Novel thiazole derivatives and pharmaceutically acceptable salts thereof

Abstract

The present invention provides novel thiazole derivatives or pharmaceutically acceptable salts thereof, and methods for preparing the same. The thiazole derivatives or pharmaceutically acceptable salts thereof of the present invention have selective inhibitory activity against cyclin-dependent kinase (CDK), and thus can be usefully used as preventive or therapeutic agents for various diseases associated with CDK.

Description

Technical Field

[0001] This application claims the benefit of Korean Patent Application No. 10-2018-0111001 filed on September 17, 2018, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to novel thiazole derivatives and pharmaceutically acceptable salts thereof, a method for preventing, alleviating or treating a disease comprising the step of administering the compound of the present invention, a method for preparing the compound of the present invention, and a pharmaceutical composition comprising the compound. Background Art

[0003] Cancers show pathological signs of uncontrolled cell division. In particular, cyclin-dependent kinases (CDKs) that promote cell cycle progression are expected to be key therapeutic targets. CDKs are a family of serine / threonine protein kinases that play an important role in cell proliferation. For example, in the pathogenesis of many cancers, proliferation is induced by CDK4 or CDK6 complexes that act on the G1 phase. In particular, the control of the S phase and G2 / M phase mediated by CDK2 and CDK1 also plays an important role in cancer. CDK1, CDK2, CDK4 and CDK6 are related to the cell cycle, while CDK8-13 are involved in gene transcription.

[0004] In mammals, CDK7 is the only structural element of CDK-activating kinase (CAK) and the common transcription factor TFIIH, and plays a crucial role in both cell cycle and transcription. CDK7 phosphorylates the C-terminal domain (CTD) of RNA polymerase (RNAP) II, thereby regulating the expression of oncogenic transcription factors that induce cancer cell growth and survival.

[0005] Compared with normal cells, cancer cells are characterized by increased genetic heterogeneity, but some cancer cells can inhibit cancer cell growth or induce apoptosis by targeting the promoter mutations of major oncogenes. However, "transcriptional cancer cells" without specific promoter mutations can be inhibited by transcriptional regulatory kinases such as CDK7 (Yubao Wang et al., Cell 163, 174-186, September 24, 2015). Therefore, compounds for treating diseases and disorders associated with selective transcriptional CDKs, especially CDK7, are needed.

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: WO 2014 / 063068

[0009] Patent Document 2: WO 2015 / 058140 Summary of the invention

[0010] According to one aspect of the present invention, there is provided a compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof:

[0011] Chemical formula (I):

[0012] In the above formula,

[0013] Ring A is cycloalkyl, aryl, heteroaryl or heterocycloalkyl;

[0014] Ring B is cycloalkyl, aryl, heteroaryl or heterocycloalkyl;

[0015] R1 is H, halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, cyano, -SR c 、-C(O)R c 、-C(O)OR c 、-C(O)N(R c )(R d )、-N(R c )(R d )、-(C(R g )2) q -N(R c )(R d ),-OR c or -(C(R g )2) q -OR c ;

[0016] R c and R d are each independently H, alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; or

[0017] R c and R d Together with the atoms to which they are attached, they form a substituted or unsubstituted heterocycloalkyl group;

[0018] Each q is independently an integer from 1 to 3;

[0019] R g is H or alkyl;

[0020] R 2V and R 2W are each independently H, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl or amino; or

[0021] R 2V and R 2W Together with the atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group;

[0022] L1 does not exist or is -N(R e )-、-CH2N(R e )-、-CH2CH2N(R e )- or alkylene, however, L1 is -CH2N(R e )-or-CH2CH2N(R e )-, Ring B is attached to the carbon terminal of the substituent and R3 is attached to the nitrogen terminal of the substituent;

[0023] Among them, R e is H or alkyl; or R e It is covalently bonded to a position on ring B to form a heteroaryl or heterocycloalkyl ring structure, and it is an unsubstituted or substituted group;

[0024] R3 is

[0025] Among them, R f1 is H, halo, alkyl or cyano;

[0026] R f2 and R f3 Each is independently H, halo, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkoxy, alkoxyalkyl, -N(R c’ )(R d’ ) or -(C(R g’ )2) q -N(R c’ )(R d’ );

[0027] Each R g’ are independently H or alkyl;

[0028] R c’ and R d’ are each independently H, alkyl, heterocycloalkyl, alkoxy or alkoxyalkyl; or

[0029] R c’ and R d’ Together with the atoms to which they are attached, they form a substituted or unsubstituted heterocycloalkyl group,

[0030] Each R a are independently H, halo, hydroxy, nitro or cyano; or are alkyl, alkoxy, alkoxyalkyl, amino, haloalkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, and are unsubstituted or substituted;

[0031] Each R b are independently H, halo, hydroxy, nitro or cyano or alkyl, alkoxy, alkoxyalkyl, amino, haloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or -NR h R j , and it is an unsubstituted or substituted group;

[0032] R h and R j Each is independently H, alkyl, -N(R h’ )(R j’ )、-(C(R g’ )2) q -N(R h’ )(R j’ ) or a heterocycloalkyl group,

[0033] R h’ and R j’ are each independently H or alkyl; or

[0034] R h’ and R j’ Together with the atoms to which they are attached, they form an unsubstituted or substituted heterocycloalkyl group;

[0035] m and n are each independently an integer selected from 1 to 4.

[0036] The compounds disclosed herein include compounds having highly selective inhibitory activity against cyclin-dependent kinases (CDKs), in particular, CDK7.

[0037] Administration of the compounds and pharmaceutical compositions disclosed herein, for example, the compounds or compositions described above, to a subject is useful for preventing or treating a CDK-related disease, in particular, a CDK7-related disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The results of western blotting confirming the phosphorylation of the C-terminal domain of RNA polymerase (RNAP) II and the expression inhibition of c-Myc protein, an oncogene, when TNBC (MDA-MB-468) cells were treated with a control substance (THZ1) and the compounds of Examples 37, 39 and 45 at different concentrations are shown. DETAILED DESCRIPTION

[0039] Hereinafter, the present invention will be described in more detail.

[0040] definition

[0041] Unless otherwise defined, all technical terms used herein have the same meaning as those commonly understood by those skilled in the art to which the present invention belongs. In particular, unless otherwise explicitly stated, the numerical values ​​recorded herein include the meaning of "about".

[0042] The definitions of the residues and substituents used herein are as follows. Unless otherwise indicated, each residue has the following definition and is used as having the same meaning as that commonly understood by a person of ordinary skill.

[0043] According to the conventional means used in the art, in the chemical formula herein, Refers to the residue or substituent "R" attached to the backbone structure.

[0044] "Alkyl" is a hydrocarbon having primary, secondary, tertiary and / or quaternary carbon atoms, and includes saturated aliphatic groups that can be linear, branched or cyclic, or combinations thereof. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to 10 carbon atoms (i.e., C1-C 10alkyl) or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Unless otherwise defined, in a preferred embodiment, alkyl refers to C1-C6 alkyl. Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)2). )CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH 2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2, 3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3, 3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3), but are not limited to these.

[0045] Furthermore, the term "alkyl" used throughout the specification, examples and claims is intended to include unsubstituted and substituted alkyl groups, wherein the latter refers to alkyl residues including halogenated alkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, and substituents replacing hydrogen on one or more carbons of the hydrocarbon backbone.

[0046] When the term "C x-y " or "C x -C y"" when used with a chemical residue such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, refers to groups containing from x to y carbons in the chain. In the case of a terminal group, C0 alkyl refers to hydrogen, and in the case of an internal group, C0 alkyl refers to a bond. For example, (C1-C6) alkyl contains from 1 to 6 carbon atoms in the chain.

[0047] "Acyl" refers to -C(=O)-alkyl, -C(=O)-carbocycle (which is substituted or unsubstituted) and -C(=O)-heterocycle (which is substituted or unsubstituted), wherein the alkyl, carbocycle or heterocycle residues are as defined herein. Non-limiting examples of "acyl" include -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH(CH3)2, -C(=O)C(CH3)3, -C(=O)-phenyl (which is substituted or unsubstituted), -C(=O)-cyclopropyl (which is substituted or unsubstituted), -C(=O)-cyclobutyl (which is substituted or unsubstituted), -C(=O)-cyclopentyl (which is substituted or unsubstituted), -C(=O)-cyclohexyl (which is substituted or unsubstituted), and -C(=O)-pyridyl (which is substituted or unsubstituted).

[0048] The term "acylamino" refers to an amino group substituted with an acyl group, which is recognized in the art, and for example, the chemical formula can be represented by a hydrocarbon group C(O)NH-.

[0049] The term "acyloxy" has the general formula of a hydrocarbon group C(O)O-, preferably a group represented by an alkyl group C(O)O-, which is recognized in the art.

[0050] "Alkoxy" refers to a group having the formula -O-alkyl in which an alkyl group, as defined above, is attached to a compound through an oxygen atom. For example, the alkyl residue of an alkoxy group can have from 1 to 20 carbon atoms (i.e., C1-C 20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C 12 alkoxy), 1 to 10 carbon atoms (i.e., C1-C 10 The alkoxy group may be a methoxy group (-O-CH3 or -OMe), an ethoxy group (-OCH2CH3 or -OEt), and a tert-butoxy group (-OC(CH3)3 or -O-tBu), but is not limited thereto.

[0051] The term "alkoxyalkyl" refers to an alkyl group substituted by an alkoxy group, and the general formula thereof can be represented by -alkyl-O-alkyl.

[0052] As used herein, the term "alkylamino" refers to an amino group substituted with one or more alkyl groups.

[0053] The term "alkylthio" used herein refers to a thio group substituted by an alkyl group, and the general formula thereof can be represented by alkylS-.

[0054] "Alkenyl" refers to a group having primary, secondary, tertiary and / or quaternary carbon atoms, including straight chain, branched chain and cyclic groups or combinations thereof, and having one or more unsaturated regions, i.e., carbon-carbon sp 2 For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C 20 alkenyl), 2 to 12 carbon atoms (i.e., C2-C 12 alkenyl), 2 to 10 carbon atoms (i.e., C2-C 10 The present invention relates to a cyclopentenyl group having 2 to 6 carbon atoms (i.e., C2-C6 alkenyl group). Examples of suitable alkenyl groups include vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2), but are not limited thereto.

[0055] "Alkynyl" is a hydrocarbon having primary, secondary, tertiary and / or quaternary carbon atoms, including straight chain, branched and cyclic groups or combinations thereof, and having one or more carbon-carbon sp triple bonds. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C2-C 20 alkynyl), 2 to 12 carbon atoms (i.e., C2-C 12 alkynyl), 2 to 10 carbon atoms (i.e., C2-C 10 The alkynyl group may be a 2- to 6-carbon atom group (i.e., a C2-C6 alkynyl group). Examples of suitable alkynyl groups include, but are not limited to, acetylene (—C≡CH) and propargyl (—CH2C≡CH).

[0056] "Alkylene" refers to a saturated hydrocarbon group with 2 valences that can be branched, straight or cyclic (or a combination of branched, straight or cyclic residues) and induced by removing 2 hydrogen atoms from the same carbon atom or 2 different carbon atoms of an alkane. For example, the alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. As a typical example of the alkylene group, 1,2-ethylene (-CH2-CH2-) can be included, but it is not limited thereto.

[0057] "Alkenylene" refers to an unsaturated hydrocarbon group that can be branched, straight or cyclic (or has a combination of branched, straight or cyclic residues) and has a valence of 2 atoms induced by removing 2 hydrogen atoms from the same carbon atom or 2 different carbon atoms of an olefin. For example, the alkenylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. As an example of a typical alkenylene group, 1,2-vinylene (-CH=CH-) can be included, but it is not limited thereto.

[0058] "Alkynylidene" refers to an unsaturated hydrocarbon group with 2 valences that can be branched, straight or cyclic (or a combination of branched, straight or cyclic residues) and induced by removing 2 hydrogen atoms from the same carbon atom or 2 different carbon atoms of an alkyne. For example, the alkynylene group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Examples of typical alkynylene groups include ethynylene (-C≡C-), propynylene (-CH2C≡C-), and 4-pentynylene (-CH2CH2CH2C≡C-), but are not limited thereto.

[0059] As used herein, the term "amide" refers to R 9 and R 10 Each independently is hydrogen or a hydrocarbon group, or or R 9 and R 10 Together with the N atom to which they are attached they form a heterocyclic ring having 4 to 8 atoms within the ring structure.

[0060] The terms "amine" and "amino" refer to unsubstituted and substituted amines and their salts which may be prepared, for example, from (Among them, R 9 , R 10 and R 10’ are each independently hydrogen or a hydrocarbon group, or R 9 and R 10 The residues represented by NH2 are those which, together with the nitrogen atoms to which they are attached, form a heterocyclic ring having 4 to 8 atoms in the ring structure, which are recognized in the art. In a specific embodiment, the amino group is -NH2.

[0061] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0062] The term "aryl" as used herein includes a monovalent or divalent aromatic hydrocarbon group that is substituted or unsubstituted as a monocyclic, bicyclic or polycyclic ring with carbon atoms as the atoms of the ring. Preferably, the aryl ring is a 6- to 20-membered ring, a 6- to 14-membered ring, a 6- to 10-membered ring, or more preferably a 6-membered ring. The aryl group can be a polycyclic system having more than 2 rings common to 2 adjacent rings with more than 2 carbon atoms, wherein more than one of the rings is aromatic, for example, other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocycloalkyl. As an aryl group, benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, etc. can be included.

[0063] The term "aralkyl" or "arylalkyl" as used herein refers to an alkyl group substituted with an aryl group. Typical examples of arylalkyl groups include benzyl, 2-phenylethane-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, naphthylbenzyl, 2-naphthylphenylethane-1-yl, etc. (which may be substituted or unsubstituted, respectively), but are not limited thereto. Arylalkyl groups may have 7 to 20 carbon atoms. For example, the alkyl residue thereof may have 1 to 6 carbon atoms, and the aryl residue thereof may have 6 to 14 carbon atoms.

[0064] "Arylalkenyl" refers to a carbon atom, typically a terminal or other sp 3 Carbon atoms (sp 2 The aryl residue of the arylalkenyl group may be any aryl group described herein, and the alkenyl residue of the arylalkenyl group may include any alkenyl group described herein. The arylalkenyl group may have 8 to 20 carbon atoms. For example, its alkenyl residue may have 2 to 6 carbon atoms, and its aryl residue may have 6 to 14 carbon atoms.

[0065] "Arylalkynyl" refers to a carbon atom, typically a terminal or other sp 3 A non-cyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom (sP carbon atom may also be used) is replaced by an aryl group. The aryl residue of the arylalkynyl group may be, for example, any aryl group described herein, and the alkynyl residue of the arylalkynyl group may include, for example, any alkynyl group described herein. The arylalkynyl group may have 8 to 20 carbon atoms. For example, its alkynyl residue may have 2 to 6 carbon atoms, and its aryl residue may have 6 to 14 carbon atoms.

[0066] "Arylheteroalkyl" refers to a heteroalkyl radical having a hydrogen atom (which may be attached to a carbon atom or a heteroatom) replaced by an aryl radical as defined herein. The aryl radical may be attached to a carbon atom of the heteroalkyl radical or to a heteroatom of the heteroalkyl radical if the resulting radical is chemically stable. For example, an arylheteroalkyl radical may have the formula -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, and the like. Furthermore, any alkylene residue in the above formula may be further substituted by any substituent as defined or exemplified herein.

[0067] The term "carbamate" refers to (Among them, R 9 and R 10 independently represents hydrogen or a hydrocarbon group), which is recognized in the art.

[0068] As used herein, the term "carbocyclylalkyl" or "cycloalkylalkyl" or "(cycloalkyl)alkyl" refers to an alkyl group substituted with a carbocyclyl or cycloalkyl group.

[0069] As used herein, the terms "carbocycle", "carbocyclyl", "carbocyclic" or "cycloalkyl" refer to non-aromatic saturated or unsaturated monovalent or divalent rings that can be monocyclic, bicyclic or polycyclic and each atom of the ring is carbon. When the cycloalkyl is monocyclic, it can have 3 to 7 carbon atoms, when the cycloalkyl is bicyclic, it can have 7 to 12 carbon atoms, when the cycloalkyl is polycyclic, it can have about 20 or less carbon atoms. Monocyclic cycloalkyls have 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls can have 7 to 12 ring atoms, which can be fused ring systems, spiral ring systems or bridged ring systems. In exemplary cycloalkyls, the atoms can be arranged in a bicyclic [4,5], [5,5], [5,6] or [6,6] system. In specific embodiments, the cycloalkyl contains 3 to 20 atoms or 3 to 10 atoms, or, more preferably, contains 3 to 7 atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Unless otherwise indicated, the cycloalkyl group may be substituted with one or more substituents described herein.

[0070] The term "carbonate" refers to -OCO2- as is recognized in the art.

[0071] The term "carboxyl group" used herein refers to a group represented by a chemical formula of -CO2H.

[0072] As used herein, the term "ester" refers to -C(O)OR 9 (Among them, R 9 represents a hydrocarbon group).

[0073] As used herein, the term "ether" refers to a hydrocarbon group connected to another hydrocarbon group through an oxygen. Therefore, the ether substituent of the hydrocarbon group can be hydrocarbon-O-. The ether can be symmetrical or asymmetrical. As examples of ethers, heterocycle-O-heterocycle and aryl-O-heterocycle can be included, but are not limited to these. Ethers include "alkoxyalkyl" whose general formula can be represented by alkyl-O-alkyl.

[0074] As used herein, the terms "halo" and "halogen" refer to halogens including chlorine, fluorine, bromine, and iodine.

[0075] "Haloalkyl" is an alkyl group as defined above in which one or more of the hydrogen atoms of the alkyl group is replaced by a halogen atom. The alkyl residue of a haloalkyl group may have from 1 to 20 carbon atoms (i.e., C1-C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C 12 haloalkyl), 1 to 10 carbon atoms (i.e., C1-C 10 The haloalkyl group may be a C1-C6 haloalkyl group or a C1-C6 haloalkyl group. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, and -CH2CF3.

[0076] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by a heteroatom, such as O, N, or S. For example, when a carbon atom of an alkyl group attached to a molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group may be an alkoxy group (e.g., -OCH3), an amine group (e.g., -NHCH3, -N(CH3)2, etc.), or a thioalkyl group (e.g., -SCH3), respectively. When a non-terminal carbon atom of an alkyl group not attached to a molecule is replaced by a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group may be an alkyl ether (e.g., -CH2CH2-O-CH3, etc.), an alkyl amine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or a thioalkyl ether (e.g., -CH2-S-CH3), respectively. In the case where the terminal carbon atom of the alkyl group is replaced by a heteroatom (e.g., O, N or S), the resulting heteroalkyl group may be a hydroxyalkyl group (e.g., -CH2CH2-OH), an aminoalkyl group (e.g., -CH2NH2) or an alkyl-SH group (e.g., -CH2CH2-SH), respectively. For example, the heteroalkyl group may have 1 to 20 carbon atoms, 1 to 10 carbon atoms or 1 to 6 carbon atoms. Preferably, the heteroalkyl group has 2 to 20, 2 to 10 or 2 to 6 total atoms (i.e., the sum of carbon atoms and heteroatoms) in the chain. C1-C6 heteroalkyl refers to a heteroalkyl group having 1 to 6 carbon atoms.

[0077] "Heteroaryl" refers to a monocyclic, bicyclic or polycyclic substituted or unsubstituted monovalent or divalent aromatic group containing one or more heteroatoms in the ring. As a non-limiting example of suitable heteroatoms that can be contained in the aromatic ring, oxygen, sulfur and nitrogen can be included. In a polycyclic heteroaryl ring system, the ring system has more than two rings common to two adjacent rings with more than two carbon groups, wherein more than one of the rings is heteroaromatic, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. For example, heteroaryl includes benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, etc. (which can be substituted or unsubstituted, respectively).

[0078] "Heteroarylalkyl" refers to an alkyl group as defined herein in which a hydrogen atom is replaced by a heteroaryl group as defined herein. Non-limiting examples of heteroarylalkyl groups include -CH2-pyridyl, -CH2-pyrrolyl, -CH2-oxazolyl, -CH2-indolyl, -CH2-isoindolyl, -CH2-furyl, -CH2-thienyl, -CH2-benzofuranyl, -CH2-benzophenylthio, -CH2-carbazolyl, -CH2-imidazolyl, -CH2-thiazolyl, -CH2-isoxazolyl, -CH2-pyrazolyl, -CH2-isothiazolyl, -CH2-quinolyl, -CH2-isoquinolyl, -CH2-pyridazinyl, -CH2-pyrimidinyl, -CH2-pyrazinyl, -CH(CH3)-pyridyl, -CH(CH3)-pyrrolyl, -CH(CH3)-pyrrolyl, -CH(CH3)-pyrazol ... 3)-oxazolyl, -CH(CH3)-indolyl, -CH(CH3)-isoindolyl, -CH(CH3)-furyl, -CH(CH3)-thienyl, -CH(CH3)-benzofuranyl, -CH(CH3)-benzophenylthio, -CH(CH3)-carbazolyl, -CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -CH(CH3)-isoxazolyl, -CH(CH3)-pyrazolyl, -CH(CH3)-isothiazolyl, -CH(CH3)-quinolyl, -CH(CH3)-isoquinolyl, -CH(CH3)-pyridazinyl, -CH(CH3)-pyrimidinyl, -CH(CH3)-pyrazinyl, and the like.

[0079] As used herein, the terms "heterocycloalkyl" and "heterocyclylalkyl" refer to an alkyl group substituted with a heterocycloalkyl group.

[0080] The terms "heterocyclyl", "heterocycle", "heterocyclic", and "heterocycloalkyl" refer to substituted or unsubstituted monovalent or divalent saturated or partially saturated non-aromatic ring structures containing one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings. The terms "heterocyclyl", "heterocycle", "heterocyclic", and "heterocycloalkyl" also include polycyclic ring systems having more than two rings with two or more carbon atoms common to two adjacent rings, wherein more than one of the rings is heterocyclic, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Bicyclic and polycyclic heterocyclyl ring systems can be fused, bridged or spiral ring systems. Substituted heterocycles include, for example, carbonyl to include heterocyclyl rings substituted with any substituents disclosed herein. For example, the heterocyclic group includes piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc. Further, as exemplary heterocyclic rings, dihydropyridyl, dihydroindolinyl, tetrahydropyridyl (piperidyl), tetrahydrophenylthio, sulfoxylated tetrahydrophenylthio, indolyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, chromenyl, xanthenyl, benzoxazinyl, 2H- The invention also includes pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazinyl, benzoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, quinuclidine, morpholinyl, and oxazolidinyl (which may be substituted or unsubstituted, respectively), but is not limited thereto.

[0081] "Heterocycloalkenyl" refers to a carbon atom, typically a terminal or sp 3 Carbon atoms (sp 2 An acyclic alkenyl group in which one of the hydrogen atoms bonded to the carbon atom(s) is replaced by a heterocyclic group (i.e., a heterocyclic-alkenylene residue).

[0082] "Heterocycloalkynyl" refers to a carbon atom, typically a terminal or sp 3 An acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom (sp carbon atom may also be used) is substituted with a heterocyclic group (ie, a heterocyclic-alkynylene residue).

[0083] As used herein, the term "hydrocarbyl" refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, typically having more than one carbon-hydrogen bond and a basic carbon skeleton but optionally containing heteroatoms. Thus, for the purposes of this invention, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl groups, but not substituents such as acetyl (having a =O substituent on the attached carbon) and ethoxy (attached through the oxygen, not through the carbon). Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0084] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0085] The term "lower" refers to a group containing less than 10, preferably less than 6, atoms in the substituent when used with chemical residues such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy. "Lower alkyl" refers to an alkyl group containing, for example, less than 10, preferably less than 6 carbon atoms. In a specific embodiment, when used alone or in combination with other substituents to represent, for example, hydroxyalkyl and aralkyl (in this case, for example, although the carbon atoms in the alkyl substituent are counted, the atoms in the aryl are not counted), the acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy.

[0086] The terms "polycyclic group", "polycyclic", and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) having two or more atoms in common for two adjacent rings (e.g., the rings are "fused rings"). The polycyclic rings may be substituted or unsubstituted. In certain embodiments, the polycyclic rings each contain 3 to 10 atoms, preferably 5 to 7 atoms in the ring.

[0087] The term "sulfate" refers to -OSO3H or a pharmaceutically acceptable salt thereof, which is recognized in the art.

[0088] The term "sulfonamide" refers to a sulfonamide of the general formula (Among them, R 9 and R 10 The groups represented by (a) independently represent hydrogen or a hydrocarbon group are recognized in the art.

[0089] The term "sulfoxide" refers to -S(O)-, which is recognized in the art.

[0090] The term "sulfonate" refers to SO3H or a pharmaceutically acceptable salt thereof, which is recognized in the art.

[0091] The term "sulfo" refers to -S(O)2-, which is recognized in the art.

[0092] "Silyloxy" refers to -O-SiR3 (wherein each R is independently an alkyl group, an aryl group (which may be substituted or unsubstituted) or a heteroaryl group (which may be substituted or unsubstituted)). Non-limiting examples of silyloxy include -O-Si(CH3)3, -O-Si(CH3)2tBu, -O-Si(tBu)2CH3, -O-Si(tBu)3, -O-Si(CH3)2Ph, -O-Si(Ph)2CH3, and -O-Si(Ph)3.

[0093] The term "optionally substituted" refers to a particular residue of a compound of the invention optionally having 1, 2 or more substituents (eg, optionally substituted aryl).

[0094] With respect to alkyl, alkylene, aryl, arylalkyl, heterocyclyl and the like, the term "substituted", e.g., "substituted alkyl", "substituted alkylene", "substituted aryl", "substituted arylalkyl", "substituted heterocyclyl", and "substituted carbocyclyl (e.g., substituted cycloalkyl)" means that one or more hydrogen atoms of the alkyl, alkylene, aryl, arylalkyl, heterocyclyl or carbocyclyl (e.g., cycloalkyl) group are each independently replaced with a non-hydrogen substituent. Substituents may include any substituent described herein, such as halogen, hydroxy, alkyl, hydroxyalkyl, haloalkyl, cyanoalkyl, alkoxyalkyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfonamide, sulfonamide, sulfonyl, heterocyclic, aralkyl or aromatic or heteroaromatic residues. It will be understood by those skilled in the art that the residues substituted on the hydrocarbon chain may themselves be substituted as appropriate.

[0095] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thio group.

[0096] As used herein, the term "thioester" refers to -C(O)SR 9 or -SC(O)R 9 (Among them, R 9 represents a hydrocarbon group).

[0097] As used herein, the term "thioether" refers to an ether in which the oxygen is replaced by sulfur.

[0098] The term "urea" may be referred to by the general formula (Among them, R9 and R 10 independently represents hydrogen or a hydrocarbon group) as is recognized in the art.

[0099] The phrase "pharmaceutically acceptable" is recognized in the art. In a specific embodiment, the above term is equivalent to a reasonable beneficial / harmful ratio within the scope of discerning medical judgment, including compositions, excipients, adjuvants, polymers and other substances and / or administration forms suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications.

[0100] "Pharmaceutically acceptable salt" or "salt" refers to an acid addition salt or base addition salt that is suitable for patient treatment or compatible as used herein. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and may also include metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di- and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, and may also include sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Monoacid or di-acid salts that may be formed may exist in a hydrated, solvated or substantially anhydrous form. Generally, acid addition salts of the compounds of the present invention are more soluble in water and various hydrophilic organic solvents than their free bases, and generally have higher melting points. It is well known to those of ordinary skill to select appropriate salts. Other non-pharmaceutically acceptable salts, for example, oxalates can be used in the isolation of the compounds of the present invention for subsequent conversion to laboratory or pharmaceutically acceptable acid addition salts. Exemplary inorganic bases for forming suitable salts may include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide. Exemplary organic bases for forming suitable salts may include aliphatic, alicyclic or aromatic organic amines, such as methylamine, trimethylamine and picoline or ammonia. Therefore, in some cases, salts contemplated in the present invention may include alkyl, dialkyl, trialkyl or tetraalkyl ammonium salts. In a specific embodiment, as the salt considered in the present invention, L-arginine, phenethylbenzylamine, benzathine, betaine, calcium hydroxide, choline, diarno, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydroxylamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, trimethylamine, and zinc salts may be included, but are not limited thereto. In a specific embodiment, as the salt considered in the present invention, Na, Ca, K, Mg, Zn or other metal salts may be included, but are not limited thereto.

[0101] The selection of an appropriate salt is well within the skill of the art.

[0102] Pharmaceutically acceptable acid addition salts may also exist with various solvates such as water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. Such solvates may originate from the solvent of crystallization, but may also be inherent to the solvent of preparation or crystallization or may be incidental to such solvent.

[0103] The term "ester thereof" refers to any ester of a compound in which any -COOH functional group of the molecule is transformed into a -COOR functional group or any -OH functional group of the molecule is transformed into -OC(=O)R. The R residue of the ester can be any carbon-containing group that forms a stable ester residue, including alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, and substituted derivatives thereof, but is not limited thereto.

[0104] In certain embodiments, the compounds of the present invention may be racemates. In certain embodiments, one enantiomer of the compounds of the present invention may be enhanced. For example, the compounds of the present invention may have at least 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee or even 95% or greater ee.

[0105] Specific compounds useful for the methods and compositions of the present invention may have more than one stereocenter in their structure. Such stereocenters can exist in R or S coordination, and the above R and S labels are used according to the rules described in the literature [Pure Appl. Chem. (1976), 45, 11-30]. The present invention contemplates all stereoisomeric forms of the compounds, their salts, prodrugs or mixtures, for example, enantiomers and diastereoisomers (including all possible mixtures of stereoisomers).

[0106] Certain compounds of the invention have more than one stereocenter. Thus, more than one diastereoisomer of the compounds of the invention may be enhanced. For example, the compounds of the invention may have at least 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de or even 95% or more de. In certain embodiments, the compounds of the invention have substantially one isomeric coordination at more than one stereocenter and multiple isomeric coordination at the remaining stereocenters.

[0107] In certain embodiments, the enantiomeric excess of a designated stereocenter in the compound is at least 40%ee, 50%ee, 60%ee, 70%ee, 80%ee, 90%ee, 92%ee, 94%ee, 95%ee, 96%ee, 98%ee or greater ee.

[0108] As used herein, single bonds shown without stereochemistry do not indicate the stereochemistry of the compound. Compounds of formula (I) provide examples of compounds where stereochemistry is not indicated.

[0109] Furthermore, certain compounds containing alkenyl groups can exist as Z (cis (zusammen)) or E (trans (entgegen)) isomers. In each case, the present invention includes mixtures as well as the individual isomers alone.

[0110] Some of the compounds may exist in tautomeric forms. Although such forms are not explicitly shown in the chemical formulae described herein, they are intended to be included in the scope of the present invention.

[0111] "Prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that forms a compound of the present invention by metabolism such as hydrolysis or oxidation in a host after administration. As a typical example of a prodrug, a compound having a biologically unstable or cleavable (protective) group on a functional residue of an active compound can be exemplified. Prodrugs include compounds that can form active compounds by oxidation, reduction, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydrolysis, alkylation, dealkylation, acylation, deacylation, phosphorylation or dephosphorylation. Examples of prodrugs using esters or aminophosphorylates as biologically unstable or cleavable (protective) groups are disclosed in U.S. Patents Nos. 6,875,751, 7,585,851 and 7,964,580, the disclosures of which are incorporated herein as references. The prodrugs of the present invention generate the compounds of the present invention by metabolism. The present invention includes within its scope the prodrugs of the compounds described herein. Existing methods for selecting and preparing suitable prodrugs are described in, for example, the literature [“Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985].

[0112] In certain embodiments, the therapeutic agent of the compound of the present invention is enhanced to better provide one enantiomer of the compound. For example, the enantiomerically enhanced mixture may contain at least 60 mole percent of one enantiomer, more preferably, at least 75 mole percent, 90 mole percent, 95 mole percent or even 99 mole percent of one enantiomer. In certain embodiments, the compound in which one enantiomer is enhanced is substantially free of the other enantiomer, wherein substantially free means, for example, in the composition or compound mixture, compared to the amount of the other enantiomer, in the substance is less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%. For example, in the case where the composition or compound mixture contains 98g of the first enantiomer and 2g of the second enantiomer, it contains 98 mole percent of the first enantiomer and only 2% of the second enantiomer.

[0113] Thiazole derivative compounds

[0114] Representative embodiments of the compounds of the present invention are described below. Compounds such as those disclosed herein are suitable for formulation into any pharmaceutical composition disclosed herein or in any method or method of treatment disclosed herein.

[0115] According to a first representative embodiment, a compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0116] Chemical formula (I):

[0117] In the above formula,

[0118] Ring A is cycloalkyl, aryl, heteroaryl or heterocycloalkyl;

[0119] Ring B is cycloalkyl, aryl, heteroaryl or heterocycloalkyl;

[0120] R1 is H, halo, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, haloalkyl, cyano, -SR c 、-C(O)R c 、-C(O)OR c 、-C(O)N(R c )(R d )、-N(R c )(R d )、-(C(R g )2) q -N(R c )(R d ),-OR c or -(C(R g )2)q -OR c ;

[0121] R c and R d are each independently H, alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl; or

[0122] R c and R d Together with the atoms to which they are attached, they form a substituted or unsubstituted heterocycloalkyl group;

[0123] Each q is independently an integer from 1 to 3;

[0124] R g is H or alkyl;

[0125] R 2V and R 2W are each independently H, halo, hydroxy, alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl or amino; or

[0126] R 2V and R 2W Together with the atoms to which they are attached, they form a cycloalkyl or heterocycloalkyl group;

[0127] L1 does not exist or is -N(R e )-、-CH2N(R e )-、-CH2CH2N(R e )- or alkylene, however, L1 is -CH2N(R e )-or-CH2CH2N(R e )-, Ring B is attached to the carbon terminal of the substituent and R3 is attached to the nitrogen terminal of the substituent;

[0128] Among them, R e is H or alkyl; or R e It is covalently bonded to a position on ring B to form a heteroaryl or heterocycloalkyl ring structure, and it is an unsubstituted or substituted group;

[0129] R3 is

[0130] Among them, R f1 is H, halo, alkyl or cyano;

[0131] R f2 and R f3 Each is independently H, halo, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkoxy, alkoxyalkyl, -N(R c’ )(R d’ ) or -(C(R g’ )2)q -N(R c’ )(R d’ );

[0132] Each R g’ are independently H or alkyl;

[0133] R c’ and R d’ are each independently H, alkyl, heterocycloalkyl, alkoxy or alkoxyalkyl; or

[0134] R c’ and R d’ Together with the atoms to which they are attached, they form a substituted or unsubstituted heterocycloalkyl group,

[0135] Each R a are independently H, halo, hydroxy, nitro or cyano; or are alkyl, alkoxy, alkoxyalkyl, amino, haloalkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl, and are unsubstituted or substituted;

[0136] Each R b are independently H, halo, hydroxy, nitro or cyano or alkyl, alkoxy, alkoxyalkyl, amino, haloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl or -NR h R j , and it is an unsubstituted or substituted group;

[0137] R h and R j Each is independently H, alkyl, -N(R h’ )(R j’ )、-(C(R g’ )2) q -N(R h’ )(R j’ ) or a heterocycloalkyl group,

[0138] R h’ and R j’ are each independently H or alkyl; or

[0139] R h’ and R j’ Together with the atoms to which they are attached, they form an unsubstituted or substituted heterocycloalkyl group;

[0140] m and n are each independently an integer selected from 1 to 4.

[0141] In a preferred embodiment, ring A may be a 6- to 10-membered aryl group; a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; or a 5- or 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. More preferably, ring A may be phenyl, pyridyl, pyrazinyl, pyrazolyl, phenylthio, thiazolyl or piperidinyl.

[0142] In a preferred embodiment, ring B may be a 6- to 10-membered aryl group; a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; or a 5- or 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. More preferably, ring B may be phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyridinyl, piperidinyl or piperazinyl.

[0143] In a preferred embodiment, R1 can be halo, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, cyano, -SR c 、-C(O)R c 、-C(O)OR c 、-N(R c )(R d ),-OR c or -C(R g )2-OR c ; R c and R d Each independently may be H or C1-C6 alkyl; R g It can be H or C1-C6 alkyl.

[0144] In a preferred embodiment, R 2V and R 2W Each independently can be H, halo or C1-C6 alkyl; or R 2V and R 2W Together with the atoms to which they are attached, they form a C3-C7 cycloalkyl group.

[0145] In a preferred embodiment, L1 may not exist, or may be -N(R e )-or-CH2N(R e )-,

[0146] Among them, R e Can be H or C1-C6 alkyl; or

[0147] R eis covalently bonded to an atom on ring B to form a 5-membered or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S; or a 5-membered or 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S,

[0148] The heteroaryl group or heterocycloalkyl group may be substituted or unsubstituted by a C1-C6 alkyl group.

[0149] More preferably, L1 may not exist, or may be -N(R e )-or-CH2N(R e )-,

[0150] Among them, R e Can be H or C1-C6 alkyl; or

[0151] R e It can be covalently bonded to an atom on ring B to form pyrrolidine or pyrrole which may be substituted with a C1-C6 alkyl group.

[0152] In a preferred embodiment, R3 can be

[0153] Among them, R f1 Can be H, C1-C6 alkyl or cyano;

[0154] R f2 and R f3 Each independently may be H, C1-C6 alkyl, C3-C7 cycloalkyl, -N(R c’ )(R d’ ) or -(CH2)N(R c’ )(R d’ );

[0155] R c’ and R d’ Each independently may be H or C1-C6 alkyl; or

[0156] R c’ and R d’ Together with the atoms to which they are attached, they form a 4-membered to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl group may be a group substituted or unsubstituted by halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy-C1-C6 alkyl. More preferably, R3 may be

[0157] Among them, R f1 Can be H, C1-C6 alkyl or cyano;

[0158] Rf2 and R f3 Each independently may be H, C1-C6 alkyl, C3-C7 cycloalkyl, -N(CH3)2 or -(CH2)N(R c’ )(R d’ );

[0159] R c’ and R d’ Each independently may be a C1-C6 alkyl group; or

[0160] R c’ and R d’ Together with the atoms to which they are attached, they form an azetidinyl group; a piperidinyl group; a morpholinyl group; a piperazinyl group which may be substituted or unsubstituted by a C1-C6 alkyl group; a 2,5-diazabicyclo[2.2.1]heptyl group which may be substituted or unsubstituted by a C1-C6 alkyl group; a 2-oxa-5-azabicyclo[2.2.1]heptyl group; or a pyrrolidinyl group which may be substituted or unsubstituted by a halogenated, hydroxyl or C1-C6 alkoxy-C1-C6 alkyl group.

[0161] In a preferred embodiment, each R a independently may be H, halo or C1-C6 alkyl;

[0162] Each R b independently may be H, halo, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, -NR h R j or a 5- to 6-membered heterocycloalkyl group containing 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl group may be a group substituted or unsubstituted by a C1-C6 alkyl group,

[0163] R h and R j Each independently may be C1-C6 alkyl, -CH2CH2N(R h’ )(R j’ );

[0164] R h’ and R j’ Each independently may be H or C1-C6 alkyl. More preferably, each R a independently may be H, halo or C1-C6 alkyl;

[0165] Each R b Independently, it may be H, halo, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, -N(CH3)-CH2CH2-N(CH3)2 or piperazinyl, which is a group which is substituted or unsubstituted by C1-C6 alkyl.

[0166] In a preferred embodiment, m and n can be 1.

[0167] In a preferred embodiment, in Formula I, Ring A is an aryl or heteroaryl group, for example, a pyrrolidinyl, furanyl, phenylthio, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl, piperazinyl, cyclohexyl, azetidinyl, benzimidazolyl, benzothiazolyl or quinolinyl group.

[0168] In a particularly preferred embodiment of this invention, ring A is phenyl. In yet another preferred embodiment of this invention, ring A is pyridyl. In another preferred embodiment of this invention, ring A is phenylthio. In yet another preferred embodiment of this invention, ring A is pyrazolyl.

[0169] In a second representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Ia).

[0170] Chemical formula (Ia):

[0171] In the above formula, X1, X2, X3 and X4 are each independently CH or N.

[0172] In a third representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Iai).

[0173] Chemical formula (Iai):

[0174] In a fourth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Iaii).

[0175] Chemical formula (Iaii):

[0176] In a fifth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Iaiii).

[0177] Chemical formula (Iaiii):

[0178] In a sixth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Ib).

[0179] Chemical formula (Ib):

[0180] In the above formula, X1, X2, X3 and X4 are each independently CH, O, S or N.

[0181] In the seventh representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Ibi).

[0182] Chemical formula (Ibi):

[0183] In an eighth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Ibii).

[0184] Chemical formula (Ibii):

[0185] In certain preferred embodiments, Ring B of Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi) or Formula (Ibii) is an aryl group or a heteroaryl group, for example, a phenyl group, a pyridyl group, a pyrimidyl group, a pyrazinyl group, a pyridazinyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a tetrahydropyridyl group, a piperidinyl group or a piperazinyl group.

[0186] In a ninth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Ic).

[0187] Chemical formula (Ic):

[0188] In the above formula, X9, X 10 , X 11 , and X 12 are each independently CH or N.

[0189] In the tenth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Ici).

[0190] Chemical formula (Ici):

[0191] In an eleventh representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Icii).

[0192] Chemical formula (Icii):

[0193] In the twelfth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Iciii).

[0194] Chemical formula (Iciii):

[0195] In the thirteenth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Iciv).

[0196] Chemical formula (Iciv):

[0197] In the fourteenth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Icv).

[0198] Chemical formula (Icv):

[0199] In the fifteenth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Icvi).

[0200] Chemical formula (Icvi):

[0201] In the sixteenth representative embodiment, the compound of Chemical Formula (I) may be a compound of the following Chemical Formula (Icvii).

[0202] Chemical formula (Icvii):

[0203] In the seventeenth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R1 is halo, alkyl, cycloalkyl, haloalkyl, cyano, -SR c 、-C(O)R c 、-C(O)OR c 、-N(R c )(R d ),-OR c or -C(R g )2-OR c ; R c are independently H or alkyl.

[0204] In an eighteenth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R 2V and R 2W Each is independently H, halo or alkyl.

[0205] In a nineteenth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R 2V and R 2W One of them is H and the other is alkyl, or R 2V and R 2W Together with the atoms to which they are attached, they form a C3-C7 cycloalkyl group.

[0206] In the twentieth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R 2V and R 2W One of them is H and the other is methyl.

[0207] In the twenty-first representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi), or Formula (Icvii) defined in any of the above representative embodiments, L1 is absent or is -N(R e )-.

[0208] In a twenty-second representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi) or Formula (Ibii) defined in any of the above representative embodiments, when Ring B is a heterocycloalkyl group and In the case of attachment to the nitrogen atom of the heterocycloalkyl group in Ring B, L1 is absent.

[0209] In the twenty-third representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi), or Formula (Icvii) defined in any of the above representative embodiments, L1 is -N(R e )-.

[0210] In the twenty-fourth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R e For H.

[0211] In a twenty-fifth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R3 is

[0212] In the twenty-sixth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R3 is

[0213] In the twenty-seventh representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R f1 H; R f2 and R f3 Each is independently H, alkyl, cycloalkyl, heterocycloalkyl, -N(R c’ )(R d’ ) or -(C(R g’ )2) q -N(R c’ )(R d’ ).

[0214] In a twenty-eighth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R3 is

[0215] In the twenty-ninth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R a is H or halogenated.

[0216] In the thirtieth representative embodiment, in Formula (I), Formula (Ia), Formula (Iai), Formula (Iaii), Formula (Iaiii), Formula (Ib), Formula (Ibi), Formula (Ibii), Formula (Ici), Formula (Icii), Formula (Iciii), Formula (Iciv), Formula (Icv), Formula (Icvi) or Formula (Icvii) defined in any of the above representative embodiments, R b is H, halo, alkyl or heterocycloalkyl.

[0217] In a thirty-first representative embodiment, a pharmaceutical composition comprising a compound defined in any of the above embodiments is contemplated.

[0218] In the thirty-second representative embodiment, a method of inhibiting CDK7 is contemplated comprising the step of administering a compound as defined in any of the first to thirtieth representative embodiments or a pharmaceutical composition of the thirty-second representative embodiment.

[0219] In the thirty-third representative embodiment, a method for treating or preventing a disease in a subject comprising administering a compound as defined in any of the first to thirtieth representative embodiments or a pharmaceutical composition as defined in the thirty-second representative embodiment is contemplated. The disease may be any disease discussed herein, preferably a disease associated with the undesirable activity of CDK7.

[0220] In particular, in a preferred embodiment, the compound of formula (I) is a compound of the following formula (Id) or a pharmaceutically acceptable salt thereof.

[0221] Chemical formula (Id):

[0222] In the above formula,

[0223] R1 is a C1-C3 alkyl group which may be substituted by halogen;

[0224] R b is CN or halogen.

[0225] Representative compounds of Formula (I) to Formula (Icvii) include compounds selected from Compound 1) to Compound 149), but are not limited thereto.

[0226] 1) N-(5-(3-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0227] 2) N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0228] 3)(R)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0229] 4) N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0230] 5)(E)-4-(dimethylamino)-N-(5-(3-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;

[0231] 6) (E)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

[0232] 7) (E)-4-(dimethylamino)-N-(5-(3-(1-((5-methylthiazol-2-yl)amino-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide hydrochloride;

[0233] 8) N-(3-fluoro-3'-(1-((5-methylthiazol-2-yl)amino-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide;

[0234] 9) 2-(3-(1-acryloylindol-5-yl)phenyl)-N-(5-methylthiazol-2-yl)propionamide;

[0235] 10) (E)-N-(5-(3-(1,1-difluoro-2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

[0236] 11) N-(6-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-4-fluorophenyl)pyridazin-3-yl)acrylamide;

[0237] 12) 2-(3-(6-acrylamidopyridazin-3-yl)phenyl)-N-(5-cyanothiazol-2-yl)-3-methylbutanamide;

[0238] 13) N-(6-(5-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)pyridazin-3-yl)acrylamide;

[0239] 14) (S)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0240] 15) (S,E)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

[0241] 16) (S)-N-(6-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide;

[0242] 17)(S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;

[0243] 18) (S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0244] 19) (S)-2-(3-(6-acrylamidopyridin-3-yl)phenyl)-N-(5-ethylthiazol-2-yl)butanamide;

[0245] 20) (S)-2-(4'-acrylamido-3'-fluoro-[1,1'-biphenyl]-3-yl)-N-(5-ethylthiazol-2-yl)butanamide;

[0246] 21)(S,E)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

[0247] 22)(S)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide;

[0248] 23) (S)-N-(3'-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide;

[0249] 24) (S)-N-(3'-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1'-biphenyl]-4-yl)acrylamide;

[0250] 25)(S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide;

[0251] 26)(S)-N-(6-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide;

[0252] 27)(S)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrimidin-2-yl)acrylamide;

[0253] 28) (S)-N-(6-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridazin-3-yl)acrylamide;

[0254] 29)(S)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-fluoropyridin-2-yl)acrylamide;

[0255] 30) (S)-N-(3-cyano-3'-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide;

[0256] 31)(S)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-6-fluoropyridin-2-yl)acrylamide;

[0257] 32)(S)-N-(6-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridazin-3-yl)acrylamide;

[0258] 33)(S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-fluoropyridin-2-yl)acrylamide;

[0259] 34)(S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-methylpyrazin-2-yl)acrylamide;

[0260] 35)(S)-N-(5-(3-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0261] 36)(S)-N-(5-(3-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide;

[0262] 37)(S)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)acrylamide;

[0263] 38)(S)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0264] 39)(S)-N-(6-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridazin-3-yl)acrylamide;

[0265] 40)(S)-N-(6-(3-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridazin-3-yl)acrylamide;

[0266] 41) N-(5'-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-[3,3'-bipyridyl]-6-yl)acrylamide;

[0267] 42) N-(4-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-[2,3'-bipyridyl]-6'-yl)acrylamide;

[0268] 43) N-(5-(5-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0269] 44) N-(5-(5-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0270] 45) N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0271] 46) N-(5-(5-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0272] 47) N-(5-(5-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0273] 48) N-(5-(5-(1-((5-acetylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0274] 49) N-(6-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyridazin-3-yl)acrylamide;

[0275] 50) N-(4-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[2,3'-bipyridyl]-6'-yl)acrylamide;

[0276] 51)(R)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0277] 52)(S)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0278] 53) N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)thiophen-3-yl)pyridin-2-yl)acrylamide;

[0279] 54) N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-5-fluorophenyl)pyridin-2-yl)acrylamide;

[0280] 55) N-(5-(5-(2-methyl-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0281] 56) (S)-2-(3-(5-(2-cyanoacetamido)pyrazin-2-yl)phenyl)-N-(5-(trifluoromethyl)thiazol-2-yl)propanamide;

[0282] 57) N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)thiophen-3-yl)pyrazin-2-yl)acrylamide;

[0283] 58) (S)-2-(3-(5-(2-cyanoacetamido)pyrazin-2-yl)phenyl)-N-(5-cyanothiazol-2-yl)propanamide;

[0284] 59) N-(5-(3-methyl-1-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)acrylamide;

[0285] 60) 2-(1'-acryloyl-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-5-yl)-N-(5-cyanothiazol-2-yl)propionamide;

[0286] 61) N-(5-(5-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0287] 62)(S)-N-(6-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)acrylamide;

[0288] 63) (E)-4-(dimethylamino)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide;

[0289] 64) 2-(5-(5-(2-cyanoacetamido)pyrazin-2-yl)pyridin-3-yl)-N-(5-(trifluoromethyl)thiazol-2-yl)propanamide;

[0290] 65)(E)-2-cyano-3-cyclopropyl-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0291] 66) N-(5-(5-(1-((5-methoxythiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0292] 67) N-(5-(5-(1-((5-fluorothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0293] 68) N-(2-(4-methylpiperazin-1-yl)-4-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)phenyl)acrylamide;

[0294] 69) (E)-2-cyano-3-(dimethylamino)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0295] 70) N-(1-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)piperidin-4-yl)acrylamide;

[0296] 71) N-(5-(5-(1-((5-(methylthio)thiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide;

[0297] 72) ethyl 2-(2-(5-(5-acrylamidopyrazin-2-yl)pyridin-3-yl)propionylamino)thiazole-5-carboxylate;

[0298] 73)(E)-N-(5-(5-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)-4-(dimethylamino)but-2-enamide;

[0299] 74)(E)-4-morpholino-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide;

[0300] 75)(E)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide;

[0301] 76) N-(5-(5-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)thiophen-3-yl)pyridin-2-yl)acrylamide;

[0302] 77) N-(5-(5-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)thiophen-3-yl)pyridin-2-yl)acrylamide;

[0303] 78) N-(5-(5-(1-((5-acetylthiazol-2-yl)amino)-1-oxopropan-2-yl)thiophen-3-yl)pyridin-2-yl)acrylamide;

[0304] 79) 2-(5-(5-propionamidopyrazin-2-yl)pyridin-3-yl)-N-(5-(trifluoromethyl)thiazol-2-yl)propanamide;

[0305] 80)(E)-4-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide;

[0306] 81)(S,E)-4-(dimethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0307] 82) N-(5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)acrylamide;

[0308] 83)(E)-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide;

[0309] 84) N-(4-fluoro-5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)acrylamide;

[0310] 85) 2-(5-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-N-(5-(trifluoromethyl)thiazol-2-yl)propanamide;

[0311] 86) 2-(5-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-N-(5-ethylthiazol-2-yl)propanamide;

[0312] 87) N-(6-(5-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)thiophen-3-yl)pyridin-3-yl)acrylamide;

[0313] 88) N-(5-cyano-5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)acrylamide;

[0314] 89) N-((5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)methyl)acrylamide;

[0315] 90) N-(5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[2,3'-bipyridyl]-5-yl)acrylamide;

[0316] 91)(S,E)-4-(dimethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0317] 92)(S,E)-4-morpholino-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0318] 93)(S,E)-N-(5-(3-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(dimethylamino)but-2-enamide;

[0319] 94)(E)-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(5-(3-((S)-1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0320] 95)(S,E)-4-(4-methylpiperazin-1-yl)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0321] 96)(E)-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0322] 97)(S,E)-N-(5-(3-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(4-methylpiperazin-1-yl)but-2-enamide;

[0323] 98)(S,E)-N-(5-(3-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-morpholinobut-2-enamide;

[0324] 99)(S,E)-4-(dimethylamino)-N-(3-fluoro-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;

[0325] 100)(S,E)-4-(dimethylamino)-N-(3-methoxy-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;

[0326] 101)(S,E)-N-(3-cyano-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

[0327] 102)(S,E)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide;

[0328] 103) (S,E)-4-(azetidin-1-yl)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0329] 104)(S,E)-N-(5-(3-(1-((5-cyclobutylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(dimethylamino)but-2-enamide;

[0330] 105) (S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-(2-hydroxypropan-2-yl)thiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0331] 106) (S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-(dimethylamino)thiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0332] 107) (E)-4-(dimethylamino)-N-(5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)but-2-enamide;

[0333] 108) (E)-N-(5-cyano-5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)-4-(dimethylamino)but-2-enamide;

[0334] 109) (S,E)-4-(dimethylamino)-N-(3-methoxy-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0335] 110)(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-(trifluoromethyl)thiazol-2-yl)propanamide;

[0336] 111)(S,E)-4-(dimethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)-3-(trifluoromethyl)pyridin-2-yl)but-2-enamide;

[0337] 112)(S,E)-4-(dimethylamino)-N-(3-methyl-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;

[0338] 113)(S,E)-N-(3-chloro-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

[0339] 114)(S,E)-4-(diethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0340] 115)(E)-4-((R)-3-fluoropyrrolidin-1-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0341] 116)(S,E)-4-(dimethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;

[0342] 117)(E)-4-((S)-3-fluoropyrrolidin-1-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0343] 118) (E)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0344] 119) (E)-4-(3-hydroxypyrrolidin-1-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide;

[0345] 120)(S,E)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)-4-(piperidin-1-yl)but-2-enamide;

[0346] 121)(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

[0347] 122)(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-ethylthiazol-2-yl)propanamide;

[0348] 123) (E)-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(3-cyano-5-(3-((S)-1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide;

[0349] 124)(S)-N-(3-cyano-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0350] 125)(S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-methylpyridin-2-yl)but-2-enamide;

[0351] 126)(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-ethylthiazol-2-yl)propanamide;

[0352] 127)(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-ethylthiazol-2-yl)propanamide;

[0353] 128) (E)-1-(3-(5-cyano-6-(4-(dimethylamino)but-2-enoylamino)pyridin-3-yl)phenyl)-N-(5-ethylthiazol-2-yl)cyclopropane-1-carboxamide;

[0354] 129) (S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-N-methylbut-2-enamide;

[0355] 130)(S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-fluoropyridin-2-yl)but-2-enamide;

[0356] 131)(E)-4-(dimethylamino)-N-(6-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxobutan-2-yl)phenyl)pyridin-3-yl)but-2-enamide;

[0357] 132) (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)-N-methylbut-2-enamide;

[0358] 133) (E)-1-(3-(1-(4-(dimethylamino)but-2-enoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-ethylthiazol-2-yl)cyclopropane-1-carboxamide;

[0359] 134) (E)-1-(3-(6-(4-(dimethylamino)but-2-enoylamino)-5-fluoropyridin-3-yl)phenyl)-N-(5-ethylthiazol-2-yl)cyclopropane-1-carboxamide;

[0360] 135) (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide;

[0361] 136) (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)but-2-enamide;

[0362] 137) (E)-N-(5-cyano-5'-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[3,3'-bipyridyl]-6-yl)-4-(dimethylamino)but-2-enamide;

[0363] 138) (E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide;

[0364] 139) (S)-2-(3-(5-cyano-6-(2-cyanoacetamido)pyridin-3-yl)phenyl)-N-(5-ethylthiazol-2-yl)propanamide;

[0365] 140) N-(5-(6-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyrazin-2-yl)pyridin-2-yl)acrylamide;

[0366] 141) N-(2'-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[3,4'-bipyridyl]-6-yl)acrylamide;

[0367] 142) N-(4-(3-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)piperidin-1-yl)phenyl)acrylamide;

[0368] 143) N-(5-(2-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)thiazol-4-yl)pyridin-2-yl)acrylamide;

[0369] 144)(S)-N-(3-cyclopropyl-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide;

[0370] 145) (S)-N-(3-((2-(dimethylamino)ethyl)(methyl)amino)-3'-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide;

[0371] 146)(S)-N-(5-ethylthiazol-2-yl)-2-(3-(6-(vinylsulfonamido)pyridin-3-yl)phenyl)propanamide;

[0372] 147)(S)-N-(3-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-1-methyl-1H-pyrazol-5-yl)acrylamide;

[0373] 148) (S)-N-(4-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-1H-imidazol-2-yl)acrylamide; and

[0374] 149) (S)-N-(4-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)thiazol-2-yl)acrylamide.

[0375] Hereinafter, unless otherwise specified, the compounds of the above chemical formulas including any pharmaceutically acceptable salts thereof as active ingredients of therapeutic agents shall be deemed to be included within the scope of the present invention. For the convenience of description, they may be referred to as the compounds of the above chemical formulas or the compounds of the present invention.

[0376] The compounds of the present invention can exist in the form of salts, especially pharmaceutically acceptable salts. As salts, salts commonly used in the art, for example, acid addition salts formed from pharmaceutically acceptable free acids, can be used without restriction. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compounds of the present invention, wherein the side effects caused by the salt do not affect the beneficial effects of the compound at a concentration that exhibits effective activity that is relatively non-toxic and harmless to the patient.

[0377] Organic acids and inorganic acids can be used as free acids. Pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, mandelic acid, fumaric acid, maleic acid, salicylic acid, etc.; or acid addition salts formed by sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. As examples of pharmaceutically acceptable carboxylates, metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc. may be included; amino acid salts such as lysine, arginine, guanidine, etc.; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. The compounds of the present invention can be converted into their salts by conventional methods.

[0378] Furthermore, the compounds of the present invention include not only pharmaceutically acceptable salts thereof but also all possible optical isomers without limitation. Stereoisomers of the compounds of the present invention can be prepared by methods known in the art.

[0379] Furthermore, the compounds of the present invention may be prepared in a crystalline form or a non-crystalline form. If the compound is prepared in a crystalline form, it may be hydrated or solvated at will. The hydrates of the compounds of the present invention include stoichiometric hydrates (i.e., a ratio of compound molecules to water molecules of 1:1) and non-stoichiometric hydrates (i.e., a ratio of compound molecules to water molecules other than 1:1). Similarly, the solvates of the compounds of the present invention include stoichiometric solvates and non-stoichiometric solvates.

[0380] Other terms have the same meanings as commonly understood in the art to which the present invention relates.

[0381] Treatment

[0382] The thiazole derivatives of the present invention, and pharmaceutically acceptable salts, optical isomers, solvates or hydrates thereof inhibit the activity of cyclin-dependent kinases, preferably CDK7, thereby exhibiting preventive or therapeutic effects on proliferative disorders or diseases associated with their activities, and infectious diseases.

[0383] Therefore, the present invention also relates to a pharmaceutical composition for preventing or treating a disorder or disease associated with CDK activity or an infectious disease, comprising the compound of the present invention or a pharmaceutically acceptable salt or optical isomer thereof as an active ingredient.

[0384] Furthermore, the present invention relates to a method for preventing or treating a disorder or disease associated with CDK activity or an infectious disease, comprising the step of administering the compound of the present invention or a pharmaceutically acceptable salt or optical isomer thereof.

[0385] Further, the present invention relates to the use of the compounds of the present invention or their pharmaceutically acceptable salts or optical isomers for preventing or treating disorders or diseases or infectious diseases associated with CDK activity. Specifically, the pharmaceutical composition of the present invention can prevent or treat diseases or disorders associated with CDK activity such as proliferative diseases or infectious diseases by inhibiting cyclin-dependent kinases. Proliferative diseases refer to diseases such as cancer, benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases or autoimmune diseases, and infectious diseases refer to diseases such as bacterial diseases or viral diseases. Proliferative disorders treated or prevented using the thiazole derivative compounds of the present invention are typically associated with abnormal activity of CDK7. The abnormal activity of CDK7 can be an increased and / or inappropriate (e.g., abnormal) activity of CDK7.

[0386] Proliferative diseases can also be associated with the inhibition of apoptosis of cells in biological samples or subjects. The inhibition of CDK7 activity may cause cytotoxicity through the induction of apoptosis. The compounds of the present invention and their pharmaceutically acceptable salts and / or optical isomers of the present invention induce apoptosis and, therefore, can be used for the treatment and / or prevention of proliferative diseases.

[0387] The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal mass of tissue whose growth exceeds that of normal tissue and does not cooperate with the growth of normal tissue. In the following, a neoplasm or tumor may be "benign" or "malignant" according to the characteristics: degree of cell differentiation (including morphology and functionality), growth rate, local infiltration, and metastasis. "Benign neoplasms" are usually well differentiated and have the characteristics of slower growth than malignant neoplasms, and remain in a localized state at the site of origin. In addition, benign neoplasms do not have the ability to infiltrate, infiltrate, or metastasize to distant sites. As exemplary benign neoplasms, lipomas, chondromas, adenomas, soft fibromas, senile hemangiomas, seborrheic keratosis, senile plaques, and sebaceous hyperplasia may be included, but are not limited thereto. In some cases, characteristic "benign" tumors may later induce malignant neoplasms, which may be caused by additional genetic changes in a lower group of neoplasm cells of the tumor, and these tumors are referred to as "pre-malignant neoplasms". An exemplary premalignant neoplasm is a teratoma. In contrast, a "malignant neoplasm" is usually poorly differentiated (regressive), characterized by progressive infiltration, infiltration, and rapid growth with collapse of surrounding tissue. Further, a malignant neoplasm usually has the ability to metastasize to distant sites.

[0388] As used herein, the term "cancer" refers to a malignant neoplasm. Exemplary cancers include: acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymph node endothelial sarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; bile duct cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary breast cancer, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical glandular carcinoma); carcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial cancer; ependymal tumors; endothelial sarcomas (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's esophagus adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., ocular melanoma, retinoblastoma); familial hypereosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumors (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), pharyngeal cancer cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancer (e.g., leukemia, e.g., acute lymphoblastic leukemia (ALL) (e.g., B cell ALL, T cell ALL), acute myeloid leukemia (AML) (e.g., B cell AML, T cell AML), chronic myeloid leukemia (CML) (e.g., B cell CML, T cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B cell CLL, T cell CLL)); lymphoma, e.g., Hodgkin lymphoma (HL) (e.g., B cell HL, T cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B cell NHL, e.g., Such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal large B-cell lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphocytic lymphoma, and primary central nervous system (CNS) lymphoma;and T-cell NHL, e.g., precursor T-lymphocytic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); mixtures of more than one leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immune cell amyloidosis; renal cancer (e.g., known as Wilms' tumor nephroblastoma, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown etiology (AMM) known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia ( CNL), hypereosinophilic syndrome (HES); neuroblastoma; neurofibroma (e.g., neurofibromatosis type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastrointestinal-pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell tumor; paraneoplastic syndrome; intraepithelial neoplasia; prostate cancer (e.g., prostate adenocarcinoma ); colorectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratinocyte (KA), melanoma, basal cell carcinoma (BCC)); small intestinal cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland cancer; small intestinal cancer; sweat gland adenocarcinoma; synovioma; testicular cancer (e.g., seminoma, embryonal testicular tumor); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva), but are not limited thereto. ;

[0389] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in the healthy body of the subject in order to heal wounds and to restore blood flow to tissues after injury. The healthy body controls angiogenesis by various means such as angiogenesis-stimulating growth factors and angiogenesis inhibitors. Many disease conditions, such as cancer, diabetic vision loss, age-related macular degeneration, rheumatoid arthritis, and psoriasis are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal angiogenesis refers to angiogenesis that is produced more than the normal body, especially angiogenesis in adults that is unrelated to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can supply nutrients to diseased tissues / or provide new blood vessels that cause normal tissues to collapse. In the case of cancer, new blood vessels allow tumor cells to escape through the circulation and stay in other organs (tumor metastasis).

[0390] As used herein, "inflammatory disease" refers to a disease caused by inflammation or caused by inflammation or causing inflammation. The term "inflammatory disease" can also refer to an inflammatory reaction that causes an over-reaction caused by macrophages, granulocytes and / or T lymphocytes that causes abnormal tissue damage and / or apoptosis. Inflammatory diseases can be acute or chronic inflammatory states, which can be caused by infectious or non-infectious causes. Inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune diseases, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendinitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjögren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type 1), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed Connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory dermatitis, usual interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talc pneumoconiosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatitis, hepatitis, delayed hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory inflammation, adult respiratory Distress syndrome (ARDS), encephalitis, immediate hypersensitivity reaction, asthma, hay fever, allergy, acute allergic reaction, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, graft-versus-host rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoductitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis media, pancreatitis, mumps, pericarditis, pharyngitis, pleurisy, phlebitis, interstitial pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis, but are not limited to these.

[0391] As used herein, "autoimmune disease" refers to a disease caused by an immune response that produces discomfort in the body of the subject against substances and tissues that are normally present in the body. In other words, the immune system mistakes a part of the body for a pathogen and attacks its own cells. This is limited to specific organs (e.g., autoimmune thyroiditis) or can be accompanied by specific tissues in different locations (e.g., Goodpasture's disease, which affects the basement membrane in both the lungs and kidneys). Treatment of autoimmune diseases is performed by typical immunosuppression, for example, drug therapy that reduces the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, periarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Rett's syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0392] The term "autoinflammatory disease" is similar to autoimmune disease, but refers to a different type of disease. The common feature of autoinflammatory and autoimmune diseases is that both groups of disorders are caused by the immune system attacking the subject's own tissues, resulting in increased inflammation. In autoinflammatory diseases, the cause of inflammation caused by the subject's innate immune system is unknown. The innate immune system will react even if it has never encountered autoantibodies or antigens in the subject. Autoinflammatory disorders are characterized by intense attacks of inflammation that cause symptoms such as fever, rash, or swollen joints. These diseases also have the risk of potentially fatal accumulation of amyloid proteins in organs as blood proteins. Autoinflammatory diseases include familial Mediterranean fever (FMF), multisystem inflammatory disease (NOMID) of neonatal onset, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), interleukin-1 receptor deficiency (DIRA), and Behcet's disease, but are not limited to this.

[0393] Compared with the compounds known in the art, the novel thiazole derivatives of the present invention have significant inhibitory activity against CDK. Specifically, compared with any compounds known in the art, the compounds of the present invention not only have highly selective inhibitory activity against CDK7, but also have reduced side effects and toxicity, which exerts significant preventive or therapeutic effects on proliferative diseases or infectious diseases associated with CDK7.

[0394] In some embodiments, the selectivity of the compounds of the present invention for CDK7 is at least 2 times greater than that of other types of CDK, especially CDK2 or CDK5. The selectivity of the compounds of the present invention for CDK7 can be at least 2 times, at least 3 times, at least 5 times, or even at least 10 times greater than that of other types of CDK, especially CDK2 or CDK5. In some embodiments, the selectivity of the compounds of the present invention for CDK7 can be at least 100 times greater than that of other types of CDK, especially CDK2 or CDK5.

[0395] Similarly, the CDK7-inhibitory activity (expressed as IC 50 quantification) is less than 1000 nM. In some embodiments, the CDK7-inhibitory activity (IC 50 ) is less than 500 nM. In a preferred embodiment, the CDK7-inhibitory activity (IC 50 ) is less than 100nM.

[0396] General synthesis method of thiazole derivative compounds

[0397] The thiazole derivative compounds of the present invention can be prepared utilizing readily available starting materials and by adapting the specific synthetic routes described below that are well known to those of ordinary skill.

[0398] As an embodiment, the intermediate 1-b and the intermediate 1-c of the compound of the present invention can be prepared according to the following reaction formula 1.

[0399] Reaction 1:

[0400]

[0401] In the above formula, ring A, R 2v , R a and m are as defined above.

[0402] Compound 1-a is dissolved in a solvent such as THF, reacted with an appropriate amount of a base such as NaHMDS or LiHMDS, and then a haloalkyl (R 2v -I) to obtain compound 1-b substituted with different alkyl groups. Then, the (S)-form compound 1-c is separated from the racemic acid form of compound 1-b. Specifically, compound 1-b is dissolved in a suitable solvent such as ACN, and a base such as (R)-1-phenylethane-1-amine that can form an acid compound and a salt (R)-form is added to precipitate the salt and filter. Recrystallization is repeated twice with ACN, and extraction and drying are performed under acidic conditions to obtain the (S)-form intermediate compound 1-c.

[0403] As an embodiment, the intermediate 2-b of the compound of the present invention can be prepared according to the following reaction formula 2-1.

[0404] Reaction 2-1:

[0405]

[0406] In the above formula, ring B, R3, R b , L1 and n are as defined above.

[0407] Compound 2-a is reacted with a commercially available acid chloride or carboxylic acid under suitable reaction conditions (e.g., SOCl2 or (COCl)2, DMF (catalytic amount), room temperature), and then reacted under suitable base conditions (e.g., triethylamine, diisopropylamine, pyridine, etc.) to obtain compound 2-b. Alternatively, compound 2-a is reacted with a carboxylic acid under suitable base conditions (e.g., pyridine, triethylamine, diisopropylethylamine, etc.) and in the presence of a suitable coupling agent such as HATU, HBTU, TBTU, EDC / HOBt or T3P to obtain compound 2-b.

[0408] Reaction 2-2:

[0409]

[0410] In the above reaction formula, compound 2-b' is obtained under the conditions of reaction formula 2-1, and compound 2-b' is reacted with dimethylamine in a suitable solvent (eg, ACN or THF) and alkaline conditions (K2CO3 or DPIEA) at a suitable temperature to obtain compound 2-b".

[0411] The compound of the present invention can be prepared according to the following reaction formula 3.

[0412] Reaction 3:

[0413]

[0414] In the above formula, ring A, ring B, R1, R 2v , R 2w , R3, R a , R b , L1, m and n are as defined above.

[0415] Under suitable reaction conditions (e.g., SOCl2 or (COCl)2, DMF (catalytic amount), room temperature), commercially available or synthesized intermediate 1-b or intermediate 1-c is reacted with an acid chloride, and then reacted under suitable alkaline conditions (e.g., pyridine, triethylamine, diisopropylethylamine, etc.) to obtain compound 3-a. Alternatively, in the presence of a suitable coupling agent, intermediate 1-b or intermediate 1-c is reacted to obtain compound 3-a. The coupling agent may include HATU, HBTU, TBTU, EDC / HOBt or T3P, and the reaction may be carried out under suitable alkaline conditions. The base may include pyridine, triethylamine, diisopropylethylamine, etc. In the presence of a catalyst such as pd(dppf)Cl2.DCM, a base such as Na2CO3, and a solvent such as 1,4-dioxane, the intermediate 3-b is synthesized by Miyaura borylation reaction. The desired compound 3-c can be synthesized under Suzuki conditions in the presence of a catalyst such as pd(dppf)Cl2.DCM or Pd(PPh3)4, a base such as Na2CO3, NaHCO3 or Cs2CO3, and a solvent such as 1,4-dioxane / water.

[0416] The compound of the present invention can be prepared according to the following reaction formula 4.

[0417] Reaction 4:

[0418]

[0419] In the above formula, ring A, ring B, R1, R 2v , R 2w , R3, R a , R b , L1, m and n are as defined above.

[0420] In the presence of a catalyst such as pd(dppf)Cl2.DCM or Pd(PPh3)4, a base such as Na2CO3 or Cs2CO3, and a solvent such as 1,4-dioxane / water, compound 4-a can be synthesized from compound 3-b, and then compound 4-b can be synthesized under the conditions of reaction formula 2.

[0421] The compound of the present invention can be prepared according to the following reaction formula 5.

[0422] Reaction 5:

[0423]

[0424] In the above formula, A, B, R1, R 2v , R 2w , R3, R a , R b , L1, m and n are as defined above.

[0425] After reacting intermediate 1-b or intermediate 1-c under acidic conditions of alcoholic solvents (esterification reaction), intermediate 5-b is obtained by Miyaura borylation in the presence of a catalyst such as pd(dppf)Cl2.DCM, a base such as Na2CO3, and a solvent such as 1,4-dioxane. Then, compound 5-c is synthesized by Suzuki reaction in the presence of a catalyst such as pd(dppf)Cl2.DCM or Pd(PPh3)4, a base such as Na2CO3 or Cs2CO3, and a solvent such as 1,4-dioxane / water. Then, compound 5-d is obtained by hydrolysis using a base such as LiOH or NaOH, and compound 5-e is obtained using a suitable coupling agent. The coupling agent may include HATU, HBTU, TBTU, EDC / HOBt or T3P, and the reaction may be carried out under suitable alkaline conditions (e.g., pyridine, triethylamine, diisopropylethylamine, etc.).

[0426] Example

[0427] The present invention will be described in detail with reference to the following examples and experimental examples, but the scope of the present invention is not limited thereto. The examples describe the synthesis methods of intermediates used to prepare the final compounds and the synthesis methods of the final compounds using the compounds of the examples.

[0428] Example 1. N-(5-(3-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridine- Synthesis of 2-methyl-acrylamide

[0429]

[0430] Step 1) Preparation of 2-(3-bromophenyl)propionic acid

[0431] 2-(3-Bromophenyl)acetic acid (21 g, 97.56 mmol) was dissolved in THF (200 ml, 0.5 M), and 1 M NaHMDS (200 ml, 200 mmol) was added dropwise at 0°C. After stirring for 30 minutes, MeI (6.07 ml, 97.56 mmol) was added and stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with 1N HCl, and the organic layer was dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by a Combi-flash column (100% gradient in EA / Hex 10) to provide the title compound (19.6 g, 92%).

[0432] Step 2) Preparation of 2-(3-bromophenyl)-N-(5-methylthiazol-2-yl)propionamide

[0433] DCM (50 ml, 0.2 M) was added to 2-(3-bromophenyl)propanoic acid (2 g, 8.73 mmol), HOBt (1.77 g, 13.1 mmol), DIPEA (4.6 ml, 26.2 mmol) and EDCI (2.5 g, 13.1 mmol). The mixture was stirred at room temperature for 30 minutes, and then 5-methylthiazol-2-amine (1 g, 8.73 mmol) was added thereto, and stirred at room temperature for 15 hours. The mixture was diluted with EtOAc, washed with 1N HCl, washed with saturated NaHCO3 solution, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by flash chromatography (EA / Hex 10 to 100% gradient) to provide the title compound (2.27 g, 80%) as a white solid.

[0434] 1 H NMR (400MHz, CDCl3) δ7.46 (s, 1H), 7.40 (d, J = 5.7Hz, 1H), 7.23-7.17 (m, 2H), 7.03 (m, 1H), 3.75 (q, J=5.1Hz, 1H), 2.41 (s, 3H), 1.60 (d, J=5.1Hz, 3H); MS (m / z): 326.0[M+1]

[0435] Step 3) N-(5-methylthiazol-2-yl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Preparation of phenyl)propionamide

[0436] Anhydrous 1,4-dioxane (15 ml, 0.2 M) was added to 2-(3-bromophenyl)-N-(5-methylthiazol-2-yl)propanamide (1.0 g, 3.07 mmol) and KOAc (904 mg, 9.21 mmol), and the reaction mixture was stirred and dealkylated. Bis(pinacolato)diboron (0.94 g, 3.69 mmol) and Pd(dppf)Cl2.DCM (253 mg, 0.31 mmol) were added, and the mixture was stirred at 85°C for 15 hours. The mixture was diluted with EtOAc, washed with water, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by flash chromatography (gradient of EA / Hex 20 to 100%) to provide the title compound (704 mg, 62%) as a white solid.

[0437] 1H NMR (400MHz, CDCl3) δ9.80 (s, 1H), 7.78-7.71 (2H), 7.43 (d, J=6.0Hz, 1H), 7.36 (t, J=5.7Hz, 1H), 7.02 (s, 1H), 3.81 (q, J=5.1Hz, 1H), 2.39 (s, 3H), 1.62 (d, J=5.4Hz, 3H), 1.34 (s, 12H); MS (m / z): 373.0[M+1]

[0438] Step 4) N-(5-(3-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridine-2-yl Preparation of acrylamide

[0439] To N-(5-methylthiazol-2-yl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide (372 mg, 1 mmol), N-(5-bromopyridin-2-yl)acrylamide (227 mg, 1 mmol) and Cs2CO3 (815 mg, 2.5 mmol) were added H2O (4 ml) and 1,4-dioxane (15 ml), and the reaction mixture was stirred and dealkylated. Then, Pd(dppf)Cl2.DCM (253 mg, 0.31 mmol) was added thereto, and the mixture was stirred at 100°C for 4 hours. The mixture was diluted with EtOAc, washed with water, further washed with brine, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by flash chromatography column (gradient of EA / Hex 50 to 100%) to afford the title compound (118 mg, 30%) as a white solid.

[0440] 1 H NMR (400MHz, CDCl3) δ10.96 (s, 1H), 9.36 (s, 1H), 8.34 (d, J=6.6Hz, 1H), 8.19 ( s, 1H), 7.82 (d, J=6.6Hz, 1H), 7.39-7.37 (m, 3H), 7.30-7.29 (m, 1H), 7.06 (s, 1 H), 6.50 (d, J=13.2Hz, 1H), 6.29 (dd, J=12.9, 7.5Hz, 1H), 5.81 (d, J=7.5Hz, 1H ), 3.90-3.86 (m, 1H), 2.40 (s, 3H), 1.64 (d, J=5.4Hz, 3H); MS (m / z): 393.0[M+1]

[0441] Example 2. N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrrolidone Synthesis of 2-pyridin-2-yl)acrylamide

[0442]

[0443] The title compound was prepared in the same manner as in Example 1, except using 5-cyclopropylthiazol-2-amine instead of 5-methylthiazol-2-amine.

[0444] 1 H NMR (400MHz, CDCl3) δ9.45 (s, 1H), 8.57 (s, 1H), 8.37-8.34 (m, 2H), 7.87 (dd, J=8.8, 2. 4Hz, 1H), 7.45-7.44 (m, 3H), 7.33-7.32 (m, 1H), 7.04 (s, 1H), 6.50 (d, J=16.8Hz, 1H), 6. 29 (dd, J=16.8, 10.0Hz, 1H), 5.84 (d, J=10.0Hz, 1H), 3.88-3.83 (m, 1H), 1.98-1.94 (m, 1H), 1.65 (d, J=7.2Hz, 3H), 0.99-0.95 (m, 2H), 0.72-0.69 (m, 2H); MS (m / z): 419.0[M+1]

[0445] Example 3. (R)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Separation of 2-(2-yl)pyridin-2-yl)acrylamide

[0446]

[0447] Only the R-configuration was separated from the compound of Example 2 using a chiral chromatography column.

[0448] 1 H NMR (400MHz, CDCl3) δ9.63 (s, 1H), 8.73 (s, 1H), 8.36 (d, J = 8.8Hz, 1H), 8.31 (s, 1H), 7.87 (d d, J=8.4, 2.4Hz, 1H), 7.45-7.43 (m, 3H), 7.33-7.31 (m, 1H), 7.05 (s, 1H), 6.50 (d, J=16.8Hz , 1H), 6.29 (dd, J=16.8, 10.4Hz, 1H), 5.84 (d, J=10.4Hz, 1H), 3.88-3.86 (m, 1H), 1.98-1.94 (m, 1H), 1.66 (d, J=7.2Hz, 3H), 0.99-0.96 (m, 2H), 0.71-0.69 (m, 2H); MS (m / z): 419.0[M+1]

[0449] Example 4. N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridine- Synthesis of 2-methyl-acrylamide

[0450]

[0451] The title compound was prepared in the same manner as in Example 1, except using 5-ethylthiazol-2-amine instead of 5-methylthiazol-2-amine.

[0452] 1 H NMR (400MHz, CDCl3) δ10.12 (s, 1H), 8.93 (s, 1H), 8.36 (d, J=8.8Hz, 1H), 8.28 (s, 1H), 7.8 6 (dd, J=8.4, 2.4Hz, 1H), 7.43-7.41 (m, 3H), 7.33-7.31 (m, 1H), 7.06 (s, 1H), 6.50 (d, J=16 .8Hz, 1H), 6.29 (dd, J=16.8, 10.4Hz, 1H), 5.83 (d, J=10.0Hz, 1H), 3.88 (q, J=7.2Hz, 1H), 2.78 (q, J=6.8Hz, 2H), 1.65 (d, J=7.2Hz, 3H), 1.29 (t, J=7.6Hz, 3H); MS (m / z): 407.2[M+1]

[0453] Example 5. (E)-4-(dimethylamino)-N-(5-(3-(1-((5-methylthiazol-2-yl)amino)-1-oxo Synthesis of (2-propane-2-yl)phenyl)pyridin-2-yl)but-2-enamide

[0454]

[0455] The title compound was prepared in the same manner as in Example 1 except that (E)-N-(5-bromopyridin-2-yl)-4-(dimethylamino)but-2-enamide was used instead of acryloyl chloride (see International Patent Publication No. WO 2015 / 154038).

[0456] 1 H NMR (400MHz, CDCl3) δ9.56 (s, 1H), 8.51 (s, 1H), 8.37-8.34 (m, 2H), 7.87 (dd, J=8.8, 2.4Hz, 1H), 7.46-7.43 (m, 3H), 7.33-7.32 (m, 1H), 7.07-6.99 (m, 2H), 6.17 (d, J = 15.6Hz, 1H), 3.87-3.86 (m, 1H), 3.16 (d, J = 5.6Hz, 2H ), 2.39 (s, 3H), 2.31 (s, 6H), 1.64 (d, J=7.2Hz, 3H); MS (m / z): 450.5[M+1]

[0457] Example 6. (E)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 4-((2-(4-((2-((4-( ...

[0458]

[0459] The title compound was prepared in the same manner as in Example 1, except that 5-cyclopropylthiazol-2-amine was used instead of 5-methylthiazol-2-amine, and (E)-N-(5-bromopyridin-2-yl)-4-(dimethylamino)but-2-enamide was used instead of acryloyl chloride.

[0460] 1 H NMR (400MHz, CDCl3) δ9.88 (s, 1H), 8.69 (s, 1H), 8.36-8.32 (m, 2H), 7.86 (dd, J=8.4 , 2.4Hz, 1H), 7.43-7.42 (m, 3H), 7.32-7.26 (m, 1H), 7.06-7.00 (m, 2H), 6.15 (d, J=15 .6Hz, 1H), 3.89-3.84(m, 1H), 3.13(d, J=6.0Hz, 2H), 2.29(s, 6H), 1.99-1.92(m, 1H) , 1.65 (d, J=7.2Hz, 3H), 0.99-0.96 (m, 2H), 0.71-0.67 (m, 2H); MS (m / z): 476.0[M+1]

[0461] Example 7. (E)-4-(dimethylamino)-N-(5-(3-(1-((5-methylthiazol-2-yl)amino-1-oxopropyl)- Synthesis of 2-( ...

[0462]

[0463] The compound of Example 5 (30 mg, 0.06 mmol) was dissolved in DCM (1 ml), and cHCl (2.5 μl) was added thereto at 0° C., followed by stirring for 5 minutes. The precipitated solid was filtered and washed with MC / Hex.

[0464] 1 H NMR (400MHz, CDCl3) δ9.45 (s, 1H), 8.57 (s, 1H), 8.37-8.34 (m, 2H), 7.87 (dd, J=8.8, 2. 4Hz, 1H), 7.45-7.44 (m, 3H), 7.33-7.32 (m, 1H), 7.04 (s, 1H), 6.50 (d, J=16.8Hz, 1H), 6. 29 (dd, J=16.8, 10.0Hz, 1H), 5.84 (d, J=10.0Hz, 1H), 3.88-3.83 (m, 1H), 1.98-1.94 (m, 1H), 1.65 (d, J=7.2Hz, 3H), 0.99-0.95 (m, 2H), 0.72-0.69 (m, 2H); MS (m / z): 450.5[M+1]

[0465] Example 8. N-(3-fluoro-3'-(1-((5-methylthiazol-2-yl)amino-1-oxopropan-2-yl)-[1,1'- Synthesis of [4-(Biphenyl)-1,4-yl)acrylamide

[0466]

[0467] The title compound was prepared in the same manner as in Example 1, except that N-(4-bromo-2-fluorophenyl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0468] 1 H NMR (400MHz, DMSO-d6) δ12.12 (s, 1H), 10.05 (s, 1H), 8.14 (t, J=8.4Hz, 1H), 7.70 (s, 1H) ), 7.61-7.57 (m, 2H), 7.49 (d, J = 7.6Hz, 1H), 7.42 (t, J = 7.6Hz, 1H), 7.35 (d, J = 7.6Hz, 1 H), 7.10 (s, 1H), 6.65 (dd, J=17.0, 10.4Hz, 1H), 6.30 (d, J=16.8Hz, 1H), 5.79 (d, J=10. 0Hz, 1H), 4.02-4.00 (m, 1H), 2.31 (s, 3H), 1.49 (d, J=6.8Hz, 3H); MS (m / z): 410.0[M+1]

[0469] Example 9. Synthesis of 2-(3-(1-acryloylindol-5-yl)phenyl)-N-(5-methylthiazol-2-yl)propanamide become

[0470]

[0471] The title compound was prepared in the same manner as in Example 1, except that 1-(5-bromoindol-1-yl)prop-2-en-1-one was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0472] 1 H NMR (400MHz, DMSO-d6) δ12.08 (s, 1H), 8.22 (d, J=7.6Hz, 1H), 7.65 (s, 1H), 7.54-7.47 (m, 3H), 7.39 (t, J=7.6Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.09 (s, 1H), 6.77 (dd, J=16.4, 10.4Hz, 1H), 6.32 (d, J=16.4Hz, 1H), 5.84 (d, J=10.4Hz, 1H), 4.27 (t, J=8.4Hz, 2H), 4.00 (q, J=6. 8Hz, 1H), 3.24 (t, J=8.8Hz, 2H), 2.30 (s, 3H), 1.48 (d, J=6.8Hz, 3H); MS (m / z): 418.0[M+1]

[0473] Example 10. (E)-N-(5-(3-(1,1-difluoro-2-((5-methylthiazol-2-yl)amino)-2-oxoethyl) Synthesis of 4-((phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide

[0474]

[0475] The title compound was prepared in the same manner as in Example 1, except that 2-(3-bromophenyl)-2,2-difluoroacetic acid was used instead of 2-(3-bromophenyl)propionic acid, and (E)-N-(5-bromopyridin-2-yl)-4-(dimethylamino)but-2-enamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0476] 1 H NMR (400MHz, DMSO-d6) δ10.77 (s, 1H), 8.64 (s, 1H), 8.28 (d, J = 8.7Hz, 1H), 8.10 (d, J = 11.4Hz, 1H), 7.86 (s, 1H), 7.82-7.80 (m, 1H), 7.60-7. 55 (m, 1H), 6.98 (s, 1H), 6.78 (d, J=16.2Hz, 1H), 6.45 (d, J=16.2Hz, 1H), 3.05 (d, J=6Hz, 2H), 2.23 (s, 3H), 2.16 (s, 6H); MS (m / z): 472.0[M+1]

[0477] Example 11. N-(6-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-4-fluorobenzene Synthesis of 3-(4-yl)pyridazine-3-yl)acrylamide

[0478]

[0479] The title compound was prepared in the same manner as in Example 1, except that 2-(5-bromo-2-fluorophenyl)acetic acid was used instead of 2-(3-bromophenyl)acetic acid, 5-cyanothiazol-2-amine was used instead of 5-methylthiazol-2-amine, and N-(6-bromopyridazin-3-yl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0480] 1H NMR (400MHz, DMSO) δ13.25 (br, 1H), 11.45 (s, 1H), 8.50 (d, J=9.6Hz, 1H), 8.36 (s, 1 H), 8.26 (d, J=9.6Hz, 1H), 8.17 (dd, J=7.2, 2.4Hz, 1H), 8.02-8.03 (m, 1H), 7.40-7. 36 (m, 1H), 6.68 (dd, J=16.8, 10.0Hz, 1H), 6.38 (dd, J=16.8, 1.2Hz, 1H), 5.88 (dd, J =10.0, 1.2Hz, 1H), 4.38-4.32 (m, 1H), 1.58 (d, J = 7.2Hz, 3H); MS (m / z): 423.0[M+1]

[0481] Example 12. 2-(3-(6-acrylamidopyridazin-3-yl)phenyl)-N-(5-cyanothiazol-2-yl)-3-methyl Synthesis of butanamide

[0482]

[0483] The title compound was prepared in the same manner as in Example 1, except that 2-iodopropane was used instead of iodomethane, 5-cyanothiazol-2-amine was used instead of 5-methylthiazol-2-amine, and N-(6-bromopyridazin-3-yl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0484] 1 H NMR (400MHz, CDCl3) δ13.68 (br, 1H), 11.32 (s, 1H), 8.84 (d, J=9.2Hz, 1H), 8.36 (s, 1H) ), 8.01 (s, 1H), 7.89-7.87 (m, 2H), 7.59 (d, J = 5.2Hz, 1H), 6.59 (dd, J = 16.8, 1.2Hz, 1H ), 6.44 (dd, J=16.8, 10.0Hz, 1H), 5.97 (dd, J=10.0, 1.2Hz, 1H), 4.61 (d, J=10.0, 1H), 2.52-2.46 (m, 1H), 0.79 (d, J=6.4Hz, 3H), 0.52 (d, J=6.4Hz, 3H); MS (m / z): 433.0[M+1]

[0485] Example 13. N-(6-(5-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-2-fluorobenzene Synthesis of 3-(4-yl)pyridazine-3-yl)acrylamide

[0486]

[0487] The title compound was prepared in the same manner as in Example 1, except that 2-(3-bromo-4-fluorophenyl)acetic acid was used instead of 2-(3-bromophenyl)acetic acid, 5-cyanothiazol-2-amine was used instead of 5-methylthiazol-2-amine, and N-(6-bromopyridazin-3-yl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0488] 1 H NMR (400MHz, DMSO-d6) δ13.21 (s, 1H), 11.52 (s, 1H), 8.54-8.52 (m, 1H), 8.34 (s, 1H), 8.09-7.95 (m, 2H), 7.55-7.51 (m, 1H), 7.41- 7.38(m, 1H), 6.71-6.66(m, 1H), 6.41-6.37(m, 1H), 5.90-5.87(m, 1H), 4.15-4.10(m, 1H), 1.55-1.48(m, 3H); MS(m / z): 423.0[M+1]

[0489] Example 14. (S)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 2-(2-yl)pyridin-2-yl)acrylamide

[0490]

[0491] Step 1) Preparation of (S)-2-(3-bromophenyl)propionic acid

[0492] After adding ACN (165 ml) to the racemic form of 2-(3-bromophenyl)propionic acid (33.13 g, 144.63 mmol), (R)-1-phenylethane-1-amine was added thereto and stirred at a temperature of 30°C to 35°C. After stirring at a temperature of 20°C to 25°C for 2 hours, the reactant was filtered, washed with ACN (100 ml) at 0°C to 5°C, and dried. ACN (165 ml) was added to the dried compound, and the mixture was stirred at a temperature of 80°C to 85°C for 1 hour. Then, the mixture was cooled to 30°C to 35°C and stirred for 1 hour. After cooling to 20°C to 25°C, the mixture was stirred for 3 hours, filtered, and dried with ACN (100 ml) cooled to 0°C to 5°C. This process was repeated twice. MC (265 ml) and 1N HCl (132 ml) were added to the obtained solid, and the solid was extracted, dried over MgSO 4 , filtered, and concentrated to obtain 6.6 g of the title compound.

[0493] 1H NMR (400MHz, CDCl3) δ9.85 (br, 1H), 7.45-7.44 (m, 1H), 7.43-7.40 (m, 1H), 7.23-7.20 (m, 2H), 7.05-7.04 (m, 1H), 3.76-3.7 1 (m, 1H), 2.00-1.94 (m, 1H), 1.60 (d, J=6.8, Hz, 3H), 1.01-0.96 (m, 2H), 0.75-0.69 (m, 2H); MS (m / z): 352.0 [M+1]; 99.6ee%

[0494] Step 2) Preparation of (S)-2-(3-bromophenyl)-N-(5-cyclopropylthiazol-2-yl)propanamide

[0495] After (S)-2-(3-bromophenyl)propanoic acid (2.6 g, 11.35 mmol) was dissolved in DCM (113 ml, 0.1 M), oxalyl chloride (1.09 ml, 12.97 mmol) was added and 2 to 3 drops of DMF were added. After the mixture was stirred at room temperature for 1 hour, it was concentrated. The concentrated mixture was dissolved in DCM (113 ml, 0.1 M) and 5-cyclopropylthiazole-2-amine (1.51 g, 10.81 mmol) was added. DIPEA (2.1 ml, 12.28 mmol) was slowly added and stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM, washed with water, dried (MgSO4), filtered and dried under reduced pressure. The residue was purified by flash preparative column (EA / Hex 0 to 60% gradient) to provide the title compound (2.97 g, 78%) as a white solid.

[0496] 1 H NMR (400MHz, CDCl3) δ9.85 (br, 1H), 7.45-7.44 (m, 1H), 7.43-7.40 (m, 1H), 7.23-7.20 (m, 2H), 7.05-7.04 (m, 1H), 3.76 -3.71 (m, 1H), 2.00-1.94 (m, 1H), 1.60 (d, J=6.8, Hz, 3H), 1.01-0.96 (m, 2H), 0.75-0.69 (m, 2H); MS (m / z): 352.0[M+1]

[0497] Step 3) (S)-N-(5-cyclopropylthiazol-2-yl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Preparation of 2-( ...

[0498] To (S)-2-(3-bromophenyl)-N-(5-cyclopropylthiazol-2-yl)propanamide (2.97 g, 8.46 mmol) and KOAc (1.66 g, 16.91 mmol) was added anhydrous 1,4-dioxane (42 ml, 0.2 M), and the reaction mixture was stirred and dealkylated. Then, bis(pinacolato)diboron (2.79 g, 10.99 mmol) and Pd(dppf)Cl2.DCM (690 mg, 0.85 mmol) were added, and the mixture was stirred at 85°C for 15 hours. The mixture was diluted with EtOAc, washed with water, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by flash chromatography (EA / Hex 0 to 60% gradient) to provide the title compound (2.12 g, 63%) as a white solid.

[0499] 1 H NMR (400MHz, CDCl3) δ8.96 (br, 1H), 7.75-7.73 (m, 2H), 7.41-7.37 (m, 2H), 7.02-7.01 (m, 21), 3.82-3.77 (m, 1H), 1.97-1.91 (m, 1H), 1.62 (d, J=7.2, Hz, 3H), 0.97-0.93 (m, 2H), 0.71-0.69 (m, 2H); MS (m / z): 399.0[M+1]

[0500] Step 4) (S)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl) Preparation of pyridin-2-yl)acrylamide

[0501] To (S)-N-(5-cyclopropylthiazol-2-yl)-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide (1.2 g, 3.0 mmol), N-(5-bromopyridin-2-yl)acrylamide (680 mg, 3.0 mmol) and Cs2CO3 (2.44 g, 7.5 mmol) were added H2O (15 ml) and 1,4-dioxane (45 ml), and the reaction mixture was stirred and dealkylated. Then, Pd(dppf)Cl2.DCM (244 mg, 0.30 mmol) was added and stirred at 100°C for 3 hours. The mixture was diluted with EtOAc, washed with water, further washed with brine, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by flash chromatography column (gradient of EA / Hex 50 to 100%) to afford the title compound (474 ​​mg, 38%) as a white solid.

[0502] 1H NMR (400MHz, CDCl3) δ9.47 (s, 1H), 8.63 (s, 1H), 8.36 (d, J=8.4Hz, 1H), 8.34 (s, 1H), 7.87 (dd , J=8.4, 2.4Hz, 1H), 7.45-7.44 (m, 3H), 7.33-7.31 (m, 1H), 7.05 (s, 1H), 6.50 (d, J=16.8Hz, 1H ), 6.29 (dd, J=16.8, 10.4Hz, 1H), 5.84 (d, J=10.4Hz, 1H), 3.89-3.84 (m, 1H), 1.99-1.94 (m, 1 H), 1.66 (d, J=7.2Hz, 3H), 0.99-0.95 (m, 2H), 0.72-0.69 (m, 2H); MS (m / z): 419.0 [M+1]; 78ee%

[0503] Example 15. (S,E)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl) Synthesis of 4-((phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide

[0504]

[0505] The title compound was prepared in the same manner as in Example 14, except using (E)-N-(5-bromopyridin-2-yl)-4-(dimethylamino)but-2-enamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0506] 1 H NMR (400MHz, CDCl3) δ9.85 (br, 1H), 8.74 (s, 1H), 8.37-8.33 (m, 2H), 7.87-7.84 (m, 1H), 7.44-7.43(m, 3H), 7.33-7.32(m, 1H), 7.05-7.00(m, 2H), 6.15(d, J=15.6Hz, 1H ), 3.88-3.84(m, 1H), 3.13(d, J=6.0, Hz, 2H), 2.28(s, 6H), 1.98-1.93(m, 1H), 1.65( d, J=6.8Hz, 3H), 0.99-0.96 (m, 2H), 0.72-0.68 (m, 2H); MS (m / z): 476.0 [M+1]; 76ee%

[0507] Example 16. (S)-N-(6-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 2-(2-yl)pyrazine-2-yl)acrylamide

[0508]

[0509] The title compound was prepared in the same manner as in Example 14, except using N-(6-bromopyrazin-2-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0510] 1 H NMR (400MHz, CDCl3) δ9.71 (br, 1H), 9.54 (s, 1H), 8.69 (s, 1H), 8.29 (s, 1H), 7. 74(s, 1H), 7.72-7.71(m, 1H), 7.33-7.32(m, 2H), 7.07(s, 1H), 6.61-6.52(m, 2 H), 5.93 (d, J=10.0Hz, 1H), 3.77-3.78 (m, 1H), 1.94-1.93 (m, 1H), 1.65 (d, J=6 .8Hz, 3H), 0.98-0.96(m, 2H), 0.69-0.68(m, 2H); MS(m / z): 420.0[M+1]; 74ee%

[0511] Example 17. (S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxo Synthesis of 2-( ...

[0512]

[0513] The title compound was prepared in the same manner as in Example 14, except that 5-ethylthiazol-2-amine was used instead of 5-cyclopropylthiazol-2-amine, and (E)-N-(5-bromopyridin-2-yl)-4-(dimethylamino)but-2-enamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0514] 1 H NMR (400MHz, DMSO) δ12.12 (s, 1H), 10.75 (s, 1H), 8.63 (d, J = 2.4Hz, 1H), 8.28 (d, J = 8.8Hz, 1H), 8.09 ( dd, J=8.4, 2.4Hz, 1H), 7.71 (s, 1H), 7.60 (d, J=7.6Hz, 1H), 7.46-7.43 (m, 1H), 7.36 (d, J=8.0Hz, 1H), 7.13 (s, 1H), 6.85-6.78 (m, 1H), 6.46 (d, J=15.6Hz, 1H), 4.04-4.02 (m, 1H), 3.05 (d, J=4.8, Hz, 2H), 2 .73-2.67(m, 2H), 2.17(s, 6H), 1.49(d, J=6.8Hz, 3H), 1.23-1.17(m, 3H); MS(m / z): 464.0[M+1]; 80ee%

[0515] Example 18. (S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl) Synthesis of 2-pyridinyl)acrylamide

[0516]

[0517] The title compound was prepared in the same manner as in Example 14, except using 2-cyanothiazol-2-amine instead of 5-cyclopropylthiazol-2-amine.

[0518] 1 H NMR (400MHz, DMSO-d6) δ13.14 (s, 1H), 10.86 (s, 1H), 8.66 (d, J = 2.0Hz, 1H), 8.34 (s, 1H), 8.30 ( d, J=8.4Hz, 1H), 8.11 (dd, J=8.4, 2.4Hz, 1H), 7.72 (s, 1H), 7.62 (d, J=7.6Hz, 1H), 7.48-7.44 (m , 1H), 7.36 (d, J=8.0Hz, 1H), 6.64 (dd, J=16.8, 10.0Hz, 1H), 6.33 (dd, J=16.8, 1.2Hz, 1H), 5.80 (dd, J=10.0, 1.2Hz, 1H), 4.11-4.09 (m, 1H), 1.53 (d, J=7.2Hz, 3H); MS (m / z): 404.0[M+1]; 75ee%

[0519] Example 19. (S)-2-(3-(6-acrylamidopyridin-3-yl)phenyl)-N-(5-ethylthiazol-2-yl)butyl Synthesis of amides

[0520]

[0521] The title compound was prepared in the same manner as in Example 14, except using 5-ethylthiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and (S)-2-(3-bromophenyl)butyric acid instead of (S)-2-(3-bromophenyl)propionic acid.

[0522] 1H NMR (400MHz, CDCl3) δ10.67 (br, 1H), 9.17 (s, 1H), 8.38 (s, 1H), 8.35 (d, J=2.4Hz, 1H), 7.8 5 (dd, J=8.8, 2.4Hz, 1H), 7.44-7.37 (m, 4H), 7.09 (s, 1H), 6.49 (dd, J=16.8, 0.8Hz, 1H), 6.3 1 (dd, J=16.8, 10.0Hz, 1H), 5.82 (dd, J=10.0, 0.8Hz, 1H), 3.63-3.59 (m, 1H), 2.82-2.77 (m, 2H), 2.34-2.28(m, 1H), 1.98-1.90(m, 1H), 1.33-1.24(m, 6H); MS (m / z): 421.0[M+1]; 72ee%

[0523] Example 20. (S)-2-(4'-acrylamido-3'-fluoro-[1,1'-biphenyl]-3-yl)-N-(5-ethylthio Synthesis of 2-oxazol-2-yl)butyramide

[0524]

[0525] The title compound was prepared in the same manner as in Example 14, except that 5-ethylthiazol-2-amine was used instead of 5-cyclopropylthiazol-2-amine, (S)-2-(3-bromophenyl)butyric acid was used instead of (S)-2-(3-bromophenyl)propionic acid, and N-(4-bromo-2-fluorophenyl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0526] 1 H NMR (400MHz, CDCl3) δ8.43 (br, 1H), 7.53 (br, 1H), 7.44-7.42 (m, 2H), 7.37-7.33 (m, 1H), 7.30- 7.26 (m, 1H), 7.22-7.29 (m, 1H), 7.12-7.09 (m, 2H), 6.80-6.68 (m, 1H), 6.48 (dd, J=16.8, 1.2Hz, 1H), 6.30 (dd, J=16.8, 10.0Hz, 1H), 5.83 (dd, J=10.0, 1.2Hz, 1H), 3.58-3.55 (m, 1H), 2.82-2.7 4(m, 2H), 2.35-2.22(m, 1H), 1.99-1.89(m, 1H), 1.31-1.24(m, 6H); MS(m / z): 438.0[M+1]; 71ee%

[0527] Example 21. (S,E)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 4-((2-(4-((2-((4-( ...

[0528]

[0529] The title compound was prepared in the same manner as in Example 14, except that 5-cyanothiazol-2-amine was used instead of 5-cyclopropylthiazol-2-amine, and (E)-N-(5-bromopyridin-2-yl)-4-(dimethylamino)but-2-enamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0530] 1 H NMR (400MHz, DMSO-d6) δ13.05 (br, 1H), 10.75 (s, 1H), 8.64 (dd, J=2.4, 0.8Hz, 1H), 8.34 (s, 1H), 8.28 (dd, J=8.8, 0.8Hz, 1H), 8.09 (dd, J=8.8, 2.4Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=8.0, 1H), 7.47-7.44(m, 1H), 7.37-7.34(m, 1H), 6.85-6.78(m, 1H), 6.49-6.45(m, 1H), 4.11-4.0 9 (m, 1H), 3.09-3.08 (m, 2H), 2.19 (s, 6H), 1.53 (d, J=7.2, 3H); MS (m / z): 461.0 [M+1]; 75ee%

[0531] Example 22. (S)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 2-(2-yl)pyrazine-2-yl)acrylamide

[0532]

[0533] The title compound was prepared in the same manner as in Example 14, except using N-(5-bromopyrazin-2-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0534] 1H NMR (400MHz, CDCl3) δ9.81 (br, 1H), 9.62 (s, 1H), 8.68 (s, 1H), 8.38 (s, 1H), 7.90 (s, 1H), 7.78- 7.76 (m, 1H), 7.46-7.42 (m, 1H), 7.38-7.36 (m, 1H), 7.06 (s, 1H), 6.54 (dd, J=16.8, 1.2Hz, 1H), 6.31 (dd, J=16.8, 10.0Hz, 1H), 5.88 (dd, J=10.0, 1.2Hz, 1H), 3.91-3.89 (m, 1H), 1.96-1.95 (m, 1H), 1.66 (d, J=7.2Hz, 3H), 0.99-0.95 (m, 2H), 0.72-0.69 (m, 2H); MS (m / z): 420.0 [M+1]; 73ee%

[0535] Example 23. (S)-N-(3'-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[1, Synthesis of 1'-biphenyl-4-yl) acrylamide

[0536]

[0537] The title compound was prepared in the same manner as in Example 14, except using N-(4-bromophenyl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0538] 1 H NMR (400MHz, CDCl3) δ9.56 (br, 1H),), 7.63 (d, J=8.0Hz, 2H), 7.52-7.45 (m, 4H), 7.41- 7.37 (m, 2H), 7.24 (s, 1H), 7.04 (s, 1H), 6.46 (dd, J=16.8, 1.2Hz, 1H), 6.27 (dd, J=16.8 , 10.8Hz, 1H), 5.80 (dd, J=10.8, 1.2Hz, 1H), 3.87-3.81 (m, 1H), 1.96-1.92 (m, 1H), 1.6 6 (d, J=7.2Hz, 3H), 0.98-0.95 (m, 2H), 0.69-0.67 (m, 2H); MS (m / z): 418.0 [M+1]; 78ee%

[0539] Example 24. (S)-N-(3'-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-3- Synthesis of fluoro-[1,1'-biphenyl]-4-yl) acrylamide

[0540]

[0541] The title compound was prepared in the same manner as in Example 14, except using N-(4-bromo-2-fluorophenyl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0542] 1 H NMR (400MHz, CDCl3) δ9.26 (s, 1H),), 8.49 (br, 1H), 7.49-7.48 (m, 2H), 7.47-7.46 (m, 1H), 7.43 -7.39 (m, 1H), 7.36-7.31 (m, 1H), 7.29-7.27 (m, 2H), 7.04 (s, 1H), 6.48 (dd, J=16.8, 1.2Hz, 1H) , 6.30 (dd, J=16.8, 10.0Hz, 1H), 5.84 (dd, J=10.0, 1.2Hz, 1H), 3.86-3.81 (m, 1H), 1.96-1.92 (m , 1H), 1.66 (d, J=7.2Hz, 3H), 0.98-0.95 (m, 2H), 0.72-0.65 (m, 2H); MS (m / z): 436.0 [M+1]; 72ee%

[0543] Example 25. (S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl) Synthesis of 2-pyrazine-2-yl)acrylamide

[0544]

[0545] The title compound was prepared in the same manner as in Example 14, except that 5-cyanothiazol-2-amine was used instead of 5-cyclopropylthiazol-2-amine, and N-(5-bromopyrazin-2-yl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0546] 1 H NMR (400MHz, CDCl3) δ9.65 (dd, J=4.8, 1.6Hz, 1H), 9.42 (br, 1H), 8.65 (dd, J=10.0, 1.6 Hz, 1H), 8.13 (s, 1H), 7.99 (s, 1H), 7.90-7.88 (m, 2H), 7.54-7.50 (m, 1H), 7.38 (d, J=10 .0Hz, 1H), 6.54 (dd, J=16.8, 0.8Hz, 1H), 6.31 (dd, J=16.8, 10.0Hz, 1H), 5.91 (dd, J=10 .0, 0.8Hz, 1H), 3.99-3.94 (m, 1H), 1.70 (d, J=7.2Hz, 3H); MS (m / z): 405.0[M+1]; 72ee%

[0547] Example 26. (S)-N-(6-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl) Synthesis of 2-pyrazine-2-yl)acrylamide

[0548]

[0549] The title compound was prepared in the same manner as in Example 14, except using 5-cyanothiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and N-(6-bromopyrazin-2-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0550] 1 H NMR (400MHz, CDCl3) δ9.58 (s, 1H), 9.46 (br, 1H), 8.78 (d, J=2.4Hz, 1H), 8.08 (s, 1H), 7.92-7.89 (m, 3H), 7.54-7.50 (m, 1H), 7.41 (d, J=7.6Hz, 1H), 6.56 (d d, J=16.8, 0.8Hz, 1H), 6.36 (dd, J=16.8, 10.0Hz, 1H), 5.93 (dd, J=10.0, 0.8H z, 1H), 3.98-3.89 (m, 1H), 1.69 (d, J=7.2Hz, 3H); MS (m / z): 405.0[M+1]; 75ee%

[0551] Example 27. (S)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 2-(2-yl)pyrimidin-2-yl)acrylamide

[0552]

[0553] The title compound was prepared in the same manner as in Example 14, except using N-(5-bromopyrimidin-2-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0554] 1H NMR (400MHz, DMSO-d6) δ12.10 (s, 1H), 10.96 (s, 1H), 8.99 (s, 2H), 7.75 (s, 1H), 7.66 (d, J=8.0Hz, 1H), 7.48 (t, J=8.0Hz, 1H), 7.41 (d, J=8.0Hz, 1H), 7.13 (s, 1H), 6.69 (dd, J=16.8Hz, 10.0Hz, 1H), 6 .32 (dd, J=17.0Hz, 2.0Hz, 1H), 5.81 (dd, J=10.0Hz, 1.6Hz, 1H), 4.03 (q, J=6.8Hz, 2H), 2.00-1.97 (m, 1H), 1.49 (d, J=6.8Hz, 3H), 0.94-0.89 (m, 2H), 0.62-0.60 (m, 2H); MS (m / z): 420.0 [M+1]; 77ee%

[0555] Example 28. (S)-N-(6-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 3-(4-yl)pyridazine-3-yl)acrylamide

[0556]

[0557] The title compound was prepared in the same manner as in Example 14, except using N-(6-bromopyridazin-3-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0558] 1 H NMR (400MHz, CDCl3) δ12.64 (s, 1H),), 11.89 (s, 1H), 8.73 (d, J=9.6Hz, 1H), 8.54 (s, 1H), 7.8 6 (d, J=9.6Hz, 1H), 7.68 (d, J=8.0Hz, 1H), 7.58 (d, J=8.0Hz, 1H), 7.52-7.48 (m, 1H), 7.12 (s, 1 H), 6.56 (s, 1H), 6.54 (d, J=2.4Hz, 1H), 5.92-5.89 (m, 1H), 4.90-4.88 (m, 1H), 2.02-1.98 (m, 1 H), 1.60 (d, J=7.2Hz, 3H), 1.03-0.98 (m, 2H), 0.76-0.72 (m, 2H); MS (m / z): 420.0 [M+1]; 78ee%

[0559] Example 29. (S)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 3-fluoropyridin-2-yl)acrylamide

[0560]

[0561] The title compound was prepared in the same manner as in Example 14, except using N-(5-bromo-3-fluoropyridin-2-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0562] 1 H NMR (400MHz, CDCl3) δ8.33 (s, 1H), 8.22 (s, 1H), 7.64 (d, J=10.4Hz, 1H), 7.46-7.36 (m, 5H), 7.05 (s, 1H), 6.55-6.50 (m, 2H), 5.87-5.84 (m , 1H), 3.88 (q, J=7.2Hz, 1H), 1.97-1.93 (m, 1H), 1.66 (d, J=6.8Hz, 3H), 1.00-0.95 (m, 2H), 0.71-0.68 (m, 2H); MS (m / z): 437.0[M+1]; 78ee%

[0563] Example 30. (S)-N-(3-cyano-3'-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropane-2-yl)- Synthesis of 4-(1,1'-biphenylyl)-[1,1'-biphenylyl]-4-yl)acrylamide

[0564]

[0565] The title compound was prepared in the same manner as in Example 14, except that 5-ethylthiazol-2-amine was used instead of 5-cyclopropylthiazol-2-amine, and N-(4-bromo-2-cyanophenyl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0566] 1 H NMR (400MHz, CDCl3) δ9.11 (br, 1H), 8.61 (d, J = 8.8Hz, 1H), 7.81-7.77 (m, 3H), 7.48- 7.46 (m, 3H), 7.35-7.33 (m, 1H), 7.05-7.04 (m, 1H), 6.52 (dd, J=16.8, 0.8Hz, 1H), 6. 34 (dd, J=16.8, 10.0Hz, 1H), 5.91 (dd, J=10.0, 0.8Hz, 1H), 3.88-3.82 (m, 1H), 2.80- 2.75 (m, 1H), 1.67 (d, J=6.4Hz, 3H), 1.31-1.27 (m, 3H); MS (m / z): 431.0 [M+1]; 73ee%

[0567] Example 31. (S)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 6-fluoropyridin-2-yl)acrylamide

[0568]

[0569] The title compound was prepared in the same manner as in Example 14, except using 5-ethylthiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and N-(5-bromo-6-fluoropyridin-2-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0570] 1 H NMR (400MHz, DMSO-d6) δ12.10 (s, 1H), 11.03 (s, 1H), 8.22 (dd, J=8.0Hz, 1.6Hz, 1H), 8.13 (dd, J =10.0Hz, 8.0Hz, 1H) 7.61 (s, 1H), 7.50-7.39 (m, 3H), 7.13 (s, 1H), 6.59 (dd, J = 16.8Hz, 10.0Hz, 1H), 6.35 (dd, J=17.0Hz, 2.0Hz, 1H), 5.84 (dd, J=10.4Hz, 2.0Hz, 1H), 4.02 (q, J=6.8Hz, 1H), 2. 71 (q, J=7.2Hz, 2H), 1.47 (d, J=6.8Hz, 3H), 1.18 (t, J=7.2Hz, 3H); MS (m / z): 425.0 [M+1]; 78ee%

[0571] Example 32. (S)-N-(6-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl) Synthesis of pyridazine-3-yl) acrylamide

[0572]

[0573] The title compound was prepared in the same manner as in Example 14, except that 5-cyanothiazol-2-amine was used instead of 5-cyclopropylthiazol-2-amine, and N-(6-bromopyridin-2-yl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0574] 1 H NMR (400MHz, CDCl3) δ13.28 (br, 1H), 11.17 (s, 1H), 8.70 (dd, J=9.6, 4.8Hz, 1H), 8 .49 (d, J=17.2Hz, 1H), 7.99 (d, J=4.0, 1H), 7.91 (d, J=9.2, 1H), 7.66-7.63 (m, 2H), 7.58-7.54 (m, 1H), 6.58 (d, J=17.2, 1H), 6.43 (dd, J=17.2, 10.0Hz, 1H), 5.96 (d, J =10.0, 1H), 4.98-4.97 (m, 1H), 1.62 (d, J = 6.8Hz, 3H); MS (m / z): 405.0 [M+1]; 75ee%

[0575] Example 33. (S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 3-fluoropyridin-2-yl)acrylamide

[0576]

[0577] The title compound was prepared in the same manner as in Example 14, except that 5-cyanothiazol-2-amine was used instead of 5-cyclopropylthiazol-2-amine, and N-(5-bromo-3-fluoropyridin-2-yl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0578] 1 H NMR (400MHz, CDCl3) δ9.66 (br, 1H), 8.30-8.29 (m, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.64 (dd, J=10.4, 2.0Hz, 1H), 7.52-7.47 (m, 2H), 7.43 (s, 1H), 7.39-7.37 (m, 1H), 6.57-6.51 (m, 2H), 5.90-5.87 (m, 1H), 3.98-3.93 (m, 1H), 1.69 (d, J=7.2Hz, 3H); MS (m / z): 422.0[M+1]; 75ee%

[0579] Example 34. (S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 3-methylpyrazine-2-yl)acrylamide

[0580]

[0581] The title compound was prepared in the same manner as in Example 14, except that 5-cyanothiazol-2-amine was used instead of 5-cyclopropylthiazol-2-amine, and N-(5-bromo-3-methylpyrazin-2-yl)acrylamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0582] 1 H NMR (400MHz, DMSO-d6) δ13.15 (s, 1H), 10.61 (s, 1H), 8.91 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 8.80 (d, J=7.2Hz, 1H), 7.51-7.45 (m, 2H), 6.54 (dd, J=17.0Hz, 10. 4Hz, 1H), 6.32 (dd, J=17.0Hz, 2.0Hz, 1H), 5.84 (dd, J=10.4Hz, 2.0Hz, 1H), 4.12 -4.08 (m, 1H), 2.48 (s, 3H), 1.53 (d, J=7.2Hz, 3H); MS (m / z): 419.0 [M+1]; 78ee%

[0583] Example 35. (S)-N-(5-(3-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 2-(2-yl)pyridin-2-yl)acrylamide

[0584]

[0585] The title compound was prepared in the same manner as in Example 14, except using 5-isopropylthiazol-2-amine instead of 5-cyclopropylthiazol-2-amine.

[0586] 1 H NMR (400MHz, DMSO-d6) δ12.13 (s, 1H), 10.88 (s, 1H), 8.66 (s, 1H), 8.31 (d, J=9.6Hz, 1H), 8.11 (dd, J=8.4Hz , 2.4Hz, 1H), 7.73 (s, 1H), 7.61 (d, J=7.6Hz, 1H), 7.45 (t, J=7.6hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.14 (s, 1H), 6.65 (dd, J=16.8Hz, 10.0Hz, 1H), 6.34 (dd, J=16.8Hz, 2.0Hz, 1H), 5.81 (dd, J=10.0Hz, 2.0Hz, 1H), 4.03 (q, J=6.8Hz, 1H), 3.10-3.05 (m, 1H), 1.50 (d, J=6.8Hz, 3H), 1.23 (d, J=6.8Hz, 6H); MS (m / z): 421.0[M+1]; 73ee%

[0587] Example 36. (S)-N-(5-(3-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 2-(2-yl)pyrazine-2-yl)acrylamide

[0588]

[0589] The title compound was prepared in the same manner as in Example 14, except using 5-isopropylthiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and N-(5-bromopyrazin-2-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0590] 1H NMR (400MHz, DMSO-d6) δ12.18(s, 1H), 11.16(s, 1H), 9.52(s, 1H), 9.02(s, 1H), 8.16(s, 1 H), 8.00 (d, J=7.6Hz, 1H), 7.51-7.45 (m, 2H), 7.14 (s, 1H), 6.65 (dd, J=16.8Hz, 10.0Hz, 1H ), 6.39 (dd, J=17.0Hz, 2.0Hz, 1H), 5.88 (dd, J=10.0Hz, 2.0Hz, 1H), 4.12-4.05 (m, 1H), 3.1 3-3.07 (m, 1H), 1.50 (d, J=7.2Hz, 3H), 1.24 (d, J=6.8Hz, 6H); MS (m / z): 422.0 [M+1]; 72ee%

[0591] Example 37. (S)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propane-2-yl)- Synthesis of 2-(4-(2-yl)phenyl)pyrazine-2-yl)acrylamide

[0592]

[0593] The title compound was prepared in the same manner as in Example 14, except using 5-(trifluoromethyl)thiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and N-(5-bromopyrazin-2-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0594] 1 H NMR (400MHz, CDCl3) δ9.66 (dd, J=4.0, 1.2Hz, 1H), 9.15 (br, 1H), 8.64 (dd, J=14.8, 1.6Hz, 1H ), 8.14 (br, 1H), 8.00-7.99 (m, 1H), 7.90-7.88 (m, 1H), 7.69 (d, J = 1.2Hz, 1H), 7.54-7.50 (m, 1 H), 7.39 (d, J=8.0, 1H), 6.55 (dd, J=16.8, 1.2Hz, 1H), 6.32 (dd, J=16.8, 10.0Hz, 1H), 5.91 (d d, J=10.0, 1.2Hz, 1H), 3.97-3.92 (m, 1H), 1.70 (d, J=7.2Hz, 3H); MS (m / z): 448.0[M+1]; 70ee%

[0595] Example 38. (S)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propane-2-yl)- Synthesis of 2-(4-(2-yl)phenyl)pyridin-2-yl)acrylamide

[0596]

[0597] The title compound was prepared in the same manner as in Example 14, except using 5-(trifluoromethyl)thiazol-2-amine instead of 5-cyclopropylthiazol-2-amine.

[0598] 1 H NMR (400MHz, CDCl3) δ9.76 (s, 1H), 8.63 (s, 1H), 8.37 (d, J = 8.8, 1H), 8.30 (d, J = 1.6Hz, 1H ), 7.87 (dd, J=8.8, 2.4Hz, 1H), 7.10 (d, J=1.2Hz, 1H), 7.49-7.45 (m, 2H), 7.44 (s, 1H), 7. 34-7.31 (m, 1H), 6.50 (dd, J=16.8, 1.2Hz, 1H), 6.27 (dd, J=16.8, 10.0Hz, 1H), 5.85 (dd, J =10.0, 1.2Hz, 1H), 3.96-3.91 (m, 1H), 1.68 (d, J = 7.2Hz, 3H); MS (m / z): 447.0 [M+1]; 69ee%

[0599] Example 39. (S)-N-(6-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propane-2-yl)- Synthesis of 3-(4-yl)phenyl)pyridazine-3-yl)acrylamide

[0600]

[0601] The title compound was prepared in the same manner as in Example 14, except using 5-(trifluoromethyl)thiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and N-(6-bromopyridazin-3-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0602] 1 H NMR (400MHz, CDCl3) δ12.75 (br, 1H), 11.16 (br, 1H), 8.76 (d, J=9.6, 1H), 8.51 (s, 1 H), 7.90 (d, J=9.2, 1H), 7.76 (d, J=1.2Hz, 1H), 7.65 (d, J=7.2Hz, 2H), 7.52-7.51 (m, 1H), 6.58 (dd, J=16.8, 1.2Hz, 1H), 6.46 (dd, J=16.8, 10.0Hz, 1H), 5.95 (dd, J=10.0 , 1.2Hz, 1H), 4.89-4.88 (m, 1H), 1.63 (d, J=7.2Hz, 3H); MS (m / z): 448.0[M+1]; 68ee%

[0603] Example 40. (S)-N-(6-(3-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)benzene Synthesis of 3-(4-yl)pyridazine-3-yl)acrylamide

[0604]

[0605] The title compound was prepared in the same manner as in Example 14, except using 5-isopropylthiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and N-(6-bromopyridazin-3-yl)acrylamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0606] 1 H NMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 11.47 (s, 1H), 8.52 (d, J = 9.6Hz, 1H), 8.25 (d, J = 9.6Hz, 1H), 8.19 (s, 1H), 7.96-7.94 (m, 1H), 7.54-7.50 (m, 2H), 7.14 (s, 1H), 6.70 (dd, J=16.8Hz, 10. 0Hz, 1H), 6.39 (dd, J=17.0Hz, 2.0Hz, 1H), 5.88 (dd, J=10.0Hz, 2.0Hz, 1H), 4.12-4.06 (m, 1H), 3.12-3.05 (m, 1H), 1.51 (d, J=6.8Hz, 3H), 1.24 (d, J=6.8Hz, 6H); MS (m / z): 422.0[M+1]; 70ee%

[0607] Example 41. N-(5'-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-[3,3'-bipyrrolidone] Synthesis of 6-pyridyl)acrylamide

[0608]

[0609] Step 1) Preparation of 2-(5-bromopyridin-3-yl)propionic acid

[0610] 2-(5-Bromopyridin-3-yl)acetic acid (5 g, 23.144 mmol) was dissolved in THF (65 ml), and 1 M NaHMDS (50.9 ml, 50.9 mmol) was added dropwise at 0°C. After stirring for 30 minutes, MeI (1.7 ml, 27.77 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc, washed with 4N HCl, and the organic layer was dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by flash chromatography (100% gradient in EA / Hex 10) to give the title compound (3.4 g, 63%).

[0611] Step 2) Preparation of 2-(5-bromopyridin-3-yl)-N-(5-cyanothiazol-2-yl)propionamide

[0612] To 2-(5-bromopyridin-3-yl)propanoic acid (500 mg, 2.173 mmol) and 5-cyanothiazol-2-amine (306 mg, 2.39 mmol) was added DCM (11 ml, 0.2 M), TEA was added thereto, and the mixture was stirred at room temperature for 5 minutes. Then, HATU was added and stirred at room temperature for 5 hours. The mixture was diluted with EtOAc, washed with saturated NaHCO3 solution, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by flash chromatography (EA / Hex 10 to 100% gradient) to provide the title compound (2.27 g, 80%) as a white solid.

[0613] 1 H NMR (400MHz, DMSO-d6) δ13.23 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H) , 8.04 (s, 1H), 4.11-4.08 (m, 1H), 1.53 (d, J=5.4Hz, 3H); MS (m / z): 338.0[M+1]

[0614] Step 3) Preparation of 2-(6'-amino-[3,3'-bipyridyl]-5-yl)-N-(5-cyanothiazol-2-yl)propionamide

[0615] To 2-(5-bromopyridin-3-yl)-N-(5-cyanothiazol-2-yl)propanamide (100 mg, 0.29 mmol) and Cs2CO3 (815 mg, 2.5 mmol) were added H2O (0.7 ml) and 1,4-dioxane (2 ml), and the reaction mixture was stirred and dealkylated. Then, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine and Pd(dppf)Cl2.DCM (24 mg, 0.03 mmol) were added and stirred at 100°C for 3 hours. The mixture was diluted with EtOAc, washed with water, further washed with brine, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by flash chromatography (gradient of EA / Hex 50 to 100%) to provide the title compound (21 mg, 20%) as a white solid.

[0616] 1 H NMR (400MHz, DMSO-d6) δ13.21 (s, 1H), 8.72 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 7.92 (s, 1H), 7.76 (d, J=6.6Hz, 1H), 6.56 (d, J=6.6Hz, 1H), 6.22 (s, 2H), 4.13-4.09 (m, 1H), 1.56 (d, J=5.1Hz, 3H); MS (m / z): 351.0[M+1]

[0617] Step 4) N-(5'-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-[3,3'-bipyrrolidone Preparation of 6-pyridyl)acrylamide

[0618] After adding THF to 2-(6'-amino-[3,3'-bipyridyl]-5-yl)-N-(5-cyanothiazol-2-yl)propionamide (20 mg, 0.057 mmol), DIPEA (30 μl, 0.17 mmol) was added, and acryloyl chloride (4.6 μl, 0.057 mol) was slowly added at 0°C. After stirring the mixture at 0°C for 30 minutes, it was diluted with EtOAc, washed with saturated NaHCO3 solution, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by TLC (MC:MeOH=15:1) to provide the title compound (1.3 mg, 6%) as a white solid.

[0619] 1 H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 8.82 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1 H), 8.32 (d, J=8.8Hz, 1H), 8.21-8.18 (m, 2H), 8.07 (s, 1H), 6.64 (dd, J=16. 8Hz, 10.0Hz, 1H), 6.34 (dd, J=16.8Hz, 2.0Hz, 1H), 5.81 (dd, J=10.0Hz, 1.6Hz, 1H), 4.04 (q, J=7.6Hz, 1H), 1.55 (d, J=7.2Hz, 3H); MS (m / z): 405.0[M+1]

[0620] Example 42. N-(4-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-[2,3'-bipyrrolidone] Synthesis of [(6'-pyridyl]-1,2-dimethyl-1-acrylamide]

[0621]

[0622] The title compound was prepared in the same manner as in Example 41, except that 2-(5-bromopyridin-3-yl)acetic acid was used instead of 2-(2-bromopyridin-4-yl)acetic acid. MS (m / z): 405.0 [M+1]

[0623] Example 43. N-(5-(5-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridine-3-yl Synthesis of 2-(2-yl)pyrazine-2-yl)acrylamide

[0624]

[0625] Step 1) Preparation of methyl 2-(5-bromopyridin-3-yl)propionate

[0626] MeOH (40 ml, 0.15 M) was added to 2-(5-bromopyridin-3-yl)propionic acid (1.5 g, 6.548 mmol) and SOCl was slowly added. The reaction mixture was stirred at 60 ° C for 18 hours and concentrated under reduced pressure. The mixture was diluted with EtOAc, washed with saturated NaHCO solution, dried (MgSO), filtered, and dried under reduced pressure. The residue was purified by flash chromatography (MC / MEOH 5 to 10% gradient) to provide the title compound (1.27 g, 79%).

[0627] Step 2) methyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)propanoate preparation

[0628] Anhydrous 1,4-dioxane (4 ml, 0.2 M) was added to methyl 2-(5-bromopyridin-3-yl)propanoate (200 mg, 0.819 mmol) and KOAc (196 mg, 2.047 mmol), and the reaction mixture was stirred and dealkylated. Bis(pinacolato)diboron (250 mg, 0.983 mmol) and Pd(dppf)Cl2.DCM (33 mg, 0.041 mmol) were added, and the mixture was stirred at 85°C for 2 hours. The mixture was diluted with EtOAc, filtered through celite, and dried under reduced pressure to provide a crude black oily title compound.

[0629] MS (m / z): 210.0 [M+1]

[0630] Step 3) Preparation of methyl 2-(5-(5-acrylamidopyrazine-2-yl)pyridin-3-yl)propionate

[0631] To methyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)propanoate (crude, 0.819 mmol), N-(5-bromopyrazin-2-yl)acrylamide (143 mg, 0.63 mmol) and Cs2CO3 (513 mg, 1.57 mmol) were added H2O (3 ml) and 1,4-dioxane (9 ml), and the reaction mixture was stirred and dealkylated. Then, Pd(dppf)Cl2.DCM (51 mg, 0.082 mmol) was added and stirred at 100°C for 1.5 hours. The mixture was diluted with EtOAc, washed with water, further washed with brine, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by flash chromatography column (gradient of EA / Hex 50 to 100%) to afford the title compound (116 mg, 45%) as a white solid.

[0632] 1H NMR (400MHz, CDCl3) δ9.71 (s, 1H), 9.09 (s, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 8.02 (s, 1H), 5.56 (d, J=17.2Hz, 1H), 6.34 ( dd, J=17.2Hz, 10.4Hz, 1H), 5.92 (d, J=10.4Hz, 1H), 3.86 (q, J=7.2Hz, 1H), 3.71 (s, 3H), 1.61 (d, J=7.2Hz, 3H); MS (m / z): 312.0[M+1]

[0633] Step 4) Preparation of 2-(5-(5-acrylamidopyrazine-2-yl)pyridin-3-yl)propanoic acid To methyl 2-(5-(5-acrylamidopyrazine-2-yl)pyridin-3-yl)propanoate (116 mg, 0.373 mmol) was added THF (2.7 ml), followed by a solution of LiOH (18 mg, 0.75 mmol) in H2O (0.9 ml). The mixture was stirred at room temperature for 2 h, diluted with EtOAc, washed with water, further washed with 1 N HCl, and extracted three times with EA. The extract was then dried (MgSO4), filtered, and dried under reduced pressure to provide the title compound (80 mg, 72%) as an apricot solid.

[0634] MS (m / z): 298.0 [M+1]

[0635] Step 5) N-(5-(5-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl) Preparation of pyrazine-2-yl) acrylamide

[0636] 2-(5-(5-acrylamidopyrazin-2-yl)pyridin-3-yl)propanoic acid (15 mg, 0.05 mmol) and 5-cyclopropylthiazol-2-amine (7 mg, 0.05 mmol) were dissolved in DCM (0.5 ml, 0.1 M), and DIPEA (26 μl, 0.15 mol) was added. HATU (21 mg, 0.06 mmol) was added while stirring at room temperature, and the mixture was stirred at room temperature for 20 minutes. The mixture was diluted with EtOAc, washed with water, dried (MgSO4), filtered, and dried under reduced pressure. The residue was purified by purification TLC (MC:MeOH=20:1) to provide the title compound (4.5 mg, 21%) as an off-white solid.

[0637] 1H NMR (400MHz, DMSO-d6) δ12.23(s, 1H), 11.22(s, 1H), 9.55(s, 1H), 9.20(s, 1H), 9.14(s, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 7.16 (s, 1H), 6.66 (dd, J=17.2Hz, 10.0Hz, 1H), 6.40 (dd, J=17.2Hz, 2.0Hz, 1H), 5.89(dd, J=10.0Hz, 2.0Hz, 1H), 4.14-4.08(m, 1H), 2.03-1.96(m , 1H), 1.54 (d, J=6.8Hz, 3H), 0.95-0.92 (m, 2H), 0.63-0.61 (m, 2H); MS (m / z): 421.0[M+1]

[0638] Example 44. N-(5-(5-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridine-3-yl Synthesis of 2-(2-yl)pyrazine-2-yl)acrylamide

[0639]

[0640] The title compound was prepared in the same manner as in Example 43, except using 5-cyanothiazol-2-amine instead of 5-cyclopropylthiazol-2-amine.

[0641] 1 H NMR (400MHz, DMSO-d6) δ13.27 (s, 1H), 11.22 (s, 1H), 9.55 (s, 1H), 9.21 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.36 (s, 1H), 6.66 (dd, J=17 .2Hz, 10.0Hz, 1H), 6.40 (dd, J=17.2Hz, 2.0Hz, 1H), 5.89 (dd, J=10.0Hz, 1.6Hz, 1H), 4.22-4.16 (m, 1H), 1.59 (d, J=7.2Hz, 3H); MS (m / z): 406.0[M+1]

[0642] Example 45. N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)

[0643] Synthesis of (amino)propane-2-yl)pyridin-3-yl)pyrazine-2-yl)acrylamide

[0644]

[0645] The title compound was prepared in the same manner as in Example 43, except using 5-(trifluoromethyl)thiazol-2-amine instead of 5-cyclopropylthiazol-2-amine.

[0646] 1H NMR (400MHz, DMSO-d6) δ11.22 (s, 1H), 9.55 (s, 1H), 9.21 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 6.65 (dd, J=17.2Hz, 10 .0Hz, 1H), 6.40 (dd, J=17.2Hz, 2.0Hz, 1H), 5.89 (dd, J=10.0Hz, 2.0Hz, 1H) 4.19 (q, J=7.2Hz, 1H), 1.59 (d, J=7.2Hz, 3H); MS (m / z): 449.0[M+1]

[0647] Example 46. N-(5-(5-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridine-3-yl Synthesis of 2-(2-yl)pyrazine-2-yl)acrylamide

[0648]

[0649] The title compound was prepared in the same manner as in Example 43, except using 5-ethylthiazol-2-amine instead of 5-cyclopropylthiazol-2-amine.

[0650] 1 H NMR (400MHz, DMSO-d6) δ12.26 (s, 1H), 11.22 (s, 1H), 9.55 (s, 1H), 9.20 (s, 1H), 9.14 (s, 1H), 8.64 (s, 1H), 8.45 (s, 1H), 7.16 (s, 1H), 6.65 (dd, J=17.2Hz, 10.0Hz, 1H), 6.4 0 (dd, J=17.2Hz, 2.0Hz, 1H), 5.89 (dd, J=10.0Hz, 2.0Hz, 1H), 4.16-4.08 (m, 1H), 2.72 (q, J=8.8Hz, 2H), 1.55 (d, J=7.2Hz, 3H), 1.18 (t, J=8.8Hz, 3H); MS (m / z): 409.0[M+1]

[0651] Example 47. N-(5-(5-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridine-3-yl Synthesis of 2-(2-yl)pyrazine-2-yl)acrylamide

[0652]

[0653] The title compound was prepared in the same manner as in Example 43, except using 5-isopropyl-thiazol-2-amine instead of 5-cyclopropylthiazol-2-amine.

[0654] 1H NMR (400MHz, DMSO-d6) δ12.26(s, 1H), 11.22(s, 1H), 9.55(s, 1H), 9.20(s, 1H), 9.14( s, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 7.16 (s, 1H), 6.65 (dd, J=17.2Hz, 10.0Hz, 1H), 6.40 (dd,, J=17.2Hz, 2.0Hz, 1H), 5.89 (dd, J=10.0Hz, 2.0Hz, 1H), 4.12 (q, J=6.8Hz, 1H), 3 .17-3.08(m, 1H), 1.55(d, J=6.8Hz, 3H), 1.24(d, J=6.8Hz, 6H); MS(m / z): 423.0[M+1]

[0655] Example 48. N-(5-(5-(1-((5-acetylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridine-3-yl Synthesis of 2-(2-yl)pyrazine-2-yl)acrylamide

[0656]

[0657] The title compound was prepared in the same manner as in Example 43, except using 1-(2-aminothiazol-5-yl)ethan-1-one instead of 5-cyclopropylthiazol-2-amine.

[0658] 1 H NMR (400MHz, DMSO-d6) δ11.20 (s, 1H), 9.55 (s, 1H), 9.20 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 6.65 (dd, J=17.2Hz, 10.0Hz, 1 H), 6.40 (dd, J=17.2Hz, 2.0Hz, 1H), 5.89 (dd, J=10.0Hz, 2.0Hz, 1H), 4.17 (q, J=7.2Hz, 1H), 2.49 (s, 3H), 1.57 (d, J=7.2Hz, 3H); MS (m / z): 423.0[M+1]

[0659] Example 49. N-(6-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)

[0660] Synthesis of (amino)propane-2-yl)pyridin-3-yl)pyridazin-3-yl)acrylamide

[0661]

[0662] The title compound was prepared in the same manner as in Example 43, except using 5-(trifluoromethyl)thiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and N-(6-bromopyridazin-3-yl)acrylamide instead of N-(5-bromopyrazin-2-yl)acrylamide.

[0663] 1 H NMR (400MHz, DMSO-d6) δ11.53 (s, 1H), 9.17 (s, 1H), 8.70 (s, 1H), 8.55 (d, J= 9.6Hz, 1H), 8.51 (s, 1H), 8.38 (d, J=9.2Hz, 1H), 8.11 (s, 1H), 6.70 (dd, J=16 .8Hz, 10.0Hz, 1H), 6.40 (dd, J=16.8Hz, 2.0Hz, 1H), 5.90 (dd, J=10.0Hz, 2.0Hz, 1H), 4.22 (q, J=6.8Hz, 1H), 1.60 (d, J=6.8Hz, 3H); MS (m / z): 449.0[M+1]

[0664] Example 50. N-(4-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[2,3'-bicyclopropane] Synthesis of [pyridinyl]-6'-yl) acrylamide

[0665]

[0666] The title compound was prepared in the same manner as in Example 43, except using 2-(2-bromopyridin-4-yl)acetic acid instead of 2-(5-bromopyridin-3-yl)acetic acid.

[0667] 1 H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 9.04 (s, 1H), 8.61 (d, J = 5.2Hz, 1H), 8.47 (d, J = 8.8Hz, 2.4Hz , 1H), 8.33 (d, J=8.8Hz, 1H), 7.98 (s, 1H), 7.32 (d, J=4.8Hz, 1H), 7.15 (s, 1H), 6.65 (dd, J=17.2Hz, 1 0.0Hz, 1H), 6.35 (dd, J=17.2Hz, 2.0Hz, 1H), 5.82 (dd, J=10.0Hz, 2.0Hz, 1H), 4.06-4.00 (m, 1H), 2. 04-1.96 (m, 1H), 1.52 (d, J=7.2Hz, 3H), 0.96-0.91 (m, 2H), 0.64-0.61 (m, 2H); MS (m / z): 420.0[M+1]

[0668] Example 51. (R)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propane-2-yl)- Synthesis of 2-(4-yl)pyridin-3-yl)pyrazine-2-yl)acrylamide Only the R-configuration was isolated from the compound of Example 45 using a chiral chromatography column.

[0669] 1H NMR (400MHz, DMSO-d6) δ11.22 (s, 1H), 9.55 (s, 1H), 9.21 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 6.65 (dd, J=12.9Hz, 7 .5Hz, 1H), 6.40 (dd, J=12.9Hz, 1.5Hz, 1H), 5.89 (dd, J=7.5Hz, 1.5Hz, 1H) 4.19 (q, J=5.4Hz, 1H), 1.59 (d, J=5.4Hz, 3H); MS (m / z): 449.0[M+1]

[0670] Example 52. (S)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propane-2-yl)- Synthesis of 2-(4-yl)pyridin-3-yl)pyrazine-2-yl)acrylamide Only the S-configuration was isolated from the compound of Example 45 using a chiral chromatography column.

[0671] 1 H NMR (400MHz, DMSO-d6) δ11.22 (s, 1H), 9.55 (s, 1H), 9.21 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 6.65 (dd, J=12.9Hz, 7 .5Hz, 1H), 6.40 (dd, J=12.9Hz, 1.5Hz, 1H), 5.89 (dd, J=7.5Hz, 1.5Hz, 1H) 4.19 (q, J=5.4Hz, 1H), 1.59 (d, J=5.4Hz, 3H); MS (m / z): 449.0[M+1]

[0672] Example 53. N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)thiazol-2-yl Synthesis of (phen-3-yl)pyridin-2-yl)acrylamide

[0673]

[0674] The title compound was prepared in the same manner as in Example 41, except that 2-(4-bromothiophen-2-yl)acetic acid was used instead of 2-(5-bromopyridin-3-yl)acetic acid, and 5-(trifluoromethyl)thiazol-2-amine was used instead of 5-cyanothiazol-2-amine.

[0675] MS (m / z): 453.0 [M+1]

[0676] Example 54. N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-5-fluorobenzene Synthesis of 2-(2-yl)pyridin-2-yl)acrylamide

[0677]

[0678] The title compound was prepared in the same manner as in Example 1, except that 5-cyclopropylthiazol-2-amine was used instead of 5-methylthiazol-2-amine, and 2-(3-bromo-5-fluorophenyl)acetic acid was used instead of 2-(3-bromophenyl)acetic acid.

[0679] 1 H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 8.30 (d, J = 8.4Hz, 1H), 8.15 (d, J = 8.8Hz, 1H), 7.5 7 (s, 1H), 7.51 (d, J=9.2Hz, 1H), 7.18 (d, J=11.2Hz, 1H), 7.12 (s, 1H), 6.64 (dd, J=16.0H z, 9.6Hz, 1H), 6.34 (d, J = 16.0Hz, 1H), 5.81 (d, J = 9.6Hz, 1H), 4.04-4.02 (m, 1H), 1.98 (m , 1H), 1.49 (d, J=7.2Hz, 3H), 0.93-0.86 (m, 2H), 0.62-0.61 (m, 2H); MS (m / z): 437.0[M+1]

[0680] Example 55. N-(5-(5-(2-methyl-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propane- Synthesis of 2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide

[0681]

[0682] The title compound was prepared in the same manner as in Example 43, except using 5-(trifluoromethyl)thiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and 2-(5-bromopyridin-3-yl)-2-methylpropionic acid instead of 2-(5-bromopyridin-3-yl)propionic acid.

[0683] 1 H NMR (400MHz, DMSO-d6) δ11.21 (s, 1H), 9.54 (s, 1H), 9.17 (s, 1H), 9.15 (s, 1H), 8.59 (s, 1H), 8.37 (t, J=2.0Hz, 1H), 7.98 (s, 1H), 6. 66 (dd, J=16.0Hz, 10.0Hz, 1H), 6.40 (dd, J=16.0Hz, 2.0Hz, 1H), 5.89 (dd, J=10.0Hz, 2.0Hz, 1H), 1.71 (s, 6H); MS (m / z): 463.0[M+1]

[0684] Example 56. (S)-2-(3-(5-(2-cyanoacetamido)pyrazin-2-yl)phenyl)-N-(5-(trifluoromethyl) Synthesis of Thiazol-2-yl) Propionamide

[0685]

[0686] The title compound was prepared in the same manner as in Example 14, except using 5-(trifluoromethyl)thiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and N-(5-bromopyrazin-2-yl)-2-cyanoacetamide instead of N-(5-bromopyridin-2-yl)acrylamide.

[0687] 1 H NMR (400MHz, CDCl3) δ9.49 (s, 1H), 9.18 (s, 1H), 8.69 (d, J = 1.6Hz, 1H), 8.51 (s, 1H), 8.00 (t, J = 1.6Hz, 1H), 7.90 (dd, J = 8.0, 1.6Hz, 1H), 7. 69 (d, J=1.6Hz, 1H), 7.53-7.51 (m, 1H), 7.42 (d, J=8.0Hz, 1H), 3.97-3.92 (m, 1H), 3.66 (s, 2H), 1.70 (d, J=7.2Hz, 3H); MS (m / z): 461.0[M+1]

[0688] Example 57. N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)thiazol-2-yl Synthesis of (phen-3-yl)pyrazine-2-yl)acrylamide

[0689]

[0690] The title compound was prepared in the same manner as in Example 43, except using 5-(trifluoromethyl)thiazol-2-amine instead of 5-cyclopropylthiazol-2-amine, and 2-(4-bromothiophen-2-yl)acetic acid instead of 2-(5-bromopyridin-3-yl)propionic acid.

[0691] 1 H NMR (400MHz, DMSO-d6) δ11.04 (s, 1H), 9.40 (s, 1H), 7.98 (s, 1H), 7.61 (s, 1H), 7.54 (s, 1H), 6.63 (dd, J=16.8, 10.0Hz, 1H), 6.36 (dd, J=16.8, 1.8Hz, 1H), 5.85 (dd, J=10.0, 1.8Hz, 1H), 3.99-3.94 (m, 1H), 1.68 (d, J=6.8Hz, 3H); MS (m / z): 454.0[M+1]

[0692] Example 58. (S)-2-(3-(5-(2-cyanoacetamido)pyrazin-2-yl)phenyl)-N-(5-cyanothiazole-2-yl)- Synthesis of 2-(4-(2-amino)propionamide

[0693]

[0694] The title compound was prepared in the same manner as in Example 14, except that 5-cyanothiazol-2-amine was used instead of 5-cyclopropylthiazol-2-amine, and N-(5-bromopyrazin-2-yl)-2-cyanoacetamide was used instead of N-(5-bromopyridin-2-yl)acrylamide.

[0695] 1 H NMR (400MHz, DMSO-d6) δ9.34 (s, 1H), 9.03 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 8.00 (d, J=7.2, 1.6Hz, 1 H), 7.52-7.47 (m, 2H), 4.06 (s, 2H), 4.04-4.00 (m, 1H), 1.53 (dd, J=6.8Hz, 3H); MS (m / z): 418.1[M+1]

[0696] Example 59. N-(5-(3-methyl-1-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propane- Synthesis of 2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)acrylamide

[0697]

[0698] The title compound was prepared in the same manner as in Example 41, except that 5-(trifluoro)thiazolamine was used instead of 5-cyanothiazolamine, and 2-(4-bromo-3-methyl-1H-pyrazol-1-yl)acetic acid was used instead of 2-(5-bromopyridin-3-yl)acetic acid.

[0699] MS (m / z): 451.0 [M+1]

[0700] Example 60. 2-(1'-acryloyl-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-5-yl)-N-(5-cyano Synthesis of 2-(2-thiazole-2-yl)propionamide

[0701]

[0702] The title compound was prepared in the same manner as in Example 41, except using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate instead of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine.

[0703] 1H NMR (400MHz, DMSO-d6) δ8.57 (s, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 7.79 (s, 1H), 6.95-6.75 (m, 1H), 6.30-6.27 (m, 1H), 6.15 (d, J=16.0Hz, 1H), 5 .72 (dd, J=10.4Hz, 2.4Hz, 1H), 4.29 (s, 1H), 4.20 (s, 1H), 4.04-4.02 (m, 2H), 3.78-3.75 (m, 3H), 1.52 (d, J=7.2Hz, 3H); MS (m / z): 394.0[M+1]

[0704] Example 61. N-(5-(5-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl) Synthesis of 2-pyrazine-2-yl)acrylamide

[0705]

[0706] The title compound was prepared in the same manner as in Example 43, except using 5-chlorothiazol-2-amine instead of 5-cyclopropylthiazol-2-amine.

[0707] 1 H NMR (400MHz, DMSO-d6) δ11.21 (s, 1H), 9.55 (d, J = 1.6Hz, 1H), 9.20 (d, J = 2.0Hz, 1H ), 9.13 (d, J = 1.6Hz, 1H), 8.64 (d, J = 2.0Hz, 1H), 8.44 (t, J = 2.0Hz, 1H), 7.49 (s, 1H) , 6.66 (dd, J=17.2Hz, 7.5Hz, 1H), 6.40 (dd, J=16.8Hz, 1.6Hz, 1H), 5.89 (dd, J=10.0 Hz, 1.6Hz, 1H), 4.12 (q, J=7.2Hz, 1H), 1.56 (d, J=7.2Hz, 1H); MS (m / z): 415.5[M+1]

[0708] Examples 62-149.

[0709] The compounds of Examples 62 to 149 were prepared according to the reactions described in the Examples shown in Table 1 below. Their NMR results are shown in Table 1.

[0710] Table 1

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750] Experimental example

[0751] The efficacy of the compounds prepared in the above examples was evaluated in the following manner and the results are shown.

[0752] Experimental Example 1: CDK7 kinase activity

[0753] The CDK7 kinase-inhibitory activity of the representative compounds of the present invention was detected in vitro using the ADP-Glo ​​platform. In detail, recombinant purified human CDK7 kinase (ThermoFisher, PV3868) and ADP Glo kinase assay kit (Promega, V9102) were used to determine CDK7 kinase-inhibitory activity. CDK7 kinase was diluted with 1× kinase reaction buffer (40mM Tris-Cl, pH 7.5, 20mM MgCl2, 0.1mg / ml BSA and 50μM DTT) and added to a 96-well plate (final CDK7 concentration per reaction: 50ng). Finally, the compound was treated with a 1% DMSO aqueous solution, and a substrate mixture containing ATP (final concentration of 90μM) and 0.2μg / μl MBP (myelin basic protein) in a total of 25μl of reaction blocks was added to a 96-well plate, thereby starting the enzymatic reaction. After 2 hours of incubation (30°C), an equal volume (25 μl per reaction) of ADP Glo was added and incubated at room temperature (30°C) for 60 minutes. Then, a kinase detection reagent (50 μl per reaction) was added and incubated at room temperature (30°C) for 30 minutes. The kinase activity was determined by an optical luminescence method according to the instructions of the ADP Glo kinase detection kit, and the CDK7-inhibitory activity of the compounds of the present invention was calculated. The results of each compound were analyzed using Microsoft Excel, and the IC was calculated using prism software. 50 The CDK7 kinase-inhibitory IC values ​​of the selected test compounds shown in Table 2 were recorded below. 50 value.

[0754] Table 2

[0755] CDK7 kinase-inhibitory activity of the compounds of the present invention

[0756]

[0757]

[0758] Experimental Example 2: CDK7 Selectivity

[0759] The assay was performed (scanMAX kinase assay panel). The scanMAX kinase assay panel contains a panel of 468 kinases including CDK2, CDK5. Compounds were screened at 1 μM and the binding interaction results (%) compared to the control group were reported.

[0760] Table 3

[0761] Percent inhibition of various kinases by the compounds of the present invention

[0762]

[0763]

[0764] As shown in Table 3, the present compound highly inhibits CDK7 and less inhibits CDK 2 and CDK 5. From the above results, it was confirmed that the present compound highly selectively inhibits CDK7.

[0765] Experimental Example 3: Confirmation of the anti-proliferative effect of the compound of the present invention on cancer cells (inhibition rate at 100 nM)

[0766] MDA-MB-468 cells

[0767] MDA-MB-468 cells are one type of triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor, and HER2 expression), a well-known malignant tumor that is difficult to diagnose in the early stages and has a high metastatic potential. These cells are generally used in experiments to inhibit the proliferation and survival of breast cancer cells.

[0768] In order to evaluate the ability to inhibit the proliferation of MDA-MB-468 cells, representative compounds of the present invention were tested at different concentrations (from 1000 nM to 25 nM). Cells were grown in RPMI 1640 (Welgene) + 10% FBS (Gibco) + 1% penicillin / streptomycin (Gibco) and cultured at 37°C in a humidified chamber in the presence of 5% CO2.

[0769] MDA-MB-468 cells cultured in 96-well cell culture plates were treated with representative compounds of the present invention and cultured for 72 hours. The antiproliferative effects of the compounds were then detected by the MTT method using tetrazolium salts, and the results are shown in Table 4 below. In Table 4 below, the value % represents the inhibition rate in a compound concentration of 100 nM.

[0770] Table 4

[0771] Inhibition rate of MDA-MB-468 cells at 100 nM

[0772]

[0773]

[0774] MV4-11 cells

[0775] MV4-11 cells are a type of acute myeloid leukemia cell line that has a FMS-like tyrosine kinase 3 (FLT3) gene mutation, and are generally used in experiments to inhibit the proliferation and survival of leukemia cells.

[0776] To evaluate the ability to inhibit the proliferation of MV4-11 cells, representative compounds of the present invention were tested at different concentrations (from 100 nM to 10 nM). Cells were grown in IMDM (Vigen) + 10% FBS (Gibco) + 1% penicillin / streptomycin (Gibco) and cultured at 37°C in a humidified chamber in the presence of 5% CO2.

[0777] MV4-11 cells cultured in a 96-well cell culture plate were treated with a representative compound of the present invention and cultured for 72 hours. The antiproliferative effect of the compound was then detected by the CCK-8 method using tetrazolium salts, and the results are shown in the following Table 5. In the following Table 4, the value % represents the inhibition rate in a compound concentration of 100 nM.

[0778] Table 5

[0779] Inhibition rate of MV4-11 cells at 100 nM

[0780]

[0781]

[0782] Experimental Example 4: Antiproliferative effect of the compounds of the present invention on cancer cells

[0783] MDA-MB-468 cells

[0784] In order to evaluate the ability to inhibit the proliferation of MDA-MB-468 cells, the compounds of the present invention were tested at different concentrations (from 1000 nM to 1 nM). The cells were grown in RPMI 1640 (Weijian) + 10% FBS (Gibco) + 1% penicillin / streptomycin (Gibco) and cultured at 37°C in a humidified chamber in the presence of 5% CO2.

[0785] MDA-MB-468 cells cultured in 96-well cell culture plates were treated with representative compounds of the present invention and cultured for 72 hours. The antiproliferative effects of the compounds were then detected by the MTT method using tetrazolium salts, and the results are shown in Table 6 below.

[0786] Table 6

[0787] Inhibitory effect of the compounds of the present invention on the proliferation of MDA-MB-468 cells

[0788]

[0789]

[0790] HepG2 cells

[0791] The ability to inhibit the proliferation of HepG2 cells, which are human hepatocellular carcinoma cells, was determined in vitro by a cell viability assay. The cells were cultured at 37°C using a medium containing MEM (Viken) + 10% FBS (Gibco) + 1% penicillin / streptomycin (Gibco) in a humidified chamber in the presence of 5% CO2. HepG2 cells cultured in 96-well cell culture plates were treated with compounds and cultured for 72 hours. Cell viability was determined by the CCK-8 method using tetrazolium salts, and the ability of the compounds of the present invention to inhibit cancer cell proliferation was calculated. The results of each compound were analyzed using Microsoft Excel, and the IC was calculated using prism software. 50 The values ​​are shown in Table 7 below.

[0792] Table 7

[0793] Inhibitory effect of the compounds of the present invention on the proliferation of HCC (HepG2) cells

[0794]

[0795]

[0796] Experimental Example 5: Inhibitory effect of the compound of the present invention on gene expression in cancer cells

[0797] MDA-MB-468 cells

[0798] In order to evaluate the ability to inhibit the expression of cancer cell proliferation-related genes in MDA-MB-468 cells, which are triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor and HER2 expression), the compounds of the present invention were tested at different concentrations (from 250 nM to 100 nM). Cells were cultured in RPMI 1640 (Vigen) + 10% FBS (Gibco) + 1% penicillin / streptomycin (Gibco) and cultured at 37° C. in a humidified chamber in the presence of 5% CO 2 .

[0799] MDA-MB-468 cells cultured in 96-well cell culture plates were treated with the compounds of the present invention and cultured for 24 hours. Proteins were then extracted from the cells using a RIPA (radioimmunoprecipitation assay) buffer containing protease and phosphatase inhibitors. Proteins were separated by SDS-PAGE according to molecular weight and transferred to a nitrocellulose membrane. RNAPII CTD p-Ser2, RNAPII CTD p-Ser5, RNAPII CTD p-Ser7, CDK7, c-Myc, and β-actin antibodies were reacted with the membrane at 4°C for 18 hours, and then the antibodies were reacted with ECL (high sensitivity chemiluminescence). The luminescence generated during the reaction was transmitted to an X-ray film for imaging, and the results are shown in Figure 1 middle.

[0800] The compound of the present invention phosphorylates RNAPII CTD, which plays an important role in the gene transcription process, and effectively inhibits MYC (a gene encoding a transcription factor) associated with proliferative diseases, thereby having excellent activity against proliferative diseases such as cancer.

[0801] References

[0802] All publications and patents mentioned herein are incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the event of a conflict, the present invention, including any definitions herein, will control.

[0803] Equivalent

[0804] Although specific embodiments of the present invention have been discussed, the above description is illustrative and non-restrictive. When reading this specification and the accompanying claims, various variations of the present invention will become apparent to those of ordinary skill. In addition to the overall scope of equivalents, the overall scope of the present invention should also be determined with reference to the claims, and in addition to these variations, the overall scope of the present invention should also be determined with reference to the specification.

Claims

1. A compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof, In the formula, Ring A is phenyl, pyridyl, pyrazinyl, pyrazolyl, thienyl, thiazolyl or piperidinyl; Ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, tetrahydropyridinyl, piperidinyl or piperazinyl; R1 is halogen, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, cyano, -SR c 、-N(R c )(R d ),-OR c or -C(R g )2-OR c ; R c and R d Each independently is H or C1-C6 alkyl; R g is H or C1-C6 alkyl; R 2V and R 2W are each independently H, halogen or C1-C6 alkyl; or R 2V and R 2W Together with the atoms to which they are attached, they form a C3-C7 cycloalkyl group; L1 does not exist or is -N(R e )-or-*CH2N(R e )-, * is the position where L1 is connected to the B ring; R e is H or C1-C6 alkyl; or R e Covalently bonded to a position on ring B to form ring B fused pyrrole or pyrrolidine, which is unsubstituted or substituted with a C1-C6 alkyl group; R3 is R f1 is H, halogen, C1-C6 alkyl or cyano; R f2 and R f3 Each is independently H, C1-C6 alkyl, C3-C7 cycloalkyl, -N(R c’ )(R d’ ) or -CH2N(R c’ )(R d’ ); R c’ and R d’ are each independently C1-C6 alkyl; or R c’ and R d’ Together with the atoms to which they are attached, they form azetidinyl; piperidinyl; morpholinyl; piperazinyl substituted or unsubstituted by C1-C6 alkyl; 2,5-diazabicyclo[2.2.1]heptyl substituted or unsubstituted by C1-C6 alkyl; 2-oxa-5-azabicyclo[2.2.1]heptyl; or pyrrolidinyl substituted or unsubstituted by halogen, hydroxyl or C1-C6 alkoxy-C1-C6 alkyl; R a is H, halogen, or C1-C6 alkyl; R b is H, halogen, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, cyano, C1-C6 haloalkyl, -N(CH3)-CH2CH2-N(CH3)2, or piperazinyl which is substituted or unsubstituted by C1-C6 alkyl; Both m and n are integers 1.

2. The compound according to claim 1, characterized in that Ring A is phenyl, pyridyl or thienyl.

3. The compound according to claim 2, characterized in that Ring A is phenyl.

4. The compound according to claim 1, characterized in that Ring B is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or piperidinyl.

5. The compound according to claim 4, characterized in that Ring B is pyridyl.

6. The compound according to claim 1, characterized in that R1 is halogen, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, cyano or -N(R c )(R d );R c and R d Each is independently H or C1-C6 alkyl.

7. The compound according to claim 6, characterized in that R1 is C1-C6 alkyl or C1-C6 haloalkyl.

8. The compound according to claim 1, characterized in that R 2V and R 2W Each independently is H or C1-C6 alkyl; or R 2V and R 2W Together with the atoms to which they are attached, they form a C3-C7 cycloalkyl group.

9. The compound according to claim 8, characterized in that R 2V and R 2W Each is independently H or C1-C6 alkyl.

10. The compound according to claim 1, characterized in that L1 is -N(R e )-; Where R e is H or C1-C6 alkyl; or R e Combined with an atom on ring B to form a ring B-fused pyrrolidine, which is unsubstituted or substituted with a C1-C6 alkyl group.

11. The compound according to claim 10, characterized in that Re is H; or Re is bonded to an atom on ring B to form a ring B-fused pyrrolidine which is unsubstituted or substituted with a C1-C6 alkyl group.

12. The compound according to claim 1, characterized in that R3 is Where R f1 is H; R f2 and R f3 Each independently is H or -CH2N(R c’ )(R d’ ), R c’ and R d’ are each independently C1-C6 alkyl; or R c’ and R d’ Together with the atoms to which they are attached, they form an azetidinyl group; a piperidinyl group; a morpholinyl group; a piperazinyl group which may be substituted or unsubstituted by a C1-C6 alkyl group; a 2,5-diazabicyclo[2.2.1]heptyl group which may be substituted or unsubstituted by a C1-C6 alkyl group; a 2-oxa-5-azabicyclo[2.2.1]heptyl group; or a pyrrolidinyl group which may be substituted or unsubstituted by a halogen, a hydroxyl group or a C1-C6 alkoxy-C1-C6 alkyl group.

13. The compound according to claim 12, characterized in that R c’ and R d’ Each is independently a C1-C6 alkyl group.

14. The compound according to claim 1, characterized in that R a For H.

15. The compound according to claim 1, characterized in that R b is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano or C1-C6 haloalkyl.

16. The compound according to claim 15, characterized in that R b is halogen or cyano.

17. A compound or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the group consisting of the following compounds: 1) N-(5-(3-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 2) N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 3)(R)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 4) N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 5)(E)-4-(dimethylamino)-N-(5-(3-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 6) (E)-N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 7) (E)-4-(dimethylamino)-N-(5-(3-(1-((5-methylthiazol-2-yl)amino-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide hydrochloride; 8) N-(3-fluoro-3'-(1-((5-methylthiazol-2-yl)amino-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide; 9) 2-(3-(1-acryloylindol-5-yl)phenyl)-N-(5-methylthiazol-2-yl)propionamide; 10) (E)-N-(5-(3-(1,1-difluoro-2-((5-methylthiazol-2-yl)amino)-2-oxoethyl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 11) N-(6-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-4-fluorophenyl)pyridazin-3-yl)acrylamide; 12) 2-(3-(6-acrylamidopyridazin-3-yl)phenyl)-N-(5-cyanothiazol-2-yl)-3-methylbutanamide; 13) N-(6-(5-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-2-fluorophenyl)pyridazin-3-yl)acrylamide; 14) (S)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 15) (S,E)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 16) (S)-N-(6-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide; 17)(S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 18) (S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 19) (S)-2-(3-(6-acrylamidopyridin-3-yl)phenyl)-N-(5-ethylthiazol-2-yl)butanamide; 20) (S)-2-(4'-acrylamido-3'-fluoro-[1,1'-biphenyl]-3-yl)-N-(5-ethylthiazol-2-yl)butanamide; 21)(S,E)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 22)(S)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide; 23) (S)-N-(3'-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide; 24) (S)-N-(3'-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-3-fluoro-[1,1'-biphenyl]-4-yl)acrylamide; 25)(S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide; 26)(S)-N-(6-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide; 27)(S)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrimidin-2-yl)acrylamide; 28) (S)-N-(6-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridazin-3-yl)acrylamide; 29)(S)-N-(5-(3-(1-(5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-fluoropyridin-2-yl)acrylamide; 30) (S)-N-(3-cyano-3'-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide; 31)(S)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-6-fluoropyridin-2-yl)acrylamide; 32)(S)-N-(6-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridazin-3-yl)acrylamide; 33)(S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-fluoropyridin-2-yl)acrylamide; 34)(S)-N-(5-(3-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-methylpyrazin-2-yl)acrylamide; 35)(S)-N-(5-(3-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 36)(S)-N-(5-(3-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)acrylamide; 37)(S)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)acrylamide; 38)(S)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)acrylamide; 39)(S)-N-(6-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridazin-3-yl)acrylamide; 40)(S)-N-(6-(3-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridazin-3-yl)acrylamide; 41) N-(5'-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-[3,3'-bipyridyl]-6-yl)acrylamide; 42) N-(4-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)-[2,3'-bipyridyl]-6'-yl)acrylamide; 43) N-(5-(5-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 44) N-(5-(5-(1-((5-cyanothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 45) N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 46) N-(5-(5-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 47) N-(5-(5-(1-((5-isopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 49) N-(6-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyridazin-3-yl)acrylamide; 50) N-(4-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[2,3'-bipyridyl]-6'-yl)acrylamide; 51)(R)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 52)(S)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 53) N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)thiophen-3-yl)pyridin-2-yl)acrylamide; 54) N-(5-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)-5-fluorophenyl)pyridin-2-yl)acrylamide; 55) N-(5-(5-(2-methyl-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 57) N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)thiophen-3-yl)pyrazin-2-yl)acrylamide; 59) N-(5-(3-methyl-1-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)acrylamide; 60) 2-(1'-acryloyl-1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-5-yl)-N-(5-cyanothiazol-2-yl)propionamide; 61) N-(5-(5-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 62)(S)-N-(6-(3-(1-((5-cyclopropylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-3-yl)acrylamide; 63) (E)-4-(dimethylamino)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide; 65)(E)-2-cyano-3-cyclopropyl-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 66) N-(5-(5-(1-((5-methoxythiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 67) N-(5-(5-(1-((5-fluorothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 68) N-(2-(4-methylpiperazin-1-yl)-4-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)phenyl)acrylamide; 69) (E)-2-cyano-3-(dimethylamino)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 70) N-(1-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)piperidin-4-yl)acrylamide; 71) N-(5-(5-(1-((5-(methylthio)thiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)acrylamide; 73)(E)-N-(5-(5-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)pyridin-3-yl)pyrazin-2-yl)-4-(dimethylamino)but-2-enamide; 74)(E)-4-morpholino-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide; 75)(E)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide; 76) N-(5-(5-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)thiophen-3-yl)pyridin-2-yl)acrylamide; 77) N-(5-(5-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)thiophen-3-yl)pyridin-2-yl)acrylamide; 80)(E)-4-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide; 81)(S,E)-4-(dimethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 82) N-(5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)acrylamide; 83)(E)-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(5-(5-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)pyridin-3-yl)pyrazin-2-yl)but-2-enamide; 84) N-(4-fluoro-5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)acrylamide; 85) 2-(5-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-N-(5-(trifluoromethyl)thiazol-2-yl)propanamide; 86) 2-(5-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-N-(5-ethylthiazol-2-yl)propanamide; 87) N-(6-(5-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)thiophen-3-yl)pyridin-3-yl)acrylamide; 88) N-(5-cyano-5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)acrylamide; 89) N-((5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)methyl)acrylamide; 90) N-(5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[2,3'-bipyridyl]-5-yl)acrylamide; 91)(S,E)-4-(dimethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 92)(S,E)-4-morpholino-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 93)(S,E)-N-(5-(3-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(dimethylamino)but-2-enamide; 94)(E)-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(5-(3-((S)-1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 95)(S,E)-4-(4-methylpiperazin-1-yl)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 96)(E)-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 97)(S,E)-N-(5-(3-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(4-methylpiperazin-1-yl)but-2-enamide; 98)(S,E)-N-(5-(3-(1-((5-chlorothiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-morpholinobut-2-enamide; 99)(S,E)-4-(dimethylamino)-N-(3-fluoro-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 100)(S,E)-4-(dimethylamino)-N-(3-methoxy-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 101)(S,E)-N-(3-cyano-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 102)(S,E)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide; 103) (S,E)-4-(azetidin-1-yl)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 104)(S,E)-N-(5-(3-(1-((5-cyclobutylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)-4-(dimethylamino)but-2-enamide; 105) (S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-(2-hydroxypropan-2-yl)thiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 106) (S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-(dimethylamino)thiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 107) (E)-4-(dimethylamino)-N-(5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)but-2-enamide; 108) (E)-N-(5-cyano-5'-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)-[3,3'-bipyridyl]-6-yl)-4-(dimethylamino)but-2-enamide; 109) (S,E)-4-(dimethylamino)-N-(3-methoxy-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 110)(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-(trifluoromethyl)thiazol-2-yl)propanamide; 111)(S,E)-4-(dimethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)-3-(trifluoromethyl)pyridin-2-yl)but-2-enamide; 112)(S,E)-4-(dimethylamino)-N-(3-methyl-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 113)(S,E)-N-(3-chloro-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 114)(S,E)-4-(diethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 115)(E)-4-((R)-3-fluoropyrrolidin-1-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 116)(S,E)-4-(dimethylamino)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 117)(E)-4-((S)-3-fluoropyrrolidin-1-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 118) (E)-4-((S)-2-(methoxymethyl)pyrrolidin-1-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 119) (E)-4-(3-hydroxypyrrolidin-1-yl)-N-(5-(3-((S)-1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)but-2-enamide; 120)(S,E)-N-(5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyrazin-2-yl)-4-(piperidin-1-yl)but-2-enamide; 121)(S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 122)(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-ethylthiazol-2-yl)propanamide; 123) (E)-4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(3-cyano-5-(3-((S)-1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)but-2-enamide; 124)(S)-N-(3-cyano-5-(3-(1-oxo-1-((5-(trifluoromethyl)thiazol-2-yl)amino)propan-2-yl)phenyl)pyridin-2-yl)acrylamide; 125)(S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-methylpyridin-2-yl)but-2-enamide; 126)(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-ethylthiazol-2-yl)propanamide; 127)(S,E)-2-(3-(1-(4-(dimethylamino)but-2-enoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-ethylthiazol-2-yl)propanamide; 128) (E)-1-(3-(5-cyano-6-(4-(dimethylamino)but-2-enoylamino)pyridin-3-yl)phenyl)-N-(5-ethylthiazol-2-yl)cyclopropane-1-carboxamide; 129) (S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-N-methylbut-2-enamide; 130)(S,E)-4-(dimethylamino)-N-(5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-3-fluoropyridin-2-yl)but-2-enamide; 131)(E)-4-(dimethylamino)-N-(6-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxobutan-2-yl)phenyl)pyridin-3-yl)but-2-enamide; 132) (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)-N-methylbut-2-enamide; 133) (E)-1-(3-(1-(4-(dimethylamino)but-2-enoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-N-(5-ethylthiazol-2-yl)cyclopropane-1-carboxamide; 134) (E)-1-(3-(6-(4-(dimethylamino)but-2-enoylamino)-5-fluoropyridin-3-yl)phenyl)-N-(5-ethylthiazol-2-yl)cyclopropane-1-carboxamide; 135) (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide; 136) (S,E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(4-methylpiperazin-1-yl)but-2-enamide; 137) (E)-N-(5-cyano-5'-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[3,3'-bipyridyl]-6-yl)-4-(dimethylamino)but-2-enamide; 138) (E)-N-(3-cyano-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-(dimethylamino)but-2-enamide; 139) (S)-2-(3-(5-cyano-6-(2-cyanoacetamido)pyridin-3-yl)phenyl)-N-(5-ethylthiazol-2-yl)propanamide; 140) N-(5-(6-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)pyrazin-2-yl)pyridin-2-yl)acrylamide; 141) N-(2'-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[3,4'-bipyridyl]-6-yl)acrylamide; 142) N-(4-(3-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)piperidin-1-yl)phenyl)acrylamide; 143) N-(5-(2-(1-((5-methylthiazol-2-yl)amino)-1-oxopropan-2-yl)thiazol-4-yl)pyridin-2-yl)acrylamide; 144)(S)-N-(3-cyclopropyl-5-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)acrylamide; 145) (S)-N-(3-((2-(dimethylamino)ethyl)(methyl)amino)-3'-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)-[1,1'-biphenyl]-4-yl)acrylamide; 146)(S)-N-(5-ethylthiazol-2-yl)-2-(3-(6-(vinylsulfonamido)pyridin-3-yl)phenyl)propanamide; 147)(S)-N-(3-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-1-methyl-1H-pyrazol-5-yl)acrylamide; 148) (S)-N-(4-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)-1H-imidazol-2-yl)acrylamide; and 149) (S)-N-(4-(3-(1-((5-ethylthiazol-2-yl)amino)-1-oxopropan-2-yl)phenyl)thiazol-2-yl)acrylamide.

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