at 100 °C for 12 h. After completion of the reaction, the reaction mixture was extracted with EA and washed with H2O and Brine. The extracted reaction mixture was purified by column chromatography with a mobile phase composition of EA:HEX = 1:2 to obtain compound 20ah (109 mg, 85%).

[0499]

[0500] 20 ah (109 mg, 85%) 1H NMR (400 MHz, DMSO-d6) δ9.25 (s, 1H), 8.18 - 8.14 (m, 1H), 8.04 (d, J = 5.3 Hz, 1H), 7.98 - 7.84 (m, 4H), 7.70 - 7.65 (m, 1H), 7.59 - 7.50 (m, 2H), 6.39 - 6.28 (m, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.52 (s, 4H), 3.28 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 25 H 23 N5O3S [M+H]+:474.1595, found: 474.20

[0501]

[0502] 20ai (80 mg, 85 %) 1 H NMR (400 MHz, CDCl3) δ9.25 (s, 1H), 8.15 (s, 1H), 7.98 (d, J = 5.3 Hz, 1H), 7.90 - 7.80 (m, 4H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 7.53 - 7.45 (m, 3H), 6.48 (d, J = 5.3 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.95 - 3.84 (m, 1H), 3.45 (q, J = 7.0 Hz, 1H), 2.18 - 2.07 (m, 2H), 1.80 (dt, J = 14.0, 3.5 Hz, 3H), 1.67 (dd, J = 9.0, 3.8 Hz, 1H), 1.50 (d, J = 10.4 Hz, 2H), 1.31 (d, J = 8.9 Hz, 2H), 1.19 (t, J = 7.0 Hz, 3H). LRMS (ESI+) calculated C 28 H 27 N5O2S [M+H]+: 498.1958, found: 498.22

[0503]

[0504] 20aj (66 mg, 69 %)1 H NMR (400 MHz, CDCl3) δ9.24 (s, 1H), 8.16 - 8.13 (m, 1H), 7.99 (d, J = 5.3 Hz, 1H), 7.90 - 7.81 (m, 3H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.54 - 7.46 (m, 2H), 6.52 (d, J = 5.3 Hz, 1H), 5.52 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.05 - 3.98 (m, 2H), 3.61 (dt, J = 12.6, 6.9 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 2.13 - 2.05 (m, 2H), 1.67 - 1.56 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H). LRMS (ESI+) calculated C 27 H 25 N5O3S [M+H]+: 500.1751, found: 500.24

[0505]

[0506] 20 ak (69 mg, 77 %) 1 H NMR (400 MHz, CDCl3) δ9.29 (s, 1H), 8.16 (s, 1H), 8.00 (d, J = 5.3 Hz, 1H), 7.92 - 7.80 (m, 4H), 7.71 (dd, J = 8.5, 1.7 Hz, 1H), 7.52 - 7.43 (m, 2H), 6.51 (d, J = 5.3 Hz, 1H), 5.58 (t, J = 5.5 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.37 (t, J = 6.0 Hz, 2H), 1.25 - 1.21 (m, 1H), 1.18 (t, J = 7.0 Hz, 3H), 0.62 - 0.55 (m, 2H), 0.34 - 0.27 (m, 2H). LRMS (ESI+) calculated C 26 H 23 N5O2S [M+H]+: 470.1645, found: 470.26

[0507]

[0508] 20bi (18 mg, 62 %) 1 H NMR (400 MHz, CDCl3) δ9.17 (s, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.79 (q, J = 1.0 Hz, 1H), 7.49 (t, J = 0.9 Hz, 2H), 6.47 (d, J = 5.2 Hz, 1H), 5.33 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.87 (dtd, J = 14.3, 7.4, 3.8 Hz, 1H), 2.16 - 2.09 (m, 2H), 1.81 (dp, J = 12.0, 3.9 Hz, 2H), 1.68 (dt, J = 12.8, 3.9 Hz, 1H), 1.49 (q, J = 11.0 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.35 - 1.28 (m, 3H). LRMS (ESI+) calculated C 24 H 23 Cl2N5O2S [M+H]+: 515.0950, found: 515.08

[0509]

[0510] 20bj (101 mg, 62 %) 1 H NMR (400 MHz, DMSO-d6) δ9.15 (s, 1H), 8.21 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.3, 2.1 Hz, 1H), 7.52 (s, 1H), 6.45 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.98 - 3.87 (m, 3H), 3.44 (t, J = 11.7 Hz, 2H), 1.96 - 1.85 (m, 2H), 1.68 - 1.53 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 23 H 21Cl2N5O3S [M+H]+: 519.0815, found: 519.02

[0511]

[0512] 20di (33 mg, 36 %) 1 H NMR (400 MHz, CDCl3) δ9.23 (s, 1H), 8.05 (d, J = 5.4 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.3, 2.1 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 5.3 Hz, 1H), 5.37 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.88 (tdd, J = 10.4, 7.3, 3.9 Hz, 1H), 2.12 (dd, J = 12.9, 4.0 Hz, 2H), 1.79 (dq, J = 12.0, 4.0 Hz, 2H), 1.68 (dt, J = 12.8, 3.6 Hz, 1H), 1.50 (q, J = 11.9 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.34 - 1.26 (m, 3H). LRMS (ESI+) calculated C 26 H 27 N5O4S [M+H]+: 506.1857, found: 506.36

[0513]

[0514] 20dj (34 mg, 37 %) 1H NMR (400 MHz, CDCl3) δ9.22 (s, 1H), 8.07 (d, J = 5.4 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.3, 2.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 5.2 Hz, 1H), 5.40 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.34 - 4.25 (m, 4H), 4.12 (ddt, J = 14.1, 6.7, 3.6 Hz, 1H), 4.03 (dt, J = 11.8, 3.5 Hz, 2H), 3.63 (t, J = 11.4 Hz, 2H), 2.15 - 2.06 (m, 2H), 1.63 (dtd, J = 12.9, 11.0, 4.3 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). LRMS (ESI+) calculated C 25 H 25 N5O5S [M+H]+: 508.1649, found: 508.16

[0515]

[0516] 20ei (195 mg, 75 %) 1H NMR (400 MHz, CDCl3) δ9.19 (s, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.52 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.20 (t, J = 8.7 Hz, 1H), 6.45 (d, J = 5.3 Hz, 1H), 5.26 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.88 (pd, J = 6.8, 4.0 Hz, 1H), 2.12 (dd, J = 12.9, 4.1 Hz, 2H), 1.81 (dt, J = 13.2, 3.9 Hz, 2H), 1.69 (dt, J = 13.0, 4.1 Hz, 1H), 1.57 - 1.48 (m, 1H), 1.42 (t, J = 7.1 Hz, 3H), 1.37 - 1.23 (m, 4H). LRMS (ESI+) calculated C 24 H 23 ClFN5O2S [M+H]+: 500.1318, found: 500.26

[0517]

[0518] 20ej (113 mg, 42 %) 1H NMR (400 MHz, CDCl3) δ9.18 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.73 (dd, J = 7.1, 2.2 Hz, 1H), 7.51 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.20 (t, J = 8.6 Hz, 1H), 6.49 (d, J = 5.3 Hz, 1H), 5.35 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 4.16 - 4.09 (m, 1H), 4.04 (ddd, J = 12.2, 4.0, 1.9 Hz, 2H), 3.70 - 3.58 (m, 2H), 2.14 - 2.08 (m, 2H), 1.65 (dtd, J = 13.0, 11.0, 4.4 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). LRMS (ESI+) calculated C 23 H 21 ClFN5O3S [M+H]+: 502.1111, found: 502.34

[0519]

[0520] 5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Arylimidazo[2,1-b]thiazole-2-carboxamide (21ah~ak, 22ah~ak, 21bi~bJ, 21di~dJ, 21ei~eJ, 22bi~bJ, 22di~dJ, 22ei~eJ)

[0521]

[0522] Compound 20ah (35 mg, 0.074 mmol) was dissolved in MeOH (0.2 ml), 7 N NH3 in MeOH (160 μl, 7.4 mmol) was added, and the mixture was stirred at room temperature for 48 h. After completion of the reaction, the reaction mixture was extracted with EA and washed with H2O and Brine. The extracted reaction mixture was purified by column chromatography with a mobile phase composition of MC:MeOH = 40:1 to obtain compound 21ah (18 mg, 54%).

[0523]

[0524] 21 ah (18 mg, 54%) 1 H NMR (400 MHz, DMSO) δ9.54 (s, 1H), 8.20 (s, 1H), 8.14 - 8.07 (m, 1H), 7.99 (t, J = 9.4 Hz, 4H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.62 - 7.51 (m, 2H), 7.18 (s, 1H), 6.40 (s, 1H), 3.54 (dt, J = 15.8, 5.3 Hz, 4H). LRMS (ESI+) calculated C 23 H 20 N6O2S [M+H]+: 445.1441, found: 445.18

[0525]

[0526] 21 ai (18 mg, 64%) 1H NMR (400 MHz, DMSO-d6) δ9.51 (s, 1H), 8.33 - 8.18 (m, 2H), 8.09 (s, 1H), 7.97 (d, J = 7.6 Hz, 3H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.61 - 7.50 (m, 2H), 6.89 (s, 1H), 6.36 (s, 1H), 3.76 (s, 1H), 1.99 (s, 2H), 1.74 (s, 1H), 1.62 (s, 1H), 1.39 - 1.04 (m, 6H). LRMS (ESI+) calculated C 26 H 24 N6OS [M+H]+: 469.1805, found: 469.28

[0527]

[0528] 21bi (2.7 mg, 57 %) 1 H NMR (400 MHz, CDCl3) δ9.17 (s, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.79 (q, J = 1.0 Hz, 1H), 7.49 (t, J = 0.9 Hz, 2H), 6.47 (d, J = 5.2 Hz, 1H), 5.33 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.87 (dtd, J = 14.3, 7.4, 3.8 Hz, 1H), 2.16 - 2.09 (m, 2H), 1.81 (dp, J = 12.0, 3.9 Hz, 2H), 1.68 (dt, J = 12.8, 3.9 Hz, 1H), 1.49 (q, J = 11.0 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.35 - 1.28 (m, 3H). LRMS (ESI+) calculated C 22 H 20 Cl2N6OS [M+H]+: 487.0869, found: 487.18

[0529]

[0530] 21di (5.3 mg, 56 %) 1H NMR (400 MHz, DMSO-d6) δ9.46 (s, 1H), 8.21 - 8.11 (m, 2H), 7.95 (s, 1H), 7.10 - 7.05 (m, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 4.29 (q, J = 5.0 Hz, 4H), 3.81 - 3.72 (m, 1H), 2.02 - 1.93 (m, 2H), 1.74 (s, 2H), 1.62 (d, J = 12.8 Hz, 1H), 1.36 - 1.13 (m, 5H). LRMS (ESI+) calculated C 24 H 24 N6O3S [M+H]+: 477.1703, found: 477.32

[0531]

[0532] 21ei (5.7 mg, 15 %) 1 H NMR (400 MHz, DMSO-d6) δ9.43 (s, 1H), 8.33 - 8.13 (m, 2H), 7.97 (s, 1H), 7.82 (dd, J = 7.3, 2.2 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.51 (s, 1H), 6.94 (s, 1H), 6.58 - 6.23 (m, 1H), 3.82 - 3.59 (m, 1H), 2.06 - 1.90 (m, 2H), 1.81 - 1.55 (m, 3H), 1.40 - 1.12 (m, 5H). LRMS (ESI+) calculated C 22 H 20 ClFN6OS [M+H]+: 471.1165, found: 471.26

[0533]

[0534] 21 aJ (16 mg, 49 %) 1H NMR (400 MHz, DMSO-d6) δ9.55 - 8.99 (m, 1H), 8.33 - 8.05 (m, 3H), 8.02 - 7.91 (m, 3H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.57 (qd, J = 7.1, 3.5 Hz, 2H), 7.41 - 6.89 (m, 1H), 6.58 - 6.34 (m, 1H), 4.01 - 3.73 (m, 3H), 3.41 (s, 1H), 2.04 - 1.78 (m, 2H), 1.65 - 1.43 (m, 2H). LRMS (ESI+) calculated C 25 H 22 N6O2S [M+H]+: 485.1754, found: 485.19

[0535]

[0536] 21bj (1.4 mg, 30 %) 1 H NMR (400 MHz, DMSO-d6) δ9.37 (s, 1H), 9.10 (s, 1H), 8.25 (s, 2H), 7.90 - 7.85 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (s, 1H), 6.52 (s, 1H), 4.01 - 3.79 (m, 4H), 3.66 - 3.57 (m, 1H), 1.95 - 1.77 (m, 2H), 1.61 - 1.46 (m, 2H). LRMS (ESI+) calculated C 21 H 18 Cl2N6O2S [M+H]+: 489.0662, found: 489.16

[0537]

[0538] 21dj (4.7 mg, 49 %) 1H NMR (400 MHz, DMSO-d6) δ9.43 (s, 1H), 9.08 (s, 1H), 8.17 (d, J = 5.5 Hz, 1H), 7.93 (s, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.04 (dd, J = 8.2, 2.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.47 (s, 1H), 4.33 - 4.23 (m, 4H), 4.08 - 3.97 (m, 1H), 3.94 - 3.84 (m, 2H), 3.46 - 3.37 (m, 2H), 2.01 - 1.87 (m, 2H), 1.63 - 1.47 (m, 2H). LRMS (ESI+) calculated C 23 H 22 N6O4S [M+H]+: 479.1496, found: 479.31

[0539]

[0540] 21ej (8.1 mg, 22 %) 1 H NMR (400 MHz, DMSO-d6) δ9.40 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 12.4 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.45 (s, 1H), 4.47 - 4.43 (m, 1H), 4.34 - 4.24 (m, 4H), 2.85 (d, J = 4.7 Hz, 3H), 2.01 - 1.93 (m, 2H), 1.82 - 1.69 (m, 4H), 1.66 - 1.59 (m, 2H), 1.50 - 1.45 (m, 4H) LRMS (ESI+) calculated C 21 H 18 ClFN6O2S [M+H]+: 473.0958, found: 473.25

[0541]

[0542] 21 ak (7 mg, 37 %)1 H NMR (400 MHz, DMSO) δ9.52 (s, 1H), 8.29 - 8.19 (m, 2H), 8.10 (s, 1H), 7.98 (d, J = 8.0 Hz, 4H), 7.72 (dd, J = 8.5, 1.7 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.21 (s, 1H), 6.39 (s, 1H), 3.25 (t, J = 6.3 Hz, 2H), 1.16 - 1.07 (m, 1H), 0.53 - 0.39 (m, 2H), 0.32 - 0.17 (m, 2H). LRMS (ESI+) calculated C 24 H 20 N6OS [M+H]+: 455.1649, found: 455.26

[0543]

[0544] 22 ah (14 mg, 36 %) 1 H NMR (400 MHz, CDCl3) δ9.25 (s, 1H), 8.18 - 8.11 (m, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.91 - 7.82 (m, 3H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.56 - 7.47 (m, 2H), 7.07 (s, 1H), 6.54 (d, J = 5.4 Hz, 1H), 5.82 - 5.62 (m, 2H), 3.72 (dd, J = 12.0, 5.0 Hz, 4H), 3.45 (s, 3H), 3.00 (d, J = 4.7 Hz, 3H). LRMS (ESI+) calculated C 24 H 22 N6O2S [M+H]+: 459.1598, found: 459.19

[0545]

[0546] 22 ai (14 mg, 37 %) 1H NMR (400 MHz, CDCl3) δ9.12 (s, 1H), 8.18 - 8.15 (m, 1H), 8.02 (d, J = 5.3 Hz, 1H), 7.93 - 7.83 (m, 3H), 7.71 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 - 7.50 (m, 2H), 6.49 (d, J = 5.3 Hz, 1H), 6.27 (s, 1H), 3.94 - 3.85 (m, 1H), 3.03 (d, J = 4.8 Hz, 3H), 2.12 (dd, J = 12.9, 3.7 Hz, 2H), 1.89 - 1.77 (m, 4H), 1.75 - 1.67 (m, 1H), 1.53 - 1.41 (m, 2H), 1.37 - 1.31 (m, 1H). LRMS (ESI+) calculated C 27 H 26 N6OS [M+H]+: 483.1962, found: 483.22

[0547]

[0548] 22bi (2.9 mg, 41 %) 1 H NMR (400 MHz, DMSO-d6) δ9.33 (s, 1H), 8.78 (s, 1H), 8.24 (s, 1H), 7.89 - 7.86 (m, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.03 - 6.91 (m, 1H), 6.59 - 6.37 (m, 1H), 3.80 - 3.66 (m, 1H), 2.84 (s, 3H), 2.04 - 1.86 (m, 2H), 1.80 - 1.52 (m, 4H), 1.42 - 1.23 (m, 4H). LRMS (ESI+) calculated C 23 H 22 Cl2N6OS [M+H]+: 501.1026, found: 501.11

[0549]

[0550] 22di (1.1 mg, 22 %) 1H NMR (400 MHz, DMSO-d6) δ9.40 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.06 (d, J = 12.4 Hz, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.45 (s, 1H), 4.47 - 4.43 (m, 1H), 4.34 - 4.24 (m, 4H), 2.85 (d, J = 4.7 Hz, 3H), 2.01 - 1.93 (m, 2H), 1.82 - 1.69 (m, 4H), 1.66 - 1.59 (m, 2H), 1.50 - 1.45 (m, 4H). LRMS (ESI+) calculated C 25 H 26 N6O3S [M+H]+: 491.1860, found: 491.25

[0551]

[0552] 22ei (8.2 mg, 24 %) 1 H NMR (400 MHz, DMSO-d6) δ9.35 (s, 1H), 8.73 (s, 1H), 8.21 (s, 1H), 7.81 (dd, J = 7.2, 2.1 Hz, 1H), 7.62 (ddd, J = 8.6, 4.8, 2.2 Hz, 1H), 7.55 - 7.44 (m, 1H), 6.90 (s, 1H), 6.54 - 6.28 (m, 1H), 3.81 - 3.64 (m, 1H), 2.83 (s, 3H), 2.02 - 1.88 (m, 2H), 1.81 - 1.67 (m, 2H), 1.38 - 1.11 (m, 6H). LRMS (ESI+) calculated C 23 H 22 ClFN6OS [M+H]+: 485.1321, found: 485.28

[0553]

[0554] 22 aJ (10 mg, 38 %) 1H NMR (400 MHz, CDCl3) δ9.15 (s, 1H), 8.16 (t, J = 1.1 Hz, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.94 - 7.83 (m, 3H), 7.70 (dd, J = 8.4, 1.7 Hz, 1H), 7.61 - 7.49 (m, 2H), 6.54 (d, J = 5.3 Hz, 1H), 6.37 (d, J = 4.8 Hz, 1H), 5.34 (d, J = 5.4 Hz, 1H), 4.12 - 4.03 (m, 3H), 3.67 - 3.56 (m, 2H), 3.05 (d, J = 4.8 Hz, 3H), 1.83 - 1.66 (m, 4H). LRMS (ESI+) calculated C 26 H 24 N6O2S [M+H]+: 485.1754, found: 485.22

[0555]

[0556] 22bj (2.3 mg, 29 %) 1 H NMR (400 MHz, DMSO-d6) δ9.28 (s, 1H), 9.05 (s, 1H), 8.79 (s, 1H), 8.06 (dd, J = 3.2, 2.0 Hz, 1H), 7.88 (dd, J = 8.5, 1.9 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 6.47 (s, 1H), 4.03 - 3.81 (m, 5H), 1.70 - 1.59 (m, 2H), 1.56 - 1.46 (m, 2H). LRMS (ESI+) calculated C 22 H 20 Cl2N6O2S [M+H]+: 503.0819, found: 503.38

[0557]

[0558] 22dj (2.4 mg, 22 %) 1H NMR (400 MHz, DMSO-d6) δ9.36 (s, 1H), 9.04 (s, 1H), 8.72 (s, 1H), 8.18 (d, J = 5.3 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.48 (s, 1H), 4.29 (dt, J = 5.2, 2.6 Hz, 4H), 4.06 - 3.97 (m, 1H), 3.90 (d, J = 12.3 Hz, 2H), 3.38 (d, J = 11.9 Hz, 2H), 2.85 (s, 3H), 1.96 - 1.87 (m, 2H), 1.63 - 1.49 (m, 2H). LRMS (ESI+) calculated C 24 H 24 N6O4S [M+H]+: 493.1653, found: 493.24

[0559]

[0560] 22eJ (10 mg, 35 %) 1 H NMR (400 MHz, DMSO-d6) δ9.31 (s, 1H), 8.74 (s, 1H), 8.23 (s, 1H), 7.81 (dd, J = 7.3, 2.1 Hz, 1H), 7.62 (ddd, J = 8.6, 4.8, 2.2 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.20 - 6.99 (m, 1H), 6.41 (s, 1H), 4.02 - 3.79 (m, 4H), 3.41 - 3.37 (m, 1H), 2.83 (d, J = 4.3 Hz, 3H), 1.94 - 1.88 (m, 2H), 1.65 - 1.47 (m, 2H). LRMS (ESI+) calculated C 22 H 20 ClFN6O2S [M+H]+: 487.1114, found: 487.27

[0561]

[0562] 22 ak (15 mg, 61 %) 1H NMR (400 MHz, DMSO-d6) δ9.45 (s, 1H), 8.76 (s, 1H), 8.22 (d, J = 1.7 Hz, 1H), 8.13 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 8.0 Hz, 3H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.57 (td, J = 6.6, 3.8 Hz, 2H), 6.41 (s, 1H), 3.25 (t, J = 6.3 Hz, 2H), 2.86 (s, 3H), 1.12 (s, 1H), 0.54 - 0.40 (m, 2H), 0.30 - 0.15 (m, 2H).

[0563] LRMS (ESI+) calculated C 25 H 22 N6OS [M+H]+: 455.1649, found: 455.28

[0564]

[0565] 5.2. 6-Aryl imidazo[2,1-b]oxazole-2-carboxilic acid derivative (Scheme 2)

[0566] Ethyl 2-aminooxazole-5-carboxylate (34)

[0567]

[0568] Ethyl 2-chloroacetate (31) 5.00 g (40.7 mmol, 1.00 mol eq) and ethyl formate (32) 3.02 g (40.7 mmol, 1.00 mol eq) were dissolved in 80 mL of abs THF, and the reaction vessel was replaced with argon gas. At -78°C, 80 mL of 1 M tBuOK in THF (81.4 mmol, 2.00 mol eq) was added dropwise for 1 h. The mixture was stirred at -78°C for 1 h, then raised to 0°C and stirred for 4 h. The pH was adjusted to 2 with 2 M HCl at 0°C. The organic layer was extracted with diethyl ether (Et2O), and then washed with brine. Afterwards, the moisture was removed with anhydrous magnesium sulfate (MgSO4), and the solvent was evaporated to obtain the liquid product ethyl 2-chloro-3-oxopropanoate 33 (6.8 g, 45 mmol).

[0569] Compound 33 (45 mmol, 1.00 mol eq) and 2.7 g (45 mmol, 1.00 mol eq) of urea were dissolved in 60 mL of water and stirred at 100°C for 1 hour. After the reaction was completed, cooled to room temperature and neutralized with saturated NaHCO3 aqueous solution. The organic layer was extracted using ethyl acetate (EtOAc), dried with anhydrous sodium sulfate (Na2SO4), and the solvent was evaporated. The residue was separated and purified by column chromatography (MC:MeOH=50:1) to obtain compound 34 (2.08 g, 31%).

[0570]

[0571] 34 (2.08 g, 31%). 1 H NMR (400 MHz, DMSO-d6) δ7.56 (s, 1H), 7.54 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H).. ; LRMS (ESI+) calculated for [M+H]+: 157.06, found 157.07.

[0572]

[0573] Ethyl 6-Arylimidazo[2,1-b]oxazole-2-carboxylate (37a-d)

[0574]

[0575] Compound 34 (1 g, 6.4 mmol) obtained from the previous reaction was dissolved in abs THF (6 ml) under an Ar gas substitution state. 2-bromo-1-(naphthalen-2-yl)ethan-1-one (1.9 mmol) was dissolved in abs ACN (10 ml) and slowly added to the above solution, and stirred at 60°C for 60 hours. After confirming the completion of the reaction, cool in an ice bath and filter using cold ACN to obtain solid compound 36a (2.2 g, 5.4 mmol) on the filter. Compound 36a (2.2 g, 5.4 mmol) was dissolved in 9 mL of abs toluene and replaced with argon gas. 11 mL (10.8 mmol) of TiCl4 (1 M in toluene) was slowly added at 0°C. After dropwise, the temperature was raised to 110°C and stirred for 16 hours. After the reaction was completed, cool to room temperature, add ice water and toluene, and stir for 1 hour. Adjust the pH to 7 with Na2CO3, add EA, and stir for 1 hour. The organic layer was extracted using EA, and the organic layer was washed with water. The moisture was removed with anhydrous sodium sulfate (Na2SO4), the solvent was evaporated, and the crude was dissolved using a small amount of MC and filtered to obtain the solid compound 37a (1.03 g, 52%) on the filter.

[0576]

[0577] 37a (1.03 g, 52%) ; 1 H NMR (400 MHz, DMSO-d6) δ8.77 (s, 1H), 8.35 (s, 1H), 8.00 - 7.95 (m, 2H), 7.90 (d, J = 18.0 Hz, 3H), 7.48 (s, 2H), 4.33 (s, 2H), 1.31 (s, 3H). ;LRMS (ESI+) calculated for C 18 H 14 N2O3[M+H]+: 307.11, found 307.14.

[0578] 37b (1.76 g, 68%). 1 H NMR (400 MHz, Chloroform-d) δ7.96 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.4, 2.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). ; LRMS (ESI+) calculated for C 14 H 10 Cl2N2O3[M+H]+: 325.01, found 325.05.

[0579] 37c (1.49 g, 75%). 1 H NMR (400 MHz, Chloroform-d) δ7.96 (s, 1H), 7.85 (dd, J = 7.1, 2.2 Hz, 1H), 7.65 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.31 (s, 1H), 7.16 (t, J = 8.7 Hz, 1H), 4.43 (t, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).; LRMS (ESI+) calculated for C 14 H 10 ClFN2O3[M+H]+: 309.04, found 309.03.

[0580] 37d (1.90 g, 60%). 1 H NMR (400 MHz, Chloroform-d) δ7.96 (s, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 2.1 Hz, 1H), 7.32 - 7.30 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.32 (s, 4H), 1.45 (t, J = 7.1 Hz, 3H).; LRMS (ESI+) calculated for C 16 H14 N2O5[M+H]+: 315.10, found 315.10.

[0581] Ethyl 5-(2-(methylthio)pyrimidin-4-yl)-6-Aryl imidazo[2,1-b]oxazole-2-carboxylate (38a~d)

[0582]

[0583] Compound 37a (1.28 g, 4.18 mmol) was dissolved in DMF (19 ml), and Pd(OAc)2 (375 mg, 1.67 mmol), Cs2CO3 (2.04 g, 6.27 mmol), PPh3 (876 mg, 3.34 mmol), and 4-chloro-2-(methylthio)pyrimidine (0.74 mL, 6.27 mmol) were added at 80°C and stirred for 2 hours under Ar gas purification. After confirming the completion of the reaction, the organic layer was filtered through celite and extracted using EA, and then washed with brine. The organic layer was dried over anhydrous sodium sulfate (Na2SO4), the solvent was evaporated, and the residue was separated and purified by column chromatography (EA:Hex=1:7) to obtain compound 37a (940 mg, 52%).

[0584]

[0585] 38a (940 mg, 52%). 1 H NMR (400 MHz, DMSO-d6) δ8.78 (s, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.26 (d, J = 1.7 Hz, 1H), 8.06 - 7.98 (m, 3H), 7.75 (dd, J = 8.5, 1.8 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.06 (d, J = 5.4 Hz, 1H), 4.42 (d, J = 7.0 Hz, 2H), 3.29 (d, J = 0.8 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H).; LRMS (ESI+) calculated for C23 H 18 N4O3S [M+H]+: 431.12, found 431.08.

[0586] 38b (321 mg, 57 %). 1 H NMR (400 MHz, Chloroform-d) δ8.69 (s, 1H), 8.34 (d, J = 5.4 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 6.94 (d, J = 5.4 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.64 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).; LRMS (ESI+) calculated for C 19 H 14 Cl2N4O3S [M+H]+: 449.02, found 449.03.

[0587] 38c (509 mg, 23 %). 1 H NMR (400 MHz, Chloroform-d) δ8.70 (s, 1H), 8.33 (d, J = 5.4 Hz, 1H), 7.73 (dd, J = 7.0, 2.2 Hz, 1H), 7.52 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.24 (t, J = 8.7 Hz, 1H), 6.91 (d, J = 5.4 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H).; LRMS (ESI+) calculated for C 19 H 14 ClFN4O3S [M+H]+: 433.05, found 433.08.

[0588] 38d (400 mg, 15 %). 1H NMR(400 MHz, DMSO-d6) δ8.70 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.13 - 7.08 (m, 2H), 7.00 - 6.94 (m, 1H), 4.40 (q, J = 7.1 Hz, 3H), 4.31 (td, J = 5.2, 3.6 Hz, 6H), 1.35 (t, J = 7.1 Hz, 3H).; LRMS (ESI+) calculated for C 21 H 18 N4O5S [M+H]+: 439.11, found 439.14.

[0589] Ethyl 5-(2-((1-(tert-butoxycarbonyl)-3l3-piperidin / pyrrolidin-3-yl)amino)pyrimidin-4-yl)-6-Aryl imidazo [2,1-b]oxazole-2-carboxylate (40a, 41a, 42a~d, 43a~d)

[0590]

[0591] Compound 38a (830 mg, 1.93 mmol) obtained in the previous experiment was dissolved in H2O (3 ml) and MeOH (3 ml), and then Oxone (3.6 g 5.79 mmol) was added and stirred at room temperature for 20 hours. After evaporating the reaction solvent using a rotary evaporator, the reaction mixture was extracted with MC, and the organic layer was washed with NaHCO3. After removing moisture with anhydrous sodium sulfate (Na2SO4) and concentrating the solvent, 969 mg of 39a was obtained. Compound 39a (243 mg, 0.57 mmol) was dissolved in DMSO (1.5 ml), and tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (212 mg, 1.14 mmol) and DIPEA (0.30 ml, 1.71 mmol) were added and stirred at room temperature for 1 hour. After confirming the completion of the reaction, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with water and brine. After removing moisture with anhydrous sodium sulfate (Na2SO4) and concentrating the solvent, the residue was purified by column chromatography using a mobile phase of EA:Hex (1:2) to obtain compound 40a (208 mg, 63%).

[0592]

[0593] 40a (208 mg, 63%). 1H NMR (400 MHz, Chloroform-d) δ8.67 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.07 (s, 1H), 7.93 - 7.81 (m, 3H), 7.74 (dd, J = 8.4, 1.7 Hz, 1H), 7.57 - 7.49 (m, 2H), 6.57 (d, J = 5.3 Hz, 1H), 4.79 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.41 (s, 1H), 3.92 (s, 1H), 3.82 - 3.69 (m, 2H), 3.55 (d, J = 11.3 Hz, 1H), 2.38 - 2.28 (m, 1H), 1.70 (s, 1H), 1.47 (d, J = 4.7 Hz, 9H), 1.44 (d, J = 7.2 Hz, 3H).; LRMS (ESI+) calculated for C 31 H 32 N6O5[M+H]+: 569.25, found 569.25.

[0594]

[0595] 41a (156 mg, 47%). 1 H NMR (400 MHz, Chloroform-d) δ8.67 (s, 1H), 8.17 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 5.3 Hz, 1H), 7.94 - 7.82 (m, 3H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 - 7.49 (m, 2H), 6.57 (d, J = 5.3 Hz, 1H), 4.79 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.42 (s, 1H), 3.92 (s, 1H), 3.75 (s, 2H), 3.55 (d, J = 11.2 Hz, 1H), 2.39 - 2.28 (m, 1H), 1.68 (s, 1H), 1.47 (d, J = 4.5 Hz, 9H), 1.44 (d, J = 7.2 Hz, 3H).; LRMS (ESI+) calculated for C 31 H32 N6O5[M+H]+: 569.25, found 569.25.

[0596]

[0597] 42a (208 mg, 82%). 1 H NMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H), 8.17 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 5.4 Hz, 1H), 7.95 - 7.84 (m, 3H), 7.74 (dd, J = 8.4, 1.7 Hz, 1H), 7.59 - 7.48 (m, 2H), 6.61 (d, J = 5.3 Hz, 1H), 5.24 (d, J = 6.9 Hz, 1H), 4.47 (qd, J = 7.1, 1.8 Hz, 2H), 4.08 - 3.98 (m, 1H), 3.56 (s, 1H), 3.33 (s, 2zH), 1.87 - 1.77 (m, 1H), 1.76 - 1.58 (m, 4H), 1.46 (d, J = 0.7 Hz, 3H), 1.45 - 1.43 (m, 9H).; LRMS (ESI+) calculated for C 32 H 34 N6O5[M+H]+: 583.27, found 583.27.

[0598]

[0599] 42b (197 mg, 80%). 1H NMR (400 MHz, Chloroform-d) δ8.63 (s, 1H), 8.14 (d, J = 5.4 Hz, 1H), 7.79 (dd, J = 1.6, 0.7 Hz, 1H), 7.54 - 7.47 (m, 2H), 6.57 (d, J = 5.3 Hz, 1H), 5.29 (s, 1H), 4.47 (qd, J = 7.1, 1.4 Hz, 2H), 4.01 (s, 1H), 3.86 (s, 1H), 3.55 (s, 1H), 3.34 (s, 1H), 2.06 (s, 1H), 1.81 (s, 1H), 1.70 - 1.62 (m, 3H), 1.47 - 1.38 (m, 12H).; LRMS (ESI+) calculated for C 28 H 30 Cl2N6O5[M+H]+: 601.17, found 601.18.

[0600] 42c (197 mg, 80%). 1 H NMR (400 MHz, Chloroform-d) δ 8.65 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.73 (dd, J = 7.0, 2.2 Hz, 1H), 7.53 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.22 (t, J = 8.7 Hz, 1H), 6.54 (d, J = 5.3 Hz, 1H), 5.40 (s, 1H), 4.46 (qd, J = 7.1, 1.7 Hz, 2H), 4.01 (qd, J = 7.8, 4.0 Hz, 1H), 3.89 (s, 1H), 3.57 (s, 1H), 3.32 (s, 2H), 2.12 - 2.06 (m, 1H), 1.82 (d, J = 8.1 Hz, 1H), 1.74 - 1.61 (m, 2H), 1.46 (s, 3H), 1.44 - 1.35 (m, 9H); LRMS (ESI+) calculated for C 28 H 30 Cl2N6O5[M+H]+: 585.20, found 585.17.

[0601]

[0602] 42d (58 mg, 71%). 1 H NMR (400 MHz, Chloroform-d) δ10.15 (s, 1H), 8.53 (s, 1H), 7.72 (s, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 6.6 Hz, 1H), 4.48 (ddd, J = 11.6, 5.9, 2.5 Hz, 1H), 4.42 (dd, J = 10.8, 7.1 Hz, 1H), 4.36 - 4.20 (m, 5H), 4.01 - 3.93 (m, 1H), 3.87 (s, 1H), 3.09 - 2.76 (m, 2H), 2.22 (s, 1H), 1.92 (d, J = 13.2 Hz, 1H), 1.75 (s, 1H), 1.69 - 1.60 (m, 1H), 1.43 (t, J = 7.2 Hz, 12H).; LRMS (ESI+) calculated for C 30 H 34 N6O7[M+H]+: 591.26, found 591.23.

[0603]

[0604] 43a (208 mg, 95%). 1H NMR (400 MHz, Chloroform-d δ8.70 (s, 1H), 8.17 (d, J = 1.7 Hz, 1H), 8.02 (d, J = 5.4 Hz, 1H), 7.95 - 7.85 (m, 3H), 7.73 (dd, J = 8.4, 1.7 Hz, 1H), 7.59 - 7.49 (m, 2H), 6.60 (d, J = 5.4 Hz, 1H), 5.27 (d, J = 7.5 Hz, 1H), 4.47 (qd, J = 7.1, 1.8 Hz, 2H), 4.03 (dt, J = 7.5, 3.8 Hz, 1H), 3.57 (s, 1H), 3.33 (s, 2H), 1.83 (d, J = 7.7 Hz, 1H), 1.74 - 1.59 (m, 4H), 1.46 (d, J = 7.1 Hz, 3H), 1.44 - 1.35 (m, 9H).; LRMS (ESI+) calculated for C 32 H 34 N6O5[M+H]+: 583.27, found 583.27.

[0605]

[0606] 43b (160 mg, 66%). 1H NMR (400 MHz, Chloroform-d) δ8.60 (s, 1H), 8.17 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.57 (d, J = 5.8 Hz, 1H), 6.18 (s, 1H), 4.72 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 4.28 (d, J = 12.7 Hz, 1H), 3.99 (d, J = 8.7 Hz, 1H), 3.76 (s, 1H), 3.69 (d, J = 5.5 Hz, 1H), 2.07 - 2.00 (m, 1H), 1.91 (ddq, J = 13.5, 6.7, 3.5 Hz, 1H), 1.77 - 1.65 (m, 2H), 1.47 - 1.37 (m, 12H).; LRMS (ESI+) calculated for C 28 H 30 Cl2N6O5[M+H]+: 601.17, found 601.18.

[0607]

[0608] 43c (163 mg, 85%). 1H NMR (400 MHz, Chloroform-d) δ8.56 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.75 (dd, J = 7.1, 2.1 Hz, 1H), 7.54 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.20 (t, J = 8.7 Hz, 1H), 6.47 (d, J = 5.2 Hz, 1H), 4.66 (d, J = 7.9 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.26 (dd, J = 12.9, 3.6 Hz, 1H), 4.00 (ddd, J = 13.5, 6.6, 3.2 Hz, 1H), 3.75 (s, 1H), 3.65 (td, J = 8.2, 3.9 Hz, 1H), 3.56 (dd, J = 12.8, 7.4 Hz, 1H), 1.98 (d, J = 3.1 Hz, 1H), 1.82 (s, 1H), 1.72 - 1.65 (m, 2H), 1.45 - 1.40 (m, 12H). ; LRMS (ESI+) calculated for C 28 H 30 ClFN6O5[M+H]+: 585.20, found 585.17.

[0609]

[0610] 43d (96 mg, 93%). 1H NMR (400 MHz, Chloroform-d) δ8.59 (s, 1H), 8.15 (d, J = 5.5 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 8.3, 2.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 5.5 Hz, 1H), 4.69 (d, J = 7.2 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.36 - 4.26 (m, 5H), 4.22 (d, J = 13.0 Hz, 1H), 3.81 - 3.61 (m, 3H), 2.04 - 1.95 (m, 1H), 1.85 (dd, J = 7.0, 3.6 Hz, 1H), 1.74 - 1.65 (m, 2H), 1.45 - 1.40 (m, 12H).; LRMS (ESI+) calculated for C 30 H 34 N6O7[M+H]+: 591.26, found 591.23.

[0611]

[0612] Ethyl 5-(2-((1-(cyclopropanecarbonyl)-3l3-piperidin / pyrrolidin-3-yl)amino)pyrimidin-4-yl)-6-Aryl imidazo[2,1-b]oxazole-2-carboxylate (44ae~46ae, 46be~de, 47ae~47de, 48af, 48bf, 49af, 49bf)

[0613]

[0614] Compound 40a (200 mg, 0.35 mmol) was dissolved in MC (1.4 ml), and TFA (0.35 ml) was added dropwise at 0°C. The mixture was slowly warmed to room temperature and stirred for 50 minutes. After confirming the completion of the reaction, the solvent was evaporated using a rotary evaporator, and the reaction mixture after evaporation was dissolved in THF (5 ml), followed by adding DIPEA (61 μl, 0.68 mmol) and cyclopropanecarbonyl chloride (0.26 ml, 1.52 mmol), and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with water and brine. The moisture was removed with anhydrous sodium sulfate (Na2SO4), the solvent was concentrated, and the residue was purified by column chromatography using a mobile phase of MC:MeOH (50:1) to obtain compound 44ae (99 mg, 51%).

[0615]

[0616] 44ae (99 mg, 51%) 1H NMR (400 MHz, CDCl3) δ8.56 (s, 1H), 8.15 (s, 1H), 8.05 (d, J = 5.4 Hz, 1H), 7.92 - 7.84 (m, 3H), 7.71 (dd, J = 8.5, 1.7 Hz, 1H), 7.56 - 7.50 (m, 2H), 6.54 (d, J = 5.4 Hz, 1H), 6.50 (d, J = 7.3 Hz, 1H), 4.73 - 4.61 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.82 (dd, J = 11.1, 5.9 Hz, 1H), 3.75 - 3.63 (m, 2H), 3.55 (d, J = 9.7 Hz, 1H), 2.28 (td, J = 13.6, 7.9 Hz, 1H), 2.00 (dd, J = 11.8, 6.3 Hz, 1H), 1.41 (t, J = 7.1 Hz, 3H), 1.06 - 1.00 (m, 1H), 0.99 - 0.93 (m, 2H), 0.72 (dt, J = 10.0, 8.4 Hz, 2H).; LRMS (ESI+) calculated for C 30 H 28 N6O4[M+H]+: 537.22, found 537.22.

[0617]

[0618] 45ae (103 mg, 86%) 1H NMR (400 MHz, CDCl3) δ8.57 (s, 1H), 8.16 (s, 1H), 8.05 (d, J = 5.4 Hz, 1H), 7.92 - 7.80 (m, 3H), 7.71 (dd, J = 8.5, 1.6 Hz, 1H), 7.57 - 7.49 (m, 2H), 6.55 (d, J = 5.4 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 4.75 - 4.65 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.83 (dd, J = 11.0, 5.8 Hz, 1H), 3.76 - 3.62 (m, 2H), 3.55 (d, J = 9.4 Hz, 1H), 2.28 (td, J = 13.5, 7.9 Hz, 1H), 2.00 (dd, J = 11.8, 6.1 Hz, 1H), 1.41 (t, J = 7.1 Hz, 3H), 1.03 (dt, J = 7.0, 4.3 Hz, 1H), 0.98 (d, J = 3.0 Hz, 2H), 0.72 (dt, J = 9.5, 8.2 Hz, 2H).; LRMS (ESI+) calculated for C 30 H 28 N6O4[M+H]+: 537.22, found 537.22.

[0619]

[0620] 46ae (36 mg, 68%) 1H NMR (400 MHz, DMSO-d6) δ9.35 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.08 (s, 1H), 8.04 - 7.97 (m, 3H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.62 - 7.55 (m, 2H), 6.42 (s, 1H), 4.43 (s, 2H), 4.29 - 4.10 (m, 1H), 3.81 (s, 1H), 3.25 (d, J = 17.1 Hz, 1H), 3.13 (s, 1H), 3.01 - 2.87 (m, 1H), 2.67 - 2.56 (m, 1H), 1.82 (s, 2H), 1.55 (s, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.23 (s, 1H), 0.70 (s, 4H).; LRMS (ESI+) calculated for C 31 H 30 N6O4[M+H]+: 551.24, found 551.24.

[0621]

[0622] 46be (197 mg, 80%); 1 H NMR (400 MHz, DMSO-d6) δ9.28 (s, 1H), 8.17 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.66 - 7.60 (m, 1H), 6.44 (s, 1H), 4.41 (s, 3H), 4.26 - 4.08 (m, 1H), 3.78 (s, 1H), 3.29 - 2.87 (m, 2H), 2.63 - 2.51 (m, 1H), 2.07 (d, J = 13.9 Hz, 1H), 1.90 - 1.71 (m, 2H), 1.53 (s, 2H), 1.35 (q, J = 5.6 Hz, 3H), 0.70 (s, 4H).; LRMS (ESI+) calculated for C 27 H 26 Cl2N6O4[M+H]+: 569.15 , found 569.15.

[0623]

[0624] 46ce (76 mg, 45%); 1 H NMR (400 MHz, Chloroform-d) δ8.65 (s, 1H), 8.12 (s, 1H), 7.73 (dd, J = 7.0, 2.1 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.22 (t, J = 8.6 Hz, 1H), 6.54 (s, 1H), 5.49 (s, 1H), 4.54 - 4.44 (m, 2H), 4.09 (d, J = 16.7 Hz, 2H), 3.84 (s, 1H), 3.57 - 3.31 (m, 2H), 2.03 (d, J = 9.8 Hz, 1H), 1.78 (s, 2H), 1.45 (t, J = 7.1 Hz, 3H), 1.01 (s, 2H), 0.83 - 0.56 (m, 4H).; LRMS (ESI+) calculated for C 27 H 26 FClN6O4[M+H]+: 553.18 , found 553.23.

[0625]

[0626] 46de (27 mg, 53%); 1H NMR (400 MHz, Chloroform-d) δ8.66 (s, 1H), 8.08 (s, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 8.3, 2.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.70 (s, 1H), 5.33 (s, 1H), 4.46 (tq, J = 7.2, 3.0 Hz, 2H), 4.31 (tt, J = 5.4, 2.9 Hz, 4H), 4.06 (s, 1H), 3.86 (dt, J = 13.0, 5.2 Hz, 1H), 3.56 - 3.26 (m, 2H), 2.14 (s, 1H), 1.76 (s, 5H), 1.44 (t, J = 7.1 Hz, 3H), 1.01 (s, 2H), 0.80 - 0.54 (m, 2H). LRMS (ESI+) calculated for C 29 H 30 N6O6[M+H]+: 559.23 , found 559.30.

[0627]

[0628] 47ae (43 mg, 71%) 1H NMR (400 MHz, CDCl3) δ8.70 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.94 - 7.84 (m, 3H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.57 - 7.48 (m, 2H), 6.61 (s, 1H), 5.35 (d, J = 36.2 Hz, 1H), 4.47 (pt, J = 10.9, 5.4 Hz, 2H), 4.05 (d, J = 19.8 Hz, 1H), 3.87 (ddd, J = 12.8, 5.7, 3.7 Hz, 1H), 3.51 (s, 1H), 3.45 - 3.26 (m, 1H), 2.16 (d, J = 9.9 Hz, 1H), 1.88 (s, 1H), 1.77 (s, 3H), 1.70 - 1.59 (m, 1H), 1.45 (t, J = 7.1 Hz, 3H), 1.05 - 0.95 (m, 2H), 0.71 (d, J = 59.8 Hz, 2H).; LRMS (ESI+) calculated for C 31 H 30 N6O4[M+H]+: 551.24, found 551.24.

[0629] 47be (102 mg, 62%); 1H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 8.17 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.78 - 7.69 (m, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.42 (s, 1H), 6.44 (s, 1H), 4.41 (s, 3H), 4.25 - 4.11 (m, 1H), 3.79 (s, 1H), 3.24 - 2.92 (m, 1H), 2.54 (dd, J = 13.7, 7.0 Hz, 1H), 2.06 (d, J = 13.9 Hz, 1H), 1.83 (d, J = 10.2 Hz, 2H), 1.69 - 1.43 (m, 2H), 1.36 (t, J = 6.9 Hz, 3H), 0.70 (s, 4H).; LRMS (ESI+) calculated for C 27 H 26 Cl2N6O4[M+H]+: 569.15 , found 569.15.

[0630]

[0631] 46ce (117 mg, 75%) 1H NMR (400 MHz, DMSO) δ8.68 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.94 (s, 1H), 7.78 (dd, J = 7.2, 2.1 Hz, 1H), 7.61 (ddd, J = 8.5, 4.8, 2.1 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 6.42 (s, 1H), 4.60 (d, J = 11.0 Hz, 1H), 4.31 (d, J = 12.8 Hz, 1H), 3.73 - 3.61 (m, 1H), 3.14 (t, J = 10.6 Hz, 1H), 3.06 - 2.95 (m, 1H), 1.96 - 1.86 (m, 1H), 1.80 (dd, J = 8.8, 4.3 Hz, 1H), 1.54 (ddd, J = 34.6, 18.1, 8.3 Hz, 3H), 0.69 (d, J = 4.4 Hz, 4H).; LRMS (ESI+) calculated for C 27 H 26 FClN6O4[M+H]+: 553.18 , found 553.23.

[0632]

[0633] 47de (59 mg, 95%) 1H NMR (400 MHz, Chloroform-d) δ8.57 (s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.27 (s, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.11 (dd, J = 8.4, 2.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 5.3 Hz, 1H), 5.92 (d, J = 7.2 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.35 - 4.27 (m, 4H), 3.84 (ddd, J = 14.4, 7.2, 3.9 Hz, 1H), 3.77 - 3.69 (m, 1H), 2.02 - 1.92 (m, 1H), 1.87 - 1.66 (m, 3H), 1.60 (tt, J = 8.3, 4.6 Hz, 1H), 1.43 (t, J = 7.1 Hz, 3H), 1.30 (dq, J = 8.3, 4.2 Hz, 1H), 1.04 (dt, J = 6.6, 3.5 Hz, 1H), 0.95 (d, J = 4.1 Hz, 1H), 0.93 - 0.90 (m, 1H), 0.72 - 0.66 (m, 2H). ; LRMS (ESI+) calculated for C 29 H 30 N6O6[M+H]+: 559.23 , found 559.30.

[0634]

[0635] 48af (77 mg, 87%) 1H NMR (400 MHz, CDCl3) δ8.74 (s, 1H), 8.17 (s, 1H), 8.01 (d, J = 5.4 Hz, 1H), 7.92 - 7.83 (m, 3H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 7.57 - 7.48 (m, 2H), 6.58 (d, J = 5.4 Hz, 1H), 5.88 (s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.09 (s, 1H), 3.60 (d, J = 11.8 Hz, 1H), 3.33 (s, 1H), 3.15 (s, 1H), 2.86 (s, 6H), 2.09 - 1.96 (m, 2H), 1.86 (ddd, J = 13.2, 7.1, 3.6 Hz, 2H), 1.69 - 1.59 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H).; LRMS (ESI+) calculated for C 30 H 31 N7O4[M+H]+: 554.25, found 554.27.

[0636] 48bf (76 mg, 42%) 1 H NMR (400 MHz, DMSO-d6) δ9.28 (s, 1H), 8.16 (s, 1H), 7.89 - 7.82 (m, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 6.43 (s, 1H), 4.41 (d, J = 8.1 Hz, 2H), 3.81 (s, 1H), 3.70 (d, J = 12.6 Hz, 1H), 3.44 (d, J = 12.9 Hz, 1H), 2.74 (s, 6H), 2.58 (d, J = 11.0 Hz, 2H), 2.01 (d, J = 9.9 Hz, 1H), 1.74 (s, 1H), 1.56 - 1.42 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H).; LRMS (ESI+) calculated for C 26 H 27Cl2N7O4[M+H]+: 572.16, found 572.18.

[0637] 49af (76 mg, 43%) 1 H NMR (400 MHz, CDCl3) δ8.74 (s, 1H), 8.17 (s, 1H), 8.01 (d, J = 5.4 Hz, 1H), 7.94 - 7.84 (m, 3H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 - 7.48 (m, 2H), 6.58 (d, J = 5.4 Hz, 1H), 5.83 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.10 (s, 1H), 3.60 (d, J = 12.6 Hz, 1H), 3.33 (s, 1H), 3.17 (s, 2H), 2.86 (s, 6H), 1.90 - 1.77 (m, 2H), 1.72 (s, 1H), 1.68 - 1.61 (m, 1H), 1.48 - 1.41 (m, 3H).; LRMS (ESI+) calculated for C 30 H 31 N7O4[M+H]+: 554.25, found 554.27.

[0638] 49bf (50 mg, 30%) 1H NMR (400 MHz, DMSO-d6) δ9.29 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.38 (s, 1H), 6.44 (s, 1H), 4.42 (d, J = 8.8 Hz, 2H), 3.84 (d, J = 10.8 Hz, 1H), 3.71 (d, J = 12.7 Hz, 1H), 3.48 - 3.41 (m, 1H), 2.74 (s, 6H), 2.68 - 2.54 (m, 2H), 2.02 (d, J = 10.6 Hz, 1H), 1.75 (s, 1H), 1.60 - 1.44 (m, 2H), 1.39 - 1.32 (m, 3H).; LRMS (ESI+) calculated for C 26 H 27 Cl2N7O4[M+H]+: 572.16, found 572.18.

[0639]

[0640] 5-(2-((1-(cyclopropanecarbonyl)-3l3-piperidin / pyrrolidin-3-yl)amino)pyrimidin-4-yl)-N-6-Arylimidazo [2,1-b]oxazole-2-carboxamide (50ae-52ae, 52be~52de, 53ae~de, 54af~54bf, 55af~55bf, 56ae~58ae, 58be~58de, 59ae-de, 60af~60bf, 61af-bf)

[0641]

[0642] Compound 44ae (39 mg, 0.072 mmol) was dissolved in 7N NH3 in MeOH (0.7 ml, 36 mmol) and stirred at room temperature for 1 hour. After confirming the completion of the reaction, the solvent was concentrated using a rotary evaporator, and then the residue was purified by column chromatography using a mobile phase of MC:MeOH (30:1) to obtain compound 50ae (24 mg, 65%).

[0643] 50ae (24 mg, 65 %) 1 H NMR (400 MHz, DMSO) δ8.60 (s, 1H), 8.38 (dd, J = 19.0, 6.8 Hz, 2H), 8.17 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.97 - 7.90 (m, 2H), 7.71 (dd, J = 8.5, 1.6 Hz, 1H), 7.61 - 7.52 (m, 2H), 6.43 (d, J = 5.3 Hz, 1H), 4.39 (s, 1H), 3.82 (d, J = 25.7 Hz, 1H), 3.68 (d, J = 32.3 Hz, 2H), 3.48 (d, J = 32.6 Hz, 1H), 2.20 (s, 1H), 1.96 (d, J = 13.4 Hz, 2H), 1.57 (ddd, J = 12.7, 7.7, 4.7 Hz, 1H), 0.70 (d, J = 4.3 Hz, 2H), 0.66 - 0.59 (m, 2H).; LRMS (ESI+) calculated for C 28 H 25 N7O3[M+H]+: 508.21, found 508.22.

[0644]

[0645] 51ae (21 mg, 55%) 1H NMR (400 MHz, CDCl3) δ8.48 (s, 1H), 8.01 (s, 1H), 7.92 (d, J = 5.2 Hz, 1H), 7.85 (dd, J = 8.0, 4.6 Hz, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.56 - 7.45 (m, 2H), 6.98 (s, 1H), 6.37 (d, J = 5.3 Hz, 1H), 6.20 (s, 1H), 4.62 (s, 1H), 3.78 (s, 1H), 3.70 - 3.60 (m, 2H), 3.56 (d, J = 10.4 Hz, 1H), 2.23 (s, 2H), 2.01 (dd, J = 15.7, 10.2 Hz, 1H), 1.45 (s, 1H), 0.96 (s, 2H), 0.76 - 0.59 (m, 2H). ; LRMS (ESI+) calculated for C 28 H 25 N7O3[M+H]+: 508.21, found 508.22.

[0646]

[0647] 52ae (21 mg, 55%) 1 H NMR (400 MHz, Chloroform-d) δ8.85 (s, 1H), 8.14 (s, 1H), 8.05 - 7.89 (m, 2H), 7.86 (t, J = 7.9 Hz, 2H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 6.52 (d, J = 5.2 Hz, 1H), 5.85 (s, 1H), 5.44 (s, 1H), 4.91 (s, 1H), 4.24 - 3.92 (m, 2H), 3.23 (s, 1H), 2.63 (s, 1H), 2.23 (s, 1H), 1.95 (d, J = 13.0 Hz, 1H), 1.82 (s, 1H), 1.76 - 1.57 (m, 3H), 0.86 (t, J = 12.6 Hz, 4H). ; LRMS (ESI+) calculated for C29 H 27 N7O3[M+H]+: 522.22, found 522.24.

[0648]

[0649] 52be (27 mg, 62%) 1 H NMR (400 MHz, DMSO-d6) δ9.13 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.93 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 8.3, 2.0 Hz, 1H), 7.53 (s, 1H), 6.43 (s, 1H), 4.47 (s, 1H), 4.15 (d, J = 13.1 Hz, 1H), 3.86 - 3.66 (m, 1H), 3.29 - 3.04 (m, 1H), 2.61 - 2.52 (m, 1H), 1.99 (d, J = 14.0 Hz, 1H), 1.82 (d, J = 13.5 Hz, 1H), 1.68 - 1.32 (m, 3H), 0.72 (s, 4H).; LRMS (ESI+) calculated for C 25 H 23 Cl2N7O3[M+H]+: 540.13, found 540.15.

[0650]

[0651] 52ce (10 mg, 66%) 1H NMR (400 MHz, Chloroform-d) δ9.06 - 8.79 (m, 1H), 8.71 - 8.49 (m, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.19 (d, J = 10.7 Hz, 1H), 8.00 (d, J = 16.9 Hz, 1H), 7.75 - 7.57 (m, 1H), 7.36 (d, J = 4.7 Hz, 1H), 7.06 (d, J = 5.5 Hz, 1H), 5.72 - 5.47 (m, 1H), 4.87 (d, J = 12.2 Hz, 1H), 4.19 - 3.99 (m, 1H), 3.69 (t, J = 12.0 Hz, 1H), 3.41 (s, 1H), 3.19 (t, J = 12.9 Hz, 1H), 2.07 - 1.98 (m, 2H), 1.76 - 1.67 (m, 3H), 1.65 - 1.43 (m, 4H). ; LRMS (ESI+) calculated for C 25 H 23 ClFN7O3[M+H]+: 524.16, found 524.14.

[0652]

[0653] 52de (2 mg, 24%) 1 H NMR (400 MHz, DMSO) δ9.14 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.55 (d, J = 17.5 Hz, 1H), 7.06 (d, J = 1.9 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.49 (s, 1H), 4.48 (s, 1H), 4.30 (d, J = 2.6 Hz, 4H), 4.16 (d, J = 12.1 Hz, 1H), 3.81 (s, 1H), 3.11 (s, 1H), 2.94 (s, 1H), 1.84 (s, 2H), 1.66 - 1.39 (m, 3H), 0.72 (s, 4H).; LRMS (ESI+) calculated for C 27 H27 N7O5[M+H]+: 530.21, found 530.30.

[0654]

[0655] 53ae (16 mg, 69%) 1 H NMR (400 MHz, DMSO-d6) δ9.20 (s, 1H), 8.25 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.04 (d, J = 11.9 Hz, 2H), 8.00 - 7.88 (m, 3H), 7.71 (dd, J = 8.6, 1.7 Hz, 1H), 7.58 (td, J = 6.6, 3.6 Hz, 2H), 7.37 (s, 1H), 6.40 (d, J = 5.2 Hz, 1H), 4.60 - 4.11 (m, 1H), 4.02 - 3.72 (m, 1H), 3.16 - 2.87 (m, 1H), 2.56 (d, J = 15.6 Hz, 1H), 2.08 - 1.96 (m, 1H), 1.81 (s, 2H), 1.68 - 1.30 (m, 3H), 0.76 - 0.52 (m, 4H). ; LRMS (ESI+) calculated for C 29 H 27 N7O3[M+H]+: 522.22, found 522.24.

[0656]

[0657] 53be (26 mg, 60%) 1H NMR (400 MHz, DMSO-d6) δ9.13 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.93 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.78 - 7.63 (m, 1H), 7.60 (dd, J = 8.3, 2.0 Hz, 1H), 7.55 - 7.30 (m, 1H), 6.43 (s, 1H), 4.27 - 4.08 (m, 1H), 3.86 - 3.67 (m, 1H), 3.27 - 2.89 (m, 2H), 2.55 (q, J = 8.8 Hz, 1H), 2.01 (s, 1H), 1.91 - 1.68 (m, 2H), 1.68 - 1.32 (m, 2H), 0.72 (s, 4H).; LRMS (ESI+) calculated for C 25 H 23 Cl2N7O3[M+H]+: 540.13, found 540.15.

[0658]

[0659] 53ce (32 mg, 97%) 1H NMR (400 MHz, DMSO-d6) δ8.68 (s, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.94 (s, 1H), 7.78 (dd, J = 7.2, 2.2 Hz, 1H), 7.61 (ddd, J = 8.6, 4.8, 2.2 Hz, 1H), 7.49 (dd, J = 9.3, 8.6 Hz, 1H), 6.42 (s, 1H), 4.60 (d, J = 12.5 Hz, 1H), 4.31 (d, J = 12.8 Hz, 1H), 3.74 - 3.62 (m, 1H), 3.14 (t, J = 11.1 Hz, 1H), 3.01 (t, J = 10.9 Hz, 1H), 1.92 (d, J = 8.4 Hz, 1H), 1.84 - 1.73 (m, 1H), 1.66 - 1.42 (m, 3H), 0.69 (dd, J = 6.4, 3.9 Hz, 4H). ; LRMS (ESI+) calculated for C 25 H 23 ClFN7O3[M+H]+: 524.16, found 524.14.

[0660]

[0661] 53de (13 mg, 57%) 1H NMR (400 MHz, DMSO) δ8.64 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.90 (s, 1H), 7.06 (s, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.46 (d, J = 5.1 Hz, 1H), 4.60 (d, J = 11.2 Hz, 1H), 4.29 (d, J = 2.6 Hz, 5H), 3.69 (d, J = 5.7 Hz, 1H), 3.18 (dd, J = 13.1, 7.8 Hz, 1H), 3.07 (d, J = 10.2 Hz, 1H), 1.92 (dd, J = 7.6, 4.0 Hz, 1H), 1.81 (dd, J = 8.9, 4.4 Hz, 1H), 1.67 - 1.43 (m, 3H), 0.73 - 0.63 (m, 4H).; LRMS (ESI+) calculated for C 27 H 27 N7O5[M+H]+: 530.21, found 530.30.

[0662]

[0663] 54af (19 mg, 59%) 1H NMR (400 MHz, CDCl3) δ9.01 (s, 1H), 8.15 (s, 1H), 7.95 (d, J = 3.7 Hz, 1H), 7.92 - 7.84 (m, 3H), 7.72 (dd, J = 8.5, 1.6 Hz, 1H), 7.58 - 7.49 (m, 2H), 6.53 (d, J = 5.3 Hz, 1H), 6.03 (s, 1H), 5.58 (s, 1H), 4.15 (d, J = 27.5 Hz, 1H), 3.49 (d, J = 12.2 Hz, 1H), 3.10 - 3.00 (m, 1H), 2.82 (d, J = 19.7 Hz, 7H), 2.20 - 1.98 (m, 2H), 1.81 (s, 1H), 1.64 (d, J = 9.8 Hz, 2H), 1.26 (s, 1H). ; LRMS (ESI+) calculated for C 28 H 28 N8O3[M+H]+: 525.24, found 525.28.

[0664]

[0665] 54bf (22 mg, 80%) 1 H NMR (400 MHz, DMSO-d6) δ9.12 (s, 1H), 8.51 - 8.21 (m, 1H), 8.16 (s, 1H), 7.93 (s, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.72 (s, 1H), 7.61 (dd, J = 8.3, 1.8 Hz, 1H), 7.52 (s, 1H), 6.55 - 6.36 (m, 1H), 3.84 (s, 1H), 3.74 - 3.66 (m, 1H), 3.43 (d, J = 9.6 Hz, 1H), 2.73 (s, 6H), 2.67 - 2.52 (m, 2H), 1.96 (d, J = 17.2 Hz, 1H), 1.73 (s, 1H), 1.58 - 1.40 (m, 2H). ; LRMS (ESI+) calculated for C 24 H 24Cl2N8O3[M+H]+: 540.13, found 540.15.

[0666] 55af (22 mg,78 %) 1 H NMR (400 MHz, Chloroform-d) δ8.71 (s, 1H), 8.14 - 8.09 (m, 1H), 7.97 (d, J = 5.4 Hz, 1H), 7.91 - 7.82 (m, 3H), 7.70 (dd, J = 8.4, 1.7 Hz, 1H), 7.55 - 7.48 (m, 2H), 6.50 (d, J = 5.4 Hz, 1H), 5.71 (s, 1H), 3.76 (d, J = 13.0 Hz, 1H), 3.38 (d, J = 13.0 Hz, 1H), 3.03 (d, J = 12.1 Hz, 2H), 2.85 (s, 6H), 2.82 (s, 2H), 2.80 - 2.77 (m, 1H), 2.05 (d, J = 9.9 Hz, 1H), 1.88 - 1.79 (m, 1H), 1.73 - 1.58 (m, 2H). ; LRMS (ESI+) calculated for C 28 H 28 N8O3[M+H]+: 525.24, found 525.28.

[0667]

[0668] 55bf (14 mg, 79%) 1H NMR (400 MHz, DMSO-d6) δ9.13 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.93 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.54 (s, 1H), 6.56 - 6.39 (m, 1H), 3.85 (s, 1H), 3.73 - 3.66 (m, 1H), 3.42 (t, J = 13.7 Hz, 1H), 2.73 (s, 6H), 2.68 - 2.53 (m, 2H), 2.06 - 1.91 (m, 1H), 1.74 (s, 1H), 1.50 (s, 2H).; LRMS (ESI+) calculated for C 24 H 24 Cl2N8O3[M+H]+: 540.13, found 540.15.

[0669] Compound 44ae (39 mg, 0.072 mmol) was dissolved in 33% MeNH2 in EtOH (0.03 ml, 72 mmol) and stirred at room temperature for 1 hour. After confirming the completion of the reaction, the solvent was concentrated using a rotary evaporator, and then the residue was purified by column chromatography using a mobile phase of MC:MeOH (30:1) to obtain compound 56ae (30 mg, 79%).

[0670]

[0671] 56ae (30 mg, 79%) 1H NMR (400 MHz, DMSO-d6) δ8.83 (q, J = 4.5 Hz, 1H), 8.54 (s, 1H), 8.41 (d, J = 6.1 Hz, 1H), 8.17 (d, J = 1.7 Hz, 1H), 8.12 (d, J = 5.3 Hz, 1H), 8.00 - 7.93 (m, 3H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 7.60 - 7.51 (m, 2H), 6.42 (d, J = 5.3 Hz, 1H), 4.39 (s, 1H), 3.70 (s, 3H), 3.44 (s, 1H), 2.81 (d, J = 4.5 Hz, 3H), 2.19 (s, 1H), 1.96 (d, J = 14.2 Hz, 1H), 1.57 (td, J = 7.7, 3.8 Hz, 1H), 0.73 - 0.62 (m, 4H).; LRMS (ESI+) calculated for C 29 H 27 N7O3[M+H]+: 522.22, found 522.24.

[0672]

[0673] 57ae (31 mg, 80%) 1 H NMR (400 MHz, DMSO-d6) δ8.86 - 8.79 (m, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 8.11 (d, J = 4.3 Hz, 1H), 8.01 - 7.93 (m, 3H), 7.70 (d, J = 8.2 Hz, 1H), 7.59 - 7.52 (m, 2H), 6.43 (d, J = 5.0 Hz, 1H), 4.39 (s, 1H), 3.70 (s, 2H), 2.82 (d, J = 4.0 Hz, 3H), 2.54 (d, J = 4.5 Hz, 1H), 2.19 (s, 1H), 1.94 (s, 1H), 1.78 (s, 1H), 1.58 (s, 1H), 0.71 (s, 2H), 0.65 (d, J = 7.1 Hz, 2H).; LRMS (ESI+) calculated for C29 H 27 N7O3[M+H]+: 522.22, found 522.24.

[0674]

[0675] 58ae (6 mg, 46%) 1 H NMR (400 MHz, CDCl3) δ8.68 (s, 1H), 8.15 (s, 1H), 7.98 (dd, J = 24.0, 9.4 Hz, 1H), 7.86 (dd, J = 11.9, 5.2 Hz, 3H), 7.71 (dd, J = 8.5, 1.6 Hz, 1H), 7.53 (s, 2H), 6.54 (s, 1H), 4.73 (s, 1H), 4.06 (d, J = 25.5 Hz, 2H), 3.31 (s, 1H), 2.98 (d, J = 3.5 Hz, 3H), 2.84 (s, 1H), 2.19 (d, J = 14.7 Hz, 1H), 1.93 (s, 1H), 1.83 (s, 1H), 1.71 (dd, J = 19.2, 10.0 Hz, 3H), 0.98 (s, 2H), 0.84 (s, 2H), 0.66 (d, J = 35.0 Hz, 1H). ; LRMS (ESI+) calculated for C 30 H 29 N7O3[M+H]+: 536.24, found 536.27.

[0676]

[0677] 58be (25 mg, 46%) 1H NMR (400 MHz, DMSO-d6) δ9.11 (s, 1H), 8.79 (d, J = 4.9 Hz, 1H), 8.15 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.72 (s, 2H), 7.60 (dd, J = 8.3, 2.0 Hz, 1H), 6.42 (s, 1H), 4.45 (s, 1H), 4.15 (d, J = 13.8 Hz, 1H), 3.79 (s, 1H), 2.81 (d, J = 4.5 Hz, 3H), 2.09 - 1.94 (m, 2H), 1.82 (s, 2H), 1.71 - 1.36 (m, 3H), 0.71 (s, 4H). ; LRMS (ESI+) calculated for C 26 H 25 Cl2N7O3[M+H]+: 554.15, found 554.18

[0678]

[0679] 58ce (10 mg, 81%) 1 H NMR (400 MHz, DMSO-d6) δ9.16 (s, 1H), 8.81 (d, J = 4.6 Hz, 1H), 8.14 (s, 1H), 7.79 (dd, J = 7.2, 2.1 Hz, 1H), 7.66 (d, J = 15.7 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.54 (d, J = 8.7 Hz, 1H), 6.37 (s, 1H), 4.50 - 4.30 (m, 1H), 4.15 (d, J = 13.7 Hz, 1H), 3.85 - 3.66 (m, 1H), 3.27 - 3.05 (m, 1H), 2.99 - 2.85 (m, 1H), 2.81 (d, J = 4.5 Hz, 3H), 2.06 - 1.97 (m, 1H), 1.79 (t, J = 15.2 Hz, 2H), 1.67 - 1.40 (m, 2H), 0.71 (s, 4H). ; LRMS (ESI+) calculated for C 26 H 25ClFN7O3[M+H]+: 538.18, found 538.16

[0680]

[0681] 58de (5 mg, 66%) 1 H NMR (400 MHz, DMSO-d6) δ9.12 (s, 1H), 8.76 (d, J = 4.9 Hz, 1H), 8.11 (s, 1H), 7.68 - 7.51 (m, 1H), 7.07 - 7.03 (m, 2H), 6.95 (d, J = 8.9 Hz, 1H), 6.48 (s, 1H), 4.47 (d, J = 12.4 Hz, 1H), 4.30 (dt, J = 4.1, 2.6 Hz, 4H), 4.16 (d, J = 14.8 Hz, 1H), 3.97 (d, J = 12.5 Hz, 1H), 3.84 - 3.70 (m, 1H), 3.26 - 3.04 (m, 1H), 2.94 (s, 1H), 2.81 (d, J = 4.6 Hz, 3H), 1.84 (s, 2H), 1.65 - 1.45 (m, 2H), 0.71 (s, 4H). ; LRMS (ESI+) calculated for C 28 H 29 N7O5[M+H]+: 544.23, found 544.32.

[0682]

[0683] 59ae (25 mg, 92%) 1H NMR (400 MHz, CDCl3) δ8.67 (s, 1H), 8.13 (s, 1H), 7.96 (d, J = 29.3 Hz, 1H), 7.85 (dd, J = 13.2, 6.1 Hz, 3H), 7.69 (dd, J = 8.5, 1.5 Hz, 1H), 7.52 (s, 2H), 6.52 (s, 1H), 5.50 (d, J = 42.6 Hz, 1H), 4.70 (s, 1H), 4.02 (s, 1H), 3.31 (s, 1H), 2.97 - 2.83 (m, 3H), 2.79 (d, J = 4.8 Hz, 1H), 2.19 (d, J = 13.7 Hz, 1H), 1.95 (d, J = 18.6 Hz, 1H), 1.83 (s, 1H), 1.69 (dd, J = 18.6, 11.1 Hz, 3H), 1.04 - 0.90 (m, 2H), 0.85 (d, J = 17.7 Hz, 2H), 0.65 (d, J = 37.6 Hz, 1H). ; LRMS (ESI+) calculated for C 30 H 29 N7O3[M+H]+: 536.24, found 536.27.

[0684]

[0685] 59be (25 mg, 56%) 1H NMR (400 MHz, DMSO-d6) δ9.10 (s, 1H), 8.78 (d, J = 4.9 Hz, 1H), 8.14 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.70 (t, J = 15.1 Hz, 2H), 7.59 (dd, J = 8.3, 2.0 Hz, 1H), 6.41 (s, 1H), 4.14 (d, J = 13.3 Hz, 1H), 3.78 (s, 1H), 3.27 - 2.92 (m, 1H), 2.81 (d, J = 4.6 Hz, 3H), 2.54 (d, J = 4.6 Hz, 1H), 2.06 - 1.91 (m, 2H), 1.84 (s, 1H), 1.61 (s, 1H), 1.58 - 1.35 (m, 2H), 0.79 - 0.48 (m, 4H). ; LRMS (ESI+) calculated for C 26 H 25 Cl2N7O3[M+H]+: 554.15, found 554.18

[0686]

[0687] 59ce (24 mg, 86%) 1H1NMR (400 MHz, DMSO) δ8.83 (q, J = 4.3 Hz, 1H), 8.54 (s, 1H), 8.22 (d, J = 5.2 Hz, 2H), 7.79 (dd, J = 7.2, 2.1 Hz, 1H), 7.62 (ddd, J = 8.5, 4.7, 2.1 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 6.46 (d, J = 4.2 Hz, 1H), 4.42 (d, J = 10.6 Hz, 1H), 4.19 (d, J = 13.3 Hz, 1H), 3.77 - 3.66 (m, 1H), 3.16 (d, J = 41.8 Hz, 2H), 2.82 (d, J = 4.6 Hz, 3H), 1.95 - 1.85 (m, 1H), 1.86 - 1.73 (m, 1H), 1.68 - 1.41 (m, 3H), 0.67 (dd, J = 9.0, 6.3 Hz, 4H).; LRMS (ESI+) calculated for C 26 H 25 ClFN7O3[M+H]+: 538.18, found 538.16

[0688]

[0689] 59de (15 mg, 73%) 1H NMR (400 MHz, DMSO-d6) δ8.81 (q, J = 4.5 Hz, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.17 (d, J = 5.3 Hz, 1H), 7.72 (s, 3H), 7.09 - 7.01 (m, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 5.2 Hz, 1H), 4.41 (d, J = 12.9 Hz, 1H), 4.29 (tt, J = 5.3, 2.5 Hz, 4H), 4.18 (d, J = 12.8 Hz, 1H), 3.73 (s, 1H), 3.19 (s, 2H), 2.81 (d, J = 4.6 Hz, 3H), 1.95 - 1.87 (m, 1H), 1.62 (d, J = 4.0 Hz, 1H), 0.70 - 0.58 (m, 4H). ; LRMS (ESI+) calculated for C 28 H 29 N7O5[M+H]+: 544.23, found 544.32.

[0690]

[0691] 60af (25 mg, 78%) 1H NMR (400 MHz, CDCl3) δ8.72 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.92 - 7.82 (m, 3H), 7.71 (dd, J = 8.5, 1.5 Hz, 1H), 7.57 - 7.48 (m, 2H), 6.51 (d, J = 5.3 Hz, 1H), 5.72 (s, 1H), 4.10 (s, 1H), 3.78 (d, J = 12.0 Hz, 1H), 3.39 (d, J = 12.2 Hz, 1H), 3.15 - 2.99 (m, 2H), 2.86 (s, 6H), 2.81 (d, J = 4.6 Hz, 3H), 2.36 - 2.19 (m, 1H), 2.06 (dd, J = 10.8, 4.1 Hz, 1H), 1.90 - 1.78 (m, 1H), 1.75 - 1.58 (m, 2H). ; LRMS (ESI+) calculated for C 29 H 30 N8O3[M+H]+: 539.25, found 539.21.

[0692]

[0693] 60bf (25 mg, 56%) 1H NMR (400 MHz, DMSO-d6) δ9.10 (s, 1H), 8.78 (d, J = 4.6 Hz, 1H), 8.15 (s, 1H), 7.84 (s, 1H), 7.77 - 7.69 (m, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 6.40 (s, 1H), 3.81 (s, 1H), 3.68 (s, 1H), 3.48 - 3.37 (m, 1H), 2.81 (d, J = 4.6 Hz, 3H), 2.71 (d, J = 14.6 Hz, 6H), 2.54 (d, J = 4.6 Hz, 2H), 2.00 (d, J = 9.9 Hz, 1H), 1.75 (d, J = 15.9 Hz, 1H), 1.56 - 1.42 (m, 2H). ; LRMS (ESI+) calculated for C 25 H 26 Cl2N8O3[M+H]+: 557.16, found 557.12.

[0694]

[0695] 61af (25 mg, 85%) 1H NMR (400 MHz, CDCl3) δ8.72 (s, 1H), 8.14 (s, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.92 - 7.83 (m, 3H), 7.71 (dd, J = 8.5, 1.6 Hz, 1H), 7.57 - 7.46 (m, 2H), 6.51 (d, J = 5.3 Hz, 1H), 5.72 (s, 1H), 4.14 - 4.05 (m, 1H), 3.78 (d, J = 12.1 Hz, 1H), 3.39 (d, J = 13.1 Hz, 1H), 3.14 - 2.96 (m, 2H), 2.86 (s, 6H), 2.82 (t, J = 4.8 Hz, 3H), 2.29 (dd, J = 17.0, 9.5 Hz, 1H), 2.12 - 2.04 (m, 1H), 1.89 - 1.79 (m, 1H), 1.66 (ddd, J = 12.8, 10.9, 7.1 Hz, 2H). ; LRMS (ESI+) calculated for C 29 H 30 N8O3[M+H]+: 539.25, found 539.21.

[0696]

[0697] 61bf (15 mg, 87%) 1H NMR (400 MHz, DMSO-d6) δ9.11 (s, 1H), 8.80 (d, J = 4.9 Hz, 1H), 8.23 - 8.10 (m, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.35 (s, 1H), 6.42 (s, 1H), 3.82 (s, 1H), 3.70 (d, J = 12.1 Hz, 1H), 3.43 (s, 1H), 2.82 (d, J = 4.6 Hz, 3H), 2.79 - 2.69 (m, 6H), 2.68 - 2.52 (m, 2H), 2.00 (s, 1H), 1.76 (d, J = 15.0 Hz, 1H), 1.58 - 1.43 (m, 2H). ; LRMS (ESI+) calculated for C 25 H 26 Cl2N8O3[M+H]+: 557.16, found 557.12.

[0698]

[0699] Ethyl 5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Ayylimidazo[2,1-b]oxazole-2-carboxylate (67ag~dg, 67ah~dh)

[0700]

[0701] Compound 39a (90 mg, 0.19 mmol) was dissolved in DMSO (0.5 ml), and cyclohexanamine (0.04 ml, 0.38 mmol) and DIPEA (0.10 ml, 0.57 mmol) were added. The mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with water and brine. The moisture was removed with anhydrous sodium sulfate (Na2SO4), the solvent was concentrated, and the residue was purified by column chromatography using a mobile phase of EA:Hex (1:4) to obtain compound 67ag (52 mg, 56%).

[0702]

[0703] 67ag (52 mg, 56%). 1 H NMR (400 MHz, CDCl3) δ8.75 (s, 1H), 8.17 (s, 1H), 7.99 (d, J = 5.3 Hz, 1H), 7.94 - 7.83 (m, 3H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 7.59 - 7.44 (m, 2H), 6.57 (d, J = 5.3 Hz, 1H), 5.14 (s, 1H), 4.53 - 4.39 (m, 2H), 3.91 - 3.80 (m, 1H), 2.18 (s, 1H), 2.16 (s, 1H), 1.86 (d, J = 13.3 Hz, 2H), 1.72 (d, J = 12.9 Hz, 1H), 1.62 (d, J = 11.8 Hz, 1H), 1.56 - 1.47 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.36 - 1.28 (m, 2H). ; LRMS (ESI+) calculated for C 28 H 27 N5O3[M+H]+: 482.22, found 482.25.

[0704]

[0705] 67bg (70 mg, 78%). 1H NMR (400 MHz, Chloroform-d) δ8.68 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.55 - 7.48 (m, 2H), 6.53 (d, J = 5.3 Hz, 1H), 5.23 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.89 - 3.77 (m, 1H), 2.15 (d, J = 10.2 Hz, 2H), 1.85 (d, J = 13.4 Hz, 2H), 1.72 (d, J = 13.0 Hz, 2H), 1.55 - 1.46 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.33 (dd, J = 17.6, 7.8 Hz, 2H). ; LRMS (ESI+) calculated for C 24 H 23 Cl2N5O3[M+H]+: 500.12, found 500.16.

[0706]

[0707] 67cg (73 mg, 71 %). 1 H NMR (400 MHz, Chloroform-d) δ8.69 (s, 1H), 8.08 (d, J = 5.3 Hz, 1H), 7.74 (dd, J = 7.1, 2.2 Hz, 1H), 7.54 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.22 (t, J = 8.6 Hz, 1H), 6.53 - 6.47 (m, 1H), 5.30 (s, 1H), 4.50 - 4.44 (m, 2H), 3.83 (dq, J = 10.6, 5.4 Hz, 1H), 2.19 - 2.11 (m, 2H), 1.85 (d, J = 13.3 Hz, 2H), 1.72 (d, J = 13.1 Hz, 2H), 1.43 (t, J = 7.0 Hz, 5H), 1.36 - 1.30 (m, 2H). ; LRMS (ESI+) calculated for C 24 H 23ClFN5O3[M+H]+: 484.16, found 484.15.

[0708]

[0709] 67dg (29 mg, 74 %). 1 H NMR (400 MHz, Chloroform-d) δ8.70 (s, 1H), 8.05 (d, J = 5.4 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 8.3, 2.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.65 (d, J = 5.4 Hz, 1H), 5.21 (s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.34 - 4.28 (m, 4H), 3.83 (ddd, J = 10.8, 6.6, 3.0 Hz, 1H), 2.19 - 2.13 (m, 2H), 1.84 (d, J = 13.3 Hz, 2H), 1.71 (d, J = 12.8 Hz, 1H), 1.49 (d, J = 12.6 Hz, 1H), 1.43 (t, J = 7.2 Hz, 3H). ; LRMS (ESI+) calculated for C 26 H 23 N5O5[M+H]+: 490.21, found 490.21.

[0710]

[0711] 67ah (84 mg, 89 %). 1H NMR (400 MHz, CDCl3) δ8.75 (s, 1H), 8.17 (s, 1H), 7.99 (d, J = 5.3 Hz, 1H), 7.94 - 7.83 (m, 3H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 7.59 - 7.44 (m, 2H), 6.57 (d, J = 5.3 Hz, 1H), 5.14 (s, 1H), 4.53 - 4.39 (m, 2H), 3.91 - 3.80 (m, 1H), 2.18 (s, 1H), 2.16 (s, 1H), 1.86 (d, J = 13.3 Hz, 2H), 1.72 (d, J = 12.9 Hz, 1H), 1.62 (d, J = 11.8 Hz, 1H), 1.56 - 1.47 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.36 - 1.28 (m, 2H). ; LRMS (ESI+) calculated for C 27 H 25 N5O4[M+H]+: 484.20, found 484.24.

[0712]

[0713] 67bh (63 mg, 72 %). 1 H NMR (400 MHz, Chloroform-d) δ8.66 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.79 (dd, J = 1.6, 0.7 Hz, 1H), 7.54 - 7.47 (m, 2H), 6.57 (d, J = 5.3 Hz, 1H), 5.24 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.09 - 4.03 (m, 3H), 3.60 (td, J = 11.6, 1.8 Hz, 2H), 2.15 - 2.06 (m, 2H), 1.65 (qd, J = 12.0, 4.3 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H). ; LRMS (ESI+) calculated for C 23 H 21Cl2N5O4[M+H]+: 502.10, found 502.06.

[0714]

[0715] 67ch (82 mg, 81 %). 1 H NMR (400 MHz, CDCl3) δ8.67 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.73 (dd, J = 7.0, 2.1 Hz, 1H), 7.53 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 5.3 Hz, 1H), 5.40 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.07 (dd, J = 13.0, 4.9 Hz, 3H), 3.60 (dd, J = 11.5, 10.2 Hz, 2H), 2.11 (dd, J = 11.2, 1.5 Hz, 2H), 1.65 (qd, J = 12.0, 4.2 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H). ; LRMS (ESI+) calculated for C 23 H 21 Cl2N5O4[M+H]+: 486.13, found 486.14.

[0716]

[0717] 67dh (33 mg, 84 %). 1H NMR (400 MHz, Chloroform-d) δ8.68 (s, 1H), 8.08 (d, J = 5.4z Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 5.4 Hz, 1H), 5.23 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.34 - 4.28 (m, 4H), 4.09 - 4.04 (m, 2H), 3.60 (td, J = 11.7, 2.1 Hz, 2H), 2.15 - 2.08 (m, 2H), 1.64 (qt, J = 12.3, 6.1 Hz, 3H), 1.45 (d, J = 7.2 Hz, 3H). ; LRMS (ESI+) calculated for C 25 H 25 N5O6[M+H]+: 492.19, found 492.20.

[0718]

[0719] 5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Arylimidazo[2,1-b]oxazole-2-carboxamide (68ag~dg, 68ah~dh, 69ag~dg, 69ah~dh)

[0720]

[0721] Compound 67ag (20 mg, 0.014 mmol) was dissolved in 7N NH3in MeOH (0.45 ml, 20 mmol) and stirred at room temperature for 7 hours. After confirming the completion of the reaction, the solvent was concentrated using a rotary evaporator, and then the residue was purified by column chromatography using a mobile phase of EA:Hex (1:1) to obtain compound 68ag (6 mg, 32%).

[0722] 68ag (6 mg, 32%). 1H NMR (400 MHz, DMSO-d6) δ9.21 (s, 1H), 8.23 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.06 - 7.96 (m, 3H), 7.91 (s, 1H), 7.72 (dd, J = 8.5, 1.7 Hz, 1H), 7.63 - 7.55 (m, 2H), 7.48 - 7.37 (m, 1H), 6.34 (s, 1H), 3.71 (s, 1H), 2.69 - 2.64 (m, 1H), 2.35 - 2.24 (m, 1H), 1.95 (d, J = 11.1 Hz, 2H), 1.73 (s, 2H), 1.61 (d, J = 12.1 Hz, 1H), 1.48 (s, 2H), 1.32 (d, J = 13.0 Hz, 2H). ; LRMS (ESI+) calculated for C 26 H 24 N6O2[M+H]+: 453.20, found 453.16.

[0723]

[0724] 68bg (13 mg, 56 %). 1 H NMR (400 MHz, DMSO-d6) δ9.17 (s, 1H), 8.24 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.64 - 7.60 (m, 1H), 7.44 (s, 1H), 6.36 (s, 1H), 3.70 (s, 1H), 1.95 (d, J = 16.1 Hz, 2H), 1.72 (s, 2H), 1.60 (d, J = 12.4 Hz, 1H), 1.33 - 1.20 (m, 5H). ; LRMS (ESI+) calculated for C 22 H 20 Cl2N6O2[M+H]+: 471.11, found 471.12.

[0725]

[0726] 68cg (9 mg, 49 %).1 H NMR (400 MHz, DMSO-d6) δ9.17 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.79 (dd, J = 7.2, 2.1 Hz, 1H), 7.63 (ddd, J = 8.6, 4.8, 2.2 Hz, 1H), 7.53 (t, J = 8.9 Hz, 1H), 7.43 (s, 1H), 6.31 (s, 1H), 3.70 (s, 1H), 1.93 (d, J = 10.3 Hz, 2H), 1.73 (d, J = 10.8 Hz, 2H), 1.61 (d, J = 12.6 Hz, 1H), 1.38 - 1.21 (m, 5H). ; LRMS (ESI+) calculated for C 22 H 20 ClFN6O2[M+H]+: 455.14, found 455.15.

[0727]

[0728] 68dg (3 mg, 33 %). 1 H NMR (400 MHz, DMSO-d6) δ9.18 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 5.4 Hz, 1H), 7.87 (s, 1H), 7.40 (s, 1H), 7.10 - 7.03 (m, 2H), 6.95 (d, J = 8.8 Hz, 1H), 6.43 (s, 1H), 4.35 - 4.22 (m, 4H), 3.76 - 3.65 (m, 1H), 1.95 (d, J = 11.6 Hz, 2H), 1.74 (d, J = 12.7 Hz, 2H), 1.62 (d, J = 12.4 Hz, 1H), 1.36 - 1.22 (m, 5H). ; LRMS (ESI+) calculated for C 24 H 24 N6O4[M+H]+: 461.19, found 461.22.

[0729]

[0730] 68ah (13 mg, 44 %). 1H NMR (400 MHz, DMSO-d6) δ9.20 (s, 1H), 8.25 (s, 1H), 8.20 - 8.15 (m, 1H), 8.09 - 8.04 (m, 1H), 8.02 - 7.91 (m, 3H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.58 (td, J = 6.5, 3.6 Hz, 3H), 6.38 (s, 1H), 3.89 (d, J = 12.8 Hz, 3H), 3.40 (d, J = 16.4 Hz, 2H), 1.95 - 1.84 (m, 2H), 1.53 (qd, J = 12.1, 4.3 Hz, 2H), 1.32 - 1.22 (m, 1H). ; LRMS (ESI+) calculated for C 25 H 22 N6O3[M+H]+: 455.18, found 455.15.

[0731]

[0732] 68bh (19 mg, 80 %). 1 H NMR (400 MHz, DMSO-d6) δ9.14 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.3, 2.0 Hz, 1H), 7.55 (s, 1H), 6.40 (s, 1H), 3.90 (t, J = 14.5 Hz, 3H), 3.38 (s, 1H), 1.99 - 1.92 (m, 1H), 1.87 (s, 2H), 1.51 (qd, J = 11.9, 3.7 Hz, 2H). ; LRMS (ESI+) calculated for C 21 H 18 Cl2N6O3[M+H]+: 473.09 , found 473.06.

[0733]

[0734] 68ch (9 mg, 49 %). 1H NMR (400 MHz, Chloroform-d) δ8.72 (s, 1H), 8.17 - 8.08 (m, 1H), 7.73 (dd, J = 7.0, 2.2 Hz, 1H), 7.53 (dd, J = 9.6, 5.0 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 6.52 (d, J = 5.4 Hz, 1H), 5.80 (s, 1H), 5.37 - 5.19 (m, 1H), 4.88 (s, 1H), 4.05 (d, J = 11.9 Hz, 2H), 3.60 (t, J = 11.5 Hz, 2H), 2.34 (d, J = 8.3 Hz, 1H), 2.07 (s, 3H). ; LRMS (ESI+) calculated for C 21 H 18 ClFN6O3[M+H]+: 457.12, found 457.14.

[0735]

[0736] 68dh (5 mg, 54 %). 1 H NMR (400 MHz, DMSO-d6) δ9.14 (s, 1H), 8.20 (s, 1H), 8.11 (d, J = 5.4 Hz, 1H), 7.89 (s, 1H), 7.60 - 7.45 (m, 1H), 7.08 - 7.02 (m, 2H), 6.99 - 6.91 (m, 1H), 6.47 (s, 1H), 4.30 (q, J = 5.4 Hz, 4H), 3.91 (t, J = 11.7 Hz, 3H), 3.41 (t, J = 11.5 Hz, 2H), 1.94 - 1.86 (m, 2H), 1.52 (d, J = 12.7 Hz, 2H). ; LRMS (ESI+) calculated for C 23 H 22 N6O5[M+H]+: 463.17, found 463.21.

[0737]

[0738] Compound 67ae (20 mg, 0.041 mmol) was dissolved in 33% MeNH2 in EtOH (0.8 ml, 20 mmol) and stirred at room temperature for 3 hours. After confirming the completion of the reaction, the solvent was concentrated using a rotary evaporator, and the residue was purified by column chromatography using a mobile phase of MC:MeOH (30:1) to obtain compound 69ag (12 mg, 63%).

[0739]

[0740]

[0741] 69ag (12 mg, 63%). 1 H NMR (400 MHz, CDCl3) δ8.71 (s, 1H), 8.14 (s, 1H), 7.99 (d, J = 4.5 Hz, 1H), 7.95 - 7.83 (m, 3H), 7.72 (d, J = 7.3 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.05 (d, J = 4.6 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.41 - 4.20 (m, 1H), 3.94 - 3.79 (m, 1H), 2.85 (d, J = 4.8 Hz, 3H), 2.17 (s, 2H), 2.13 (s, 1H), 1.77 (dd, J = 44.4, 12.6 Hz, 4H), 1.52 (d, J = 10.6 Hz, 3H). ; LRMS (ESI+) calculated for C 27 H 26 N6O2[M+H]+: 467.22, found 467.19.

[0742]

[0743] 69bg (20 mg, 82%). 1H NMR (400 MHz, Chloroform-d) δ8.65 (s, 1H), 8.12 (d, J = 5.0 Hz, 1H), 7.78 (d, J = 1.7 Hz, 1H), 7.56 - 7.47 (m, 2H), 6.73 (d, J = 4.8 Hz, 1H), 6.50 (d, J = 5.3 Hz, 1H), 5.21 (d, J = 6.6 Hz, 1H), 3.85 (qd, J = 9.1, 5.9 Hz, 1H), 3.01 (d, J = 4.9 Hz, 3H), 2.13 (d, J = 9.9 Hz, 2H), 1.90 - 1.79 (m, 2H), 1.72 (d, J = 12.6 Hz, 2H), 1.51 (d, J = 10.8 Hz, 2H), 1.34 (dd, J = 17.9, 7.7 Hz, 2H). ; LRMS (ESI+) calculated for C 23 H 22 Cl2N6O2[M+H]+: 485.12 , found 485.10.

[0744]

[0745] 69cg (19 mg, 74 %). 1 H NMR (400 MHz, DMSO-d6) δ9.14 (s, 1H), 8.78 (d, J = 6.5 Hz, 1H), 8.16 - 8.05 (m, 1H), 7.78 (dd, J = 7.2, 2.1 Hz, 1H), 7.62 (ddd, J = 8.5, 4.8, 2.2 Hz, 1H), 7.52 (t, J = 8.9 Hz, 2H), 6.30 (s, 1H), 3.69 (s, 1H), 2.81 (d, J = 4.6 Hz, 3H), 1.93 (d, J = 10.6 Hz, 2H), 1.79 - 1.69 (m, 2H), 1.61 (d, J = 12.5 Hz, 1H), 1.38 - 1.22 (m, 5H). ; LRMS (ESI+) calculated for C 23 H 22 ClFN6O2[M+H]+: 469.15, found 469.18.

[0746]

[0747] 69dg (6 mg, 81 %). 1 H NMR (400 MHz, DMSO-d6) δ9.14 (s, 1H), 8.75 (s, 1H), 8.08 (d, J = 5.3 Hz, 1H), 7.47 (s, 1H), 7.05 (d, J = 6.0 Hz, 2H), 6.99 - 6.93 (m, 1H), 6.43 (s, 1H), 4.30 (q, J = 4.8 Hz, 4H), 3.70 (d, J = 7.3 Hz, 1H), 2.80 (d, J = 4.6 Hz, 3H), 1.95 (d, J = 11.6 Hz, 2H), 1.75 (d, J = 12.5 Hz, 2H), 1.63 (d, J = 11.5 Hz, 1H), 1.29 (d, J = 9.4 Hz, 5H). ; LRMS (ESI+) calculated for C 25 H 26 N6O4[M+H]+: 475.21, found 475.24.

[0748]

[0749] 69ah (19 mg, 51 %). 1 H NMR (400 MHz, DMSO-d6) δ9.17 (s, 1H), 8.80 (s, 1H), 8.18 (s, 1H), 8.08 - 7.96 (m, 4H), 7.74 - 7.68 (m, 1H), 7.63 - 7.53 (m, 2H), 6.37 (s, 1H), 3.89 (d, J = 9.6 Hz, 3H), 3.38 (s, 2H), 2.83 (d, J = 4.5 Hz, 3H), 1.88 (d, J = 10.7 Hz, 2H), 1.53 (tt, J = 11.5, 6.2 Hz, 2H), 1.36 - 1.20 (m, 1H). ; LRMS (ESI+) calculated for C 26 H 24 N6O3[M+H]+: 469.20, found 469.18.

[0750]

[0751] 69bh (21 mg, 86 %). 1 H NMR (400 MHz, Chloroform-d) δ8.64 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.55 - 7.46 (m, 2H), 6.64 (d, J = 4.9 Hz, 1H), 6.54 (d, J = 5.3 Hz, 1H), 5.22 (d, J = 7.6 Hz, 1H), 4.05 (dt, J = 12.2, 3.7 Hz, 2H), 3.61 (t, J = 11.2 Hz, 2H), 3.03 (d, J = 5.0 Hz, 3H), 2.13 - 2.05 (m, 2H), 1.68 (dd, J = 10.7, 4.4 Hz, 3H). ; LRMS (ESI+) calculated for C 22 H 20 Cl2N6O3[M+H]+: 487.10 , found 487.09.

[0752]

[0753] 69ch (18 mg, 77 %). 1 H NMR (400 MHz, CDCl3) δ8.65 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.72 (dd, J = 7.0, 1.9 Hz, 1H), 7.54 - 7.43 (m, 1H), 7.22 (t, J = 8.6 Hz, 1H), 6.71 (s, 1H), 6.50 (d, J = 5.3 Hz, 1H), 5.23 (s, 1H), 4.05 (d, J = 11.5 Hz, 4H), 3.61 (t, J = 11.1 Hz, 2H), 3.01 (d, J = 4.8 Hz, 3H), 2.09 (d, J = 11.8 Hz, 3H). ; LRMS (ESI+) calculated for C 22 H 20 ClFN6O3[M+H]+: 471.13, found 471.17.

[0754]

[0755] 69dh (3 mg, 35%). 1 H NMR (400 MHz, DMSO-d6) δ9.13 (s, 1H), 8.77 (s, 1H), 8.11 (d, J = 5.4 Hz, 1H), 7.58 (s, 1H), 7.10 - 7.02 (m, 2H), 6.99 - 6.93 (m, 1H), 6.47 (s, 1H), 4.34 - 4.27 (m, 4H), 3.92 (t, J = 11.9 Hz, 3H), 3.42 (t, J = 11.6 Hz, 2H), 2.82 (d, J = 4.6 Hz, 3H), 1.95 - 1.86 (m, 2H), 1.53 (q, J = 11.1 Hz, 2H). ; LRMS (ESI+) calculated for C 24 H 24 N6O5[M+H]+: 477.19, found 477.23.

[0756]

[0757] 5.3. Imidazo[2,1-b]thiazole-based covalent JNK3 inhibitors (Scheme 3)

[0758] 5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-phenylimidazo[2,1-b]thiazole-2-carboxylic acid (77ad~cd, ae~ce)

[0759]

[0760] Compound 76ad (56 mg, 0.11 mmol) was dissolved in EtOH (0.55 ml), and 2 M NaOH aqueous solution (55 μl, 0.11 mmol) was added and stirred at 45 °C for 4 hours. After completion of the reaction, the pH was adjusted to 2 with 1 M HCl aqueous solution, and the resulting solid was filtered to obtain yellow solid compound 77ad (39 mg, 76%).

[0761]

[0762] 77ad (39 mg, 76 %) 1 H NMR (400 MHz, DMSO) δ9.17 (s, 1H), 8.22 (s, 1H), 8.12 - 7.96 (m, 4H), 7.80 - 7.72 (m, 1H), 7.63 - 7.55 (m, 2H), 6.37 (s, 1H), 3.83 - 3.72 (m, 1H), 2.04 - 1.92 (m, 2H), 1.82 - 1.72 (m, 2H), 1.68 - 1.59 (m, 1H), 1.47 - 1.26 (m, 4H), 1.22 - 1.11 (m, 1H). LRMS (ESI+) calculated C 26 H 23 N5O2S [M+H]+: 470.1645, found: 470.31

[0763]

[0764] 77bd (45 mg, 66 %) 1 H NMR (400 MHz, DMSO) δ9.09 (s, 1H), 8.16 (d, J = 5.5 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 6.46 (s, 1H), 3.75 - 3.70 (m, 1H), 1.95 (d, J = 9.8 Hz, 2H), 1.75 (d, J = 10.5 Hz, 2H), 1.62 (d, J = 12.7 Hz, 1H), 1.33 (t, J = 10.5 Hz, 3H), 1.24 - 1.12 (m, 1H). LRMS (ESI+) calculated C 22 H 19 C l2 N5O2S [M+H]+: 488.071, found: 488.31

[0765]

[0766] 77cd (240 mg, 81 %) 1H NMR (400 MHz, DMSO) δ9.10 (s, 1H), 8.15 (d, J = 5.4 Hz, 1H), 7.88 (dd, J = 7.1, 2.2 Hz, 1H), 7.73 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.18 (t, J = 8.7 Hz, 1H), 6.48 (d, J = 5.4 Hz, 1H), 4.14 (s, 1H), 3.84 - 3.73 (m, 1H), 2.15 - 2.08 (m, 2H), 1.84 - 1.77 (m, 2H), 1.72 - 1.65 (m, 1H), 1.50 - 1.42 (m, 2H), 1.34 - 1.27 (m, 2H). LRMS (ESI+) calculated C 22 H 19 ClFN5O2S [M+H]+: 472.1005, found: 472.21

[0767]

[0768] 77ae (45 mg, 63 %) 1 H NMR (400 MHz, DMSO) δ9.19 (s, 1H), 8.20 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 5.5 Hz, 1H), 8.05 - 7.93 (m, 3H), 7.71 (dd, J = 8.5, 1.8 Hz, 1H), 7.64 - 7.52 (m, 2H), 6.39 (s, 1H), 4.07 - 3.95 (m, 1H), 3.95 - 3.86 (m, 2H), 3.49 - 3.39 (m, 2H), 1.94 - 1.85 (m, 2H), 1.66 - 1.48 (m, 2H). LRMS (ESI+) calculated C 25 H 21 N5O3S [M+H]+: 472.1438, found: 472.30

[0769]

[0770] 77be (30 mg, 32 %) 1H NMR (400 MHz, DMSO) δ9.13 (s, 1H), 8.19 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 6.45 (s, 1H), 3.99 - 3.88 (m, 3H), 3.41 (m, 2H), 1.95 - 1.84 (m, 2H), 1.64 - 1.52 (m, 2H). LRMS (ESI+) calculated C 21 H 17 Cl2N5O3S [M+H]+: 490.0502, found: 490.30

[0771] 77ce (253 mg, 85 %) 1 H NMR (400 MHz, DMSO) δ9.13 (s, 1H), 8.18 (d, J = 5.4 Hz, 1H), 7.90 (dd, J = 7.1, 2.2 Hz, 1H), 7.75 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.20 (t, J = 8.7 Hz, 1H), 6.50 (d, J = 5.4 Hz, 1H), 4.16 (s, 1H), 3.94 - 3.83 (m, 2H), 3.51 - 3.45 (m, 2H), 1.86 - 1.79 (m, 2H), 1.74 - 1.67 (m, 2H). LRMS (ESI+) calculated C 21 H 17 ClFN5O3S [M+H]+: 474.0798, found: 474.20

[0772]

[0773] tert-butyl (5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Aryl-imidazo[2,1-b]thiazol-2-yl)carbamate (78ad~cd, 78ae~ce)

[0774]

[0775] 77ad (35 mg, 0.074 mmol) was dissolved in anhydrous t-buOH (0.6 ml), and DPPA (18 μl, 0.082 mmol) and TEA (16 μl, 0.11 mmol) were added, and the mixture was stirred at 80 °C for 22 h. The reaction mixture was extracted with EA and washed with H2O and Brine. The extracted reaction mixture was purified with anhydrous magnesium sulfate (MgSO4) to remove residual moisture, and purified using PrepTLC with a mobile phase composition of EA:HEX = 1:2 to obtain compound 78ad (12 mg, 30%).

[0776]

[0777] 78ad (12 mg, 30%) 1 H NMR (400 MHz, CDCl3) δ8.35 (s, 1H), 8.10 (t, J = 1.1 Hz, 1H), 7.89 (s, 1H), 7.85 - 7.79 (m, 4H), 7.68 - 7.64 (m, 1H), 7.50 - 7.45 (m, 2H), 6.42 (d, J = 5.4 Hz, 1H), 5.36 (s, 1H), 3.94 - 3.81 (m, 1H), 2.16 - 2.02 (m, 4H), 1.84 - 1.72 (m, 3H), 1.70 - 1.59 (m, 3H), 1.53 (s, 9H). LRMS (ESI+) calculated C 30 H 32 N6O2S [M+H]+: 541.238, found: 541.22

[0778]

[0779] 78bd (22mg, 40%) 1H NMR (400 MHz, CDCl3) δ8.10 (s, 1H), 7.91 (d, J = 5.4 Hz, 1H), 7.64 - 7.60 (m, 1H), 7.33 - 7.27 (m, 2H), 7.27 - 7.24 (m, 1H), 6.29 (d, J = 5.4 Hz, 1H), 5.39 - 5.05 (m, 1H), 3.75 - 3.65 (m, 1H), 1.95 - 1.90 (m, 2H), 1.66 - 1.58 (m, 2H), 1.54 - 1.45 (m, 1H), 1.38 (s, 9H), 1.31 - 1.23 (m, 2H), 1.13 - 1.09 (m, 3H). LRMS (ESI+) calculated C 26 H 28 Cl2N6O2S [M+H]+: 559.1445, found: 559.28

[0780]

[0781] 78cd (112 mg, 47 %) 1 H NMR (400 MHz, CDCl3) δ8.28 (s, 1H), 8.06 (d, J = 5.4 Hz, 1H), 7.71 (dd, J = 7.1, 2.2 Hz, 1H), 7.49 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.16 (t, J = 8.7 Hz, 1H), 7.00 (s, 1H), 6.42 (d, J = 5.4 Hz, 1H), 5.14 (s, 1H), 3.92 - 3.81 (m, 1H), 2.13 - 2.06 (m, 2H), 1.82 - 1.75 (m, 2H), 1.70 - 1.63 (m, 1H), 1.53 (s, 9H), 1.48 - 1.40 (m, 2H), 1.32 - 1.25 (m, 3H). LRMS (ESI+) calculated C 26 H 28 ClFN6O2S [M+H]+: 543.174, found: 543.21

[0782]

[0783] 78ae (10 mg, 20 %) 1 H NMR (400 MHz, CDCl3) δ8.39 (s, 1H), 8.10 (t, J = 1.1 Hz, 1H), 7.91 (d, J = 5.5 Hz, 1H), 7.86 - 7.79 (m, 4H), 7.65 (dd, J = 8.4, 1.7 Hz, 1H), 7.50 - 7.46 (m, 2H), 6.47 (d, J = 5.4 Hz, 1H), 5.44 (s, 1H), 4.15 - 4.09 (m, 1H), 4.04 - 3.98 (m, 2H), 3.63 - 3.54 (m, 2H), 2.11 - 2.02 (m, 2H), 1.74 - 1.64 (m, 2H), 1.53 (s, 9H). LRMS (ESI+) calculated C 29 H 30 N6O3S [M+H]+: 543.2173, found: 543.29

[0784]

[0785] 78be (9 mg, 28 %) 1 H NMR (400 MHz, CDCl3) δ8.30 (s, 1H), 8.09 (d, J = 5.4 Hz, 1H), 7.76 (t, J = 1.2 Hz, 1H), 7.45 (d, J = 1.2 Hz, 2H), 7.21 (s, 1H), 6.49 (d, J = 5.3 Hz, 1H), 4.17 - 4.08 (m, 1H), 4.09 - 3.99 (m, 2H), 3.60 (dd, J = 11.6, 2.2 Hz, 2H), 2.12 - 2.03 (m, 2H), 1.72 - 1.60 (m, 2H), 1.53 (s, 9H). LRMS (ESI+) calculated C 25 H 26 Cl2N6O3S [M+H]+: 561.1237, found: 561.22

[0786]

[0787] 78ce (100 mg, 50 %) 1H NMR (400 MHz, CDCl3) δ8.32 (s, 1H), 8.08 (d, J = 5.4 Hz, 1H), 7.70 (dd, J = 7.1, 2.1 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.30 (s, 1H), 7.16 (t, J = 8.7 Hz, 1H), 6.46 (d, J = 5.3 Hz, 1H), 5.20 (s, 1H), 4.12 (q, J = 7.1 Hz, 1H), 4.02 (dt, J = 11.8, 3.6 Hz, 2H), 3.59 (td, J = 11.6, 2.2 Hz, 2H), 2.07 (dd, J = 12.0, 3.5 Hz, 2H), 1.71 - 1.59 (m, 2H), 1.53 (s, 9H). LRMS (ESI+) calculated C 25 H 26 ClFN6O3S [M+H]+: 545.1533, found: 545.21

[0788]

[0789] N-(5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Aryl-imidazo[2,1-b]thiazol-2-yl)acrylamide (80ad~cd, 80ae~ce)

[0790]

[0791] Compound 78ad (12 mg, 0.022 mmol) was dissolved in MC (0.22 ml), and TFA (35 μl) was added dropwise at 0 °C, then the mixture was warmed to room temperature and stirred for 1 hour and 30 minutes. After completion of the reaction, the residue was washed three times with MC and evaporated to remove residual acid, and the next reaction was carried out without purification. The reaction mixture was dissolved in THF (0.22 ml), and TEA (61 μl, 0.44 mmol) and acrloyl chloride (4.8 μl, 0.02 mmol) were added dropwise at 0 °C, then the mixture was warmed to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was extracted with EA and washed with H2O and Brine. The extracted reaction mixture was purified to remove residual moisture with anhydrous magnesium sulfate (MgSO4) and purified using PrepTLC with a mobile phase composition of EA:HEX = 1:1 to obtain compound 80ad (2.7 mg, 25%).

[0792]

[0793] 80ad (2.7 mg, 25%) 1 H NMR (400 MHz, CDCl3) δ8.52 (s, 1H), 8.36 (s, 1H), 8.14 (t, J = 1.1 Hz, 1H), 7.97 (d, J = 5.4 Hz, 1H), 7.88 - 7.80 (m, 4H), 7.70 (dd, J = 8.5, 1.7 Hz, 1H), 7.52 - 7.47 (m, 2H), 6.52 (d, J = 17.0 Hz, 1H), 6.46 (dd, J = 12.2, 5.3 Hz, 1H), 6.25 (dd, J = 16.8, 10.3 Hz, 1H), 5.87 (dd, J = 10.2, 1.1 Hz, 1H), 3.93 - 3.83 (m, 1H), 2.09 (d, J = 9.7 Hz, 2H), 1.82 - 1.74 (m, 4H), 1.48 - 1.37 (m, 4H). LRMS (ESI+) calculated C 28 H 26N6OS [M+H]+: 495.1962, found: 495.18

[0794]

[0795] 80bd (9 mg, 83 %) 1 H NMR (400 MHz, CDCl3) δ8.45 (s, 1H), 8.16 (s, 1H), 8.08 (d, J = 5.4 Hz, 1H), 7.78 (t, J = 1.2 Hz, 1H), 7.48 (d, J = 1.3 Hz, 1H), 7.37 - 7.29 (m, 1H), 6.54 (d, J = 16.8 Hz, 1H), 6.47 (d, J = 5.3 Hz, 1H), 6.26 (dd, J = 16.9, 10.3 Hz, 1H), 5.91 (d, J = 10.3 Hz, 1H), 5.33 (s, 1H), 3.87 (s, 1H), 2.14 - 2.05 (m, 2H), 1.83 - 1.76 (m, 4H), 1.45 - 1.39 (m, 4H). LRMS (ESI+) calculated C 24 H 22 Cl2N6OS [M+H]+: 513.1026, found: 513.14

[0796]

[0797] 80cd (1.7 mg, 41 %) 1 H NMR (400 MHz, CDCl3) δ8.51 (s, 1H), 8.11 (d, J = 5.5 Hz, 1H), 7.75 (dd, J = 7.1, 2.1 Hz, 1H), 7.57 - 7.51 (m, 1H), 7.20 (t, J = 8.7 Hz, 1H), 6.57 (d, J = 16.8 Hz, 1H), 6.47 (d, J = 5.4 Hz, 1H), 6.29 (s, 1H), 5.94 (d, J = 10.3 Hz, 1H), 3.97 - 3.86 (m, 1H), 2.17 - 2.01 (m, 3H), 1.91 - 1.62 (m, 7H). LRMS (ESI+) calculated C 24 H 22ClFN6OS [M+H]+: 497.1321, found: 497.41

[0798]

[0799] 80ae (0.8 mg, 9 %) 1 H NMR (400 MHz, CDCl3) δ8.15 (s, 1H), 8.11 - 8.07 (m, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.91 - 7.80 (m, 4H), 7.71 (dd, J = 8.4, 1.7 Hz, 1H), 7.54 - 7.48 (m, 2H), 6.56 (d, J = 5.5 Hz, 1H), 6.50 (d, J = 5.9 Hz, 1H), 6.25 (dd, J = 16.9, 10.3 Hz, 1H), 5.89 (dd, J = 10.3, 1.1 Hz, 1H), 5.36 - 5.29 (m, 1H), 4.14 - 4.06 (m, 2H), 4.03 (d, J = 8.7 Hz, 1H), 3.65 - 3.56 (m, 2H), 2.06 - 2.00 (m, 3H), 1.68 - 1.54 (m, 2H). LRMS (ESI+) calculated C 27 H 24 N6O2S[ M+H]+: 497.1754, found: 497.32

[0800]

[0801] 80be (0.6 mg, 8 %) 1H NMR (400 MHz, DMSO-d6) δ10.20 (s, 1H), 8.35 (s, 1H), 8.20 (d, J = 5.3 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.58 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (d, J = 6.0 Hz, 1H), 6.48 (d, J = 5.0 Hz, 1H), 6.40 (d, J = 8.5 Hz, 1H), 6.37 (dd, J = 1.3 Hz, 1H), 3.89 - 3.85 (m, 1H), 2.21 - 2.14 (m, 1H), 2.00 - 1.96 (m, 1H), 1.92 - 1.83 (m, 2H), 1.58 - 1.45 (m, 4H). LRMS (ESI+) calculated C 23 H 20 Cl2N6O2S [M+H]+: 515.0819, found: 515.23

[0802]

[0803] 80ce (3.1 mg, 6 %)

[0804] 1 H NMR (400 MHz, CDCl3) δ8.73 (s, 1H), 8.62 (s, 1H), 8.08 (d, J = 5.4 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.53 - 7.46 (m, 1H), 7.19 (t, J = 8.7 Hz, 1H), 6.56 - 6.48 (m, 2H), 6.24 (dd, J = 16.9, 10.3 Hz, 1H), 5.88 (dd, J = 10.3, 1.0 Hz, 1H), 5.32 (s, 1H), 4.08 (d, J = 11.9 Hz, 2H), 4.04 - 3.97 (m, 1H), 3.65 - 3.57 (m, 2H), 2.14 - 1.90 (m, 4H). LRMS (ESI+) calculated C 23 H 20 ClFN6O2S [M+H]+: 499.1114, found: 499.21

[0805]

[0806] 5-(2-(cycloalkylamino)pyrimidin-4-yl)-N-methoxy-N-methyl-6-Aryl-imidazo[2,1-b]thiazole-2-carboxamide (82ad~cd, 82ae~ce)

[0807]

[0808] 77ad (75 mg, 0.16 mmol) was dissolved in MC (0.32 ml), and DMF (9.9 μl, 0.13 mmol) and Oxalyl Chloride (16 μl, 0.19 mmol) were added dropwise at 0 °C, then the mixture was warmed to room temperature and stirred for 1 h. After completion of the reaction, the residue was washed three times with MC and evaporated to wash away the residual acid, and the next reaction was carried out without purification. The reaction mixture was dissolved in THF (1.6 ml), and DIPEA (47 μl, 0.48 mmol) and methoxymethylamine (23 mg, 0.24 mmol) were added, and the mixture was stirred for 2 h. The reaction mixture was extracted with EA and washed with H2O and Brine. The extracted reaction mixture was purified by removing residual moisture with anhydrous magnesium sulfate (MgSO4) and using column chromatography with a composition of mobile phase EA:HEX = 1:1 to obtain compound 82ad (2.7 mg, 25%).

[0809]

[0810] 82ad (8 mg, 13%) 1H NMR (400 MHz, CDCl3) δ9.37 (s, 1H), 8.21 - 8.17 (m, 1H), 8.00 (d, J = 5.4 Hz, 1H), 7.92 - 7.85 (m, 3H), 7.73 (dd, J = 8.4, 1.7 Hz, 1H), 7.56 - 7.49 (m, 2H), 6.49 (d, J = 5.4 Hz, 1H), 5.23 (s, 1H), 3.99 - 3.90 (m, 1H), 3.85 (s, 3H), 3.42 (s, 3H), 2.16 - 2.09 (m, 2H), 1.83 - 1.75 (m, 3H), 1.71 - 1.64 (m, 1H), 1.57 - 1.44 (m, 3H), 1.36 - 1.31 (m, 2H). LRMS (ESI+) calculated C 28 H 28 N6O2S [M+H]+: 513.2067, found: 513.24

[0811]

[0812] 82bd (20 mg, 53 %) 1 H NMR (400 MHz, CDCl3) δ9.26 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.80 (dd, J = 1.5, 0.8 Hz, 1H), 7.49 (t, J = 1.1 Hz, 2H), 6.46 (d, J = 5.2 Hz, 1H), 5.29 (s, 1H), 4.17 - 4.08 (m, 1H), 3.95 - 3.87 (m, 1H), 3.83 (s, 3H), 3.41 (s, 3H), 2.14 - 2.08 (m, 2H), 1.78 (dt, J = 13.3, 4.0 Hz, 2H), 1.71 - 1.64 (m, 1H), 1.49 (d, J = 12.6 Hz, 2H), 1.37 - 1.27 (m, 3H). LRMS (ESI+) calculated C 24 H 24 Cl2N6O2S [M+H]+: 531.1132, found: 531.21

[0813]

[0814] 82cd (55 mg, 71 %) 1 H NMR (400 MHz, CDCl3) δ9.29 (s, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.52 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 6.44 (d, J = 5.3 Hz, 1H), 5.26 - 5.19 (m, 1H), 3.93 - 3.87 (m, 1H), 3.84 (s, 3H), 3.41 (s, 3H), 2.15 - 2.06 (m, 2H), 1.84 - 1.74 (m, 3H), 1.70 - 1.62 (m, 1H), 1.56 - 1.42 (m, 2H), 1.36 - 1.24 (m, 3H). LRMS (ESI+) calculated C 24 H 24 ClFN6O2S [M+H]+: 515.1427, found: 515.19

[0815]

[0816] 82ae (55 mg, 47 %) 1 H NMR (400 MHz, CDCl3) δ9.39 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.01 (d, J = 5.4 Hz, 1H), 7.92 - 7.84 (m, 3H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.56 - 7.50 (m, 2H), 6.54 (d, J = 5.4 Hz, 1H), 5.28 (d, J = 8.0 Hz, 1H), 4.19 - 4.11 (m, 1H), 4.03 (dt, J = 11.4, 3.8 Hz, 2H), 3.86 (s, 3H), 3.71 - 3.61 (m, 2H), 3.42 (s, 3H), 2.16 - 2.09 (m, 2H), 1.71 - 1.59 (m, 2H). LRMS (ESI+) calculated C 27 H 26N6O3S [M+H]+: 515.186, found: 515.32

[0817]

[0818] 82be (80 mg, 65 %) 1 H NMR (400 MHz, CDCl3) δ9.28 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.79 (t, J = 1.2 Hz, 1H), 7.49 (d, J = 1.2 Hz, 2H), 6.51 (d, J = 5.3 Hz, 1H), 5.35 (s, 1H), 4.18 - 4.09 (m, 1H), 4.06 - 3.99 (m, 2H), 3.84 (s, 3H), 3.69 - 3.60 (m, 2H), 3.41 (s, 3H), 2.16 - 2.06 (m, 2H), 1.67 - 1.56 (m, 2H). LRMS (ESI+) calculated C 23 H 22 Cl2N6O3S [M+H]+: 533.0924, found: 533.19

[0819]

[0820] 82ce (62 mg, 71 %) 1 H NMR (400 MHz, CDCl3) δ9.30 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.52 (ddd, J = 8.5, 4.6, 2.1 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.48 (d, J = 5.3 Hz, 1H), 5.29 - 5.24 (m, 1H), 4.13 (dddd, J = 15.4, 11.7, 6.4, 2.6 Hz, 1H), 4.08 - 4.01 (m, 2H), 3.84 (s, 3H), 3.63 (td, J = 11.3, 6.2 Hz, 2H), 3.41 (s, 3H), 2.13 - 2.07 (m, 2H), 1.62 (dtd, J = 12.9, 11.1, 4.4 Hz, 2H). LRMS (ESI+) calculated C23 H 22 ClFN6O3S [M+H]+: 517.122, found: 517.16

[0821]

[0822] (E)-1-(5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Aryl-imidazo[2,1-b]thiazol-2-yl)-3-(dimethylamino)prop-2-en-1-one (84ad~cd, 84ae~ce)

[0823]

[0824] 82ad (8 mg, 0.016 mmol) was dissolved in ether (0. 4 ml), 3.1 M CH3Li in dimethoxy methane (10 μl, 0.032 mmol) was added, and the mixture was stirred for 30 min. The reaction mixture was extracted with EA and washed with a supersaturated NH4Cl solution, H2O, and Brine. The residual moisture was removed with anhydrous magnesium sulfate (MgSO4), and the residue was purified using PrepTLC with a mobile phase composition of EA:HEX = 1:1 to obtain compound 83ad (3.1 mg, 41%). The previously obtained compound 83ad (3.1 mg, 0.006 mmol) was dissolved in DMFDMA (0.5 ml), and the mixture was stirred at MW 120 ℃ for 1 h. The reaction solvent was evaporated on a rotary evaporator, and the residue was purified using PrepTLC with a mobile phase composition of MC:MeOH = 40:1 to obtain compound 84ad (1.2 mg, 38%).

[0825]

[0826] 83ad (3.1 mg, 41%) 1H NMR (400 MHz, CDCl3) δ9.23 (s, 1H), 8.23 - 8.17 (m, 1H), 8.03 (s, 1H), 7.94 - 7.83 (m, 3H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.59 - 7.48 (m, 2H), 6.53 (d, J = 5.3 Hz, 1H), 5.21 (s, 1H), 3.94 (d, J = 6.7 Hz, 1H), 2.64 (s, 3H), 2.19 - 2.10 (m, 2H), 1.89 - 1.80 (m, 2H), 1.74 - 1.64 (m, 2H), 1.51 - 1.37 (m, 4H). LRMS (ESI+) calculated C 27 H 25 N5OS [M+H]+: 468.1853, found: 468.29

[0827]

[0828] 83bd (1.3 mg, 14 %) 1 H NMR (400 MHz, CDCl3) δ9.12 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.51 (s, 2H), 6.51 (d, J = 5.2 Hz, 1H), 5.21 (s, 1H), 3.90 (s, 1H), 2.62 (s, 3H), 2.16 - 2.09 (m, 2H), 1.86 - 1.79 (m, 2H), 1.74 - 1.67 (m, 1H), 1.58 - 1.53 (m, 3H), 1.46 - 1.41 (m, 2H). LRMS (ESI+) calculated C 23 H 21 Cl2N5OS [M+H]+: 486.0917, found: 486.19

[0829]

[0830] 83cd (9 mg, 17 %) 1H NMR (400 MHz, CDCl3) δ9.14 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.76 - 7.74 (m, 1H), 7.53 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.20 (t, J = 8.7 Hz, 1H), 6.48 (d, J = 5.2 Hz, 1H), 5.31 (s, 1H), 3.95 - 3.86 (m, 1H), 2.62 (s, 3H), 2.15 - 2.08 (m, 2H), 1.83 (dt, J = 12.8, 3.8 Hz, 2H), 1.69 (d, J = 14.7 Hz, 2H), 1.50 - 1.37 (m, 4H). LRMS (ESI+) calculated C 23 H 21 ClFN5OS [M+H]+: 470.1212, found: 470.16

[0831]

[0832] 83ae (10 mg, 37 %) 1 H NMR (400 MHz, CDCl3) δ9.17 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 5.3 Hz, 1H), 7.95 - 7.83 (m, 3H), 7.72 (dd, J = 8.5, 1.8 Hz, 1H), 7.60 - 7.49 (m, 2H), 6.57 (d, J = 5.3 Hz, 1H), 5.24 (s, 1H), 4.20 - 4.12 (m, 1H), 4.06 (dq, J = 7.4, 5.4 Hz, 2H), 3.58 (td, J = 11.5, 2.3 Hz, 2H), 2.63 (s, 3H), 2.18 - 2.10 (m, 2H), 1.68 (tt, J = 15.4, 7.6 Hz, 2H). LRMS (ESI+) calculated C 26 H 23 N5O2S [M+H]+: 470.1645, found: 470.34

[0833]

[0834] 83be (8 mg, 22 %) 1 H NMR (400 MHz, CDCl3) δ9.07 (s, 1H), 8.17 (d, J = 5.3 Hz, 1H), 7.80 (t, J = 1.2 Hz, 1H), 7.50 (d, J = 1.3 Hz, 2H), 6.54 (s, 1H), 5.24 (s, 1H), 4.15 - 4.11 (m, 1H), 4.05 (dd, J = 11.9, 3.7 Hz, 2H), 3.58 (td, J = 11.6, 2.3 Hz, 2H), 2.62 (s, 3H), 2.16 - 2.07 (m, 2H), 1.73 - 1.62 (m, 2H). LRMS (ESI+) calculated C 22 H 19 Cl2N5O2S [M+H]+: 488.071, found: 488.22

[0835]

[0836] 83ce (34 mg, 60 %) 1 H NMR (400 MHz, CDCl3) δ9.08 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.73 (dd, J = 7.0, 2.2 Hz, 1H), 7.51 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.19 (t, J = 8.6 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 5.35 (s, 1H), 4.15 - 4.09 (m, 1H), 4.03 (dt, J = 11.9, 3.7 Hz, 2H), 3.58 (dd, J = 11.5, 2.2 Hz, 2H), 2.60 (s, 3H), 2.15 - 2.07 (m, 2H), 1.72 - 1.59 (m, 2H). LRMS (ESI+) calculated C 22 H 19 ClFN5O2S [M+H]+: 472.1005, found: 472.24

[0837]

[0838] 84ad (1.4 mg, 23 %)1 H NMR (400 MHz, DMSO-d6) δ9.33 (s, 1H), 9.04 (s, 1H), 8.22 (s, 1H), 8.09 (d, J = 5.2 Hz, 1H), 8.02 - 7.95 (m, 3H), 7.82 (d, J = 12.1 Hz, 1H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.60 - 7.53 (m, 2H), 6.37 (s, 1H), 5.96 (s, 1H), 3.82 - 3.74 (m, 1H), 3.29 (s, 3H), 3.20 (s, 3H), 2.02 - 1.94 (m, 2H), 1.79 - 1.68 (m, 2H), 1.65 - 1.51 (m, 2H), 1.37 - 1.25 (m, 4H). LRMS (ESI+) calculated C 30 H 30 N6OS [M+H]+: 523.2275, found: 523.38

[0839]

[0840] 84bd (1.1 mg, 15 %) 1 H NMR (400 MHz, CDCl3) δ8.92 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 12.1 Hz, 1H), 7.82 (d, J = 1.9 Hz, 1H), 7.55 - 7.47 (m, 2H), 6.48 (d, J = 5.2 Hz, 1H), 5.43 (d, J = 12.1 Hz, 1H), 3.98 - 3.89 (m, 1H), 3.21 (s, 3H), 2.97 (s, 3H), 2.13 - 2.08 (m, 2H), 2.05 - 1.98 (m, 2H), 1.83 - 1.63 (m, 6H). LRMS (ESI+) calculated C 26 H 26 Cl2N6OS [M+H]+: 541.1339, found: 541.38

[0841]

[0842] 84cd (0.6 mg, 6 %)1 H NMR (400 MHz, DMSO-d6) δ8.33 (s, 1H), 8.17 (s, 1H), 7.85 - 7.79 (m, 2H), 7.74 - 7.71 (m, 1H), 7.68 - 7.65 (m, 1H), 7.55 - 7.46 (m, 2H), 7.34 (d, J = 6.2 Hz, 1H), 3.18 (s, 3H), 2.99 (s, 3H), 2.00 - 1.92 (m, 3H), 1.78 - 1.69 (m, 4H), 1.59 - 1.45 (m, 6H). LRMS (ESI+) calculated C 27 H 27 ClFN5OS [M+H]+: 524.1682, found: 524.32

[0843]

[0844] 84ae (5.0 mg, 45 %) 1 H NMR (400 MHz, CDCl3) δ9.06 (s, 1H), 8.18 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 5.6 Hz, 1H), 7.93 - 7.83 (m, 4H), 7.72 (dd, J = 8.5, 1.8 Hz, 1H), 7.58 - 7.50 (m, 2H), 6.55 (d, J = 5.5 Hz, 1H), 5.42 (d, J = 12.1 Hz, 1H), 4.24 - 4.14 (m, 1H), 4.04 (dt, J = 11.9, 3.8 Hz, 2H), 3.64 (t, J = 11.1 Hz, 2H), 3.23 (s, 2H), 2.97 (s, 2H), 2.18 - 2.11 (m, 2H), 1.76 - 1.63 (m, 2H). LRMS (ESI+) calculated C 29 H 28 N6O2S [M+H]+: 525.2067, found: 525.27

[0845]

[0846] 84be (2.8 mg, 43 %) 1H NMR (400 MHz, CDCl3) δ8.95 (s, 1H), 8.09 (d, J = 10.9 Hz, 1H), 7.89 (d, J = 12.0 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.56 - 7.45 (m, 2H), 6.54 (d, J = 5.5 Hz, 1H), 5.39 (d, J = 12.0 Hz, 1H), 4.22 - 4.12 (m, 1H), 4.03 (dd, J = 9.7, 6.0 Hz, 2H), 3.64 (t, J = 11.1 Hz, 2H), 3.22 (s, 3H), 2.98 (s, 3H), 2.16 - 2.09 (m, 2H), 2.08 - 1.98 (m, 2H). LRMS (ESI+) calculated C 25 H 24 Cl2N6O2S [M+H]+: 543.1132, found: 543.39

[0847]

[0848] 84ce (2. 4 mg, 7 %) 1 H NMR (400 MHz, DMSO-d6) δ9.22 (s, 0H), 8.20 (d, J = 10.6 Hz, 1H), 7.82 (dd, J = 9.4, 6.3 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.42 - 7.34 (m, 1H), 6.44 (s, 1H), 5.91 (d, J = 8.7 Hz, 1H), 4.02 - 3.94 (m, 1H), 3.93 - 3.86 (m, 2H), 3.82 - 3.69 (m, 2H), 3.20 (s, 3H), 2.99 (s, 3H), 1.95 - 1.84 (m, 2H), 1.60 - 1.50 (m, 2H). LRMS (ESI+) calculated C 25 H 24 ClFN6O2S [M+H]+: 527.1427, found: 527.17

[0849]

[0850] 1-(5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Arylimidazo[2,1-b]thiazol-2-yl)prop-2-en-1-one (85ad, 85ae)

[0851]

[0852] Compound 82ad (8 mg, 0.016 mmol) was dissolved in anhydrous THF (0.16 ml), and 1.0 M Vinyl Magnesium Bromide in THF (80 μl, 0.08 mmol) was added and stirred for 30 min. The reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature and stirred for an additional 3 h. The solvent was evaporated under reduced pressure, and the mixture was concentrated. The reaction was quenched with saturated NH4Cl, diluted with EA, and washed with deionized water and saturated brine. Anhydrous Na2SO4 was used to remove moisture, and the solvent was concentrated. Compound 85ad (1.4 mg, 19%) was obtained through preparative TLC (EA=1:1).

[0853]

[0854] 85ad (1.4 mg, 19%) 1 H NMR (400 MHz, CDCl3) δ8.19 (s, 1H), 7.94 - 7.85 (m, 5H), 7.73 (d, J = 8.8 Hz, 2H), 7.59 - 7.52 (m, 3H), 6.65 (d, J = 16.6 Hz, 1H), 6.55 (d, J = 5.8 Hz, 1H), 6.01 (d, J = 11.7 Hz, 1H), 2.36 - 2.30 (m, 2H), 2.20 - 2.12 (m, 3H), 2.06 - 2.00 (m, 2H), 1.89 - 1.83 (m, 3H). LRMS (ESI+) calculated C 28 H 25 N5OS [M+H]+: 480.1853, found: 480.26

[0855]

[0856] 85ae (2.8 mg, 17 %) 1 H NMR (400 MHz, CDCl3) δ9.27 (s, 1H), 8.19 (s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.90 (q, J = 8.2 Hz, 4H), 7.73 (dd, J = 8.5, 1.8 Hz, 1H), 7.59 - 7.50 (m, 3H), 6.64 (dd, J = 17.0, 1.3 Hz, 1H), 6.58 (d, J = 5.3 Hz, 1H), 6.02 (dd, J = 10.4, 1.3 Hz, 1H), 4.15 - 4.02 (m, 3H), 3.65 - 3.56 (m, 2H), 2.18 - 2.11 (m, 2H), 2.06 - 1.99 (m, 2H). LRMS (ESI+) calculated C 27 H 23 N5O2S [M+H]+: 482.1645, found: 482.27

[0857]

[0858] 5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Aryl-N-(prop-2-yn-1-yl)imidazo[2,1-b]thiazole-2-carboxamide (86ad~cd, 86ae~ce)

[0859]

[0860] 77ad (67 mg, 0.14 mmol) was dissolved in MC (0.28 ml), and DMF (8.0 μl, 0.1 mmol) and oxalyl chloride (14 μl, 0.17 mmol) were added dropwise at 0 °C, then the mixture was warmed to room temperature and stirred for 1 h. After completion of the reaction, the residue was washed three times with MC and evaporated to wash away the residual acid, and the next reaction was carried out without purification. The reaction mixture was dissolved in THF (1.6 ml), and DIPEA (47 μl, 0.48 mmol) and propagyllamine (8.2 μl, 0.13 mmol) were added, and the mixture was stirred for 2 h. The reaction mixture was extracted with EA and washed with H2O and Brine. The extracted reaction mixture was purified by removing residual moisture with anhydrous magnesium sulfate (MgSO4) and using column chromatography with a mobile phase composition of EA:HEX = 1:3 to obtain compound 86ad (9.0 mg, 13%).

[0861]

[0862] 86ad (9 mg, 13%) 1 H NMR (400 MHz, CDCl3) δ9.08 (s, 1H), 8.14 - 8.09 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.95 - 7.86 (m, 2H), 7.64 (dd, J = 8.3, 1.7 Hz, 1H), 7.62 - 7.55 (m, 3H), 6.55 (d, J = 6.8 Hz, 1H), 6.26 (s, 1H), 4.29 (dd, J = 5.2, 2.6 Hz, 2H), 4.03 - 3.94 (m, 1H), 2.35 (t, J = 2.6 Hz, 1H), 2.19 - 2.09 (m, 2H), 1.95 - 1.84 (m, 2H), 1.78 - 1.69 (m, 1H), 1.62 - 1.44 (m, 4H), 1.38 - 1.28 (m, 1H). LRMS (ESI+) calculated C 29 H 26N6OS [M+H]+: 507.1962, found: 507.27

[0863] 86bd (6 mg, 5 %) 1 H NMR (400 MHz, CDCl3) δ9.04 (s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.79 (t, J = 1.1 Hz, 1H), 7.49 (s, 2H), 6.48 (d, J = 5.3 Hz, 1H), 6.10 (s, 1H), 5.26 (d, J = 8.0 Hz, 1H), 4.28 (dd, J = 5.2, 2.6 Hz, 2H), 3.92 - 3.84 (m, 1H), 2.34 (t, J = 2.6 Hz, 1H), 2.17 - 2.06 (m, 2H), 1.91 - 1.78 (m, 2H), 1.54 - 1.40 (m, 3H), 1.38 - 1.31 (m, 3H). LRMS (ESI+) calculated C 25 H 22 Cl2N6OS [M+H]+: 525.1026, found: 525.18

[0864] 86cd (3.2 mg, 5 %) 1 H NMR (400 MHz, CDCl3) δ9.03 (s, 1H), 7.73 (d, J = 6.7 Hz, 1H), 7.70 (dd, J = 6.9, 2.2 Hz, 1H), 7.48 (ddd, J = 8.5, 4.5, 2.2 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 6.6 Hz, 1H), 6.07 (s, 1H), 4.29 (dd, J = 5.2, 2.6 Hz, 2H), 4.01 - 3.90 (m, 1H), 2.36 (t, J = 2.6 Hz, 1H), 2.17 - 2.09 (m, 2H), 1.97 - 1.87 (m, 2H), 1.78 - 1.68 (m, 1H), 1.63 - 1.46 (m, 4H), 1.40 - 1.30 (m, 1H). LRMS (ESI+) calculated C 25 H22 ClFN6OS [M+H]+: 509.1321, found: 509.16

[0865] 86ae (21 mg, 34 %) 1 H NMR (400 MHz, CDCl3) δ9.13 (s, 1H), 8.07 - 8.05 (m, 1H), 7.96 (d, J = 5.4 Hz, 1H), 7.86 - 7.81 (m, 2H), 7.77 (dd, J = 7.7, 1.7 Hz, 1H), 7.61 (dd, J = 8.4, 1.7 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.36 (s, 1H), 6.46 (d, J = 5.4 Hz, 1H), 4.24 (dd, J = 5.3, 2.6 Hz, 2H), 4.06 - 3.95 (m, 3H), 3.55 (td, J = 11.8, 2.2 Hz, 2H), 2.31 (t, J = 2.5 Hz, 1H), 2.08 - 1.98 (m, 2H), 1.77 - 1.55 (m, 2H). LRMS (ESI+) calculated C 28 H 24 N6O2S [M+H]+: 509.1754, found: 509.35

[0866] 86be (21 mg, 15 %) 1 H NMR (400 MHz, CDCl3) δ9.05 (s, 1H), 7.88 (s, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 7.09 (s, 1H), 6.56 (d, J = 6.2 Hz, 1H), 4.26 (d, J = 2.5 Hz, 2H), 4.13 (d, J = 11.9 Hz, 2H), 4.01 (s, 1H), 3.67 - 3.56 (m, 2H), 2.33 (t, J = 2.5 Hz, 1H), 2.26 - 2.00 (m, 4H). LRMS (ESI+) calculated C 24 H 20Cl2N6O2S [M+H]+: 527.0819, found: 527.17

[0867] 86ce (30 mg, 39 %) 1 H NMR (400 MHz, CDCl3) δ9.05 (s, 1H), 7.94 (s, 1H), 7.66 (dd, J = 7.0, 2.2 Hz, 1H), 7.46 (ddd, J = 8.5, 4.5, 2.2 Hz, 1H), 7.26 (s, 1H), 7.21 (t, J = 8.6 Hz, 1H), 6.49 (d, J = 5.8 Hz, 1H), 4.24 (dd, J = 5.4, 2.5 Hz, 2H), 4.08 (dt, J = 12.0, 3.3 Hz, 2H), 4.04 - 3.94 (m, 1H), 3.60 (dd, J = 11.3, 2.6 Hz, 2H), 2.32 (t, J = 2.5 Hz, 1H), 2.07 - 1.84 (m, 4H). LRMS (ESI+) calculated C 24 H 20 ClFN6O2S [M+H]+: 511.1114, found: 511.34

[0868]

[0869] 5.4. Imidazo[2,1-b]oxazole-based covalent JNK3 inhibitors (Scheme 4)

[0870] 5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-phenylimidazo[2,1-b]oxazole-2-carboxylic acid (100ad~cd, 100ae~ce)

[0871]

[0872] Compound 99ad (100 mg, 0.21 mmol) was dissolved in EtOH (1.05 ml) and H2O (1.05 ml), 2 M NaOH (0.13 ml, 0.25 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction, 2 M HCl was added at 0°C to adjust the pH to 2, and filtered using H2O. The filtercake was dried in an oven to obtain compound 100ad (86 mg, 90%).

[0873] 100ad (86 mg, 90%) 1 H NMR (400 MHz, DMSO-d6) δ9.33 (s, 1H), 8.20 (s, 1H), 8.01 (q, J = 7.0 Hz, 4H), 7.72 (d, J = 8.5 Hz, 1H), 7.59 (dd, J = 9.8, 5.5 Hz, 3H), 6.35 (s, 1H), 3.70 (s, 1H), 1.96 (d, J = 9.8 Hz, 2H), 1.75 (d, J = 10.5 Hz, 3H), 1.62 (d, J = 12.3 Hz, 2H), 1.31 (t, J = 10.7 Hz, 4H).; LRMS (ESI+) calculated for C 26 H 23 N5O3[M+H]+: 453.19, found 453.20.

[0874]

[0875] 100bd (136 mg, 91%) 1H NMR (400 MHz, DMSO-d6) δ9.26 (s, 1H), 8.11 (d, J = 5.2 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 8.4, 2.1 Hz, 1H), 7.57 - 7.34 (m, 1H), 6.36 (s, 1H), 3.76 - 3.51 (m, 2H), 1.93 (d, J = 10.3 Hz, 2H), 1.73 (dd, J = 9.2, 3.5 Hz, 2H), 1.61 (d, J = 12.1 Hz, 1H), 1.37 - 1.08 (m, 5H). ; LRMS (ESI+) calculated for C 22 H 19 Cl2N5O3[M+H]+: 472.09, found 472.10

[0876]

[0877] 100cd (101 mg, 85%) 1 H NMR (400 MHz, DMSO-d6) δ9.21 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 1H), 7.54 (s, 1H), 6.53 (s, 1H), 6.36 (s, 1H), 3.70 (s, 2H), 1.93 (d, J = 10.3 Hz, 2H), 1.73 (s, 2H), 1.65 - 1.56 (m, 1H), 1.29 (s, 2H), 1.22 - 1.10 (m, 2H).; LRMS (ESI+) calculated for C 22 H 19 ClFN5O3[M+H]+: 456.12, found 456.10.

[0878]

[0879] 100ae (175 mg, 69%) ; 1H NMR (400 MHz, DMSO-d6) δ9.30 (s, 1H), 8.19 (d, J = 1.7 Hz, 1H), 8.04 (s, 2H), 8.02 - 7.95 (m, 3H), 7.72 (dd, J = 8.4, 1.7 Hz, 2H), 7.62 - 7.54 (m, 2H), 6.39 (s, 1H), 3.89 (d, J = 11.7 Hz, 3H), 3.38 (s, 2H), 1.89 (d, J = 12.7 Hz, 2H), 1.59 - 1.46 (m, 2H).LRMS (ESI+) calculated for C 25 H 21 N5O4[M+H]+: 456.17, found 456.19.

[0880]

[0881] 100be (110 mg, 88%) 1 H NMR (400 MHz, DMSO-d6) δ9.25 (s, 1H), 8.20 - 8.14 (m, 1H), 7.86 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.3, 2.0 Hz, 2H), 6.52 (s, 1H), 6.42 (d, J = 8.1 Hz, 1H), 3.89 (ddd, J = 11.7, 4.3, 2.2 Hz, 3H), 1.87 (s, 2H), 1.57 - 1.45 (m, 2H), 1.18 (s, 2H).; LRMS (ESI+) calculated for C 21 H 17 Cl2N5O4[M+H]+: 474.07, found 474.10.

[0882]

[0883] 100ce(179 mg, 83%) 1H NMR (400 MHz, DMSO-d6) δ9.26 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.81 (dd, J = 7.2, 2.1 Hz, 1H), 7.64 (ddd, J = 8.6, 4.8, 2.2 Hz, 2H), 7.55 (t, J = 8.9 Hz, 1H), 7.40 (s, 1H), 6.52 (s, 1H), 6.37 (d, J = 6.7 Hz, 1H), 3.90 (ddd, J = 11.6, 4.3, 2.2 Hz, 4H), 1.95 - 1.79 (m, 2H), 1.59 - 1.45 (m, 2H).; LRMS (ESI+) calculated for C 21 H 17 ClFN5O4[M+H]+: 458.10, found 458.18.

[0884]

[0885] N-cycloalkyl-4-(2-isocyanato-6-Aryl-imidazo[2,1-b]oxazol-5-yl)pyrimidin-2-amine (101ad~bd, 101ae~ce)

[0886]

[0887] Compound 100ad (179 mg, 0.39 mmol) was dissolved in anhydrous ACN (2 ml), and DPPA (0.10 ml, 0.47 mmol) and TEA (0.08 ml, 0.59 mmol) were added, and the mixture was stirred at 70°C for 30 min. After confirming the completion of the reaction, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with NaHCO3 and brine. After removing moisture with anhydrous sodium sulfate (Na2SO4), the solvent was concentrated, and the residue was purified by column chromatography using a mobile phase of EA:Hex (1:4) to obtain compound 101ad (121 mg, 69%).

[0888] 101ad (121 mg, 69%). 1H NMR (400 MHz, Chloroform-d) δ8.82 (s, 1H), 8.17 (t, J = 1.1 Hz, 1H), 7.99 (d, J = 5.2 Hz, 1H), 7.95 - 7.84 (m, 4H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 - 7.50 (m, 2H), 6.57 (d, J = 5.4 Hz, 1H), 3.90 - 3.82 (m, 1H), 2.20 - 2.12 (m, 2H), 1.86 (d, J = 13.0 Hz, 2H), 1.73 (d, J = 13.0 Hz, 1H), 1.50 (t, J = 12.7 Hz, 2H), 1.40 - 1.30 (m, 3H). ; LRMS (ESI+) calculated for C 26 H 22 N6O2[M+H]+: 451.19, found 451.17.

[0889]

[0890] 101bd (59 mg, 45 %). 1 H NMR (400 MHz, Chloroform-d) δ8.76 (s, 1H), 8.11 (d, J = 5.4 Hz, 1H), 7.80 - 7.77 (m, 1H), 7.51 (d, J = 1.7 Hz, 2H), 6.53 (d, J = 5.3 Hz, 1H), 5.34 (d, J = 5.5 Hz, 1H), 3.84 (dtd, J = 10.4, 7.5, 3.9 Hz, 1H), 2.17 - 2.09 (m, 2H), 1.84 (d, J = 12.8 Hz, 2H), 1.72 (d, J = 12.9 Hz, 2H), 1.49 (d, J = 12.3 Hz, 2H), 1.32 (d, J = 10.3 Hz, 2H). ; LRMS (ESI+) calculated for C 22 H 18 Cl2N6O2[M+H]+: 469.09, found 469.08.

[0891]

[0892] 101cd (53 mg, 57%). 1 H NMR (400 MHz, Chloroform-d) δ8.77 (s, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.74 (dd, J = 7.1, 2.2 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.22 (t, J = 8.6 Hz, 2H), 6.50 (d, J = 5.3 Hz, 1H), 5.35 (d, J = 6.2 Hz, 1H), 3.87 - 3.80 (m, 1H), 2.16 - 2.11 (m, 2H), 1.85 (d, J = 13.2 Hz, 3H), 1.75 - 1.68 (m, 4H).; LRMS (ESI+) calculated for C 22 H 18 ClFN6O2[M+H]+:453.12 , found .453.16

[0893]

[0894] 101ae (193 mg, 79 %). 1 H NMR (400 MHz, Chloroform-d) δ8.79 (s, 1H), 8.17 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.94 - 7.84 (m, 3H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 - 7.50 (m, 2H), 6.61 (d, J = 5.4 Hz, 1H), 5.24 (s, 1H), 4.07 (dd, J = 11.5, 3.9 Hz, 2H), 3.61 (t, J = 11.5 Hz, 2H), 2.12 (d, J = 12.9 Hz, 2H), 1.72 - 1.60 (m, 3H). ; LRMS (ESI+) calculated for C 25 H 20 N6O3[M+H]+: 453.17, found 453.16.

[0895]

[0896] 101be (60 mg, 45%). 1H NMR (400 MHz, Chloroform-d) δ8.73 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.53 - 7.44 (m, 2H), 6.58 (d, J = 5.4 Hz, 1H), 5.59 (s, 1H), 4.08 - 4.02 (m, 2H), 3.66 - 3.54 (m, 2H), 2.10 (ddd, J = 12.8, 4.6, 2.2 Hz, 2H), 1.66 (qd, J = 11.2, 4.3 Hz, 3H). ; LRMS (ESI+) calculated for C 21 H 16 Cl2N6O3[M+H]+: 471.07, found 471.07.

[0897]

[0898] 101ce (100 mg, 56%). 1 H NMR (400 MHz, Chloroform-d) δ8.74 (s, 1H), 8.13 (d, J = 5.4 Hz, 1H), 7.75 - 7.72 (m, 1H), 7.56 - 7.50 (m, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.55 (d, J = 5.3 Hz, 1H), 5.30 (s, 1H), 4.07 (d, J = 12.3 Hz, 2H), 3.61 (t, J = 11.9 Hz, 2H), 2.11 (d, J = 13.2 Hz, 2H), 1.67 (s, 3H). ; LRMS (ESI+) calculated for C 21 H 16 ClFN6O3[M+H]+: 455.10, found 455.06.

[0899]

[0900] N-(5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Aryl-imidazo[2,1-b]oxazol-2-yl)acrylamide (103ad~cd, 103ae~ce)

[0901]

[0902] Compound 101ad (121 mg, 0.27 mmol) was dissolved in 1,4-Dioxane (1 ml), water (5 μl, 0.27 mmol) was added, and the mixture was stirred at 90°C for 3 hours. After confirming the completion of the reaction, the solvent was concentrated using a rotary evaporator, and the residue was purified by column chromatography using a mobile phase of EA:Hex (1:1) to obtain compound 102ad (61 mg, 52%).

[0903] Compound 102ad (61 mg, 52%) was dissolved in anhydrous THF, and TEA (0.37 ml, 2.1 mmol) and acryloyl chloride (0.01 ml, 0.13 mmol) were added, and the mixture was stirred for 20 minutes. After confirming the completion of the reaction, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with NaHCO3 and brine. After removing moisture with anhydrous sodium sulfate (Na2SO4), the solvent was concentrated, and the residue was purified by column chromatography using a mobile phase of EA:Hex (1:4) to obtain compound 103ad (18 mg, 27%).

[0904]

[0905] 102ad (61 mg, 52%). 1H NMR (400 MHz, Chloroform-d) δ11.67 (s, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 4H), 7.55 - 7.47 (m, 2H), 7.45 (dd, J = 8.5, 1.8 Hz, 1H), 6.24 (d, J = 5.3 Hz, 1H), 5.90 (s, 1H), 5.11 (s, 2H), 3.89 (d, J = 10.4 Hz, 1H), 2.10 - 2.04 (m, 2H), 1.83 - 1.73 (m, 2H), 1.70 - 1.61 (m, 1H), 1.48 - 1.37 (m, 2H), 1.35 - 1.26 (m, 3H). ; LRMS (ESI+) calculated for C 25 H 24 N6O [M+H]+: 425.21, found 425.21.

[0906]

[0907] 102bd (30 mg, 52 %). 1 H NMR (400 MHz, Chloroform-d) δ11.44 (s, 1H), 8.08 (s, 1H), 7.57 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.34 - 7.23 (m, 1H), 6.31 (d, J = 5.1 Hz, 1H), 5.70 - 5.28 (m, 1H), 5.08 (s, 2H), 3.89 (s, 1H), 2.06 (d, J = 12.6 Hz, 3H), 1.79 (s, 2H), 1.66 (s, 2H), 1.44 (q, J = 12.1 Hz, 3H). ; LRMS (ESI+) calculated for C 21 H 20 Cl2N6O [M+H]+: 443.11, found 443.12.

[0908]

[0909] 102cd (53 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ11.56 (s, 1H), 8.07 (d, J = 5.6 Hz, 1H), 7.74 (dd, J = 7.1, 2.0 Hz, 1H), 7.69 - 7.55 (m, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.48 - 7.44 (m, 1H), 6.26 - 6.13 (m, 1H), 5.22 - 4.99 (m, 2H), 4.67 (s, 1H), 3.95 - 3.58 (m, 2H), 1.92 - 1.84 (m, 2H), 1.71 (d, J = 11.5 Hz, 2H), 1.59 (d, J = 12.9 Hz, 1H), 1.35 (d, J = 12.3 Hz, 1H), 1.24 - 1.09 (m, 2H). ; LRMS (ESI+) calculated for C 22 H 18 ClFN6O2[M+H]+:427.14 , found 427.10.

[0910]

[0911] 102ae (100 mg, 51%). 1 H NMR (400 MHz, Chloroform-d) δ10.99 (s, 1H), 7.96 (d, J = 1.8 Hz, 2H), 7.90 - 7.83 (m, 3H), 7.59 - 7.52 (m, 2H), 7.46 (dd, J = 8.5, 1.8 Hz, 1H), 6.33 (d, J = 5.3 Hz, 1H), 5.62 - 5.41 (m, 1H), 5.07 (s, 2H), 4.02 (dt, J = 11.7, 3.6 Hz, 2H), 3.62 - 3.55 (m, 2H), 2.07 (d, J = 2.2 Hz, 1H), 2.05 (q, J = 2.1 Hz, 1H), 1.69 - 1.56 (m, 3H). ; LRMS (ESI+) calculated for C 24 H 22 N6O2[M+H]+: 427.19, found 427.20.

[0912]

[0913] 102be (28 mg, 48 %). 1 H NMR (400 MHz, Chloroform-d) δ10.98 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.30 (dd, J = 8.3, 2.1 Hz, 1H), 6.35 (d, J = 5.1 Hz, 1H), 5.46 (s, 1H), 5.02 (s, 2H), 4.02 (dt, J = 11.6, 3.5 Hz, 2H), 3.58 (td, J = 11.6, 2.2 Hz, 2H), 2.07 (s, 1H), 1.65 (t, J = 7.9 Hz, 2H), 1.62 - 1.56 (m, 2H). ; LRMS (ESI+) calculated for C 20 H 18 Cl2N6O2[M+H]+: 445.09, found 445.11.

[0914]

[0915] 102ce (23 mg, 57%). 1 H NMR (400 MHz, Chloroform-d) δ9.38 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.49 (dd, J = 6.8, 2.3 Hz, 1H), 7.31 (ddd, J = 8.6, 4.5, 2.2 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.28 (d, J = 5.2 Hz, 1H), 5.23 (s, 1H), 5.03 (s, 2H), 4.02 (d, J = 11.8 Hz, 2H), 3.58 (t, J = 11.5 Hz, 3H), 2.06 (d, J = 10.9 Hz, 4H). ; LRMS (ESI+) calculated for C 20 H 18 ClFN6O2[M+H]+: 429.12, found 429.09.

[0916]

[0917] 103ad (18 mg, 27%). 1 H NMR (400 MHz, Chloroform-d) δ7.89 (dd, J = 10.3, 8.2 Hz, 2H), 7.86 - 7.81 (m, 1H), 7.80 - 7.74 (m, 2H), 7.55 (dd, J = 6.9, 1.5 Hz, 1H), 7.52 (t, J = 1.7 Hz, 1H), 7.50 - 7.48 (m, 1H), 7.45 (d, J = 6.6 Hz, 1H), 7.44 - 7.40 (m, 1H), 6.48 (dd, J = 16.9, 1.5 Hz, 1H), 5.95 (dd, J = 10.4, 1.5 Hz, 1H), 5.83 (d, J = 5.2 Hz, 1H), 5.24 (d, J = 3.0 Hz, 1H), 5.16 (s, 1H), 3.85 (s, 1H), 2.08 - 2.02 (m, 2H), 1.77 (dt, J = 13.3, 4.0 Hz, 2H), 1.70 - 1.60 (m, 2H), 1.47 - 1.40 (m, 2H), 1.28 (s, 2H). ; LRMS (ESI+) calculated for C 28 H 26 N6O2[M+H]+: 479.22, found 479.32.

[0918]

[0919] 103bd (1.4 mg, 9%). 1H NMR (400 MHz, Chloroform-d) δ7.81 (s, 1H), 7.64 - 7.57 (m, 1H), 7.54 (dd, J = 9.2, 5.1 Hz, 1H), 7.47 - 7.36 (m, 2H), 7.18 (dd, J = 8.3, 2.1 Hz, 1H), 6.56 (dd, J = 17.0, 1.3 Hz, 1H), 6.05 (d, J = 10.5 Hz, 1H), 5.93 (d, J = 6.0 Hz, 1H), 5.14 (s, 1H), 5.10 (s, 2H), 3.93 (s, 1H), 1.84 (s, 3H), 1.66 (s, 2H), 1.47 - 1.37 (m, 4H), 1.33 (s, 2H). ; LRMS (ESI+) calculated for C 24 H 22 Cl2N6O2[M+H]+: 497.12, found 497.32.

[0920]

[0921] 103cd (1.4 mg, 2%). 1 H NMR (400 MHz, Chloroform-d) δ7.77 (s, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.41 - 7.39 (m, 1H), 7.36 (d, J = 10.4 Hz, 1H), 7.28 (s, 1H), 7.26 - 7.24 (m, 1H), 6.57 (dd, J = 16.9, 1.3 Hz, 1H), 6.07 (dd, J = 10.4, 1.3 Hz, 1H), 5.92 (d, J = 6.4 Hz, 1H), 5.14 (d, J = 6.4 Hz, 1H), 5.11 (s, 1H), 3.96 (s, 1H), 2.01 (d, J = 12.2 Hz, 2H), 1.86 (d, J = 12.7 Hz, 2H), 1.68 (d, J = 12.4 Hz, 1H), 1.53 - 1.46 (m, 2H), 1.41 (d, J = 12.4 Hz, 2H), 1.32 (s, 1H). ; LRMS (ESI+) calculated for C24 H 22 ClFN6O2[M+H]+: 481.15, found 481.31.

[0922]

[0923] 103ae (33 mg, 30%). 1 H NMR (400 MHz, Chloroform-d) δ7.93 - 7.88 (m, 2H), 7.88 - 7.86 (m, 1H), 7.80 - 7.76 (m, 1H), 7.75 (d, J = 1.7 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.53 (t, J = 1.9 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.45 (d, J = 6.5 Hz, 1H), 7.43 - 7.40 (m, 1H), 6.49 (dd, J = 17.0, 1.5 Hz, 1H), 5.96 (dd, J = 10.4, 1.5 Hz, 1H), 5.89 (d, J = 5.2 Hz, 1H), 5.20 (d, J = 5.8 Hz, 1H), 5.10 (s, 1H), 4.00 (ddd, J = 12.0, 4.1, 2.5 Hz, 2H), 3.56 (t, J = 11.4 Hz, 2H), 2.01 (dt, J = 4.6, 2.2 Hz, 1H), 1.65 - 1.53 (m, 4H). ; LRMS (ESI+) calculated for C 27 H 24 N6O3[M+H]+: 481.20, found 481.31.

[0924]

[0925] 103be (0.5 mg, 3%). 1H NMR (400 MHz, Chloroform-d) δ7.86 (s, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.38 - 7.27 (m, 1H), 6.97 (d, J = 6.8 Hz, 1H), 6.65 (d, J = 6.8 Hz, 1H), 6.34 (d, J = 6.5 Hz, 1H), 5.34 (s, 1H), 5.19 (s, 1H), 4.06 (d, J = 5.5 Hz, 2H), 3.62 - 3.55 (m, 4H), 3.17 (d, J = 7.0 Hz, 2H), 2.35 (t, J = 7.6 Hz, 2H), 1.60 (s, 1H).; LRMS (ESI+) calculated for C 24 H 22 Cl2N6O2[M+H]+: 497.12, found 497.13.

[0926]

[0927] 103ce (0.4 mg, 2%). 1 H NMR (400 MHz, Chloroform-d) δ7.91 (s, 1H), 7.63 - 7.53 (m, 1H), 7.48 (s, 1H), 7.45 - 7.39 (m, 1H), 7.35 (s, 1H), 7.27 - 7.21 (m, 1H), 6.58 (d, J = 16.8 Hz, 1H), 6.07 (d, J = 10.5 Hz, 1H), 5.97 (d, J = 5.8 Hz, 1H), 5.39 (s, 1H), 5.05 (s, 1H), 4.15 (s, 1H), 4.05 (d, J = 11.8 Hz, 2H), 3.59 (t, J = 11.4 Hz, 2H), 3.46 - 3.36 (m, 1H), 2.77 (s, 1H), 2.03 (d, J = 12.5 Hz, 2H). ; LRMS (ESI+) calculated for C 23 H 20ClFN6O3[M+H]+: 483.13, found 483.30

[0928]

[0929] 5-(2-(cycloalkylamino)pyrimidin-4-yl)-N-methoxy-N-methyl-6-Aryl-imidazo[2,1-b]oxazole-2-carboxamide (105ad~cd, 105ce)

[0930]

[0931] Compound 100ad (107 mg, 0.23 mmol) was dissolved in anhydrous MC (0.2 ml), and at 0°, DMF (0.01 ml, 0.18 mmol) and oxalyl chloride (0.1 ml, 1.15 mmol) were added. The temperature was slowly raised to room temperature and stirred for 1 hour. The solvent was evaporated using an evaporator, and the reaction mixture 104ad after evaporation was dissolved in THF (2 ml), DIPEA (0.43 ml) was added, and N,O-Dimethylhydroxylamine hydrochloride (40 mg, 0.41 mmol) was added and stirred at room temperature for 5 minutes. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with water and brine. After removing moisture with anhydrous sodium sulfate (Na2SO4) and concentrating the solvent, the residue was purified by column chromatography using a mobile phase of EA:Hex (2:1) to obtain compound 105ad (56 mg, 48%).

[0932] 105ad (56 mg, 48%). 1H NMR (400 MHz, Chloroform-d) δ8.71 (s, 1H), 8.19 - 8.16 (m, 1H), 7.99 (d, J = 5.3 Hz, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.87 (ddt, J = 7.7, 5.0, 2.6 Hz, 2H), 7.75 (dd, J = 8.5, 1.7 Hz, 1H), 7.57 - 7.49 (m, 2H), 6.56 (d, J = 5.3 Hz, 1H), 5.22 (s, 1H), 3.89 (s, 4H), 3.41 (s, 3H), 2.15 - 2.07 (m, 2H), 1.80 (dt, J = 13.2, 3.9 Hz, 2H), 1.68 (dt, J = 8.3, 4.3 Hz, 1H), 1.48 (tdd, J = 13.8, 8.9, 3.3 Hz, 2H), 1.34 (q, J = 10.1 Hz, 3H). ; LRMS (ESI+) calculated for C 28 H 28 N6O3[M+H]+: 497.23, found 497.18

[0933]

[0934] 105bd (37 mg, 60%). 1 H NMR (400 MHz, Chloroform-d) δ8.64 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.81 (dd, J = 1.6, 0.8 Hz, 1H), 7.51 (t, J = 1.2 Hz, 2H), 6.53 (d, J = 5.3 Hz, 1H), 5.17 (s, 1H), 3.88 (s, 4H), 3.41 (s, 3H), 2.13 - 2.05 (m, 2H), 1.80 (dt, J = 13.3, 4.1 Hz, 2H), 1.68 (dt, J = 8.2, 4.1 Hz, 1H), 1.52 - 1.41 (m, 2H), 1.33 (d, J = 13.9 Hz, 3H). ; LRMS (ESI+) calculated for C 24 H 24ClN6O3[M+H]+: 515.14, found 515.14

[0935]

[0936] 105cd (46 mg, 42%). 1 H NMR (400 MHz, Chloroform-d) δ8.65 (s, 1H), 8.09 (d, J = 5.0 Hz, 1H), 7.75 (dd, J = 7.1, 2.1 Hz, 1H), 7.54 (ddd, J = 8.4, 4.6, 2.2 Hz, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.50 (d, J = 5.3 Hz, 1H), 5.20 (s, 1H), 3.89 (d, J = 10.4 Hz, 4H), 3.47 - 3.38 (m, 3H), 2.15 - 2.06 (m, 2H), 1.80 (dd, J = 9.1, 4.0 Hz, 2H), 1.73 - 1.64 (m, 1H), 1.55 - 1.42 (m, 2H), 1.33 (d, J = 10.8 Hz, 3H). ; LRMS (ESI+) calculated for C 24 H 24 ClFN6O3[M+H]+:499.17 , found 499.12

[0937]

[0938] 105ae (46 mg, 42%). 1H NMR (400 MHz, Chloroform-d) δ8.70 (s, 1H), 8.18 (t, J = 1.2 Hz, 1H), 8.02 (d, J = 5.4 Hz, 1H), 7.94 - 7.86 (m, 3H), 7.75 (dd, J = 8.5, 1.7 Hz, 1H), 7.57 - 7.49 (m, 2H), 6.60 (s, 1H), 5.13 (d, J = 7.9 Hz, 1H), 4.07 - 4.01 (m, 2H), 3.90 (s, 3H), 3.60 (td, J = 11.5, 2.3 Hz, 2H), 3.42 (s, 3H), 2.14 - 2.07 (m, 2H), 1.65 (q, J = 4.8 Hz, 3H). ; LRMS (ESI+) calculated for C 27 H 26 N6O4[M+H]+: 499.21, found 499.22

[0939]

[0940] 105be (35 mg, 60%). 1 H NMR (400 MHz, Chloroform-d) δ8.62 (s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.79 (t, J = 1.1 Hz, 1H), 7.51 (d, J = 1.1 Hz, 2H), 6.57 (d, J = 5.3 Hz, 1H), 5.33 (s, 1H), 4.04 (ddt, J = 12.0, 7.0, 3.8 Hz, 3H), 3.89 (s, 3H), 3.59 (td, J = 11.6, 2.1 Hz, 2H), 3.41 (s, 3H), 2.13 - 2.06 (m, 2H), 1.70 - 1.58 (m, 2H). ; LRMS (ESI+) calculated for C 23 H 22 Cl2N6O4[M+H]+: 517.11, found 517.13.

[0941]

[0942] 105ce (32 mg, 58%). 1H NMR (400 MHz, Chloroform-d) δ8.63 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.74 (dd, J = 7.1, 2.1 Hz, 1H), 7.54 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.54 (d, J = 5.3 Hz, 1H), 5.29 (s, 1H), 4.09 - 4.01 (m, 3H), 3.89 (s, 3H), 3.59 (td, J = 11.6, 2.0 Hz, 2H), 3.41 (s, 3H), 2.12 - 2.06 (m, 2H), 1.69 - 1.58 (m, 2H).; LRMS (ESI+) calculated for C 23 H 22 ClFN6O4[M+H]+:501.14 , found 501.11

[0943]

[0944] (E)-1-(5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Aryl-imidazo[2,1-b]oxazol-2-yl)-3-(dimethylamino)prop-2-en-1-one (107ad~cd, 107ae~ce)

[0945]

[0946] Compound 105ad (30 mg, 0.06 mmol) was dissolved in anhydrous THF (0.6 ml), and 3.1 M CH3Li in Diethoxymethane (39 μl, 0.12 mmol) was stirred at -78°C for 2 hours and 30 minutes under Ar gas. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with ammonium chloride (NH4Cl) and brine. After removing moisture with anhydrous sodium sulfate (Na2SO4), the solvent was concentrated, and the residue was purified by column chromatography using a mobile phase of EA:Hex (1:3) to obtain compound 106ad (18.8 mg, 67%). Compound 106ad (18.8 mg, 0.042 mmol) was dissolved in DMF (1 ml), and N,N-Dimethylformamide Dimethyl Acetal (0.06 ml) was added, followed by stirring at 80°C for 15 min. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with water and brine. The moisture was removed with anhydrous sodium sulfate (Na2SO4), the solvent was concentrated, and the residue was purified by column chromatography using a mobile phase of MC:MeOH (40:1) to obtain compound 107ad (11 mg, 52%).

[0947]

[0948] 106ad (18.8 mg, 67%). 1H NMR (400 MHz, Chloroform-d) δ8.73 (s, 1H), 8.17 (d, J = 1.7 Hz, 1H), 8.01 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 7.1 Hz, 2H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 7.54 (dq, J = 6.0, 3.7 Hz, 2H), 6.57 (d, J = 5.4 Hz, 1H), 5.24 (s, 1H), 3.86 (dtd, J = 10.7, 7.1, 3.9 Hz, 1H), 2.59 (s, 3H), 2.19 - 2.09 (m, 2H), 1.89 - 1.79 (m, 2H), 1.72 (d, J = 12.8 Hz, 1H), 1.49 (q, J = 12.7 Hz, 2H), 1.31 (dd, J = 12.1, 8.5 Hz, 3H). ; LRMS (ESI+) calculated for C 27 H 25 N5O2[M+H]+: 452.21, found 452.17

[0949]

[0950] 106bd (18 mg, 70 %). 1 H NMR (400 MHz, Chloroform-d) δ8.68 (s, 1H), 8.12 (d, J = 5.8 Hz, 1H), 7.82 - 7.78 (m, 1H), 7.52 (d, J = 1.4 Hz, 2H), 6.53 (d, J = 5.3 Hz, 1H), 5.18 (s, 1H), 3.84 (s, 1H), 2.59 (s, 3H), 2.13 (d, J = 12.3 Hz, 2H), 2.02 (s, 2H), 1.83 (d, J = 13.4 Hz, 2H), 1.44 (d, J = 17.5 Hz, 4H).; LRMS (ESI+) calculated for C 23 H 21 Cl2N5O2[M+H]+: 470.11, found 470.12.

[0951]

[0952] 106cd (20 mg, 79 %). 1 H NMR (400 MHz, Chloroform-d) δ8.68 (s, 1H), 8.10 (d, J = 5.3 Hz, 1H), 7.74 (dd, J = 7.0, 2.2 Hz, 1H), 7.54 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.22 (t, J = 8.7 Hz, 1H), 6.50 (d, J = 5.3 Hz, 1H), 5.34 (s, 1H), 3.90 - 3.79 (m, 1H), 2.59 (s, 3H), 2.13 (d, J = 9.9 Hz, 2H), 1.84 (d, J = 13.1 Hz, 2H), 1.72 (d, J = 12.8 Hz, 1H), 1.48 (q, J = 12.2 Hz, 2H), 1.38 - 1.30 (m, 3H). ; LRMS (ESI+) calculated for C 23 H 21 ClFN5O2[M+H]+: 454.14, found 454.11.

[0953]

[0954] 106ae (23 mg, 62%). 1 H NMR (400 MHz, Chloroform-d) δ8.72 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 5.4 Hz, 1H), 7.94 - 7.86 (m, 3H), 7.74 (dd, J = 8.4, 1.7 Hz, 1H), 7.58 - 7.51 (m, 2H), 6.61 (d, J = 5.4 Hz, 1H), 5.19 (s, 1H), 4.09 - 4.03 (m, 3H), 3.60 (t, J = 11.5 Hz, 2H), 2.62 (s, 3H), 2.10 (s, 2H), 1.67 (s, 2H).; LRMS (ESI+) calculated for C 26 H 23N5O3+H]+: 454.19, found 454.20.

[0955]

[0956] 106be (2.2 mg, 6.9 %). 1 H NMR (400 MHz, Chloroform-d) δ8.66 (s, 1H), 8.15 (d, J = 5.3 Hz, 1H), 7.80 (dd, J = 1.7, 0.7 Hz, 1H), 7.52 (dd, J = 1.9, 1.2 Hz, 2H), 6.57 (d, J = 5.3 Hz, 1H), 5.19 (s, 1H), 4.06 (d, J = 11.9 Hz, 3H), 3.63 - 3.56 (m, 3H), 2.60 (s, 3H), 2.09 (dd, J = 9.7, 4.9 Hz, 2H), 1.72 - 1.50 (m, 1H). ; LRMS (ESI+) calculated for C 22 H 19 Cl2N5O3[M+H]+: 472.09, found 472.11

[0957]

[0958] 106ce (3.3 mg, 13 %). 1 H NMR (400 MHz, Chloroform-d) δ8.67 (s, 1H), 8.13 (d, J = 5.3 Hz, 1H), 7.74 (dd, J = 7.0, 2.1 Hz, 1H), 7.23 (t, J = 8.6 Hz, 1H), 6.54 (d, J = 5.3 Hz, 1H), 5.16 (s, 1H), 4.09 - 4.04 (m, 3H), 3.60 (t, J = 10.8 Hz, 2H), 2.60 (s, 3H), 2.10 (d, J = 10.7 Hz, 2H), 1.70 - 1.60 (m, 3H). ; LRMS (ESI+) calculated for C 22 H 19 ClFN5O3[M+H]+: 456.12, found 472.10

[0959]

[0960] 107ad (11 mg, 52%). 1 H NMR (400 MHz, DMSO-d6) δ9.11 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 4.6 Hz, 1H), 8.01 - 7.94 (m, 3H), 7.88 (d, J = 12.2 Hz, 1H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.50 - 7.12 (m, 1H), 6.35 (s, 1H), 5.68 (d, J = 12.3 Hz, 1H), 3.71 (s, 1H), 3.21 (s, 3H), 2.97 (s, 3H), 1.97 (d, J = 10.3 Hz, 2H), 1.73 (s, 2H), 1.61 (d, J = 12.2 Hz, 1H), 1.29 (q, J = 12.5 Hz, 5H). ; LRMS (ESI+) calculated for C 30 H 30 N6O2[M+H]+: 507.25, found 507.46.

[0961]

[0962] 107bd (9.8 mg, 68%). 1 H NMR (400 MHz, DMSO-d6) δ7.95 (s, 1H), 7.89 (s, 1H), 7.86 - 7.84 (m, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.62 (dd, J = 8.4, 2.0 Hz, 2H), 6.38 (s, 1H), 5.66 (d, J = 12.3 Hz, 2H), 3.21 (s, 3H), 2.97 (s, 3H), 1.94 (s, 4H), 1.73 (s, 3H), 1.60 (s, 2H). ; LRMS (ESI+) calculated for C 26 H 26 Cl2N6O2[M+H]+: 525.16, found 525.18.

[0963]

[0964] 107cd (17.3 mg, 76%). 1 H NMR (400 MHz, Chloroform-d) δ8.56 (s, 1H), 8.08 (s, 1H), 7.93 (d, J = 12.4 Hz, 1H), 7.75 (dd, J = 7.1, 2.1 Hz, 1H), 7.54 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.48 (d, J = 5.3 Hz, 1H), 5.73 (d, J = 12.4 Hz, 1H), 5.20 (d, J = 8.0 Hz, 1H), 3.92 - 3.79 (m, 1H), 3.22 (s, 3H), 3.00 (s, 3H), 2.13 (d, J = 12.1 Hz, 2H), 1.86 - 1.77 (m, 3H), 1.70 (d, J = 13.3 Hz, 2H), 1.51 (d, J = 12.9 Hz, 3H). ; LRMS (ESI+) calculated for C 26 H 26 ClFN6O2[M+H]+: 509.19, found 509.17.

[0965]

[0966] 107ae (18.3 mg, 71%). 1H NMR (400 MHz, CDCl3) δ8.62 (s, 1H), 8.17 (s, 1H), 8.00 (d, J = 5.4 Hz, 1H), 7.90 (ddd, J = 15.0, 10.6, 6.3 Hz, 4H), 7.76 (dd, J = 8.5, 1.6 Hz, 1H), 7.57 - 7.48 (m, 2H), 6.59 (d, J = 5.4 Hz, 1H), 5.75 (d, J = 12.4 Hz, 1H), 5.27 (s, 1H), 4.09 - 4.00 (m, 2H), 3.61 (t, J = 11.3 Hz, 2H), 3.22 (s, 3H), 3.00 (s, 3H), 2.11 (d, J = 10.1 Hz, 2H), 1.71 - 1.59 (m, 2H). ; LRMS (ESI+) calculated for C 29 H 28 N6O3[M+H]+: 509.23, found 509.55.

[0967]

[0968] 107be (2.2 mg, 70%). 1 H NMR (400 MHz, CDCl3) δ8.56 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H), 7.94 (d, J = 12.4 Hz, 1H), 7.80 (t, J = 1.2 Hz, 1H), 7.51 (d, J = 1.1 Hz, 2H), 6.55 (d, J = 5.4 Hz, 1H), 5.73 (d, J = 12.4 Hz, 1H), 5.34 (dd, J = 7.1, 5.0 Hz, 1H), 4.08 - 4.02 (m, 2H), 3.61 (t, J = 11.3 Hz, 2H), 3.24 (s, 3H), 3.01 (s, 3H), 2.11 (s, 2H), 1.67 (dd, J = 11.3, 4.6 Hz, 2H). ; LRMS (ESI+) calculated for C 25 H 24 Cl2N6O3[M+H]+: 527.14, found 527.18.

[0969]

[0970] 107ce (2.3 mg, 71 %). 1 H NMR (400 MHz, Chloroform-d) δ8.56 (s, 1H), 8.10 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 12.4 Hz, 1H), 7.74 (dd, J = 7.1, 2.2 Hz, 1H), 7.55 - 7.51 (m, 1H), 7.21 (t, J = 8.7 Hz, 1H), 6.52 (d, J = 5.3 Hz, 1H), 5.73 (d, J = 12.4 Hz, 1H), 5.19 (s, 1H), 4.05 (dd, J = 11.7, 3.8 Hz, 2H), 3.61 (t, J = 11.5 Hz, 2H), 3.23 (s, 3H), 3.01 (s, 3H), 2.11 (s, 2H), 1.64 (dd, J = 12.8, 4.4 Hz, 3H). ; LRMS (ESI+) calculated for C 25 H 24 ClFN6O3[M+H]+: 511.17, found 511.27.

[0971]

[0972] 1-(5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Aryl-imidazo[2,1-b]oxazol-2-yl)prop-2-en-1-one (108ad, 108ae)

[0973]

[0974] Compound 105ad (36.2 mg, 0.073 mmol) was dissolved in anhydrous THF (0.5 ml), and vinylmagnesium bromide (0.09 ml, 0.66 mmol) was added at 0°C under Ar gas substitution, and the mixture was slowly warmed to room temperature and stirred for two days. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with ammonium chloride (NH4Cl) and brine. After removing moisture with anhydrous sodium sulfate (Na2SO4), the solvent was concentrated, and then purified by column chromatography using a mobile phase of EA:Hex (4:1) to obtain compound 108ad (1.1 mg, 3%).

[0975]

[0976] 108ae (1.1 mg, 3%). 1 H NMR (400 MHz, Chloroform-d) δ8.17 (d, J = 14.4 Hz, 1H), 8.04 (d, J = 5.2 Hz, 1H), 7.87 (t, J = 9.0 Hz, 3H), 7.78 - 7.71 (m, 1H), 7.58 - 7.50 (m, 2H), 6.54 (s, 1H), 5.35 (s, 1H), 3.71 - 3.58 (m, 2H), 3.10 (d, J = 7.5 Hz, 2H), 2.33 (dt, J = 16.3, 8.0 Hz, 1H), 2.10 (s, 2H), 1.68 (s, 6H). ; LRMS (ESI+) calculated for C 27 H 23 N5O3[M+H]+: 466.19, found 466.33.

[0977]

[0978] 5-(2-(cycloalkylamino)pyrimidin-4-yl)-6-Aryl-N-(prop-2-yn-1-yl)imidazo[2,1-b]thiazole-2-carboxamide (109ad~cd, 109ae~ce)

[0979]

[0980] Compound 100ad (40 mg, 0.09 mmol) was dissolved in ACN (0.5 ml), EDCI (25 mg, 0.11 mmol), HOBt (18 mg, 0.11 mmol), and TEA (0.03 ml, 0.18 mmol) were added, and the mixture was stirred for 1 hour, and then propargyl amine (7 μl, 0.11 mmol) was added. The temperature was raised to 80°C and stirred for 2 days. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (EtOAc), and the organic layer was washed with ethyl acetate (EtOAc) and brine. The moisture was removed with anhydrous sodium sulfate (Na2SO4), and the solvent was concentrated. The residue was purified by column chromatography using a mobile phase of EA:Hex (1:3) to obtain compound 109ad (12 mg, 27%).

[0981] 109ad (12 mg, 27%). 1H NMR (400 MHz, Chloroform-d) δ8.73 (s, 1H), 8.14 (d, J = 1.7 Hz, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.88 (ddt, J = 8.6, 7.3, 2.5 Hz, 2H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.11 (t, J = 5.5 Hz, 1H), 6.51 (d, J = 5.4 Hz, 1H), 5.30 (s, 1H), 4.14 (dd, J = 5.5, 2.6 Hz, 2H), 3.86 (dddd, J = 14.3, 10.3, 7.8, 3.8 Hz, 1H), 2.27 (t, J = 2.5 Hz, 1H), 2.13 (d, J = 12.3 Hz, 2H), 1.82 (dt, J = 13.3, 3.8 Hz, 2H), 1.71 (d, J = 13.0 Hz, 1H), 1.51 (d, J = 12.9 Hz, 2H), 1.36 - 1.30 (m, 3H). ;LRMS (ESI+) calculated for C 29 H 26 N6O2[M+H]+: 491.22, found 491.35.

[0982]

[0983] 109bd (2.3 mg, 6 %). 1H NMR (400 MHz, Chloroform-d) δ8.58 (s, 1H), 7.79 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 8.3, 2.0 Hz, 1H), 6.65 (t, J = 5.5 Hz, 1H), 6.56 (d, J = 6.4 Hz, 1H), 5.41 - 5.25 (m, 1H), 4.30 (dd, J = 5.5, 2.6 Hz, 2H), 3.89 (s, 1H), 2.36 (t, J = 2.6 Hz, 1H), 2.12 (s, 3H), 1.89 (s, 2H), 1.75 (d, J = 13.1 Hz, 1H), 1.52 (s, 4H). ;LRMS (ESI+) calculated for C 25 H 22 Cl2N6O2[M+H]+: 509.12, found 509.26.

[0984]

[0985] 109cd (20 mg, 36 %). 1 H NMR (400 MHz, Chloroform-d) δ8.59 (s, 1H), 7.81 (s, 1H), 7.70 (dd, J = 6.9, 2.2 Hz, 1H), 7.50 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 6.67 (t, J = 5.4 Hz, 1H), 6.52 (d, J = 6.2 Hz, 1H), 5.35 (s, 1H), 4.30 (dd, J = 5.5, 2.6 Hz, 2H), 3.88 (s, 1H), 2.35 (t, J = 2.6 Hz, 1H), 2.12 (d, J = 8.9 Hz, 3H), 1.88 (s, 2H), 1.73 (s, 1H), 1.50 (s, 4H). ;LRMS (ESI+) calculated for C 25 H 22 ClFN6O2[M+H]+: 493.16, found 493.25.

[0986]

[0987] 109ae (5 mg, 11 %). 1 H NMR (400 MHz, Chloroform-d) δ8.74 (s, 1H), 8.15 (t, J = 1.1 Hz, 1H), 8.02 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.91 - 7.85 (m, 2H), 7.72 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 - 7.50 (m, 2H), 6.91 (t, J = 5.4 Hz, 1H), 6.57 (d, J = 5.4 Hz, 1H), 5.22 (s, 1H), 4.21 (dd, J = 5.5, 2.6 Hz, 2H), 4.08 - 4.02 (m, 2H), 3.61 (t, J = 11.5 Hz, 2H), 2.31 ( t, J = 2.5 Hz, 1H), 2.10 (d, J = 12.5 Hz, 2H), 1.69 - 1.63 (m, 3H). ;LRMS (ESI+) calculated for C 28 H 24 N6O3[M+H]+: 493.20, found 493.44.

[0988]

[0989] 109be (1.4 mg, 4 %). 1H NMR (400 MHz, Chloroform-d) δ8.68 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 7.78 (dd, J = 1.9, 0.5 Hz, 1H), 7.54 - 7.51 (m, 1H), 7.49 (dd, J = 8.3, 1.8 Hz, 1H), 6.63 (d, J = 5.6 Hz, 1H), 6.55 (d, J = 5.4 Hz, 1H), 5.19 (s, 1H), 4.29 (dd, J = 5.4, 2.6 Hz, 2H), 4.05 (d, J = 12.4 Hz, 2H), 3.59 (d, J = 11.7 Hz, 2H), 2.35 (t, J = 2.5 Hz, 1H), 2.09 (d, J = 13.0 Hz, 2H), 1.71 - 1.65 (m, 3H). ;LRMS (ESI+) calculated for C 24 H 20 Cl2N6O3[M+H]+: 511.10, found 511.25.

[0990]

[0991] 109ce (15 mg, 25 %). 1 H NMR (400 MHz, Chloroform-d) δ8.70 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 7.72 (dd, J = 7.1, 2.1 Hz, 1H), 7.52 (ddd, J = 8.4, 4.6, 2.2 Hz, 1H), 7.23 (td, J = 8.6, 1.8 Hz, 1H), 6.98 (t, J = 5.5 Hz, 1H), 6.50 (d, J = 5.3 Hz, 1H), 5.27 (s, 1H), 4.23 (dd, J = 5.4, 2.5 Hz, 2H), 4.08 - 4.02 (m, 2H), 3.61 (t, J = 11.4 Hz, 2H), 2.33 (t, J = 2.5 Hz, 1H), 2.13 - 2.05 (m, 2H), 1.79 (s, 1H), 1.65 (qd, J = 11.3, 4.3 Hz, 2H). ;LRMS (ESI+) calculated for C24 H 20 ClFN6O3[M+H]+: 495.13, found 495.14.

[0992]

[0993] For example, for purposes of claim construction, the claims set forth below should not be construed narrowly beyond their literal language, and thus, exemplary embodiments from the specification should not be construed as claims. Therefore, it should be understood that the present invention has been described by way of example only, and not as a limitation on the scope of the claims. Accordingly, the present invention is limited only by the claims below. All publications, issued patents, patent applications, books, and journal articles cited in this application are hereby incorporated by reference in their entirety.

Claims

1. A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X is O, or S, R4 is -(CH2) l O(CH2) m CH3, , , , , or , l is an integer from 1 to 3, m is an integer from 0 to 2, n is an integer from 1 to 3, R1 is a C3 to C5 cycloalkyl, or an amine which is optionally substituted with one or two C1 to C3 alkyls, R5 is , , , , or , wherein R2 is -OMe, -OEt, an amine which is unsubstituted or substituted with one or two C1 to C3 alkyl groups, The above Ar is phenyl substituted with methyl, which is optionally substituted with F; phenyl substituted with a halogen group element at one or more positions; phenyl substituted with methyl, which is optionally substituted with F, and phenyl substituted with a halogen group element; phenyl substituted with a cyclized -OCH2O-, or -OCH2CH2O-; or substituted or unsubstituted naphthyl.

2. In paragraph 1, R4 is , , , , or , n is an integer from 1 to 3, R1 is , or And, R5 is , , , , or , wherein R2 is -OEt, -NH2, or -NHMe, The above Ar is , , , or am.

3. In paragraph 1, The compound of the above chemical formula 1 is a compound having a structure of the following chemical formula 2: [Chemical Formula 2] In the above chemical formula 2, The above R1 is , or And, wherein R2 is -OEt, -NH2, or -NHMe, Above silver , , , or am.

4. In paragraph 1, The compound of the above chemical formula 1 is a compound having a structure of the following chemical formula 3: [Chemical Formula 3] In the above chemical formula 3, The above R3 is , , , or And, wherein R2 is -OEt, -NH2, or -NHMe, Above silver , , , or am.

5. In paragraph 1, The compound of the above chemical formula 1 is a compound having the structure of the following chemical formula 4: [Chemical Formula 4] In the above chemical formula 4, The above R1 is , or And, wherein R2 is -OEt, -NH2, or -NHMe, Above silver , , , or And, n is 1 or 2.

6. In paragraph 1, The compound of the above chemical formula 1 is a compound having a structure of the following chemical formula 5: [Chemical Formula 5] In the above chemical formula 5, The above R3 is , or And, wherein R2 is -OEt, -NH2, or -NHMe, Above silver , , , or am.

7. In paragraph 1, The compound of the above chemical formula 1 is a compound having a structure of the following chemical formula 6: [Chemical Formula 6] In the above chemical formula 6, The above R is , or And, The above X is , , , or And, Above silver , , or am.

8. In paragraph 1, The compound of the above chemical formula 1 is a compound having a structure of the following chemical formula 7: [Chemical Formula 7] In the above chemical formula 7, The above R is , or And, The above X is , , , or And, Above silver , , or am.

9. In paragraph 1, The compound of the above chemical formula 1 is one of the compounds shown in Tables 1 to 6 below: [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] .

10. A pharmaceutical composition for preventing or treating a degenerative brain disease, comprising a compound of any one of claims 1 to 9, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

11. A pharmaceutical composition according to claim 10, wherein the degenerative brain disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, Lou Gehrig's disease, or stroke.

12. A pharmaceutical composition according to claim 10, wherein the compound, a derivative thereof, or a pharmaceutically acceptable salt thereof inhibits the activity of JNK3 (c-Jun N-terminal kinase 3).

13. A method for preventing or treating a degenerative brain disease, comprising administering to a subject a compound of any one of claims 1 to 9, a derivative thereof, a pharmaceutically acceptable salt thereof, or a composition comprising the same.

14. A method for preventing or treating a degenerative brain disease, wherein the subject is a person diagnosed with a degenerative brain disease, for example, Alzheimer's disease, or at risk of suffering from Alzheimer's disease, in accordance with paragraph 13.

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