Benzothiazole compounds and methods of using same to treat neurodegenerative disorders - Patents.com

Abstract

To provide a compound having c-abl kinase inhibitory activity, and a method useful to treat or prevent neurodegenerative diseases comprising administering the compound.SOLUTION: The present disclosure provides a compound represented by the formula (I) in the figure or a pharmaceutically acceptable salt thereof. (In the formula, R1 is cyclopropyl, cyclobutyl, or the like; R2 and R3 are H, halo, alkyl, alkoxy, or the like; and R4 is aryl, heteroaryl, cycloalkyl, or the like.)SELECTED DRAWING: None

Description

[Technical field]

[0001] Technical Field FIELD OF THE DISCLOSURE This disclosure relates generally to compounds with enzyme inhibitor activity, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat disease.

[0002] This application claims the benefit of and priority to U.S. Provisional Application Nos. 62 / 566,649, filed October 2, 2017, 62 / 666,800, filed May 4, 2018, and 62 / 696,432, filed July 11, 2018. The entire disclosures of the applications identified in this paragraph are incorporated herein by reference.

[0003] Background technology Alpha-synuclein is part of a large family of proteins that includes beta- and gamma-synuclein and synoretin. Alpha-synuclein is expressed in normal conditions associated with synapses and is thought to play a role in neuroplasticity, learning and memory. Several studies suggest that alpha-synuclein plays a central role in the pathogenesis of Parkinson's disease. Molecular changes in the alpha-synuclein protein that increase protein misfolding and aggregation have a direct role in the pathogenesis of the disease. Aggregation of alpha-synuclein is involved in the formation of Lewy bodies and neutrophils, which are pathological hallmarks of Parkinson's disease and alpha-synucleinopathies. Activation of the tyrosine kinase c-abl is involved in alpha-synuclein-induced neurodegeneration.

[0004] The tyrosine kinase c-abl is a tightly regulated non-receptor protein tyrosine kinase involved in a wide range of cellular processes including growth, survival and stress response (Nat Rev Mol Cell Biol, 2004, 5:33-44), and c-abl is involved in the regulation of several cellular processes and is involved in the development of the central nervous system by controlling neurogenesis. More recently, increasing evidence from various experimental model systems has revealed that c-abl is also activated in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Niemann-Pick type C disease and tauopathy (Human Molecular Genetics, 2014, Vol. 23, No.11).

[0005] The stress signaling non-receptor tyrosine kinase c-abl links parkin to sporadic Parkinson's disease through tyrosine phosphorylation. Tyrosine phosphorylation of parkin by c-abl is the major post-translational modification that leads to loss of parkin function and disease progression in sporadic Parkinson's disease. Inhibition of c-abl provides a new therapeutic opportunity to block Parkinson's disease progression (The Journal of Neuroscience, 2011, 31(1):157-163). Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive death of motor neurons. Knockdown of c-abl by small interfering RNA (siRNA) also rescued ALS motor neuron degeneration (Imamura et al., Sci. Transl. Med. 9, 2017). Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disease with no current treatment. In MSA, α-synuclein accumulates in neurons and oligodendrocytes of the substantia nigra, striatum, olivopontocerebellar structures and spinal cord (J Neural Transm Vienna Austria 1996. 2016;123(6)).

[0006] Administration of the tyrosine kinase inhibitor nilotinib reduces c-abl activity and improves autophagic clearance of α-synuclein in transgenic and lentiviral transgenic models. Activation of c-abl in the mouse forebrain induces neurodegeneration in the hippocampus and striatum. Thus, phosphorylation-mediated enhancement of c-abl activity may be associated with α-synuclein pathology detected in Parkinson's disease and other neurodegenerative diseases (Hum Mol Genet. 2013 Aug 15).

[0007] C-abl is a potential therapeutic target for α-synucleinopathy, Parkinson's disease, Alzheimer's disease, ALS, dementia with Lewy bodies and MSA.

[0008] WO 2010 / 008847 describes compounds having a heterobicyclic core, such as benzothiazole, substituted with an amide-containing moiety, such as acetamide, for treating cancer.

[0009] Disclosure of the Invention technical challenges One object of the present disclosure is to provide compounds having c-abl kinase inhibitory activity, compositions containing the compounds, and pharmaceutical compositions containing the compounds as effective drugs for treating or preventing neurodegenerative diseases, and medical uses thereof. Another object of the present disclosure is to provide a method for treating or ameliorating a neurodegenerative disease, comprising administering to a subject in need of treatment a compound having c-abl kinase inhibitory activity of the present disclosure, ameliorating or treating a neurodegenerative disorder.

[0010] Solution to the problem overview The present disclosure provides compounds having c-abl kinase inhibitory activity, compositions comprising the compounds, and methods useful for treating neurodegenerative diseases. In embodiments, the compounds have the formula (I): [ka] [In the formula, R 1 is cyclopropyl, cyclobutyl, or 3- or 4-membered heterocyclyl, where R 1 is optionally substituted with one or more groups selected from the group consisting of halo, alkyl, hydroxyalkyl, and haloalkyl; R 2 and R 3 are independently -H, halo, alkyl, alkoxy, -CF3, or -OCF3; R 4 is heteroaryl, cycloalkyl, heterocyclyl, or heteroalkyl, where R 4 is halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, trimethylsilylethoxymethyl, -NO2, -NR a R b , -NR a C(=O)R b , -NR a C(=O)NR a R b , -NR a C(=O)OR b , -OR a , -CN, -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -OC(=O)R a , -OC(=O)OR a , -OC(=O)NR a R b , -SR a , azetidinyl, oxetanyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, phenyl, tetrahydropyranyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; R aand R b are independently -H, halo, amino, alkyl, or haloalkyl. or a pharma- ceutically acceptable salt thereof.

[0011] In another embodiment, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein and a pharma- ceutically acceptable carrier.

[0012] In yet another embodiment, the disclosure provides a method for preventing or treating a neurodegenerative disease, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds described herein.

[0013] Detailed Description The following description is merely exemplary in nature and is in no way intended to limit the present disclosure, its application, or uses.

[0014] definition Common terms used in this disclosure are defined herein for the sake of clarity.

[0015] As used herein, the terms "substituent," "radical," "group," "moiety," and "fragment" are used interchangeably.

[0016] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon group having at least one site of unsaturation, i.e., a carbon-carbon sp2 double bond. In embodiments, an alkenyl has 2 to 12 carbon atoms. In some embodiments, an alkenyl has C2 to C6 10 alkenyl group or a C2-C6 alkenyl group. Examples of alkenyl groups include, but are not limited to, ethylene or vinyl (-CH-CH2), allyl (-CH2CH-CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH-CH2).

[0017] As used herein, the term "alkoxy" refers to RO-, where R is alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy and propoxy.

[0018] As used herein, the term "alkoxyalkyl" refers to an alkyl moiety substituted with an alkoxy group. Examples of alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, and ethoxyethyl.

[0019] As used herein, the term "alkoxycarbonyl" refers to ROC(O)-, where R is an alkyl group as defined herein. In various embodiments, R is a C1-C 10 It is an alkyl group or a C1 to C6 alkyl group.

[0020] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbonyl group. In embodiments, an alkyl has 1 to 12 carbon atoms. In some embodiments, an alkyl has C1 to C6. 10 An alkyl group or a C1-C6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "Lower alkyl" means an alkyl group having 1 to 4 carbon atoms.

[0021] As used herein, when the term "C1-C6" is used, it means that the number of carbon atoms is 1 to 6. For example, C1-C6 alkyl means an alkyl having any integer number of carbon atoms from 1 to 6.

[0022] As used herein, the term "alkylamino" refers to an amino group substituted with one or more alkyl groups. "N-(alkyl)amino" is RNH- and "N,N-(alkyl)2amino" is R2N-, where the R groups are alkyl as defined herein and are the same or different. In various embodiments, R is a C1-C 10 It is an alkyl group or a C1 to C6 alkyl group. Examples of the alkylamino group include methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino and methylethylamino.

[0023] As used herein, the term "alkylaminoalkyl" refers to an alkyl moiety substituted with an alkylamino group, where alkylamino is as defined herein. Examples of alkylaminoalkyl groups include methylaminomethyl and ethylaminomethyl.

[0024] As used herein, the term "alkynyl" refers to a straight or branched carbon chain group having at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. In embodiments, an alkynyl has 2 to 12 carbon atoms. In some embodiments, an alkynyl has C2 to C6. 10 An alkynyl group or a C2-C6 alkynyl group. Examples of alkynyl groups include acetylene (-C≡CH) and propargyl (-CH2C≡CH).

[0025] As used herein, the term "aryl" refers to any monocyclic or bicyclic carbocyclic ring of up to seven atoms in each ring, where at least one ring is an aromatic ring system of 5 to 14 carbon atoms, including a carbocyclic aromatic group fused to an aromatic or 5- or 6-membered cycloalkyl group. Representative examples of aryl groups include, but are not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and indanyl. Carbocyclic aromatic groups can be unsubstituted or optionally substituted.

[0026] As used herein, the term "cycloalkyl" refers to a hydrocarbyl group that contains at least one saturated or partially unsaturated ring structure and is bonded through a ring carbon. In various embodiments, it is a saturated or partially unsaturated C-C 12 It refers to a cyclic moiety, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. "Cycloalkyloxy" is RO-, where R is cycloalkyl.

[0027] As used herein, the terms "halogen" and "halo" refer to chloro (-Cl), bromo (-Br), fluoro (-F) or iodo (-I). "Haloalkoxy" refers to an alkoxy group substituted with one or more halo groups. Examples of haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2 and -OCH2F. "Haloalkoxyalkyl" refers to an alkyl moiety substituted with a haloalkoxy group, where haloalkoxy is as defined herein. Examples of haloalkoxyalkyl groups include trifluoromethoxymethyl, trifluoroethoxymethyl and trifluoromethoxyethyl. "Haloalkyl" refers to an alkyl moiety substituted with one or more halo groups. Examples of haloalkyl groups include -CF3 and -CHF2.

[0028] As used herein, the term "heteroalkyl" refers to a straight- or branched-chain alkyl group having 2 to 14 carbons (and in some embodiments 2 to 10 carbons) in the chain, one or more of the carbons being replaced by a heteroatom selected from S, O, P, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.

[0029] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic group of 2 to 14 ring carbon atoms, and in addition to the ring carbon atoms, 1 to 4 heteroatoms selected from P, N, O, and S. In various embodiments, the heterocyclic group is attached to other moieties through a carbon or through a heteroatom and is optionally substituted at a carbon or heteroatom. An example of a heterocyclyl is azetidinyl. , O Heterocyclyloxy includes xazoline, isoxazoline, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzothiophenyl, dihydrofuranyl, dihydroindolyl, dihydrooxadiazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrotetrazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and their N-oxides. Heterocyclyloxy is RO-, where R is heterocyclyl. Heterocyclylthio is RS-, where R is heterocyclyl.

[0030] As used herein, the term "3- or 4-membered heterocyclyl" refers to a monocyclic ring having 3 or 4 ring atoms, where at least one ring atom is a heteroatom selected from the group consisting of N, O, and S. Non-limiting examples of 3- or 4-membered heterocyclyls include aziridinyl, 2H-azirinyl, oxiranyl, thiiranyl, azetidinyl, 2,3-dihydroazetyl, azetyl, 1,3-diazetidinyl, oxetanyl, 2H-oxetyl, thietanyl, and 2H-thiethyl.

[0031] As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring having up to seven atoms in each ring, where at least one ring is aromatic and contains from 1 to 4 heteroatoms in each ring selected from the group consisting of N, O, and S. Non-limiting examples of heteroaryl include pyridyl, thienyl, furanyl, pyrimidyl, imidazolyl, pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, benzothienyl, indolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoindolyl, benzotriazolyl, purinyl, thianaphthenyl, and pyrazinyl. The attachment of heteroaryl can occur through an aromatic ring or through a non-aromatic ring or ring that does not contain a heteroatom, if the heteroaryl is bicyclic or tricyclic and one of the rings is not aromatic or does not contain a heteroatom. "Heteroaryl" is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. "Heteroaryloxy" is RO-, where R is a heteroaryl.

[0032] As used herein, the term "hydroxyalkoxy" refers to an alkoxy group substituted with a hydroxyl group (-OH), where alkoxy is as defined herein. An example of a hydroxyalkoxy is hydroxyethoxy.

[0033] As used herein, the term "hydroxyalkyl" refers to a linear or branched, monovalent C1-C alkyl group substituted with at least one hydroxy group. 10 refers to a hydrocarbon group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0034] As used herein, the term "pharmaceutical acceptable" means suitable for use in pharmaceutical preparations that are generally considered safe for such use, officially approved by a national or state government regulatory agency for such use, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, especially humans.

[0035] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier or other ingredient that is pharma- ceutically acceptable and is administered with a compound of the invention.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that can enhance the desired pharmacological activity. Examples of pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids, metal salts, and amine salts. Examples of acid addition salts formed with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of acid addition salts formed with organic acids include salts with acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentapropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorosulfonic acid, benzoic ... It can be formed with benzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2.2.2]oct-2-enyl-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxy-naphthoic acid, salicylic acid, stearic acid and mucoic acid. Examples of metal salts include salts with sodium, potassium, calcium, magnesium, aluminum, iron and zinc ions. Examples of amine salts include salts with ammonia and organic nitrogen bases strong enough to form salts with carboxylic acids.

[0037] As used herein, the term "substituted" refers to any of the above groups (i.e., alkyl, aryl, heteroaryl, heterocycle, or cycloalkyl) in which at least one hydrogen atom of the substituted moiety is replaced by a substituent. In one embodiment, each carbon atom of the substituted group is replaced by no more than two substituents. In another embodiment, each carbon atom of the substituted group is replaced by no more than one substituent. In the case of a keto substituent, two hydrogen atoms are replaced by oxygen attached to the carbon through a double bond. Unless otherwise specified, the substituents are halogen, hydroxyl, (lower) alkyl, haloalkyl, mono- or di-alkylamino, aryl, heterocycle, -NO2, B(OH)2, BPin, -NR a R b , -NR a C(=O)R b , -NR a C(=O)NR a R b , -NR a C(=O)OR b , -NR a SO2R b , -OR a , -CN, -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -OC(=O)R a , -OC(=O)OR a , -OC(=O)NR a R b , -NR a SO2R b , -PO3R a , -PO(OR a )(OR b ), -SO2R a , -S(O)R a , -SO(N)R a (e.g., sulfoximine), -(R a )S=NR b (e.g., sulfilimine) and -SR a (In the formula, R a and R bare the same or different and are independently hydrogen, halogen, amino, alkyl, haloalkyl, haloalkyl, aryl or heterocycle, or where R a and R b together with the nitrogen atom to which they are attached form a heterocycle. a and R b can be multiple based on the atom to which they are attached.

[0038] As used herein, the term "therapeutically effective amount" when applied to a compound of the present invention is intended to refer to an amount of compound sufficient to ameliorate, alleviate, stabilize, reverse, slow or delay the progression of a disorder or disease state or symptoms of a disorder or disease. In an embodiment, the method of the present invention provides for the administration of a combination of compounds. In such a case, the "therapeutically effective amount" is the amount of a compound of the present invention in the combination sufficient to cause the intended biological effect.

[0039] As used herein, the term "treatment" or "treating" refers to improving or reversing the progression or severity of a disease or disorder or improving or reversing one or more symptoms or side effects of such a disease or disorder. As used herein, "treatment" or "treating" also refers to inhibiting or preventing the progression of a disease or disorder system, condition or state, such as in delaying, halting, inhibiting, hindering or blocking. For purposes of the present invention, "treatment" or "treating" further refers to an approach to obtain beneficial or desired clinical results, where "beneficial or desired clinical results" include, but are not limited to, alleviation of symptoms, reduction in the extent of the disorder or disease, stabilized (i.e., not worsening) disease or disorder state, slowing or slowing of the disease or disorder state, improvement or alleviation of the disease or disorder state, and remission of the disease or disorder, whether partial or total.

[0040] In another embodiment, the compounds of formula (I) are used to modulate the activity of the protein kinase c-abl.

[0041] As used herein, the term "modulating" or "modulation" refers to a change in the catalytic activity of a protein kinase. In particular, modulating refers to the activation or inhibition of the catalytic activity of a protein kinase, depending on the concentration of a compound or salt to which the protein kinase is exposed, or more preferably, the inhibition of the catalytic activity of the protein kinase. As used herein, the term "catalytic activity" refers to the rate of phosphorylation of tyrosine, serine, or threonine under the direct or indirect influence of a protein kinase.

[0042] The three main classes into which pharmacological inhibitors of kinase activity are classified are: (1) type I or "DFG-in" ATP-competitive inhibitors, which directly compete with ATP at the ATP-binding site (i.e., the dual SRrc-abl inhibitor dasatinib); (2) type II or "DFG-out" ATP-competitive inhibitors, which, in addition to binding to the ATP-binding site, also engage an adjacent hydrophobic binding site that is accessible only when the kinase is in an inactivated conformation (i.e., the activation loop is positioned in a conformation that would block substrate binding) (i.e., imatinib, nilotinib); and (3) non-ATP-competitive inhibitors (i.e., GNF-2), which bind at a site other than the ATP-binding site affecting the activity of the kinase.

[0043] As used herein, the term "compounds of the present disclosure" includes any compound of formula (I) and clathrates, hydrates, solvates, or polymorphs thereof. In addition, even if the term "compounds of the present disclosure" does not refer to a pharma- ceutically acceptable salt thereof, the term includes the salt. In one embodiment, the compounds of the present disclosure include stereochemically pure compounds, e.g., compounds that are substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee, or greater than 99% ee). That is, when the compounds of formula (I) of the present disclosure or salts thereof are tautomers and / or stereoisomers (e.g., geometric and conformational isomers), such isolated isomers and mixtures thereof are also included within the scope of the present disclosure. When the compounds of the present disclosure or salts thereof have asymmetric carbons in their structure, their active optical isomers and racemic mixtures thereof are also included within the scope of the present disclosure.

[0044] As used herein, the term "polymorph" refers to a solid crystalline form of a compound of the present disclosure or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and / or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., against heat or light), compressibility and density (important in dosage forms and product manufacturing) and dissolution rate (which may affect bioavailability). Differences in stability may result from changes in chemical reactivity (e.g., differences in oxidation, such that a dosage form discolors more quickly when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g., a tablet that disintegrates on storage because a kinetically desirable polymorph converts to a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to disintegration at high humidity). Different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvates and more difficult to filter or wash impurities from than another polymorph, for example, due to its particle shape or size distribution.

[0045] As used herein, the term "solvate" refers to a compound of the present disclosure or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and / or acceptable for administration to humans in trace amounts.

[0046] As used herein, the term "hydrate" means a compound of the present disclosure or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0047] As used herein, the term "clathrate" means a compound or a salt thereof in the form of a crystal lattice containing spaces (e.g., channels) with guest molecules (e.g., solvent or water) trapped within.

[0048] Compounds of the Disclosure The present disclosure provides a compound of formula (I): [ka] [In the formula, R 1 is cyclopropyl, cyclobutyl, or 3- or 4-membered heterocyclyl, where R 1 is optionally substituted with one or more groups selected from the group consisting of halo, alkyl, hydroxyalkyl, haloalkyl, and monoalkylaminoalkyl; R 2 and R 3 are independently -H, halo, alkyl, alkoxy, -CF3, or -OCF3; R 4 is aryl, heteroaryl, cycloalkyl, heterocyclyl, or heteroalkyl, where R 4 is halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, trimethylsilylethoxymethyl, -NO2, -NR a R b , -NR a C(=O)R b , -NRa C(=O)NR a R b , -NR a C(=O)OR b , -OR a , -CN, -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -OC(=O)R a , -OC(=O)OR a , -OC(=O)NR a R b , -SR a , azetidinyl, oxetanyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, phenyl, tetrahydropyranyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; R a and R b are independently -H, halo, amino, alkyl, or haloalkyl. or a pharma- ceutically acceptable salt thereof.

[0049] In some embodiments, R 1 is cyclopropyl, cyclobutyl, or 3- or 4-membered heterocyclyl, where R 1 is optionally substituted with one or more groups selected from the group consisting of halo, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl; R 2 and R 3 are independently -H, halo, C1-C3 alkyl, C1-C3 alkoxy, -CF3, or -OCF3; R 4 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, where R 4is halo, hydroxyl, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 haloalkyl, mono-C1-C3 alkylamino, di-C1-C3 alkylamino, -NO2, -NR a R b , -NR a C(=O)R b , -NR a C(=O)NR a R b , -NR a C(=O)OR b , -OR a , -CN, -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -OC(=O)R a , -OC(=O)OR a , -OC(=O)NR a R b , -SR a , azetidinyl, oxetanyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, phenyl, tetrahydropyranyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; a and R b are independently -H, halo, amino, C1-C3 alkyl, or C1-C3 haloalkyl.

[0050] In various embodiments, R 1 is cyclopropyl or cyclobutyl, where R 1 is optionally substituted with one or more groups selected from the group consisting of halo, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl. 1is cyclopropyl, fluorocyclopropyl, hydroxycyclopropyl, hydroxymethylcyclopropyl, difluorocyclopropyl, methylaminomethylcyclopropyl, cyclobutyl, fluorocyclobutyl or difluorocyclobutyl. 1 is cyclopropyl, fluorocyclopropyl, cyclobutyl or fluorocyclobutyl.

[0051] In some other embodiments, R 1 is 3- or 4-membered heterocyclyl, where R 1 is optionally substituted with one or more groups selected from the group consisting of halo, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl. In certain embodiments, the 3- or 4-membered heterocyclyl is selected from the group consisting of aziridinyl, 2H-azirinyl, oxiranyl, thiiranyl, azetidinyl, 2,3-dihydroazetyl, azetyl, 1,3-diazetidinyl, oxetanyl, 2H-oxetyl, thietanyl, and 2H-thiethyl.

[0052] In some embodiments, R 2 and R 3 is independently -H, methyl or fluoro.

[0053] In some embodiments, R 4 is phenyl, pyridinyl, pyrimidinyl, indolinyl, pyrazolyl, thiazolyl, oxoindolinyl, pyrrolopyridinyl, pyrazolyl, pyrazolopyridinyl, oxodihydropyrrolopyridinyl, thiophenyl or isothiazolyl, where R 4 is optionally substituted with one or more groups selected from the group consisting of halo, alkyl, alkenyl, alkynyl, hydroxyalkyl, amino, cyano, acetyl, hydroxy, and haloalkyl. 4is fluoromethylphenyl, chloromethylphenyl, dimethylphenyl, acetamidomethylphenyl, hydroxymethylphenyl, hydroxypropanylmethylphenyl, methylpropenylphenyl, methylpyridinylethynylphenyl, methylpyrrolylphenyl, methylthiazolylphenyl, imidazolylmethylphenyl, cyanomethylphenyl, methylpyrazolylphenyl, ethynylmethylphenyl, methylpyridinyl, fluoromethylmethylaminophenyl, dimethylpyridinyl, fluoromethylpyridinyl, fluoromethylmethylpyridinyl, cyanopyridinyl, trifluoromethylmethylpyridinyl, hydroxymethylpyridinyl, hydroxymethylmethylpyridinyl, hydroxyethylmethylpyridinyl, In certain embodiments, R is selected from the group consisting of phenyl, ... 4is fluoromethylphenyl, chloromethylphenyl, bimethylphenyl, acetamidomethylphenyl, hydroxymethylphenyl, methylpropenylphenyl, ethynylmethylphenyl, fluoromethylmethylaminophenyl, methylpyrrolylphenyl, methylthiazolylphenyl, cyanomethylphenyl, imidazolylmethylphenyl, methylpyridinyl, chloromethylpyridinyl, fluoromethylpyridinyl, fluoromethylmethylpyridinyl, bimethylpyridinyl, aminopyridinyl, aminodimethylpyridinyl, methoxypyridinyl, acetylmethylpyridinyl In certain embodiments, R is methyl, hydroxymethylpyridinyl, hydroxymethylmethylpyridinyl, hydroxyethylmethylpyridinyl, cyanopyridinyl, trifluoromethylpyridinyl, methylthiophenyl, methylindolinyl, methylpyrimidinyl, dimethylpyrimidinyl, pyrazolyl, methylpyrazolyl, methylindolinyl, methyloxoindolinyl, pyrrolopyridinyl, methylpyrrolopyridinyl, methylpyrrolyl, pyrazolopyridinyl, dihydropyrrolopyridinyl, methylisothiazolyl, dimethylisothiazolyl, methylindazolyl, or methylbibenzothiazolyl. 4 is pyridinyl or phenyl having one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, hydroxyl, hydroxyalkyl, haloalkyl, cyano, amino, alkoxy, and haloalkoxy. 4 teeth, [ka] is selected from the group consisting of:

[0054] In some embodiments, R 1 is cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, cyclobutyl, fluorocyclobutyl or difluorocyclobutyl; R 2 and R 3 are independently -H, methyl or fluoro; R 4is fluoromethylphenyl, chloromethylphenyl, bimethylphenyl, acetamidomethylphenyl, hydroxymethylphenyl, methylpropenylphenyl, ethynylmethylphenyl, fluoromethylmethylaminophenyl, methylpyrrolylphenyl, methylthiazolylphenyl, cyanomethylphenyl, imidazolylmethylphenyl, methylpyridinyl, chloromethylpyridinyl, fluoromethylpyridinyl, fluoromethylmethylpyridinyl, bimethylpyridinyl, aminopyridinyl, aminodimethylpyridinyl, methoxypyridinyl, acetylmethylpyridinyl nyl, hydroxymethylpyridinyl, hydroxymethylmethylpyridinyl, hydroxyethylmethylpyridinyl, cyanopyridinyl, trifluoromethylpyridinyl, methylthiophenyl, methylindolinyl, methylpyrimidinyl, dimethylpyrimidinyl, pyrazolyl, methylpyrazolyl, methylindolinyl, methyloxoindolinyl, pyrrolopyridinyl, methylpyrrolopyridinyl, methylpyrrolyl, pyrazolopyridinyl, dihydropyrrolopyridinyl, methylisothiazolyl, dimethylisothiazolyl, methylindazolyl or methylbibenzothiazolyl.

[0055] The present inventors have synthesized and evaluated many compounds and have found compounds that have good c-abl inhibitory activity and high selectivity for c-abl, and thus have good effects against neurodegenerative diseases.

[0056] More specifically, R 1 And compounds in which the benzothiazole is linked via -SO-NH-, -C(O)O-NH- or -NH-CO-NH- rather than -CO-NH- do not show good efficacy according to the present disclosure. 1 When R is not a C3-C4 cycloalkyl, the compound exhibits poor pharmacokinetic properties or intrinsic activity, which properties reduce efficacy. 1 When the cycloalkyl substituent of is Br or Cl, bioconjugation with reactive nucleophiles, such as glutathione, can lead to relatively toxic materials.

[0057] R2 or R 3 In the case of bulky, e.g., aryl, such compounds are less favorable IC 50 In particular, R 3 More preferred in this regard are compounds in which R is hydrogen. 3 If the aryl or cyclyl substituents of are too bulky, the IC 50 will also become larger.

[0058] R 4 When the substituents of R include -NHSO2- and the like, such compounds exhibit low efficacy and low permeability of the blood-brain barrier. 4 When the cyclyl ring of R is a monocyclic or bicyclic indole, the ortho positions preferably contain CH3, Cl, Br, CF3, CHF2, CH2F, methoxy, ethyl, cyclopropyl, acetylene or vinyl. Even if the ortho positions do not contain such groups, good activity can be maintained even without such substituents at the ortho positions due to the presence of a hydrogen bond source at the meta positions. Preferably, R 4 When the cyclyl ring is a monocyclic or bicyclic indole, the ortho positions preferably contain CH, Cl, Br, CF, CHF, CHF, methoxy, ethyl, cyclopropyl, acetylene or vinyl and the meta and / or para positions contain a hydrogen bond source, e.g., -OH, -NH or F.

[0059] In some embodiments, R 1 is an unsubstituted cyclopropyl, non-limiting examples include the following compound and pharma- ceutically acceptable salts thereof: N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(5-acetamido-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(6-aminopyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(6-fluoro-5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; and N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide.

[0060] In some embodiments, R 1 is fluorocyclopropyl, non-limiting examples include the following compounds and pharma- ceutically acceptable salts thereof: 2-Fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-chloro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2,6-dimethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(prop-1-en-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-(2-hydroxypropan-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(6-amino-2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methylindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-fluoro-6-methylphenyl)thiazolo[4,5-c]pyridin-2-yl)cyclopropane-1-carboxamide; N-(6-(1-acetyl-5-methylindolin-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-fluoro-6-methyl-3-(methylamino)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylthiophen-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 3-(2-(2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-4-methylpyridine 1-oxide; (2-(2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)boronic acid; 2-Fluoro-N-(6-(4-methylpyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(6-acetyl-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4,6-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(6-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-(1-hydroxyethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-pyrazole-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(pyridin-2-ylethynyl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(1H-pyrazol-1-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(4-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(4-fluoro-6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methylthiazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4,6-dimethylpyrimidin-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(7-methyl-2-oxoindolin-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(5-ethynyl-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4-chloropyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4-cyanopyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(trifluoromethyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(1H-pyrrol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(thiazol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(5-cyano-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methyl-1H-pyrazole-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(1H-pyrrol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(1H-pyrazol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methyl-2-oxoindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(4-methyl-2-oxo-2,3-dihydro-[5,6'-bibenzo[d]thiazol]-2'-yl)cyclopropane-1-carboxamide; N-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylisothiazol-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-chloro-3-methylisothiazol-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(7-methyl-1H-indazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(7-methyl-1H-indazol-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(3,4-dimethylisothiazol-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(5-(1H-imidazol-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6'-methyl-[6,7'-bibenzo[d]thiazol]-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-(fluoromethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-fluoro-5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(5-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylpyridin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylpyridin-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-ethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-vinylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-ethynylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4-bromopyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(trifluoromethoxy)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-(difluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(5-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4,5-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-fluoro-5-methylindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(o-tolyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-ethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-vinylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-ethynylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2-bromophenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methoxyphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-(trifluoromethoxy)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-(trifluoromethyl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-(difluoromethyl)phenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-(hydroxymethyl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-fluoro-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(3-chloro-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2,3-dimethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(4-chloro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)-4-(trifluoromethyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(4-methoxy-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(4-methyl-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(5-chloro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)-5-(trifluoromethyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(5-methoxy-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(5-methyl-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-imidazol-2-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methyl-1H-imidazol-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-imidazol-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-1H-imidazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylpyrazin-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methyloxazol-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methyl-1H-pyrrol-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-benzo[d]imidazol-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methyl-1H-benzo[d]imidazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-pyrrolo[2,3-b]pyridin-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridazin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methylpyridazin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; and 2-Fluoro-N-(6-(5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide Includes.

[0061] In some embodiments, R 1 is hydroxymethylcyclopropyl, non-limiting examples include the following compounds and pharma- ceutically acceptable salts thereof: 2-(hydroxymethyl)-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-(hydroxymethyl)-N-(6-(5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; and N-(6-(6-fluoro-5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide Includes.

[0062] In some embodiments, R 1 is hydroxycyclopropyl or difluorocyclopropyl, non-limiting examples include the following compounds and pharma- ceutically acceptable salts thereof: 2-Hydroxy-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Hydroxy-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2,2-Difluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2,2-difluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; and 2,2-Difluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide Includes.

[0063] In some embodiments, R 1 is unsubstituted cyclobutyl, non-limiting examples include the following compounds and pharma- ceutically acceptable salts thereof: N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclobutanecarboxamide; N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutanecarboxamide; and N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutanecarboxamide Includes.

[0064] In some embodiments, R 1 is fluorocyclobutyl, non-limiting examples include the following compounds and pharma- ceutically acceptable salts thereof: 3-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; 3-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; 3-Fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; 3-Fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; 3-Fluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; 3,3-Difluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; 3,3-difluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; and 3,3-Difluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide Includes.

[0065] In certain embodiments, the compounds of the present disclosure have the following structure: 2-Fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-chloro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2,6-dimethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; 2-Fluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-(hydroxymethyl)-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(5-acetamido-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(2-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(prop-1-en-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(6-aminopyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; 2-Fluoro-N-(6-(3-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(6-amino-2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methylindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1-acetyl-5-methylindolin-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2,2-Difluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 3-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; 2,2-Difluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutanecarboxamide; 2-Fluoro-N-(6-(2-fluoro-6-methyl-3-(methylamino)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; 2,2-Difluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutanecarboxamide; 3-Fluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; 3,3-Difluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclobutane-1-carboxamide; 2-Fluoro-N-(6-(4-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylthiophen-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 3-(2-(2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-4-methylpyridine 1-oxide; N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(6-acetyl-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; N-(6-(4,6-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(6-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-(1-hydroxyethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-pyrazole-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(1H-pyrazol-1-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; 2-Fluoro-N-(6-(5-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(4-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methylthiazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(7-methyl-2-oxoindolin-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(5-ethynyl-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4-chloropyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4-cyanopyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; 2-Fluoro-N-(6-(2-methyl-5-(1H-pyrrol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(thiazol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(5-cyano-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methyl-1H-pyrazole-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(1H-pyrrol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-5-(1H-pyrazol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methyl-2-oxoindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; N-(6-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; 2-Fluoro-N-(6-(3-methylisothiazol-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(7-methyl-1H-indazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(7-methyl-1H-indazol-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(3,4-dimethylisothiazol-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(5-(1H-imidazol-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6'-methyl-[6,7'-bibenzo[d]thiazol]-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-(fluoromethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; and 2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide is selected from the group consisting of:

[0066] In certain embodiments, the compound is: (1S,2S)-2-Fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; and (1S,2S)-2-Fluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide is selected from the group consisting of:

[0067] As used herein, where applicable, acceptable isomers are included, such as tautomers, racemates, enantiomers, diastereomers, atropisomers, configurational isomers of double bonds (E- and / or Z-), cis- and trans-configurations in ring substitution patterns, and isotopic isomers. In various embodiments, the compound has the formula (II): [ka] [In the formula, R 2 , R 3 and R 4 is as defined above, and R 5 is selected from the group consisting of halo, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 haloalkyl. In certain embodiments, R 4is fluoromethylphenyl, chloromethylphenyl, bimethylphenyl, acetamidomethylphenyl, hydroxymethylphenyl, methylpropenylphenyl, ethynylmethylphenyl, fluoromethylmethylaminophenyl, methylpyrrolylphenyl, methylthiazolylphenyl, cyanomethylphenyl, imidazolylmethylphenyl, methylpyridinyl, chloromethylpyridinyl, fluoromethylpyridinyl, fluoromethylmethylpyridinyl, bimethylpyridinyl, aminopyridinyl, aminodimethylpyridinyl, methoxypyridinyl, acetylmethylpyridinyl nyl, hydroxymethylpyridinyl, hydroxymethylmethylpyridinyl, hydroxyethylmethylpyridinyl, cyanopyridinyl, trifluoromethylpyridinyl, methylthiophenyl, methylindolinyl, methylpyrimidinyl, dimethylpyrimidinyl, pyrazolyl, methylpyrazolyl, methylindolinyl, methyloxoindolinyl, pyrrolopyridinyl, methylpyrrolopyridinyl, methylpyrrolyl, pyrazolopyridinyl, dihydropyrrolopyridinyl, methylisothiazolyl, dimethylisothiazolyl, methylindazolyl or methylbibenzothiazolyl.

[0068] Non-realistic examples of compounds of the present disclosure include the following compounds and pharma- ceutically acceptable salts thereof: (1S,2S)-2-Fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(2-chloro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(2,6-dimethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(prop-1-en-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(2-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(5-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(5-(2-hydroxypropan-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(3-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(6-amino-2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(5-methylindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-fluoro-6-methylphenyl)thiazolo[4,5-c]pyridin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(1-acetyl-5-methylindolin-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-fluoro-6-methyl-3-(methylamino)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(4-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(3-methylthiophen-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 3-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-4-methylpyridine 1-oxide; (2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)boronic acid; (1S,2S)-2-Fluoro-N-(6-(4-methylpyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(6-acetyl-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(4,6-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(4-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-(1-hydroxyethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(4-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(1H-pyrazole-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(pyridin-2-ylethynyl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(1H-pyrazole-1-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(5-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(4-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(4-fluoro-6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(5-methylthiazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(4,6-dimethylpyrimidin-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(7-methyl-2-oxoindolin-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethynyl-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(4-chloropyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(4-cyanopyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(4-(trifluoromethyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(1H-pyrrol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(thiazol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-cyano-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(4-methyl-1H-pyrazole-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(1H-pyrrol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(1H-pyrazole-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(5-methyl-2-oxoindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(4-methyl-2-oxo-2,3-dihydro-[5,6'-bibenzo[d]thiazol]-2'-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(3-methylisothiazol-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(4-chloro-3-methylisothiazol-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(7-methyl-1H-indazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(7-methyl-1H-indazol-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(3,4-dimethylisothiazol-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(1H-imidazol-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6'-methyl-[6,7'-bibenzo[d]thiazol]-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-(fluoromethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(6-fluoro-5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(5-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; and (1S,2S)-2-Fluoro-N-(6-(6-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide Includes.

[0069] In yet another embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0070] In another embodiment, a method for treating a neurodegenerative disease or disorder is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. That is, a medical use of formula (I) or a pharma- ceutically acceptable salt thereof is provided, in which formula (I) or a pharma- ceutically acceptable salt thereof is used as an active agent. In one embodiment, the medical use is for the treatment or prevention of a neurodegenerative disease or disorder.

[0071] Medical Uses and Methods of Treatment Using the Compounds of the Disclosure The present disclosure further provides a method for treating a neurodegenerative disease or disorder in a subject having or susceptible to having a neurodegenerative disease or disorder by administering to the subject a therapeutically effective amount of one or more of the compounds described above. In one embodiment, the treatment is a preventative treatment. In another embodiment, the treatment is a palliative treatment. In another embodiment, the treatment is a restorative treatment.

[0072] 1. Disease or condition The compounds of the present disclosure for inhibiting c-abl activity are useful for treating or preventing neurodegenerative diseases or disorders. The compounds can be used to inhibit or interfere with c-abl kinase activity and treat neurodegenerative diseases or disorders or prevent the worsening of such diseases. Thus, the present disclosure provides a method for inhibiting or interfering with c-abl activity in a cell, wherein the cell is contacted with an effective amount of a compound of the present disclosure. In one embodiment, such a cell is present in a subject (e.g., an Alzheimer's patient). In another embodiment, a medical use is provided for treating or preventing a neurodegenerative disease or disorder in a subject using a compound of the present disclosure. The method of the present disclosure includes administering to a subject in need of treatment or prevention a pharmaceutical composition containing a therapeutically or prophylactically effective amount of a c-abl inhibitor. Neurodegenerative diseases or disorders include, but are not limited to, alpha-synucleinopathy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy (MSA), Alzheimer's disease, or amyotrophic lateral sclerosis (ALS).

[0073] 2. Target Subjects suitable for treatment according to the present disclosure include mammalian subjects. Mammals of the present disclosure include, but are not limited to, humans, dogs, cats, cows, goats, horses, sheep, pigs, rodents, lagomorphs, primates, and the like, including mammals in utero. Subjects may be of either gender and at any stage of development. In one embodiment, subjects suitable for treatment according to the present disclosure are humans.

[0074] 3. Administration and Dosage The compounds of the present disclosure are generally administered in a therapeutically effective amount. The compounds of the present disclosure can be administered by any suitable route, in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the intended treatment. An effective dose is typically in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 0.01 to about 50 mg / kg / day, in single or divided doses. Depending on the age, species, and disease or condition being treated, dosage levels below the lower end of this range may be appropriate. In other cases, even larger doses can be used without adverse side effects. Also, smaller doses can be divided into several doses to administer the larger doses throughout the day. Methods for determining appropriate doses are well known in the art to which the present disclosure pertains. For example, Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000 can be used.

[0075] Pharmaceutical compositions, dosage forms and routes of administration For the treatment of the above mentioned diseases or conditions, the compounds described herein, or a pharma- ceutically acceptable salt thereof, can be administered as follows:

[0076] Oral route Compounds of the disclosure can be administered orally, including swallowing, so that the compound enters the gastrointestinal tract or is absorbed into the bloodstream directly from the mouth (eg, buccal or sublingual administration).

[0077] Compositions suitable for oral administration include solid, liquid, gel or powder preparations, having dosage forms such as tablets, lozenges, capsules, granules or powders.

[0078] Compositions for oral administration may be formulated as immediate or modified release (including delayed or sustained release), optionally with an enteric coating.

[0079] Liquid formulations can include solutions, syrups and suspensions, which can be used in soft or hard capsules. Such formulations can include pharma- ceutically acceptable carriers, such as water, ethanol, polyethylene glycol, cellulose or oil. The formulations can also include one or more emulsifying agents and / or suspending agents.

[0080] In tablet dosage forms, the amount of drug present can be from about 0.05% to about 95% by weight of the dosage form, more typically from about 2% to about 50% by weight. In addition, tablets can contain a disintegrant comprising from about 0.5% to about 35% by weight of the dosage form, more typically from about 2% to about 25% by weight. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

[0081] Suitable lubricants for use in tablets may be present in amounts from about 0.1% to about 5% by weight and include, but are not limited to, talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like.

[0082] Binders suitable for use in tablets include, but are not limited to, gelatin, polyethylene glycol, sugars, gums, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. Diluents suitable for use in tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose and starch.

[0083] Solubilizers suitable for use in the tablet may be present in an amount of about 0.1% to about 3% by weight and include, but are not limited to, polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol, castor oil (natural or hydrogenated), HCOR™ (Nikkol), oleyl esters, Gelucire™, caprylic / caprylic acid mono / diglycerides, sorbitan fatty acid esters, and Solutol HS™.

[0084] Parenteral Administration The compounds of the present disclosure can be administered directly into the blood stream, muscle, or an internal organ. Suitable means for parenteral administration include intravenous, intramuscular, subcutaneous, intraarterial, intraperitoneal, intrathecal, intracranial, etc. Suitable devices for parenteral administration include syringes (including needle and needle-free syringes) and infusion techniques.

[0085] Compositions for parenteral administration can be formulated as immediate release or modified release, including delayed or sustained release. Most parenteral formulations are aqueous solutions containing excipients, including salts, buffers, and isotonicity agents. Parenteral formulations can also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations can be used with a suitable vehicle, such as sterile water. Solubility enhancers can also be used to prepare parenteral solutions.

[0086] Transdermal Administration The compounds of the present disclosure can be administered topically or transdermally to the skin. The formulations for topical administration can include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, etc. Pharmaceutically acceptable carriers for topical administration formulations can include water, alcohol, mineral oil, glycerin, polyethylene glycol, etc. Topical or transdermal administration can also be performed by electroporation, iontophoresis, migration, etc.

[0087] Compositions for topical administration may be formulated as immediate release or modified release, including delayed or sustained release.

[0088] Combination therapy The pharmaceutical composition of the present disclosure may contain one or more additional therapeutic agents, for example, to improve efficacy or reduce side effects.Thus, in some embodiments, the pharmaceutical composition further contains one or more additional therapeutic agents selected from active ingredients useful for treating or inhibiting diseases directly or indirectly mediated by c-abl kinase.Examples of such active ingredients include, but are not limited to, agents for treating neurodegenerative diseases or disorders.

[0089] References for preparing pharmaceutical compositions Methods for preparing pharmaceutical compositions for treating or preventing a disease or condition are well known in the art to which this disclosure pertains. th ed.), Remington: The Science and Practice of Pharmacy (20 th ed.), Encyclopedia of Pharmaceutical Technology (3 rdPharmaceutically acceptable excipients, carriers, additives, etc. can be selected based on the principles of the present invention and then mixed with the compounds of the present disclosure to prepare pharmaceutical compositions.

[0090] The present disclosure provides a compound having various pharmacological effects by inhibiting c-abl activity, a pharmaceutical composition having the compound as an effective drug, and in particular, a medical use of the compound for treating neurodegenerative diseases or disorders, and a method of treatment or prevention comprising administering the compound to a subject in need of such treatment or prevention. The compound of the present disclosure and its pharmacologic acceptable salts have good safety and high selectivity for c-abl, and therefore exhibit excellent properties as a drug.

[0091] Advantageous Effects of the Invention The present disclosure provides a compound having various pharmacological effects by inhibiting c-abl activity, a pharmaceutical composition having the compound as an effective drug, and in particular, a medical use of the compound for treating neurodegenerative diseases or disorders, and a method of treatment or prevention comprising administering the compound to a subject in need of such treatment or prevention. The compound of the present disclosure and its pharmacologic acceptable salts have good safety and high selectivity for c-abl, and therefore exhibit excellent properties as a drug. [Brief description of the drawings]

[0092] [Figure 1-3] Figures 1, 2 and 3 show the effects of Example 4 and nilotinib on Aβ25-35-induced cognitive impairment in mice. a: spontaneous alternation impairment, b: step-through latency, c: escape latency. *p<0.05, **p<0.01, ***p<0.001 vs. Sc.Aβ / vehicle group, #p<0.05, ###p<0.001 vs. Aβ25-35 / vehicle group. [Figure 4-6]Figures 4, 5 and 6 show the effects of Example 8 and nilotinib on Aβ25-35-induced cognitive impairment in mice. a: spontaneous alternation impairment, b: step-through latency, c: escape latency. ***p<0.001 vs. Sc.Aβ / vehicle group, ###p<0.001 vs. Aβ25-35 / vehicle group. [Figure 7] Figure 7 shows that oral administration of Example 4 at 3 mg / kg and 10 mg / kg once daily completely inhibited lipid peroxidation, indicating a reduction in oxidative stress.

[0093] Mode of invention Hereinafter, the present disclosure will be described in detail by examples to help those skilled in the art understand the present disclosure. However, the following examples are provided as illustrations and are not intended to limit the scope of the present invention. It is clear that various modifications can be made without departing from the spirit and scope of the present invention or sacrificing all of the advantages of its materials.

[0094] Synthesis of compounds of formula (I) The following compounds were prepared using synthetic methods A to X. Below are described illustrative synthetic examples of some compounds of the present disclosure, and other compounds can be prepared by methods similar to those described below using different starting materials or reactants.

[0095] Synthesis method A Example 1. (1S,2S)-2-Fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0096] Step 1) 6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-amine To a solution of compound 1 (300 mg, 1.31 mmol, 1 equiv) and compound 2 (403.18 mg, 2.62 mmol, 2 equiv) in dioxane (8 mL) and HO (2 mL) was added SPhosbiphenylG2 (94.36 mg, 130.95 μmol, 0.1 equiv) and K3PO4 (416.95 mg, 1.96 mmol, 1.5 equiv). The mixture was stirred at 80 °C under N2 for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. Water (20 mL) was added to the reaction mixture, and then the mixture was extracted with EA (20 mL × 2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE:EA = 10:1 to 5:1) to give compound 3 (485 mg, crude) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ = 7.61 (d, J=8.3 Hz, 1H), 7.51 (d, J=1.4 Hz, 1H), 7.26 - 7.19 (m, 2H), 7.08 (d, J=7.5 Hz, 1H), 6.99 (t, J=8.7 Hz, 1H), 5.34 (br s, 2H), 2.19 (s, 3H).

[0097] Step 2) (1S,2S)-2-Fluoro-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of compound 3 (200 mg, 774.25 μmol, 1 eq.) and compound 4 (80.58 mg, 774.25 μmol, 1 eq.) in DMF (2 mL) was added HATU (588.79 mg, 1.55 mmol, 2 eq.) and TEA (235.04 mg, 2.32 mmol, 323.30 μL, 3 eq.). The mixture was stirred at 25° C. for 2 h. Then the mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of water and extracted with EA (20 mL×2). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (basic conditions; column: Phenomenex Gemini 150×25 mm×10 μm; mobile phase: [water (0.05 v / v% ammonium hydroxide)-ACN]; B%: 50%-80%, 12 min). Example 1 (50 mg, 136.17 μmol, 17% yield, 93% purity) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.75 (br s, 1H), 7.92 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.33 (br d, J=8.2 Hz, 2H), 7.20 - 7.11 (m, 2H), 5.16 - 4.92 (m, 1H), 2.23 (td, J=6.7, 13.4 Hz, 1H), 2.14 (s, 3H), 1.82 - 1.68 (m, 1H), 1.37 - 1.25 (m, 1H).

[0098] Synthesis method B Example 3. (1S,2S)-N-(6-(2,6-dimethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide [ka]

[0099] Step 1) 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine To a solution of compound 1 (500 mg, 2.18 mmol, 1 equiv) and B2Pin2 (665.06 mg, 2.62 mmol, 1.2 equiv) in dioxane (8 mL) was added Pd(dppf)Cl2 (159.69 mg, 218.25 μmol, 0.1 equiv) and KOAc (321.29 mg, 3.27 mmol, 1.5 equiv). The mixture was stirred at 110 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 50 mL of brine and extracted with 20 mL of EA (20 mL × 3). The combined organic layers were filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 5: 1 to 3: 1). Compound 2 (907 mg, 1.55 mmol, 71% yield, 47% purity) was obtained as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ = 8.06 (s, 1H), 7.77 - 7.74 (m, 1H), 7.60 (d, J=7.2 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 1.28 (s, 12H).

[0100] Step 2) 6-(2,6-dimethylphenyl)benzo[d]thiazol-2-amine To a solution of compound 2 (200 mg, 342.12 μmol, 1 equiv.) and compound 3 (75.98 mg, 410.54 μmol, 54.66 μmol, 1.2 equiv.) in dioxane (5 mL) and H2O (2 mL), Na2CO3 (54.39 mg, 513.18 μmol, 1.5 equiv.) and Pd(PPh3)2Cl2 (24.01 mg, 34.21 μmol, 0.1 equiv.) were added. The mixture was stirred at 110 °C under N2 for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10:1 to 8:1). Compound 4 (123 mg, 267.57 μmol, 78% yield, 55% purity) was obtained as a red-brown oil. 1H NMR (400MHz, CDCl3) δ = 7.63 - 7.54 (m, 2H), 7.33 (t, J=7.1 Hz, 1H), 7.19 - 7.14 (m, 1H), 7.14 - 7.08 (m, 2H), 5.21 (br s, 2H), 2.05 (s, 6H).

[0101] Step 3) (1S,2S)-N-(6-(2,6-dimethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide To a solution of compound 4 (123 mg, 267.57 μmol, 1 eq.) and compound 5 (27.85 mg, 267.57 μmol, 1 eq.) in DMF (3 mL) was added HATU (203.48 mg, 535.14 μmol, 2 eq.) and TEA (81.23 mg, 802.71 μmol, 111.73 μL, 3 eq.). The mixture was stirred at 25° C. for 12 h. The mixture was then stirred at 25° C. for 12 h. The reaction mixture was diluted with 20 mL of EA and extracted with 20 mL of brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions, column: Phenomenex Synergi C18 150×30 mm×4 um; mobile phase: [water (0.225% FA)-ACN]; B%: 50%-80%, 10 min). Example 3 (15.8 mg, 41.31 μmol, yield 15%, purity 89%) was obtained as a white solid. 1 H NMR (400MHz, CDCl3) δ = 7.83 (d, J=8.3 Hz, 1H), 7.60 (d, J=1.0 Hz, 1H), 7.24 (dd, J=1.6, 8.3 Hz, 2H), 7.20 - 7.17 (m, 1H), 7.15 - 7.11 (m, 2H), 5.03 - 4.81 (m, 1H), 2.04 (d, J=2.5 Hz, 6H), 1.97 (d, J=5.4 Hz, 1H), 1.43 - 1.35 (m, 1H), 1.26 (br s, 1H).

[0102] Synthesis method C Example 5. N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide [ka]

[0103] Step 1) N-(6-bromobenzo[d]thiazol-2-yl)cyclopropanecarboxamide To a solution of compound 1 (200 mg, 872.98 μmol, 1 eq.) and compound 2 (75.15 mg, 872.98 μmol, 1 eq.) in DMF (2 mL) was added HATU (497.89 mg, 1.30 mmol, 2 eq.) and TEA (265.01 mg, 2.61 mmol, 365 uL, 3 eq.). The mixture was stirred at 60° C. for 12 h. The reaction mixture was then concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of water and extracted with EA (20 mL×2). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, methylene chloride / methanol=20:1). Compound 3 (194 mg, 654.73 μmol, 75% yield) was obtained as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 12.71 (s, CONH), 8.23 ​​(s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 2.03-2.00 (m, 1H), 0.97-0.94 (m, 4H).

[0104] Step 2) N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide To a solution of compound 3 (100 mg, 0.336 mmol, 1 equiv.) and compound 4 (92 mg, 0.672 mmol, 2 equiv.) in dioxane (8 mL) and H2O (2 mL), Pd(dppf)Cl2 (24 mg, 0.0336 mmol, 0.1 equiv.) and Ns2CO3 (71 mg, 0.672 mmol, 2 equiv.) were added. The mixture was stirred at 120 °C under N2 for 8 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. Water (10 mL) was added to the reaction mixture, then the mixture was extracted with EA (10 mL x 2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, n-hexane:EA = 1:2) to give Example 5 (88 mg, 85% yield) as a white solid.

[0105] Synthesis method D Example 14. (1S,2S)-2-Fluoro-N-(6-(5-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0106] Step 1) 3-(2-aminobenzo[d]thiazol-6-yl)-4-methylphenol To a solution of compound 1 (306.31 mg, 1.34 mmol, 1 equiv.) and compound 2 (313 mg, 1.34 mmol, 1 equiv.) in dioxane (5 mL) and H2O (1 mL), Pd(PPh3)2Cl2 (93.85 mg, 133.70 μmol, 0.1 equiv.) and Na2CO3 (212.57 mg, 2.01 mmol, 1.5 equiv.) were added. The mixture was stirred at 110 °C under N2 for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1:1). Compound 3 (207 mg, 807.58 μmol, 60% yield) was obtained as a red oil. 1H NMR (400MHz, CDCl3) δ = 7.69 - 7.66 (m, 1H), 7.57 - 7.55 (m, 1H), 7.50 - 7.44 (m, 2H), 7.13 (d, J=7.8 Hz, 1H), 6.75 (s, 1H), 5.26 (br s, 2H), 2.20 (s, 3H).

[0107] Step 2) 6-(5-((tert-butyldimethylsilyl)oxy)-2-methylphenyl)benzo[d]thiazol-2-amine To a solution of compound 3 (157 mg, 612.51 μmol, 1 equiv) in DCM (5 mL) was added imidazole (125.09 mg, 1.84 mmol, 3 equiv) and TBSCl (230.80 mg, 1.53 mmol, 187.64 μL, 2.5 equiv) at 0° C. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 30 mL of water and extracted with EA (30 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 1:1). Compound 4 (211 mg, 546.60 μmol, 89% yield, 96% purity) was obtained as a pale yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 7.61 (d, J=1.8 Hz, 1H), 7.49 (s, 2H), 7.36 (d, J=8.3 Hz, 1H), 7.17 - 7.11 (m, 2H), 6.73 (dd, J=2.6, 8.2 Hz, 1H), 6.67 (d, J=2.6 Hz, 1H), 2.16 (s, 3H), 0.95 (s, 9H), 0.19 - 0.16 (m, 6H).

[0108] Step 3) (1S,2S)-N-(6-(5-(tert-butyldimethylsilyl)oxy)-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide To a solution of compound 4 (211 mg, 546.60 μmol, 1 eq.) and compound 5 (68.27 mg, 655.92 μmol, 1.2 eq.) in MeCN (5 mL) was added MsCl (125.23 mg, 1.09 mmol, 84.61 uL, 2 eq.) and 3-methylpyridine (254.51 mg, 2.73 mmol, 266.12 uL, 5 eq.) at 0° C. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 30 mL of water and extracted with EA (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, PE:EA=1:1). Compound 6 (185 mg, 392.97 μmol, 71% yield, 97% purity) was obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.71 (s, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.38 (dd, J=1.8, 8.3 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.78 (dd, J=2.6, 8.3 Hz, 1H), 6.72 (d, J=2.5 Hz, 1H), 5.15 - 4.93 (m, 1H), 2.22 (br d, J=5.5 Hz, 1H), 2.17 (s, 3H), 1.81 - 1.71 (m, 1H), 1.31 (br dd, J=9.3, 12.9 Hz, 1H), 0.95 (s, 9H), 0.18 (s, 6H).

[0109] Step 4) (1S,2S)-2-Fluoro-N-(6-(5-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of compound 6 (165 mg, 350.49 μmol, 1 equiv) in MeCN (8 mL) was added CsF (159.72 mg, 1.05 mmol, 38.77 μL, 3 equiv). The mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 30 mL of water and extracted with EA (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA condition; column: Boston pH-lex 150×25 10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 35%-65%, 10 min). Example 14 (83.6 mg, 183.17 μmol, 52% yield, 100% purity, TFA) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.73 (br s, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.36 (dd, J=1.8, 8.3 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 6.72 - 6.64 (m, 2H), 5.17 - 4.93 (m, 1H), 2.27 - 2.17 (m, 1H), 2.12 (s, 3H), 1.82 - 1.68 (m, 1H), 1.31 (tdd, J=6.3, 8.9, 12.8 Hz, 1H); LCMS (electrospray) m / z 343.2(M+H)+.

[0110] Synthesis method E Example 15. (1S,2S)-2-Fluoro-N-(6-(5-(2-hydroxypropan-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0111] Step 1) 2-(3-bromo-4-methylphenyl)propan-2-ol A mixture of compound 1 (500 mg, 2.18 mmol, 1 equiv) in THF (10 mL) was degassed and purged with N2 three times, then the mixture was stirred at 0° C. under N2 atmosphere for 0.5 h, then MeMgBr (3 M, 2.91 mL, 4 equiv) was added slowly to the solution. The solution was then stirred and slowly warmed to 25° C. for 1.5 h. The residue was purified by preparative TLC (SiO2, PE:EA=7:1). Compound 2 (400 mg, 1.75 mmol, 80% yield) was obtained as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 1.58 (s, 6 H), 2.40 (s, 3 H), 7.22 (d, J=8.03 Hz, 1 H), 7.33 (dd, J=7.97, 1.95 Hz, 1 H), 7.69 (d, J=2.01 Hz, 1 H).

[0112] Step 2) 2-(3-(2-aminobenzo[d]thiazol-6-yl)-4-methylphenyl)propan-2-ol To a solution of compound 3 (506.25 mg, 1.83 mmol, 1.5 equiv.) and compound 2 (280 mg, 1.22 mmol, 1 equiv.) in dioxane (5 mL) and H2O (2 mL), Pd(PPh3)2Cl2 (85.78 mg, 122.21 μmol, 0.1 equiv.) and Na2CO3 (194.29 mg, 1.83 mmol, 1.5 equiv.) were added. The mixture was stirred at 110 °C under N2 for 12 h. The residue was purified by preparative TLC (SiO2, PE:EA=1:1). Compound 4 (210 mg, 703.75 μmol, 57% yield) was obtained as a pale yellow oil.

[0113] Step 3) (1S,2S)-2-Fluoro-N-(6-(5-(2-hydroxypropan-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a mixture of compound 4 (300 mg, 1.01 mmol, 1 equiv) in DCM (10 mL) at 0 °C under N2 atmosphere was added TEA (203.46 mg, 2.01 mmol, 279.87 μL, 2 equiv), then (1R,2S)-2-fluorocyclopropanecarbonyl chloride (147.82 mg, 1.21 mmol, 1.2 equiv) was added to the mixture, which was then stirred at 25 °C for 0.5 h. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 40%-60%, 7.8 min], then by preparative HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 45%-75%, 10 min).

[0114] Example 15 (23 mg, 59.82 μmol, 6% yield, 100% purity) was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 1.29 (dq, J=15.12, 6.42 Hz, 1 H), 1.43 (s, 6 H), 1.66 - 1.84 (m, 1 H), 2.16 - 2.22 (m, 1 H), 2.23 (s, 3 H), 4.91 - 5.14 (m, 1 H), 4.98 (s, 1 H), 7.22 (d, J=8.53 Hz, 1 H), 7.32 - 7.36 (m, 2 H), 7.38 (dd, J=8.28, 1.51 Hz, 1 H), 7.76 (d, J=8.28 Hz, 1 H), 7.92 (s, 1 H), 12.61 (br s, 1 H); LCMS (electrospray) m / z 385.3 (M+H)+.

[0115] Example 16 (52 mg, 126.58 μmol, 12% yield, 97% purity) was obtained as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 1.23 - 1.36 (m, 1 H), 1.46 (s, 6 H), 1.67 - 1.82 (m, 1 H), 2.16 - 2.23 (m, 1 H), 2.25 (s, 3 H), 3.00 (s, 3 H), 4.91 - 5.16 (m, 1 H), 7.24 (s, 1 H), 7.28 (s, 2 H), 7.40 (br d, J=8.28 Hz, 1 H), 7.77 (d, J=8.28 Hz, 1 H), 7.95 (s, 1 H), 11.92 - 13.28 (m, 1 H); LCMS (electrospray) m / z 399.4(M+H)+.

[0116] Example 17 (9.5 mg, 24.37 μmol, 2% yield, 94% purity) was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 1.29 (br s, 1 H), 1.64 - 1.80 (m, 1 H), 2.11 (s, 3 H), 2.18 (br s, 1 H), 2.24 (s, 3 H), 4.93 - 5.12(m, 1 H), 5.07 (s, 1 H), 5.44 (s, 1 H), 7.29 (d, J=7.91 Hz, 1 H), 7.35 (s, 1 H), 7.38 (br d, J=8.53 Hz, 1 H), 7.42 (br d, J=7.91 Hz, 1 H), 7.74 (br d, J=8.16 Hz, 1 H), 7.93 (s, 1 H), 11.65 - 13.53 (m, 1 H); LCMS (electrospray) m / z 367.3 (M+H)+.

[0117] Synthesis method F Example 18. (1S,2S)-2-Fluoro-N-(6-(4-methylpyridin-3-yl)thiazolo[4,5-b]pyridin-2-yl)cyclopropane-1-carboxamide [ka]

[0118] Step 1) tert-Butyl (6-bromothiazolo[4,5-b]pyridin-2-yl)carbamate To a solution of compound 1 (500 mg, 2.17 mmol, 1 equiv) and di-tert-butyl dicarbonate (711 mg, 3.26 mmol, 1.5 equiv) in THF (10 mL) was added 4-dimethylaminopyridine (398 mg, 3.25 mmol, 1.5 equiv) and triethylamine (0.6 mL, 4.34 mmol, 2.0 equiv). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. Water (20 mL) was added to the reaction mixture, then the mixture was extracted with EA, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, MC:MeOH=95:5) to give compound 2 (454 mg, 63% yield) as a white solid.

[0119] Step 2) tert-Butyl (6-(4-methylpyridin-3-yl)thiazolo[4,5-b]pyridin-2-yl)carbamate To a solution of compound 2 (65 mg, 0.20 μmol, 1 equiv.) and compound 3 (40 mg, 0.30 μmol, 1.5 equiv.) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl2 (7 mg, 0.01 mmol, 0.05 equiv.) and Na2CO3 (42 mg, 0.40 mmol, 2 equiv.) in HO (0.2 mL). The mixture was stirred at 120 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by MPLC (EA:Hex=1:1 to MC:MeOH=95:5) to give compound 4 (46 mg, 67% yield) as a white solid. LCMS (electrospray) m / z=343.1 (M+H)+.

[0120] Step 3) 6-(4-methylpyridin-3-yl)thiazolo[4,5-b]pyridin-2-amine.2HCl salt To a solution of compound 4 (41 mg, 0.12 mmol) in tetrahydrofuran (0.6 mL) was added 4M HCl in dioxane. The mixture was stirred at room temperature for 12 h. The residue was then concentrated in vacuo. Compound 5 (45 mg, clean crude, red-brown oil) was used without further purification. LCMS (electrospray) m / z 343.1 (M+H)+.

[0121] Step 4) (1S,2S)-2-Fluoro-N-(6-(4-methylpyridin-3-yl)thiazolo[4,5-b]pyridin-2-yl)cyclopropane-1-carboxamide A mixture of compound 5 (45 mg, 0.14 mmol, 1 equiv.), compound 6 (30 mg, 0.28 mmol, 2.0 equiv.), HATU (109 mg, 0.28 mmol, 2 equiv.) and DIPEA (93 mg, 0.72 mmol, 5 equiv.) in DMF (1 mL) was stirred at 70 °C for 12 h. The solvent was evaporated, diluted with HO, extracted with DCM and MeOH, and the combined organic phase was washed with brine (15 mL), dried over NaSO, filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (MC:MeOH = 95:5 to 9:1). Example 18 (12 mg, 24% yield, 97% purity) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 13.06(s, 1H), 8.57-8.55(m, 2H), 8.49-8.47(m, 2H), 7.40-7.38(m, 1H), 5.16-4.99(m, 1H), 2.23(s, 3H), 2.28-2.25(m, 1H), 1.80-1.74(m, 1H), 1.37-1.32(m, 1H); LCMS (electrospray) m / z 329.0(M+H)+.

[0122] Synthesis method G Example 28. (1S,2S)-2-Fluoro-N-(5-(6-(1-hydroxyethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0123] To a solution of Example 21 (100 mg, 270.70 μmol, 1 equiv) in MeOH (5 mL) was added NaBH4 (30.72 mg, 812.10 μmol, 3 equiv) at 0° C. and then stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The reaction mixture was then diluted with H2O (20 mL) and then the mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 22%-52%, 10 min). Example 28 (51 mg, 137.31 μmol, 50% yield, 100% purity) was obtained as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 1.29 - 1.39 (m, 1 H), 1.58 (d, J=6.60 Hz, 3 H), 1.94 - 2.10 (m, 2 H), 2.32 (s, 3 H), 4.33 (br s, 1 H), 4.71 - 4.92 (m, 1 H), 4.93 - 5.00 (m, 1 H), 7.24 (s, 1 H), 7.26 - 7.28 (m, 1 H), 7.72 (d, J=1.34 Hz, 1 H), 7.90 (d, J=8.07 Hz, 1 H), 8.41 (s, 1 H), 10.63 (br s, 1 H); LCMS (electrospray) m / z 372.2(M+H)+.

[0124] Synthesis method H Example 29. (1S,2S)-2-Fluoro-N-(5-(6-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0125] Step 1) 5-(4-methyl-6-(((triisopropylsilyl)oxy)methyl)pyridin-3-yl)benzo[d]thiazol-2-amine A mixture of compound 2 (600 mg, 1.67 mmol, 1 equiv), compound 1 (461.19 mg, 1.67 mmol, 1 equiv), Pd(PPh3)2Cl2 (117.22 mg, 167.00 μmol, 0.1 equiv), Na2CO3 (265.50 mg, 2.51 mmol, 1.5 equiv) in dioxane (20 mL) HO (5 mL) was degassed and purged with N2 three times, then the mixture was stirred at 110 °C under N2 atmosphere for 16 h. The reaction mixture was diluted with HO (20 mL), then the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2:1). Compound 3 (380 mg, 888.52 μmol, 53% yield) was obtained as a pale yellow solid.

[0126] Step 2) (1S,2S)-2-Fluoro-N-(5-(4-methyl-6-(((triisopropylsilyl)oxy)methyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of compound 3 (180.00 mg, 420.88 μmol, 1 equiv) in DMF (10 mL) was added compound 4 (52.57 mg, 505.05 μmol, 1.2 equiv), 3-methylpyridine (195.98 mg, 2.10 mmol, 204.92 μL, 5 equiv), MsCl (96.42 mg, 841.76 μmol, 65.15 μL, 2 equiv) under N2 at 0 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with H2O (20 mL), and then the mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:1). Compound 5 (200 mg, 389.30 μmol, 92% yield) was obtained as a pale yellow liquid. 1 H NMR (400 MHz, CDCl3) δ = 1.06 (s, 1 H), 1.11 - 1.15 (m, 18 H), 1.18 - 1.22 (m, 3 H), 1.30 - 1.37 (m, 1 H), 1.78 - 1.81 (m, 1 H), 2.35 (s, 3 H), 4.71 - 4.74 (m, 1 H), 4.98 (s, 2 H), 7.29 (br d, J=1.22 Hz, 1 H), 7.53 (s, 1 H), 7.64 (s, 1 H), 7.87 (d, J=8.07 Hz, 1 H), 8.40 (s, 1 H).

[0127] Step 3) (1S,2S)-2-Fluoro-N-(5-(6-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of compound 5 (180.00 mg, 350.37 μmol, 1 equiv) in THF (6 mL) was added pyridine; hydrogen fluoride (3.30 g, 23.31 mmol, 3 mL, 70% purity, 66.52 equiv). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H2O (20 mL), and then the mixture was extracted with EA (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 20%-50%, 12 min).

[0128] Example 29 (12 mg, 29.55 μmol, 8% yield, 88% purity) was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 1.31 (dq, J=15.10, 6.46 Hz, 1 H), 1.69 - 1.82 (m, 1 H), 2.18 - 2.26 (m, 1 H), 2.31 (s, 3 H), 4.58 (br d, J=3.79 Hz, 2 H), 4.91 - 5.17 (m, 1 H), 5.42 (br s, 1 H), 7.31 (d, J=8.07 Hz, 1 H), 7.42 (s, 1 H), 7.72 (s, 1 H), 8.06 (d, J=8.07 Hz, 1 H), 8.33 (s, 1 H), 12.70 (br s, 1 H); LCMS (electrospray) m / z 358.3 (M+H)+.

[0129] Synthesis method I Example 31. (1S,2S)-2-Fluoro-N-(5-(5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0130] To a solution of Example 25 (170 mg, 342.96 μmol, 1 equiv) in THF (3 mL) was added TBAF (269.01 mg, 1.03 mmol, 3 equiv) and ethane-1,2-diamine (103.06 mg, 1.71 mmol, 114.76 μL, 5 equiv). The mixture was stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (silica gel, petroleum ether:ethyl acetate=1:1). The residue was purified by preparative HPLC (basic conditions; column: Waters Xbridge 150×25 5u; mobile phase: [water (0.05 v / v% ammonium hydroxide)-ACN]; B%: 35%-65%, 10 min).

[0131] Example 31 (52.2 mg, 142.85 μmol, 41% yield, 100% purity) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.73 (br s, 1H), 11.06 (br s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.67 (d, J=1.1 Hz, 1H), 7.35 - 7.22 (m, 3H), 7.05 (d, J=8.3 Hz, 1H), 6.00 (br s, 1H), 5.18 - 4.89 (m, 1H), 2.28 - 2.18 (m, 4H), 1.83 - 1.70 (m, 1H), 1.31 (tdd, J=6.3, 9.0, 12.8 Hz, 1H);LCMS (electrospray) m / z 366.2(M+H)+.

[0132] Synthesis method J Example 32. (1S,2S)-N-(6-(1-acetyl-5-methylindolin-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide [ka]

[0133] To a solution of Example 24 (59 mg, 149.33 μmol, 1 equiv) in DCM (3 mL) was added TEA (15.11 mg, 149.33 μmol, 20.79 μL, 1 equiv). The mixture was cooled to 0° C. and acetyl chloride (11.72 mg, 149.33 μmol, 10.66 μL, 1 equiv) was added dropwise. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of water and extracted with DCM (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (TFA condition; column: Boston pH-lex 150×25 10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 40%-70%, 10 min). Example 32 (8.9 mg, 16.15 μmol, 10% yield, 95% purity, TFA) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.74 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.88 (d, J=1.4 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.29 (dd, J=1.7, 8.2 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 5.18 - 4.91 (m, 1H), 4.02 (br t, J=8.4 Hz, 2H), 2.85 (br s, 2H), 2.27 - 2.19 (m, 1H), 2.13 (s, 3H), 2.05 (s, 3H), 1.82 - 1.67 (m, 1H), 1.37 - 1.21 (m, 1H); LCMS (electrospray) m / z 410.1 (M+H)+.

[0134] Synthesis method K Example 33. (1S,2R)-N-(5-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide [ka]

[0135] Step 1) Methyl (1R,2S)-2-((5-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)carbamoyl)cyclopropane-1-carboxylate To a solution of compound 1 (200 mg, 774.25 μmol, 1 equiv.) and compound 2 (cis) (111.59 mg, 774.25 μmol, 1 equiv.) in MeCN (5 mL) was added MsCl (177.38 mg, 1.55 mmol, 119.85 μL, 2 equiv.) and 3-methylpyridine (360.52 mg, 3.87 mmol, 376.95 μL, 5 equiv.) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 30 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=10 / 1 to 1:1). Compound 3 (cis) (222 mg, 577.49 μmol, 74% yield) was obtained as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ = 7.86 (d, J=8.1 Hz, 1H), 7.61 (d, J=0.6 Hz, 1H), 7.24 (dt, J=1.8, 8.0 Hz, 2H), 7.09 (d, J=7.7 Hz, 1H), 7.00 (t, J=8.6 Hz, 1H), 3.70 (s, 3H), 2.32 - 2.21 (m, 2H), 2.17 (s, 3H), 1.94 - 1.87 (m, 1H), 1.48 - 1.41 (m, 1H).

[0136] Step 2) (1S,2R)-N-(5-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide To a solution of compound 3 (cis) (100 mg, 260.13 μmol, 1 equiv.) in THF (5 mL) was added LiBHEt3 (1M, 1.04 mL, 4 equiv.). The mixture was stirred at -40°C for 0.5 h. The reaction mixture was quenched by adding 1 mL of water at -40°C. The mixture was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1:1). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Gemini 150×25 5u; mobile phase: [water (0.05 v / v% ammonium hydroxide)-ACN]; B%: 37%-67%, 12 min]. Example 33 (cis) (6 mg, 16.83 μmol, 6% yield) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.95 (br d, J=7.9 Hz, 1H), 7.54 (s, 1H), 7.36 - 7.27 (m, 1H), 7.17 (d, J=7.6 Hz, 1H), 7.15 - 7.09 (m, 2H), 3.69 (dd, J=5.6, 11.3 Hz, 1H), 3.54 - 3.45 (m, 1H), 2.14 (s, 3H), 2.05 - 1.95 (m, 1H), 1.60 - 1.48 (m, 1H), 1.12 - 0.98 (m, 2H); LCMS (electrospray) m / z 357.1 (M+H)+.

[0137] Synthesis method L Example 46. (1S,2S)-2-Fluoro-N-(6-(2-fluoro-6-methyl-3-(methylamino)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0138] Step 1) 3-Bromo-2-fluoro-4-methylbenzoic acid To a solution of compound 1 (10 g, 52.90 mmol, 1 equiv) in THF (200 mL) was added LDA (2 M, 27.77 mL, 1.05 equiv) under N2 at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h. CO2 (6.98 g, 158.71 mmol, 3 equiv) (solid) was added. The mixture was stirred at 20 °C for 1.5 h. TLC (PE:EA = 1:1) showed that the starting material disappeared and a new major spot was detected. Water (100 mL) was added and the aqueous phase was extracted with EA (50 mL x 2). The aqueous phase was treated with 1 M HCl until PH = 3-4, then the mixture was filtered and the filter cake was concentrated in vacuum to give the product. Compound 2 (12 g, 51.49 mmol, 97% yield) was obtained as a white solid, which was used directly in the next step. 1 H NMR (400MHz, methanol-d4) δ = 7.80 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 2.62 - 2.41 (m, 3H).

[0139] Step 2) tert-Butyl (3-bromo-2-fluoro-4-methylphenyl)carbamate To a solution of compound 2 (1 g, 4.29 mmol, 1 equiv) in toluene (20 mL) was added TEA (477.65 mg, 4.72 mmol, 657.02 μL, 1.1 equiv) and DPPA (1.30 g, 4.72 mmol, 1.02 mL, 1.1 equiv). The reaction mixture was stirred at 120° C. for 1.5 h. Then t-BuOH (477.11 mg, 6.44 mmol, 615.62 μL, 1.5 equiv) was added. The mixture was stirred at 120° C. for 3.5 h. TLC (PE:EA=3:1) showed the disappearance of the starting material and a new major spot was detected. LCMS showed 44% desired mass and no starting material. The reaction was concentrated in vacuo. Water (50 mL) was added and the aqueous phase was extracted with DCM (50 mL×2). The combined organic phase was washed with saturated brine (10 mL×2) and the organic layer was dried over anhydrous Na2SO4. The mixture was concentrated in vacuum. The crude product was purified by preparative TLC (PE:EA=3:1) to give the product. Compound 5 (520 mg, 1.66 mmol, yield 38%, purity 97%) was obtained as a white solid, which was used directly in the next step. 1 H NMR (400MHz, CDCl3) δ = 8.08 - 7.76 (m, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.68 - 6.46 (m, 1H), 2.41 - 2.33 (m, 3H), 1.53 (s, 9H).

[0140] Step 3) tert-Butyl (3-bromo-2-fluoro-4-methylphenyl)(methyl)carbamate To a solution of compound 3 (0.42 g, 1.34 mmol, 1 equiv) in THF (15 mL) was added NaH (64.29 mg, 1.61 mmol, 60% purity, 1.2 equiv). The reaction mixture was stirred at 0° C. for 0.5 h. Then MeI (228.14 mg, 1.61 mmol, 100.06 μL, 1.2 equiv) was added. The mixture was stirred at 20° C. for 1.5 h. TLC (PE:EA=3:1) showed the disappearance of starting material and a new major spot was detected. LCMS showed 88% desired mass and no starting material. The reaction was concentrated in vacuum. Water (50 mL) was added and the aqueous phase was extracted with EA (30 mL×2). The combined organic phase was washed with saturated brine (30 mL×2) and the organic layer was dried over anhydrous Na2SO4. The mixture was concentrated in vacuum. The crude product was purified by preparative TLC (PE:EA=3:1) to give the product. Compound 4 (350 mg, 1.10 mmol, 82% yield) was obtained as a pale yellow liquid, which was used directly in the next step. 1 H NMR (400MHz, CDCl3) δ =7.16 - 6.95 (m, 2H), 3.26 - 3.16 (m, 3H), 2.49 - 2.31 (m, 3H), 1.39 - 1.10 (m, 9H).

[0141] Step 4) tert-Butyl (3-(2-aminobenzo[d]thiazol-6-yl)-2-fluoro-4-methylphenyl)(methyl)carbamate To a solution of compound 5 (343.70 mg, 1.24 mmol, 1.2 equiv) in dioxane / H2O (10 mL) was added Pd(PPh3)2Cl2 (72.80 mg, 103.71 μmol, 0.1 equiv), compound 4 (330 mg, 1.04 mmol, 1 equiv) and Na2CO3 (219.85 mg, 2.07 mmol, 2 equiv) under N2. The mixture was stirred at 80 °C for 16 h. LCMS showed 36% desired mass and 26% starting material 2. Water (10 mL) was added and the aqueous phase was extracted with EA (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2) and concentrated in vacuo. The crude product was purified by preparative TLC (PE:EA = 2:1) to give the product. Compound 6 (280 mg, 375.77 μmol, yield 36%, purity 52%) was obtained as a pale yellow liquid.

[0142] Step 5) tert-Butyl (2-fluoro-3-(2-(1S,2S)-2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-4-methylphenyl)(methyl)carbamate To a solution of compound 6 (260 mg, 348.93 μmol, 1 eq) in MeCN (10 mL) was added MsCl (79.94 mg, 697.86 μmol, 54.01 μL, 2 eq), compound 7 (79.90 mg, 767.65 μmol, 2.2 eq) and 3-methylpyridine (64.99 mg, 697.86 μmol, 67.95 μL, 2 eq) under N2. The mixture was stirred at 20° C. for 2 h. LCMS showed 34% desired mass and no starting material. Water (10 mL) was added and the aqueous phase was extracted with EA (10 mL×2). The combined organic phase was washed with saturated brine (10 mL×2) and concentrated in vacuo. The crude product was purified by preparative TLC (PE:EA=1:1) to give example 45 (256 mg, purity 47%). This crude product (56 mg) was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 40% to 70%, 9 min). Example 45 (5 mg, purity 86%) was obtained as a white solid. 1H NMR (400MHz, methanol-d4) δ = 7.98 - 7.66 (m, 2H), 7.47 - 7.03 (m, 3H), 5.20 - 4.99 (m, 1H), 3.23 - 3.09 (m, 3H), 2.25 - 2.02 (m, 4H), 1.97 - 1.77 (m, 1H), 1.60 - 1.24 (m, 10H); LCMS (electrospray) m / z 474.7 (M+H)+.

[0143] Step 6) (1S,2S)-2-Fluoro-N-(6-(2-fluoro-6-methyl-3-(methylamino)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of Example 45 (200 mg, 198.51 μmol, 1 eq) in DCM (10 mL) was added TFA (67.90 mg, 595.52 μmol, 44.09 μL, 3 eq). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuum. The crude product was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 35%-58%, 7 min) to give the product. Example 46 (46.3 mg, 73.90 μmol, yield 37%, purity 96%, 2 TFA) was obtained as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 7.88 - 7.80 (m, 1H), 7.68 - 7.62 (m, 1H), 7.58 - 7.54 (m, 1H), 7.35 (br d, J=7.8 Hz, 1H), 7.27 - 7.19 (m, 1H), 5.14 - 5.01 (m, 1H),3.19 - 2.83 (m, 3H), 2.43 - 2.06 (m, 4H), 2.01 - 1.76 (m, 1H),1.44 - 1.09 (m, 1H); LCMS (electrospray) m / z 374.1(M+H)+.

[0144] Synthesis method M Example 53. N-methyl-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-amine [ka]

[0145] Step 1) tert-Butyl (6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)carbamate To a solution of compound 1 (100 mg, 414.40 μmol, 1 equiv.) in THF / H2O (5 mL), Na2CO3 (87.84 mg, 828.81 μmol, 2 equiv.) and tert-butoxycarbonyl tert-butyl carbonate (108.53 mg, 497.28 μmol, 114.24 μL, 1.2 equiv.) were added. The mixture was stirred at 25° C. for 12 h. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1:1). Compound 2 (120 mg, 351.47 μmol, 84% yield) was obtained as a pale yellow solid.

[0146] Step 2) tert-Butyl methyl(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)carbamate To a solution of compound 2 (120 mg, 351.47 μmol, 1 equiv.) in THF (5 mL), NaH (28.11 mg, 702.93 μmol, 60% purity, 2 equiv.) was added at 0° C. for 0.5 h, and then after stirring at 25° C. for 1.5 h, MeI (74.83 mg, 527.20 μmol, 32.82 μL, 1.5 equiv.) was added to the mixture. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=3:1). Compound 3 (100 mg, 281.33 μmol, 80% yield) was obtained as a pale yellow solid.

[0147] Step 3) N-methyl-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-amine To a solution of compound 3 (100 mg, 281.33 μmol, 1 equiv.) in DCM (2 mL), TFA (0.4 mL) was added. The mixture was stirred at 25° C. for 1 h. The residue was purified by preparative HPLC (column: Boston pH-lex 150×25 10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 1%-30%, 10 min). Example 53 (9.8 mg, 19.46 μmol, yield 6%, purity 96%, 2 TFA) was obtained as a pale yellow solid. 1 H NMR (400 MHz, methanol-d4) δ = 2.62 (s, 3 H), 3.19 (s, 3 H), 7.51 (dd, J=8.31, 1.71 Hz, 1 H), 7.66 (d, J=8.31 ​​Hz, 1 H), 7.88 (d, J=1.47 Hz, 1 H), 8.03 (d, J=5.87 Hz, 1 H), 8.66 - 8.78 (m, 2 H); LCMS (electrospray) m / z 256.2 (M+H)+.

[0148] Example 54 (10.3 mg, 25.66 μmol, 9% yield, 92% purity, TFA) was obtained as a pale yellow solid. 1 H NMR (400 MHz, methanol-d4) δ = 2.57 (s, 3 H), 3.87 (s, 3 H), 7.71 (dd, J=8.56, 1.71 Hz, 1 H), 7.82 (d, J=8.56 Hz, 1 H), 7.96 - 8.03 (m, 2 H), 8.68 - 8.76 (m, 2H).

[0149] Synthesis method N Example 55. (1S,2S)-2-Fluoro-N-(6-(4-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0150] Step 1) (1S,2S)-N-(6-bromobenzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide To a solution of compound 1 (1.2 g, 5.24 mmol, 1.2 equiv) in MeCN (15 mL) was added compound 2 (454.30 mg, 4.36 mmol, 1 equiv), 3-methylpyridine (2.03 g, 21.82 mmol, 2.13 mL, 5 equiv), MsCl (1.00 g, 8.73 mmol, 675.69 μL, 2 equiv) at 0 °C, and the mixture was then stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The reaction mixture was diluted with H2O (20 mL), and the mixture was then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 3 (1.2 g, 3.81 mmol, 87% yield) as a pale yellow solid, which was used directly in the next step. 1 H NMR (400 MHz, DMSO-d6) δ = 1.31 (ddt, J=12.79, 9.00, 6.40, Hz, 1 H), 1.65 - 1.83 (m, 1 H), 2.13 - 2.29 (m, 1 H), 4.87 - 5.18 (m, 1 H), 7.51 - 7.60 (m, 1 H), 7.68 (d, J=8.56 Hz, 1 H), 8.25 (d, J=1.96 Hz, 1 H), 12.78 (s, 1 H).

[0151] Step 2) (1S,2S)-2-Fluoro-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide A mixture of compound 3 (1.1 g, 3.49 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.33 g, 5.24 mmol, 1.5 equiv.), KOAc (1.03 g, 10.47 mmol, 3 equiv.), Pd(dppf)Cl2.CH2Cl2 (285.03 mg, 349.03 μmol, 0.1 equiv.) in dioxane (20 mL) was degassed and purged with N2 three times, then the mixture was stirred at 110° C. under N2 atmosphere for 16 h. The reaction mixture was diluted with H2O (20 mL), and then the mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2:1). Compound 4 (1.15 g, 3.17 mmol, 90% yield) was obtained as a pale yellow solid. 1 H NMR (400 MHz, methanol-d4) δ = 1.20 (s, 12 H), 1.33 - 1.27 (m, 1H), 1.93 - 1.80 (m, 1H), 2.22 - 2.12 (m, 1H), 4.87 - 5.18 (m, 1 H), 7.69 - 7.75 (m, 1 H), 7.76 - 7.82 (m, 1 H), 8.23 ​​(s, 1 H).

[0152] Step 3) (1S,2S)-2-Fluoro-N-(6-(4-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide A mixture of compound 4 (150 mg, 414.11 μmol, 1 equiv), 3-bromo-4-methoxy-pyridine (77.86 mg, 414.11 μmol, 1 equiv), Pd(PPh3)2Cl2 (29.07 mg, 41.41 μmol, 0.1 equiv), Na2CO3 (87.78 mg, 828.21 μmol, 2 equiv) in dioxane / HO (10 mL) was degassed and purged with N2 three times, then the mixture was stirred at 110 °C under N2 atmosphere for 3 h. The reaction mixture was diluted with HO (20 mL), then the mixture was extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 0:1). The residue was then purified by preparative HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 24%-54%, 10 min). Example 55 (23 mg, 63.63 μmol, 15% yield, 95% purity) was obtained as a pale yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 1.33 - 1.44 (m, 1 H), 1.91 - 2.13 (m, 2 H), 3.94 (s, 3 H), 4.79 - 5.05 (m, 1 H), 6.96 (d, J=5.87 Hz, 1 H), 7.63 (dd, LCMS (electrospray) m / z 344.3(M+H)+.

[0153] Synthesis method O Example 58. (2-((1S,2S)-2-Fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)boronic acid. HCl salt [ka]

[0154] To a solution of compound 1 (200 mg, 552.14 μmol, 1 equiv) in acetone (5 mL) and H2O (5 mL) was added NaIO4 (708.59 mg, 3.31 mmol, 183.57 μL, 6 equiv) and NH4HCO3 (261.90 mg, 3.31 mmol, 272.81 μL, 6 equiv). The mixture was stirred at 40 °C for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (20 mL), and then the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10um; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-41%, 8 min). Example 58 (58 mg, 172.24 μmol, yield 31%, purity 94%, HCl) was obtained as a pale yellow solid. 1 H NMR (400 MHz, methanol-d4) δ = 1.26 - 1.39 (m, 1 H), 1.81 - 1.94 (m, 1 H), 2.19 (dtd, J=9.19, 6.87, 6.87, 4.34 Hz, 1 H), 4.87 - 5.18 (m, 1 H), 7.69 - 7.75 (m, 1 H), 7.81 (br d, J=7.82 Hz, 1 H), 8.22 (s, 1 H); LCMS (electrospray) m / z 281.2 (M+H)+.

[0155] Synthesis method P Example 71. (1S,2R)-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-(((methylamino)methyl)cyclopropane-1-carboxamide [ka]

[0156] To a solution of Example 63 (210 mg, 589.20 μmol, 1 eq) in THF (10 mL) was added TEA (59.62 mg, 589.20 μmol, 82.01 μL, 1 eq) and MsCl (67.49 mg, 589.20 μmol, 45.60 μL, 1 eq) at 0° C. The mixture was stirred at 25° C. for 2 h. Then methanamine (2M, 2.95 mL, 10 eq) was added. The mixture was stirred at 40° C. for 16 h. LCMS showed 40% desired mass and 25% starting material. Water (10 mL) was added and the aqueous phase was extracted with EA (10 mL×2). The combined organic phase was washed with saturated brine (20 mL×2) and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 20%-40%, 7.8 min] to give the product Example 71 (47 mg, 100.93 μmol, yield 17%, purity 95%, 2HCl) as a pale yellow solid. 1 H NMR ( 400MHz, methanol-d4) δ = 7.74 (s, 1H), 7.87 - 7.71 (m, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.49 - 7.40 (m, 1H), 7.30 (dt, J=5.7, 7.9 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.02 (t, J=8.9 Hz, 1H), 3.88 (br d, J=6.5 Hz, 2H), 2.74 (s, 3H), 2.16 (s, 3H), 1.87 (dt, J=5.7, 8.2 Hz, 1H), 1.71 (qd, J=7.9, 15.3 Hz, 1H), 1.30 - 1.06 (m, 2H);LCMS (electrospray) m / z 370.0 (M+H)+.

[0157] Synthesis method Q Example 80. (1S,2S)-2-Fluoro-N-(4-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0158] Step 1) 6-bromo-4-fluorobenzo[d]thiazol-2-amine To a solution of compound 1 (1 g, 5.26 mmol, 1 equiv) in AcOH (10 mL) was added potassium thiocyanato (2.05 g, 21.05 mmol, 2.05 mL, 4 equiv). To this solution, bromine (1.68 g, 10.53 mmol, 542.61 μL, 2 equiv) in AcOH (3 mL) was added dropwise at 25 °C for 15 min. After the addition was completed, the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove AcOH. The PH was adjusted to 7 with 1 M NaOH, and the mixture was extracted with EA (50 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 0:1). Compound 2 (307 mg, 1.24 mmol, 23% yield) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.86 (s, 2H), 7.77 (d, J=1.2 Hz, 1H), 7.35 (dd, J=1.8, 10.5 Hz, 1H).

[0159] Step 2) 4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine To a solution of compound 2 (307 mg, 1.24 mmol, 1 equiv.) and B2Pin2 (473.27 mg, 1.86 mmol, 1.5 equiv.) in dioxane (5 mL), Pd(dppf)Cl2.CH2Cl2 (101.47 mg, 124.25 μmol, 0.1 equiv.) and AcOK (365.82 mg, 3.73 mmol, 3 equiv.) were added. The mixture was stirred at 110 °C for 12 h under N2. Then, the mixture was stirred at 110 °C for 3 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10 / 1 to 1:1). Compound 3 (322 mg, 1.09 mmol, 88% yield) was obtained as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.89 (s, 2H), 7.77 (s, 1H), 7.21 (d, J=11.1 Hz, 1H), 1.29 (s, 12H).

[0160] Step 3) 4-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-amine To a solution of compound 3 (150 mg, 509.94 μmol, 1 equiv.) and compound 4 (105.27 mg, 611.93 μmol, 67.91 μL, 1.2 equiv.) in dioxane (5 mL) and H2O (1 mL), Pd(PPh3)2Cl2 (35.79 mg, 50.99 μmol, 0.1 equiv.) and Na2CO3 (162.14 mg, 1.53 mmol, 3 equiv.) were added. The mixture was stirred at 110 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (silica gel plate, petroleum ether:ethyl acetate = 0:1). Compound 5 (50 mg, 160.05 μmol, 31% yield, 83% purity) was obtained as a white solid.

[0161] Step 4) (1S,2S)-2-fluoro-N-(4-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of compound 5 (50 mg, 160.05 μmol, 1 eq.) and compound 6 (19.99 mg, 192.05 μmol, 1.2 eq.) in DMF (2 mL), EDCI (61.36 mg, 320.09 μmol, 2 eq.) and HOBt (43.25 mg, 320.09 μmol, 2 eq.) were added at 0° C. The mixture was stirred at 60° C. for 12 h. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 15%-36%, 7 min). Example 80 (8.9 mg, 13.94 μmol, 8% yield, 89% purity, 2TFA) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 13.07 (s, 1H), 8.64 (br d, J=7.7 Hz, 2H), 7.95 (br d, J=1.2 Hz, 1H), 7.68 (br s, 1H), 7.47 (br d, J=11.5 Hz, 1H), 5.17 - 4.96 (m, 1H), 2.43 (br s, 3H), 2.23 (td, J=6.9, 13.5 Hz, 1H), 1.83 - 1.70 (m, 1H), 1.34 (qd, J=6.4, 15.1 Hz, 1H); LCMS (electrospray) m / z 346.3(M+H)+.

[0162] Example 85. (1S,2S)-N-(6-(5-ethynyl-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide The title compound was obtained as described for synthesis method B using ((3-bromo-4-methylphenyl)ethynyl)trimethylsilane.

[0163] Synthesis method R Example 91. 3-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)thiazolo[5,4-b]pyridin-5-yl)-N,4-dimethylbenzamide. 2HCl salt [ka]

[0164] Step 1) 1-(triisopropylsilyl)-1H-pyrrole n-BuLi (2.2M, 16.21 mL, 1.20 equiv) was added dropwise to a solution of compound 1 (2 g, 29.81 mmol, 2.07 mL, 1 equiv) in THF (40 mL) at -65°C, and the whole mixture was stirred at -65°C for 0.5 h. TIPSCl (6.32 g, 32.76 mmol, 7.01 mL, 1.10 equiv) was added to the mixture, and the whole mixture was stirred at -65°C for 4 h. A saturated aqueous solution of ammonium chloride (40 mL) was added to the mixture at 0°C, and the whole mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (100-200 mesh silica gel, petroleum ether) to give compound 2 (5.6 g, 25.06 mmol, 84% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ = 6.81 (t, J=1.8 Hz, 2H), 6.32 (t, J=1.9 Hz, 2H), 1.52 - 1.39 (m, 3H), 1.10 (d, J=7.5 Hz, 18H).

[0165] Step 2) 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-pyrrole To a solution of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (47.47 mg, 71.61 μmol, 0.02 equiv) in THF (15 mL) was added 3,4,7,8-tetramethyl-1,10-phenanthroline (33.84 mg, 143.22 μmol, 0.04 equiv) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45.82 mg, 358.06 μmol, 51.95 μL, 0.1 equiv). The mixture was degassed and purged with nitrogen three times, then the mixture was stirred under nitrogen at 15° C. for 0.5 h. Compound 2 (800 mg, 3.58 mmol, 884.96 μL, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (909.24 mg, 3.58 mmol, 1 eq) were then added. The mixture was degassed and purged with nitrogen three times, then the mixture was stirred at 70° C. under nitrogen atmosphere for 16 h. The reaction mixture was quenched by diluting with EtOAc (40 mL) and then filtered through celite. The filtrate was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (100-200 mesh silica gel, petroleum ether / ethyl acetate=1 / 0-100 / 1, the product was generated with petroleum ether / ethyl acetate=100 / 1) to give compound 3 (900 mg, 2.58 mmol, 71% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 7.23 (t, J=1.4 Hz, 1H), 6.81 (t, J=2.2 Hz, 1H), 6.62 (dd, J=1.2, 2.5 Hz, 1H), 1.46 (quin, J=7.5 Hz, 3H), 1.32 (s, 12H), 1.09 (d, J=7.5 Hz, 19H).

[0166] Step 3) 3-(3-bromo-4-methylphenyl)-1-(triisopropylsilyl)-1H-pyrrole To a solution of compound 3 (180 mg, 515.18 μmol, 1 equiv.) and compound 4 (137.68 mg, 463.67 μmol, 0.9 equiv.) in dioxane (4 mL) and H2O (1 mL) was added Na2CO3 (109.21 mg, 1.03 mmol, 2 equiv.) and Pd(dppf)Cl2 (37.70 mg, 51.52 μmol, 0.1 equiv.). The mixture was degassed and purged with nitrogen three times, then the mixture was stirred at 60 °C under nitrogen atmosphere for 4 h. The reaction mixture was quenched by diluting with EtOAc (40 mL) and then filtered through celite. The filtrate was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=20 / 1, Rf=0.8) to give compound 5 as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ = 7.70 (d, J=1.7 Hz, 1H), 7.36 (dd, J=1.7, 7.8 Hz, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.01 (t, J=1.7 Hz, 1H), 6.79 (t, J=2.4 Hz, 1H), 6.56 (dd, J=1.4, 2.6 Hz, 1H), 2.37 (s, 3H), 1.48 (quin, J=7.5 Hz, 3H), 1.12 (d, J=7.5 Hz, 19H).

[0167] Step 4) (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of compound 5 (130 mg, 311.38 μmol, 1 equiv.) and compound 6 (112.79 mg, 311.38 μmol, 1 equiv.) in dioxane (3 mL) and H2O (0.6 mL) was added Na2CO3 (66.01 mg, 622.76 μmol, 2 equiv.) and Pd(dppf)Cl2 (22.78 mg, 31.14 μmol, 0.1 equiv.). The mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 60° C. under nitrogen atmosphere for 16 h. The reaction mixture was diluted with EtOAc (40 mL), and the resulting organic phase was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and the resulting organic phase was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate=10 / 1-1 / 1, the product was generated with petroleum ether / ethyl acetate=2 / 1) to give compound 7 as a brown oil.

[0168] Step 5) (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(1H-pyrrol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide.2HCl salt To a solution of compound 7 (110 mg, 190.76 μmol, 1 equiv) in THF (4 mL) was added pyridine; hydrogen fluoride (1.10 g, 11.10 mmol, 1 mL). The mixture was stirred at 35° C. for 3 h. LC-MS showed that 2% compound 7 remained. The mixture was stirred at 35° C. for 2 h. The reaction mixture was diluted with ethyl acetate (20 mL), and the resulting organic phase was then washed with aqueous HCl (4 mL, 0.5 M), brine (4 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (HCl condition, column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 41%-61%, 11 min), followed by lyophilization. However, HNMR showed the product was impure, so it was diluted with water and lyophilized again to give Example 91 as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 12.70 (s, 1H), 10.87 (br s, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.48 - 7.36 (m, 3H), 7.27-7.18 (m, 2H), 6.77 (q, J=2.3 Hz, 1H), 6.43 (d, J=1.7 Hz, 1H), 5.17-4.91 (m, 1H), 2.27-2.23 (m, 1H), 2.21 (s, 3H), 1.83-1.67 (m, 1H), 1.31 (tdd, J=6.4, 9.0, 12.8 Hz, 1H); LCMS (electrospray) m / z 392.1 (M+H)+.

[0169] Synthesis method S Example 92. (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(thiazol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide. 2HCl salt [ka]

[0170] Step 1) (3-Bromo-4-methylphenyl)boronic acid Compound 1 (3 g, 10.10 mmol, 1 equiv) in THF (30 mL) was placed in a 250 mL round bottom flask. The reaction solution was cooled to -65 °C under nitrogen atmosphere. n-BuLi (2.2 M, 5.05 mL, 1.1 equiv) was slowly added dropwise to the cooled solution, and the mixture was stirred at the same temperature for 1 h. Trimethylborate (1.26 g, 12.12 mmol, 1.37 mL, 1.2 equiv) was added dropwise to the above solution at the same temperature. The mixture was stirred at -65 °C for 1 h. Then, the cold bath was removed, and the mixture was stirred at -65 to 10 °C for 16 h. The mixture was acidified by dropwise addition of HCl solution (2 M, 5 mL), and the reaction solution was stirred for 1.5 h. The mixture was concentrated in vacuo to give a residue. The residue was purified by reverse MPLC (FA condition, A: water, B: MeCN, 40% B). The fractions were concentrated to remove the solvent, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give compound 2 (1.3 g, 6.05 mmol, 59% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 8.15 (s, 0.5H), 7.95 (s, 0.3H), 7.93 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.66 (d, J=7.5 Hz, 0.3H), 7.37 (d, J=7.5 Hz, 1H), 7.32 (d, J=7.6 Hz, 0.3H), 2.37 (s, 3H), 2.34 (s, 0.9H).

[0171] Step 2) 2-(3-bromo-4-methylphenyl)thiazole To a solution of compound 2 (255 mg, 1 equiv.) and 2-bromothiazole (220 mg, 1.34 mmol, 120.88 μL, 1.13 equiv.) in dioxane (5 mL) and H2O (1 mL) was added Pd(dppf)Cl2 (86.84 mg, 118.69 μmol, 0.1 equiv.) and Na2CO3 (251.59 mg, 2.37 mmol, 2 equiv.). The mixture was degassed and purged with nitrogen three times, then the mixture was stirred at 80 °C under nitrogen atmosphere for 6 h. The reaction mixture was diluted with ethyl acetate (40 mL), and then the resulting organic phase was filtered through celite. The filtrate was washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (300-400 mesh silica gel, petroleum ether / ethyl acetate=1 / 0-100 / 1, product was generated with petroleum ether / ethyl acetate=100 / 1) to give the crude product, which was purified by reverse-phase MPLC (FA condition, A: water, B: MeCN, 55% B) to give compound 4 (40 mg, 157.39 μmol, 13% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ = 8.16 (d, J=1.6 Hz, 1H), 7.86 (d, J=3.2 Hz, 1H), 7.78 (dd, J=1.8, 7.9 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 2.44 (s, 3H).

[0172] Step 3) (1S,2S)-2-Fluoro-N-(6-(2-methyl-5-(thiazol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide.2HCl salt To a solution of (1S,2S)-2-fluoro-N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (57.01 mg, 157.39 μmol, 1 equiv.) and compound 4 (40 mg, 157.39 μmol, 1 equiv.) in dioxane (1 mL) and H2O (0.2 mL), Na2CO3 (33.36 mg, 314.78 μmol, 2 equiv.) and Pd(dppf)Cl2 (11.52 mg, 15.74 μmol, 0.1 equiv.) were added. The mixture was degassed and purged with nitrogen three times, and then the mixture was stirred at 60 °C under nitrogen atmosphere for 16 h. The reaction mixture was diluted with EtOAc (40 mL), and the resulting organic phase was then washed with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (200-300 mesh silica gel, petroleum ether / ethyl acetate=5 / 1-0 / 1) to give the product. The product was purified by preparative HPLC (HCl condition, column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 48%-65%, 10 min), followed by lyophilization to give Example 92 (25.8 mg, 53.00 μmol, yield 33%, purity 99%, 2HCl) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 12.88 (br s, 1H), 8.16 (d, J=1.3 Hz, 1H), 8.02 (d, J=3.2 Hz, 1H), 7.98 (dd, J=1.8, 7.9 Hz, 1H), 7.95-7.90 (m, 2H), 7.88 (d, J=3.2 Hz, 1H), 7.63-7.53 (m, 2H), 5.33 - 5.01 (m, 1H), 2.42 (s, 3H), 2.40-2.33 (m, 1H), 1.96-1.77 (m, 1H), 1.53-1.36 (m, 1H);LCMS (electrospray) m / z 410.2(M+H)+.

[0173] Synthesis method T Example 95. (1S,2S)-2-Fluoro-N-(6-(4-methyl-1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0174] Step 1) 4-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole To a solution of compound 1 (2 g, 24.36 mmol, 1.96 mL, 1 equiv) in DCM (30 mL) was added PPTS (612.16 mg, 2.44 mmol, 0.1 equiv) and 3,4-dihydro-2H-pyran (6.15 g, 73.08 mmol, 6.68 mL, 3 equiv). The mixture was stirred at 55 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 80 mL and extracted with ethyl acetate (80 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 5:1). Compound 2 (2.5 g, 15.04 mmol, 61% yield) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ = 7.37 (d, J=6.0 Hz, 2H), 5.32 (dd, J=2.4, 9.7 Hz, 1H), 4.09 - 3.99 (m, 1H), 3.69 (dt, J=2.8, 11.3 Hz, 1H), 2.08 (s, 3H), 2.07 - 1.99 (m, 2H), 1.78 - 1.51 (m, 4H).

[0175] Step 2) 3-Bromo-4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole To a solution of compound 2 (2.3 g, 13.84 mmol, 1 equiv.) in MeCN (23 mL) was added NBS (2.46 g, 13.84 mmol, 1 equiv.). The mixture was stirred at 55° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=1:0 to 50:1). Compound 3 (2.4 g, 9.79 mmol, 70% yield) was obtained as a yellow oil. 1 H NMR (400MHz CDCl3) δ = 7.34 (s, 1H), 5.26 (dd, J=2.4, 9.4 Hz, 1H), 4.09 - 3.99 (m, 1H), 3.72 - 3.62 (m, 1H), 2.06 - 2.03 (m, 2H), 2.02 (d, J=0.7 Hz, 3H), 1.78 - 1.54 (m, 4H).

[0176] Step 3) 6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)benzo[d]thiazol-2-amine To a solution of compound 3 (1 g, 4.08 mmol, 1 equiv.) and compound 4 (1.13 g, 4.08 mmol, 1 equiv.) in dioxane (10 mL) and HO (3 mL), Na2CO3 (864.81 mg, 8.16 mmol, 2 equiv.) and Pd(dppf)Cl2 (298.51 mg, 407.97 μmol, 0.1 equiv.) were added. The mixture was stirred at 90 °C under N2 for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 20 / 1 to 1:1). Compound 5 (780 mg, 2.11 mmol, 51% yield, 85% purity) was obtained as a yellow solid.

[0177] Step 4) (1S,2S)-2-Fluoro-N-(6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of compound 5 (350 mg, 946.23 μmol, 1 eq.) and compound 6 (136.43 mg, 1.31 mmol, 1.39 eq.) in DMF (5 mL) was added EDCI (418.80 mg, 2.18 mmol, 2.31 eq.) and HOBt (295.20 mg, 2.18 mmol, 2.31 eq.) at 0° C. The mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Luna C18 150×25 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 48%-68%, 7.8 min). Example 94 (200 mg, 482.83 μmol, 51% yield, 96% purity) was obtained as a white solid (50 mg will be obtained). 1 H NMR (400MHz, DMSO-d6) δ = 12.72 (br s, 1H), 8.22 (s, 1H), 7.81 - 7.71 (m, 3H), 5.36 (dd, J=2.1, 10.0 Hz, 1H), 5.16 - 4.92 (m, 1H), 3.94 (br d, J=11.9 Hz, 1H), 3.68 - 3.58 (m, 1H), 2.28 - 2.19 (m, 4H), 2.16 - 2.05 (m, 1H), 2.02 - 1.89 (m, 2H), 1.81 - 1.65 (m, 2H), 1.60 - 1.50 (m, 2H), 1.31 (tdd, J=6.4, 8.9, 12.8 Hz, 1H); LCMS (electrospray) m / z 401.1 (M+H)+.

[0178] Step 5) (1S,2S)-2-Fluoro-N-(6-(4-methyl-1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide Example 94 (140 mg, 338.61 μmol, 1 eq) was added to HCl / dioxane (4M, 3 mL, 35.44 eq). The mixture was stirred at 25° C. for 2 h. LCMS showed that about 59% starting material remained and about 40% desired mass was detected. The mixture was then stirred at 40° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of water and extracted with DCM (20 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column: Luna C18 150×25 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 31%-51%, 7.8 min). Example 95 (41.4 mg, 130.87 μmol, 38% yield, 100% purity) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.46 (br s, 2H), 8.15 (s, 1H), 7.80 - 7.75 (m, 1H), 7.74 - 7.66 (m, 1H), 7.47 (br s, 1H), 5.12 - 4.88 (m, 1H), 2.30 - 2.19 (m, 4H), 1.85 - 1.70 (m, 1H), 1.36 - 1.22 (m, 1H); LCMS (electrospray) m / z 317.2 (M+H)+.

[0179] Synthesis method U Example 99. (1S,2S)-2-Fluoro-N-(4-methyl-2-oxo-2,3-dihydro-[5,6'-bibenzo[d]thiazol]-2'-yl)cyclopropane-1-carboxamide [ka]

[0180] Step 1) 4-Bromo-3-methyl-2-nitrobenzenethiol To a solution of Na2S.9H2O (16.42 g, 68.37 mmol, 11.48 mL, 2 equiv.) in EtOH (80 mL) was added compound 1 (8 g, 34.18 mmol, 1 equiv.) dropwise. The mixture was stirred at 50° C. for 2 h. The reaction was slowly quenched with HCl to pH=5, then extracted with ethyl acetate (80 mL×2). The combined organic phase was washed with water (80 mL×2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Compound 2 (2.5 g crude) was obtained as a green solid. 1 H NMR (400MHz, CDCl3) δ = 7.21 (d, J=8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 4.53 (br s, 1H), 2.32 - 2.29 (m, 3H).

[0181] Step 2) 2-Amino-4-bromo-3-methylbenzenethiol To a solution of compound 2 (2.5 g, 10.08 mmol, 1 equiv) (crude) in EtOH (25 mL) was added HCl (55.11 g, 151.15 mmol, 54.03 mL, 10% purity, 15 equiv) at 0° C. Then Zn (7.06 g, 107.92 mmol, 10.71 equiv) was added and the mixture was stirred at 35° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The aqueous phase was then washed with petroleum ether (100 mL×2). The aqueous phase was then slowly brought to pH=5 with solid NaHCO3, filtered, the filter cake was concentrated in vacuum, and the filtrate was then extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. Compound 3 (0.99 g, 4.54 mmol, 45% yield) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.14 - 7.09 (m, 1H), 6.94 - 6.86 (m, 1H), 5.59 - 5.49 (m, 2H), 2.28 (s, 3H).

[0182] Step 3) 5-Bromo-4-methylbenzo[d]thiazol-2(3H)-one To a solution of CDI (661.64 mg, 4.08 mmol, 1 equiv.) in THF (9 mL) was added compound 3 (0.89 g, 4.08 mmol, 1 equiv.) dropwise at 0° C. Then the reaction mixture was added and the mixture was stirred at 35° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with water (100 mL×2). The organic layer was dried over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo. Compound 4 (1.05 g, crude) was obtained as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ= 12.28 - 11.73 (m, 1H), 7.33 (d, J=4.0 Hz, 2H), 2.39 (s, 3H).

[0183] Step 4) (1S,2S)-2-Fluoro-N-(4-methyl-2-oxo-2,3-dihydro-[5,6'-bibenzo[d]thiazol]-2'-yl)cyclopropane-1-carboxamide A mixture of compound 4 (500 mg, 2.05 mmol, 1 equiv), compound 5 (506.47 mg, 1.40 mmol, 6.82 e-1 equiv), Pd(dppf)Cl2 (75.00 mg, 102.50 μmol, 0.05 equiv), Na2CO3 (434.55 mg, 4.10 mmol, 2 equiv) in dioxane (10 mL) and H2O (2 mL) was degassed and purged with N2 three times, then the mixture was stirred at 80 °C under N2 atmosphere for 16 h. The reaction mixture was concentrated in vacuum. The crude product was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 × 10 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 35%-55%, 11 min) to give the product. Example 99 (53 mg, 117.93 μmol, 5% yield, 97% purity, HCl) was obtained as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 12.75 - 12.70 (m, 1H), 11.78 - 11.74 (m, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.41 - 7.37 (m, 1H), 7.08 (s, 1H), 5.17 - 4.94 (m, 1H), 2.29 - 2.18 (m, 4H), 1.81 - 1.71 (m, 1H), 1.36 - 1.28 (m, 1H):LCMS (electrospray) m / z 400.1(M+H)+.

[0184] Synthesis method V Example 107. (1S,2S)-2-Fluoro-N-(6-(7-methyl-1H-indazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0185] Step 1) 1-Bromo-2,4-dimethyl-3-nitrobenzene To a solution of compound 1 (5 g, 33.08 mmol, 4.50 mL, 1 equiv), FeBr3 (195.52 mg, 661.54 μmol, 0.02 equiv) and Fe (461.80 mg, 8.27 mmol, 0.25 equiv) in DCM (50 mL) was added Br2 (5.81 g, 36.38 mmol, 1.88 mL, 1.1 equiv) in DCM (5 mL) dropwise at 15 °C. The mixture was stirred at 30 °C for 20 h. TLC showed the reaction was complete. The mixture was washed with saturated aqueous sodium sulfite solution (100 mL × 2), and the organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate (Na2SO4), filtered and concentrated in vacuum. The residue was used in the next step without any purification. Compound 2 (7.2 g, 31.30 mmol, 94% yield) was obtained as a white solid. 1H NMR (400MHz, CDCl3) δ = 7.56 (d, J=8.2 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 2.35 (s, 3H), 2.26 (s, 3H).

[0186] Step 2) 3-Bromo-2,6-dimethylaniline To a solution of compound 2 (7.2 g, 31.30 mmol, 1 equiv.) in AcOH (80 mL) was added Fe (6.99 g, 125.19 mmol, 4 equiv.) at 10° C. The mixture was stirred at 80° C. for 18 h. TLC showed the reaction was complete. The mixture was filtered and the filtrate was neutralized with saturated aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate (100 mL×2), and the organic phase was washed with brine (150 mL), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate=5:1. Compound 3 (4.6 g, 22.99 mmol, 73% yield) was obtained as a brown oil. 1 H NMR (400MHz, CDCl3) δ = 6.94 (d, J=8.1 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 3.84 - 3.49 (m, 2H), 2.30 (s, 3H), 2.14 (s, 3H).

[0187] Step 3) 4-Bromo-7-methyl-1H-indazole To a solution of compound 3 (4.1 g, 20.49 mmol, 1 equiv) in AcOH (50 mL) was added NaNO (1.70 g, 24.59 mmol, 1.2 equiv) in H2O (10 mL) dropwise at 0 °C for 30 min. The mixture was stirred at 15 °C for 18 h. LC-MS showed the reaction was complete. The mixture was poured into H2O (100 mL) and the aqueous phase was extracted with ethyl acetate (150 mL x 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 5 g of crude product. 2 g of the crude product was separated and purified by HPLC (column: Phenomenex luna C18 250×50 mm×10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-60%, 30 min, 40 min), followed by freeze-drying to give 0.3 g white solid. 0.3 g white solid was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-50%, 11 min), followed by freeze-drying. Compound 4 (75 mg, 355.35 μmol, 1% yield) was obtained as a white solid. Compound 4A (195 mg, 923.92 μmol, 4% yield) was obtained as a white solid.

[0188] compound 4 1 H NMR (400MHz, methanol-d4) δ = 8.02 (s, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 2.61 (s, 3H).

[0189] Compound 4A 1 H NMR (400MHz, methanol-d4) δ = 7.99 (s, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.04 (dd, J=0.9, 7.5 Hz, 1H), 2.52 (d, J=0.6 Hz, 3H).

[0190] Step 4) (1S,2S)-2-Fluoro-N-(6-(7-methyl-1H-indazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of compound 4A (195 mg, 923.92 μmol, 1 equiv.) and compound 5 (401.60 mg, 1.11 mmol, 1.2 equiv.) in dioxane (3 mL) and HO (0.5 mL) was added NaCO (293.77 mg, 2.77 mmol, 3 equiv.) and Pd(dppf)Cl (135.21 mg, 184.78 μmol, 0.2 equiv.) at 10° C. The mixture was stirred at 60° C. for 18 h. LC-MS showed the reaction was complete. The mixture was poured into HO (10 mL) and a large amount of yellow solid was produced which was filtered and the filter cake was concentrated in vacuo. The filter cake was purified by triturating with methanol (10 mL), filtered and the filter cake was concentrated. Example 107 (149.2 mg, 385.61 μmol, 41% yield, 94% purity) was obtained as a yellow solid. 1 H NMR (400MHz, DMSO--d6) δ = 13.30 (br s, 1H), 12.74 (br s, 1H), 8.35 - 8.20 (m, 2H), 7.90 - 7.83 (m, 1H), 7.81 - 7.74 (m, 1H), 7.21 (br s, 2H), 5.17 - 4.93 (m, 1H), 2.57 (s, 3H), 2.24 (br s, 1H), 1.83 - 1.69 (m, 1H), 1.31 (br s, 1H); LCMS (electrospray) m / z 367.0(M+H)+.

[0191] Example 108. (1S,2S)-2-Fluoro-N-(6-(7-methyl-1H-indazol-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide Step 1) (1S,2S)-2-Fluoro-(6-(7-methyl-1H-indazol-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide To a solution of compound 4 (75 mg, 355.35 μmol, 1 equiv.) and compound 5 (154.46 mg, 426.42 μmol, 1.2 equiv.) in dioxane (2 mL) and H2O (0.5 mL) was added Na2CO3 (112.99 mg, 1.07 mmol, 3 equiv.) and Pd(dppf)Cl2 (52.00 mg, 71.07 μmol, 0.2 equiv.) at 10° C. The mixture was stirred at 60° C. for 18 h. LC-MS showed the reaction was complete. The mixture was poured into petroleum ether (10 mL), filtered through silica gel, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10um; mobile phase: [water (0.05% HCl)-ACN]; B%: 30%-60%, 10 min) followed by lyophilization. Example 108 (26.4 mg, 59.61 μmol, 16% yield, 99% purity, 2HCl) was obtained as a white solid, which was confirmed by 2D NMR. 1 H NMR (400MHz, methanol-d4) δ = 8.31 (s, 1H), 7.90 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 5.09 - 4.97 (m, 1H), 5.09 - 4.94 (m, 1H), 2.51 (s, 3H), 2.24 - 2.16 (m, 1H), 1.95 - 1.82 (m, 1H), 1.39 - 1.27 (m, 1H): LCMS (electrospray) m / z 367.1(M+H)+.

[0192] Synthesis method W Example 111. (1S,2S)-2-Fluoro-N-(6'-methyl-[6,7'-bibenzo[d]thiazol]-2-yl)cyclopropane-1-carboxamide [ka]

[0193] Step 1) N-((3-bromo-4-methylphenyl)carbamothioyl)benzamide To a solution of compound 1 (5 g, 26.87 mmol, 1 equiv.) in acetone (50 mL), benzoyl isothiocyanate (4.39 g, 26.87 mmol, 3.62 mL, 1 equiv.) in acetone (10 mL) was added dropwise at 60° C. The mixture was refluxed at 60° C. for 4 h. TLC (petroleum ether / ethyl acetate=5 / 1) showed that compound 1 was consumed, showing a major spot. The mixture was concentrated. The residue was purified by trituration with petroleum ether (60 mL) and ethyl acetate (6 mL). Compound 2 (8.77 g, 25.11 mmol, 93% yield) was obtained as a white solid. 1 H NMR (400MHz, CDCl3) δ = 12.58 - 12.23 (m, 1H), 9.20 - 9.02 (m, 1H), 8.01 - 7.85 (m, 3H), 7.72 - 7.64 (m, 1H), 7.60 - 7.54 (m, 3H), 7.30 (s, 1H), 2.46 - 2.40 (m, 3H).

[0194] Step 2) 1-(3-bromo-4-methylphenyl)thiourea To a solution of compound 2 (8.77 g, 25.11 mmol, 1 equiv.) in H2O (80 mL) was added NaOH (4.02 g, 100.45 mmol, 4 equiv.) at 10°C. The mixture was stirred at 70°C for 18 h. TLC (petroleum ether / ethyl acetate = 5 / 1) showed that compound 2 was consumed and the main spot. The mixture was acidified with hydrochloric acid solution (2N) to PH = 2-3, and a large amount of white solid was formed. The reaction mixture was filtered and the filter cake was dried. The residue was purified by trituration with ethyl acetate (40 mL). Compound 3 (4.65 g, 18.97 mmol, 75% yield) was obtained as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 7.61 (s, 1H), 7.31 - 7.26 (m, 1H), 7.24 - 7.19 (m, 1H), 2.37 (s, 3H).

[0195] Step 3) 7-Bromo-6-methylbenzo[d]thiazol-2-amine To a solution of compound 3 (4.65 g, 18.97 mmol, 1 equiv) in CH3COOH (80 mL) was added Br2 (3.33 g, 20.87 mmol, 1.08 mL, 1.1 equiv) at 10 °C. The mixture was stirred at 80 °C for 18 h. The mixture was poured into H2O (80 mL) and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by trituration with petroleum ether (50 mL) and ethyl acetate (10 mL), filtered and the filter cake was concentrated to give 7-bromo-6-methyl-1,3-benzothiazol-2-amine. The filtrate was concentrated and purified by silica gel chromatography eluting with petroleum ether / ethyl acetate = 1:1 to give 5-bromo-6-methyl-1,3-benzothiazol-2-amine. Compound 4 (1.3 g, 5.34 mmol, 28% yield, 99% purity) was obtained as a white solid. Compound 4A (870 mg, 3.58 mmol, 18% yield) was obtained as a white solid.

[0196] compound 4 1 H NMR (400MHz, DMSO-d6) δ = 7.55 (s, 2H), 7.24 - 7.20 (m, 1H), 7.19 - 7.15 (m, 1H), 2.35 (s, 3H).

[0197] Compound 4A 1 H NMR (400MHz, CDCl3) δ = 7.73 (s, 1H), 7.45 (s, 1H), 5.21 (br s, 2H), 2.45 (s, 3H).

[0198] Step 4) 7-Bromo-6-methylbenzo[d]thiazole To a solution of compound 4 (300 mg, 1.23 mmol, 1 equiv) in THF (10 mL) was added isoamyl nitrite (288.81 mg, 2.47 mmol, 331.97 μL, 2 equiv) at 10° C. The mixture was stirred at 70° C. for 18 h. LC-MS showed compound 4 was consumed and a main peak of the desired mass was observed. The mixture was poured into H2O (20 mL) and the aqueous solution was extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. TLC (petroleum ether / ethyl acetate=10:1) showed a major spot. The residue was purified by silica gel chromatography eluting with petroleum ether / ethyl acetate=10:1. Compound 5 (180 mg, 788.31 μmol, 63% yield, 99% purity) was obtained as a yellow solid.

[0199] Step 5) (1S,2S)-2-fluoro-N-(6'-methyl-[6,7'-bibenzo[d]thiazol]-2-yl)cyclopropane-1-carboxamide To a solution of compound 5 (160 mg, 700.72 μmol, 1 equiv.) and compound 6 (304.58 mg, 840.86 μmol, 1.2 equiv.) in dioxane (3 mL) and HO (0.6 mL) was added Pd(dppf)Cl (102.54 mg, 140.14 μmol, 0.2 equiv.) and NaCO (74.27 mg, 700.72 μmol, 1 equiv.) at 10° C. The mixture was stirred at 60° C. for 18 h. The mixture was poured into petroleum ether (10 mL), filtered through silica gel, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10um; mobile phase: [water (0.05% HCl)-ACN]; B%: 44%-64%, 9 min), followed by lyophilization. Example 111 (60 mg, 156.31 μmol, yield 22%, purity 99%) was obtained as a yellow solid. 1H NMR (400MHz, methanol-d4) δ = 9.60 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.52 (dd, J=1.7, 8.3 Hz, 1H), 5.05 (dt, J=3.9, 6.2 Hz, 1H), 2.39 (s, 3H), 2.22 (dtd, J=4.3, 6.9, 9.1 Hz, 1H), 1.96 - 1.83 (m, 1H), 1.39 - 1.28 (m, 1H): LCMS (electrospray) m / z 384.0 (M+H)+.

[0200] Synthesis method Example 112. (1S,2S)-2-Fluoro-N-methyl-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide [ka]

[0201] MeI (28 μL, 0.45 mmol, 1.5 equiv) was dissolved in N,N-dimethylformamide (1 mL) and added dropwise to a stirred solution of Example 4 (100 mg, 0.3 mmol, 1 equiv) and K2CO3 (124 mg, 0.9 mmol, 3 equiv) in N,N-dimethylformamide (2 mL). The mixture was stirred at 50 °C under N2 for 2 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (20 mL × 2) and water (20 mL), and the combined organic layers were dried over Mg2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by a short path of silica gel column chromatography (EA 100% gradient). The resulting precipitate was collected by filtration, washed with ether and dried to give Example 112 as a white solid (47 mg, 0.14 mmol, 46% yield). 1H NMR (400MHz, DMSO-d6) δ = 8.44-8.41 (m, 2H), 8.04 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.47 (dd, J12 = 1.6 Hz, J13 = 8.4 Hz, 1H), 7.35 (t, J = 7.35 Hz, 1H), 5.21 (J12 = 2.9 Hz, J13 = 66.27 Hz, 1H), 3.95 (s, N-CH3, 3H), 2.66-2.62 (m, 1H), 2.29 (s, Me, 3H), 1.83-1.79 (m, 1H), 1.35-1.31 (m, 1H): LCMS (electrospray) m / z 342.1 (M+H)+.

[0202] Synthesis method Y Example 113. (1S,2S)-2-Fluoro-N-(6-(6-(fluoromethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide. TFA salt [ka]

[0203] To a solution of Example 29 (380 mg, 1.06 mmol, 1 equiv) in DCM (5 mL) was added DAST (685.52 mg, 4.25 mmol, 561.90 μL, 4 equiv) at 0° C. The mixture was stirred at 30° C. under N2 atmosphere for 3 h. The reaction mixture was diluted with DCM (5 mL), and the resulting organic phase was then washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 20%-50%, 10 min).

[0204] Example 113 (62 mg, 102.38 μmol, 9% yield, 97% purity, 2TFA) was obtained as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 1.32 (ddt, J=12.84, 8.99, 6.33, 6.33 Hz, 1 H), 1.69 - 1.82 (m, 1 H), 2.20 - 2.28 (m, 1 H), 2.36 (s, 3 H), 4.93 - 5.17 (m, 1 H), 5.46 (s, 1 H), 5.57 (s, 1 H), 7.48 (dd, J=8.31, 1.83 Hz, 1 H), 7.53 (s, 1 H), 7.84 (d, J=8.31 ​​Hz, 1 H), 8.07 (d, J=1.59 Hz, 1 H), 8.48 (s, 1 H), 12.77 (br s, 1 H); LCMS (electrospray) m / z 360.0 (M+H)+.

[0205] Synthesis method Z Example 114. (1S,2S)-2-Fluoro-N-(6-(6-fluoro-5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide. 2HCl salt [ka]

[0206] Step 1) 4-Bromo-6-fluoro-1-(triisopropylsilyl)-1H-indole To a solution of compound 1 (900 mg, 4.20 mmol, 1 equiv) in THF (9 mL) was added NaH (201.82 mg, 5.05 mmol, 60% purity, 1.2 equiv) at 0 °C for 30 min. Then, TIPSCl (972.86 mg, 5.05 mmol, 1.08 mL, 1.2 equiv) was added to the mixture. The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:0 to 100:1). Compound 2 (1.5 g, 4.05 mmol, 96% yield) was obtained as a yellow oil. 1 H NMR (400MHz, CDCl3) δ = 7.28 - 7.26 (m, 1H), 7.19 - 7.10 (m, 2H), 6.65 (dd, J=0.9, 3.3 Hz, 1H), 1.67 (m, J=7.5 Hz, 3H), 1.15 (d, J=7.6 Hz, 18H).

[0207] Step 2) 4-Bromo-6-fluoro-5-methyl-1-(triisopropylsilyl)-1H-indole To a solution of compound 2 (500 mg, 1.35 mmol, 1 equiv) in THF (5 mL) was added LDA (2 M, 1.01 mL, 1.5 equiv) under N2 atmosphere at -78 °C for 30 min. Then MeI (287.42 mg, 2.02 mmol, 126.06 μL, 1.5 equiv) was added to the mixture. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (3 mL) at 25 °C, then diluted with 20 mL of water and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. Compound 3 (500 mg, crude) was obtained as a yellow oil, which was used in the next step without further purification.

[0208] Step 3) 4-Bromo-6-fluoro-5-methyl-1H-indole To a solution of compound 3 (500 mg, 1.30 mmol, 1 equiv) in THF (8 mL) was added TBAF·THF (1 M, 1.30 mL, 1 equiv) at 0°C. The mixture was stirred at 0°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of water and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (silica gel plate, petroleum ether:ethyl acetate=5:1) to give the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 48%-78%, 10 min). The cut fraction was concentrated under reduced pressure to remove ACN, and the residue was washed with saturated aqueous NaHCO3 (10 mL). The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the product. Compound 4 (100 mg, 438.48 μmol, 33% yield) was obtained as a yellow solid. 1 H NMR (400MHz, CDCl3) δ = 8.21 (s, 1H), 7.20 (dd, J=2.4, 3.2 Hz, 1H), 7.06 (d, J=9.8 Hz, 1H), 6.60 - 6.52 (m, 1H), 2.44 (d, J=2.6 Hz, 3H).

[0209] Step 4) (1S,2S)-2-Fluoro-N-(6-(6-fluoro-5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide.2HCl salt To a solution of compound 4 (100 mg, 438.48 μmol, 1 equiv.) and compound 5 (190.59 mg, 526.18 μmol, 1.2 equiv.) in dioxane (2 mL) and H2O (0.5 mL), Pd(dppf)Cl2 (32.08 mg, 43.85 μmol, 0.1 equiv.) and Na2CO3 (92.95 mg, 876.96 μmol, 2 equiv.) were added under N2 atmosphere. The mixture was stirred at 60 °C under N2 atmosphere for 16 h. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25×10um; mobile phase: [water (0.05% HCl)-ACN]; B%: 43%-63%, 10 min). Example 114 (14.4 mg, 27.77 μmol, yield 6%, purity 88%, 2HCl) was obtained as a purple solid. 1 H NMR (400MHz, DMSO-d6) δ = 12.75 (s, 1H), 11.14 (s, 1H), 7.98 (d, J=1.4 Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.45 - 7.40 (m, 1H), 7.29 - 7.25 (m, 1H), 7.19 (d, J=10.5 Hz, 1H), 6.04 - 6.00 (m, 1H), 5.16 - 4.94 (m, 1H), 2.30 - 2.19 (m, 1H), 2.14 (d, J=2.6 Hz, 3H), 1.84 - 1.68 (m, 1H), 1.38 - 1.25 (m, 1H); LCMS (electrospray) m / z 384.10 (M+H)+.

[0210] Table 1 below lists example compounds along with the general synthetic methods used to prepare these compounds and characterization data.

[0211] Table 1. Example compounds [Table 1] TIFF0007605898000032.tif228165 TIFF0007605898000033.tif245165 TIFF0007605898000034.tif230165 TIFF0007605898000035.tif207165 TIFF0007605898000036.tif199165 TIFF0007605898000037.tif211165 TIFF0007605898000038.tif209165 TIFF0007605898000039.tif214165 TIFF0007605898000040.tif239165 TIFF0007605898000041.tif211165 TIFF0007605898000042.tif221165 TIFF0007605898000043.tif247165 TIFF0007605898000044.tif218165 TIFF0007605898000045.tif220165 TIFF0007605898000046.tif217165 TIFF0007605898000047.tif201165 TIFF0007605898000048.tif235165 TIFF0007605898000049.tif219165 TIFF0007605898000050.tif243165 TIFF0007605898000051.tif209165 TIFF0007605898000052.tif211165 TIFF0007605898000053.tif234165 TIFF0007605898000054.tif238165 TIFF0007605898000055.tif250165 TIFF0007605898000056.tif212165 TIFF0007605898000057.tif180165

[0212] Compound evaluation c-abl kinase assay ADP-Glo ​​assay kit was purchased from Promega. Magnesium chloride (MgCl2), bovine serum albumin (BSA), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), tween-20, 1,4-dithiothreitol (DTT) and dimethylsulfoxide (DMSO) were purchased from Sigma-Aldrich. HEPES buffer was purchased from Gibco. ABL1 kinase and Abltide were purchased from Signalchem.

[0213] c-abl kinase activity was measured by Promega's ADP-Glo™ assay. In this assay, His-tagged recombinant human ABL1 (0.25 ng / μL) was incubated with 5 μL of compound (0.5% DMSO), 5 μL of Abltide (0.01 μg / μL) and 5 μL of ATP (25 μM) in buffer (50 mM HEPES, 7.5; 10 mM MgCl2; 1 mM EGTA; 0.05% BSA; 0.01% Tween-20; 2 mM DTT). The assay was initiated by incubating the reaction mixture in a 96-well plate at 30° C. for 30 minutes. After incubation, 25 μL of ADP-Glo ​​reagent was added and the reaction was incubated at room temperature for 40 minutes to stop the reaction and decompose the remaining ATP. The ADP product was then converted to ATP by adding 50 μL of detection reagent per well. Luminescence was detected after 30 min incubation at room temperature using a Molecular device I3X plate reader. IC 50Values ​​were calculated from a series of % inhibition values ​​determined over a range of inhibitory concentrations using software routines implemented in GraphPad Prism 7 software or SigmaPlot 13.0.

[0214] Table 2 shows the IC for the compounds of the examples. 50 Shows.

[0215] Table 2. In vitro activity against c-abl data [Table 2]

[0216] c-KIT kinase assay ADP-Glo ​​assay kit was purchased from Promega. Magnesium chloride (MgCl2), manganese(II) chloride (MnCl2), bovine serum albumin (BSA) and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich. Tris-HCl buffer was purchased from Biosesang. c-Kit kinase and poly(4:1 Glu,Tyr) peptide were purchased from Signalchem.

[0217] c-KIT kinase activity was measured by Promega's ADP-Glo™ assay. In this assay, recombinant human c-Kit (100 ng) is incubated with 5 μL of compound (0.5% DMSO), 5 μL of poly(4:1 Glu,Tyr) peptide (250 ng / μL) and 5 μL of ATP (250 μM) in buffer (40 mM Tris, 7.5; 20 mM MgCl2; 0.1 mg / μL BSA; 2 mM MnCl2; 50 μM DTT). The assay was initiated by incubating the reaction mixture in a 96-well plate at 30° C. for 2 hours. After incubation, 25 μL of ADP-Glo ​​reagent was added and the reaction was incubated at 30° C. for 40 minutes to stop the reaction and decompose the remaining ATP. The ADP product was then converted to ATP by adding 50 μL of detection reagent per well. Luminescence was detected after 30 min incubation at room temperature using a Molecular device I3X plate reader. IC 50 Values ​​were calculated from a series of % inhibition values ​​determined over a range of inhibitory concentrations using software routines implemented in GraphPad Prism 7 software or SigmaPlot 13.0.

[0218] PDGFRα kinase assay ADP-Glo ​​assay kit was purchased from Promega. Magnesium chloride (MgCl2), bovine serum albumin (BSA) and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich. Tris-HCl buffer was purchased from Biosesang. PDGFRα kinase and poly(4:1 Glu,Tyr) peptide were purchased from Signalchem.

[0219] PDGFRα kinase activity was measured by Promega's ADP-Glo™ assay. In this assay, recombinant human PDGFRα (40 ng) was incubated with 5 μL of compound (0.5% DMSO), 5 μL of poly(4:1 Glu,Tyr) (0.5 μg / μL) and 5 μL of ATP (125 μM) in buffer (40 mM Tris, 7.5; 20 mM MgCl2; 0.1 mg / μL BSA; 50 μM DTT). The assay was initiated by incubating the reaction mixture in a 96-well plate at 30° C. for 1 hour. After incubation, 25 μL of ADP-Glo ​​reagent was added and the reaction was incubated at room temperature for 45 minutes to stop the reaction and degrade the remaining ATP. The ADP product was then converted to ATP by adding 50 μL of detection reagent per well. Luminescence was detected using a Molecular device I3X plate reader after 30 min incubation at room temperature. IC 50 Values ​​were calculated from a series of % inhibition values ​​determined over a range of inhibitory concentrations using software routines implemented in GraphPad Prism 7 software or SigmaPlot 13.0.

[0220] Table 3 shows the IC 50 Values ​​are expressed for c-abl, c-Kit and PDGF Ra kinases, and the following nomenclature is used: ND = not tested.

[0221] Table 3. Biochemical activities to test kinase selectivity [Table 3]

[0222] Kinase inhibition assay The kinase inhibition profile of the compounds (Examples 1, 4, 8 and 17) was tested using the SelectScreen Kinase Profiling service (93 kinase panel or 485 kinase panel) from ThermoFisher SCIENTIFIC. We tested the % inhibition against a variety of human kinase activities. Using these panels, the compounds were tested for IC 50 The assay protocols for each kinase are published in ThermoFisher SCIENTIFIC.

[0223] This kinase screening assay is a competitive binding assay that profiles the selectivity of compounds that showed greater than 80% c-abl kinase inhibition, while PI3K, c-kit and PDGFR kinase activity was less than 20%.

[0224] The compounds include AAK1, ACVR1 (ALK2), ACVR1B (ALK4), ACVR2A, ADCK3, ADRBK1 (GRK2), ADRBK2 (GRK3), AKT1 (PKB alpha), AKT2 (PKB beta), AKT3 (PKB gamma), ALK, ALK C1156Y, ALK F1174L, ALK L1196M, ALK R1275Q, ALK T1151_L1152insT, AMPK(A1 / B1 / G2), AMPK(A1 / B1 / G3), AMPK(A1 / B2 / G1), AMPK(A1 / B2 / G2), AMPK(A1 / B 2 / G3), AMPK(A2 / B1 / G2), AMPK(A2 / B1 / G3), AMPK(A2 / B2 / G1), AMPK(A2 / B2 / G2), AMPK(A2 / B2 / G3), AMPK A1 / B1 / G1, AMPK A2 / B1 / G1, AURKA(Aurora A), AURKB(Aurora B), AURKC(Aurora C), AXL, AXL R499C, BLK, BMPR1A (ALK3), BMPR1B (ALK6), BMPR2, BMX, BRAF (lantha), BRAF (Z-LYTE), BRAF V599E (lantha), BRAF V599E (Z-LYTE), BRSK1 (SAD1), BRSK2, BTK, CAMK1 (CaMK1), CAMK1D (CaMKII delta), CAMK1G (CAMKI gamma), CAMK2A (CaMKII alpha), CAMK2B (CaMKII beta), CAMK2D (CaMKII delta), CAMK2G (CaMKII gamma), CAMK4 (CaMKIV), CAMKK1 (CAMKKA), CAMKK2 (CaMKK beta), CASK, CDC42 BPA (MRCKA), CDC42 BPB (MRCKB), CDC42BPG(MRCKG), CDC7 / DBF4, CDK1 / cyclin B, CDK11(inactive), CDK11 / cyclin C, CDK13 / cyclin K, CDK14(PFTK1) / cyclin Y, CDK16(PCTK1) / cyclin Y, CDK17 / cyclin Y, CDK18 / cyclin Y, CDK2 / cyclin A, CDK2 / cyclin A1, CDK2 / cyclin E1, CDK2 / cyclin O, CDK3 / cyclin E1, CDK4 / cyclin D1, CDK4 / cyclin D3, CDK5(inactive), CDK5 / p25, CDK5 / p35, CDK6 / cyclin D1, CDK7 / cyclin H / MNAT1, CDK8 / cyclin C, CDK9(inactive), CDK9 / cyclin K, CDK9 / cyclin T1, CDKL5, CHEK1 (CHK1), CHEK2 (CHK2), CHUK (IKK alpha), CLK1, CLK2, CLK4, CSK, CSNK1A1 (CK1 alpha 1), CSNK1A1L, CSNK1D (CK1 delta), CSNK1E (CK1 epsilon) R178C, CSNK1G1 (CK1 gamma 1), CSNK1G2 (CK1 gamma 2), CSNK1G3 (CK1 gamma 3), CSNK2A1 (CK2 alpha 1), CSNK2A2 (CK2 alpha 2), DAPK1, DAPK2, DAPK3 (ZIPK), DCAMKL1 (DCLK1), DCAMKL2 (DCK2), DDR1, DDR2, DDR2 T654M, DMPK, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, EEF2K, EGFR(ErbB1), EGFR(ErbB1) C797S, EGFR(ErbB1) d746-750, EGFR(ErbB1) d747-749 A750P, EGFR(ErbB1) G719C, EGFR(ErbB1) G719S, EGFR(ErbB1) L858R, EGFR(ErbB1) L861Q, EGFR(ErbB1) T790M, EGFR(ErbB1) T790M C797S L858R, EGFR(ErbB1) T790M L858R, EIF2AK2(PKR), EPHA1, EPHA6, EPHA7, EPHB1, EPHB3, EPHB4, ERBB2(HER2), ERBB4(HER4), ERN1, ERN2, FER, FES(FPS), FGFR1, FGFR1V561M、FGFR2、FGFR2 N549H、FGFR3、FGFR3 G697C、FGFR3 K650E、FGFR3 K650M、FGFR3 V555M、FGFR4、FLT1(VEGFR1)、FLT3、FLT3 D835Y、FLT3 ITD、FLT4(VEGFR3)、FRAP1(mTOR)、FRK(PTK5)、FYN A、GAK、GRK1、GRK4、GRK5、GRK6、GRK7、GSG2(Haspin)、GSK3A(GSK3アルファ)、GSK3B(GSK3ベータ)、HCK、HIPK1(Myak)、HIPK2、HIPK3(YAK1)、HIPK4、HUNK、ICK、IGF1R、IKBKB(IKKベータ)、IKBKE(IKKイプシロン)、INSR、INSRR(IRR)、IRAK4、ITK、JAK1、JAK2、JAK2 JH1 JH2、JAK2 JH1 JH2 V617F、JAK3、KDR(VEGFR2)、KIT、KIT A829P、KIT D816H、KIT D816V、KIT D820E、KIT N822K、KIT T670E、KIT T670I、KIT V559D、KIT V559D T670I、KIT V559D V654A、KIT V560G、KIT V654A、KIT Y823D、KSR2、LATS1、LATS2、LIMK1、LIMK2、LRRK2 I2020T、LRRK2 R1441C、LTK(TYK1)、MAP2K1(MEK1)(lantha)、MAP2K1(MEK1)(Z-LYTE)、MAP2K1(MEK1) S218D S222D、MAP2K2(MEK2)(lantha)、MAP2K2(MEK2)(Z-LYTE)、MAP2K4(MEK4)、MAP2K5(MEK5)、MAP2K6(MKK6)(lantha)、MAP2K6(MKK6)(Z-LYTE)、MAP2K6(MKK6) S207ET211E, MAP3K10(MLK2), MAP3K11(MLK3), MAP3K14(NIK), MAP3K19(YSK4), MAP3K2(MEKK2), MAP3K3(MEKK3), MAP3K5(ASK1), MAP3K7 / MAP3K7IP1(TAK1-TAB1), MAP3K8(COT), MAP3K9(MLK1), MAP4K2(GCK), MAP4K3(GLK), MAP4K5(KHS1), MAPK1(ERK2), MAPK10(JNK3)(lantha), MAPK10(JNK3)(Z-LYTE), MAPK11(p38 beta), MAPK12(p38 gamma), MAPK13(p38 delta), MAPK14(p38 alpha), MAPK14(p38 alpha) Direct, MAPK15(ERK7), MAPK3(ERK1), MAPK7(ERK5), MAPK8(JNK1)(lantha), MAPK8(JNK1)(Z-LYTE), MAPK9(JNK2)(lantha), MAPK9(JNK2) (Z-LYTE), MAPKAPK2, MAPKAPK3, MAPKAPK5(PRAK), MARK1(MARK), MARK2, MARK3, MARK4, MASTL, MATK(HYL), MELK, MERTK(cMER), MERTK(cMER) A708S, MET(cMet), MET(cMET) Y1235D, MET M1250T, MKNK1 (MNK1), MKNK2 (MNK2), MLK4, MST1R (RON), MST4, MUSK, MYLK (MLCK), MYLK4, MYO3A (MYO3 alpha), NEK1, NEK2, NEK4, NEK6, NEK7, NEK8, NEK9, NIM1K, NLK, NUAK1 (ARK5), NUAK2, PAK1, PAK2 (PAK65), PAK3, PAK4, PAK6, PAK7 (KIAA1264), PASK, PDGFRA (PDGFR alpha), PDGFRA D842V, PDGFRA T674I, PDGFRB (PDGFR beta), PDK1, PDK1Direct, PHKG1, PHKG2, PI4K2A (PI4K2 alpha), PI4K2B (PI4K2 beta), PI4KA (PI4K alpha), PI4KB (PI4K beta), PIM1, PIM2, PIM3, PIP4K2A, PIP5K1A, PIP5K1B, PIP5K1C, PKMYT1, PKN1 (PRK1), PKN2 (PRK2), PLK1, PLK2, PLK3, PLK4, PRKACA (PKA), PRKACB (PRKAC beta), PRKACG (PRKAC gamma), PRKCA (PKC alpha), PRKCB1 (PKC beta I), PRKCB2 (PKC beta II), PRKCD (PKC delta), PRKCE (PKC epsilon), PRKCG (PKC gamma), PRKCH (PKC eta), PRKCI (PKC iota), PRKCN (PKD3), PRKCQ (PKC theta), PRKCZ (PKC zeta), PRKD2 (PKD2), PRKG1, PRKG2 (PKG2), PRKX, PTK2 (FAK), PTK2B (FAK2), PTK6 (Brk), RAF1 (cRAF) Y340D Y341D(lantha), RAF1(cRAF) Y340D Y341D(Z-LYTE), RET, RET A883F, RET G691S, RET M918T, RET S891A, RET V804E, RET V804L, RET V804M, RETY791F, ROCK1, ROCK2, ROS1, RPS6KA1(RSK1), RPS6KA2(RSK3), RPS6KA3(RSK2), RPS6KA4(MSK2), RPS6KA5(MSK1), RPS6KA6(RSK4), RPS6KB1( p70S6K), RPS6KB2(p70S6Kb), SBK1, SGK(SGK1), SGK2, SGKL(SGK3), SIK1, SIK3, SLK, SNF1LK2, SPHK1, SPHK2, SRMS(Srm), SRPK1, SRPK2, STK 16(PKL12), STK17A(DRAK1), STK17B(DRAK2), STK22B(TSSK2), STK22D(TSSK1), STK23(MSSK1), STK24(MST3), STK25(YSK1), STK3(MST2), S TK32B(YANK2), STK32C(YANK3), STK33, STK38(NDR), STK38L(NDR2), STK39(STLK3), STK4(MST1), TAOK1, TAOK3(JIK), TBK1, TEC, TEK(TIE2) It showed less than 40% inhibition against R849W, TEK(TIE2) Y1108F, TEK (TIE2) Y897S, TESK1, TESK2, TGFBR1(ALK5), TGFBR2, TLK1, TLK2, TNK1, TNK2(ACK), TTK, TXK, TYK2, TYRO3(RSE), ULK1, ULK2, ULK3, VRK2, WEE1, WNK1, WNK2, WNK3, ZAK, and ZAP70.

[0225] Oral dose pharmacokinetic study in mice Oral dose pharmacokinetic parameters of Examples 1, 4, 5, 6, 8 and nilotinib were evaluated in mice.

[0226] Male ICR mice were fasted for 15 hours before starting the pharmacokinetic experiments and were orally administered a single dose of 5 mg / kg of compound dissolved in 20% dimethyl sulfoxide (DMSO) / 1% Tween-20 / 79% NS solution. To observe the pharmacokinetics of the compound, blood from each mouse was collected from the retroorbital plexus at specific time points after administration (5, 15, 30 and 60 min, 1.5, 2, 3, 4, 6, 8, 10 and 24 h, n=3 for each time point) using sodium heparin-treated capillary tubes. Plasma samples were separated by centrifugation at 10,000 rpm for 5 min and stored at -80°C until analysis. For compound exposure, mouse brains were collected at 30 and 60 min, 2, 4 and 24 h (n=1 for each time point) after treatment with 5 mg / kg compound, and matching plasma samples were also collected and then stored at -80°C until analysis. Freshly thawed brain samples were weighed and homogenized in 3 volumes of PBS.

[0227] Plasma and homogenized brain were treated with acetonitrile to precipitate proteins. After shaking and centrifugation, the supernatant was diluted 3-fold with distilled water and analyzed using an ExionLC™ ultra-performance liquid chromatograph (SCIEX, USA) coupled with a SCIEX 6500+ triple quadrupole mass spectrometry (SCIEX, USA) (LC-MS / MS). Ten microliters of each sample was injected onto a CORTECS C18+ 2.1 mm×50 mm ID, 2.7 um column (Water, USA) and separated at a flow rate of 0.3 mL / min by gradient conditions using mobile phases (A: 0.1% formic acid in water, B: 0.1% formic acid in ACN). Peak integration and areas were determined using Analyst software (SIEX, USA) and non-compartmental pharmacokinetic analysis by mean concentrations was performed using Phoenix WinNonlin® software version 8.0 (Pharsight Corp, USA).

[0228] Plasma AUC after oral administration at a dose of 5 mg / kg INFThe results (min x ng / mL) and brain / plasma concentration ratios (BP ratios) are shown in Table 4. All examples show better brain exposure than nilotinib.

[0229] Table 4. Pharmacokinetic parameters of Examples 1, 4, 5, 6, 8 and Nilotinib [Table 4] a BP ratios from brain and matched plasma AUC INF Calculations were made based on the values.

[0230] In vitro efficacy verification c-abl is active in Parkinson's disease, and recent studies have shown that c-abl is activated in a time-dependent manner by treatment with α-synuclein preformed fibrils (PFFs), and α-synuclein PFFs are significantly reduced in neurons by treatment with the c-abl inhibitor nilotinib (Zui-Hua Zhou et al. Neurol Sci. 2016).

[0231] However, nilotinib is known to cause cardiovascular adverse events, such as QTc prolongation and irregular heart rate, which may lead to sudden death. These adverse events (black box warning) may be due to its hERG activity. Nilotinib, ponatinib, and dasatinib have hERG IC values ​​of 0.13, 2.33, and 14.3 μM, respectively. 50 Furthermore, nilotinib does not display c-ABL kinase selectivity or high BBB penetration, which may mean that nilotinib is not suitable for use in chronic neurodegenerative diseases.

[0232] Examples 4 and 8 showed little hERG activity (23.87% and 12.61% inhibition at 10 μM, respectively), indicating that the compounds are unlikely to cause adverse cardiovascular events. Example 4 reduced α-synuclein PFF-induced pathological aggregation (Lewy body-like pathology), and Examples 4 and 8 dose-dependently (doses: 0.5, 1, 5, 10, 100 nM) inhibited PFF-induced neuronal toxicity.

[0233] Examples 4 and 8 have a better PK profile and better brain exposure than nilotinib in mice.

[0234] Table 5. Comparison of Nilotinib with Examples 4 and 8 [Table 5]

[0235] Validation of in vivo efficacy in AD and PD models The pharmacological activity of Examples 4 and 8 was 25-35 This was estimated in α-synuclein preformed fibrils (PFFs)-induced Alzheimer's disease (AD) and α-synuclein preformed fibrils (PFFs)-induced Parkinson's disease (PD) mouse models.

[0236] In vivo efficacy in PD models The phosphorylation of α-synuclein at ser129 was increased in the α-synuclein PFF-induced PD model, and was statistically reduced by approximately 50% and 80% by oral administration of Example 4 (3 and 10 mg / kg, qd), respectively. Meanwhile, nilotinib (3 and 10 mg / kg, qd) had no statistical effect on the phosphorylation of α-synuclein. This means that Example 4 is a strong candidate for improving Lewy body pathology.

[0237] In α-synuclein PFF-induced PD mice, Example 4 (0.3, 1, 3 and 10 mg / kg) and nilotinib (3, 10 and 30 mg / kg) were orally administered once a day for 5 months, and a pole test was performed to evaluate the motor disorder of the α-synuclein PFF-induced PD mice. The extension of the pole climbing time (seconds) caused by α-synuclein PFF injection was dose-dependently restored by treatment with Example 4. 0.3 mg / kg Example 4 brought about a 50% improvement in the pole climbing time, and 10 mg / kg completely restored it. Meanwhile, nilotinib showed only a slight improvement at 10 mg / kg.

[0238] The compound dose-dependently induced behavioral recovery in mice from α-synuclein PFF-induced motor dysfunction, indicating that the compound is a disease-modifying agent for neurodegenerative disorders including Parkinson's disease and potentially dementia with Lewy bodies.

[0239] In vivo efficacy in AD models Example 4 (1, 3 and 10 mg / kg), Example 8 (1 and 3 mg / kg) and nilotinib (3 mg / kg) were used to treat Aβ 25-35 Induced AD mice were orally administered once daily for 10 days and then subjected to spontaneous alternation ability in a Y-maze, spatial working memory, and step-through passive avoidance (STPA) tests. The Y-maze test was used as a behavioral test to evaluate the rodents' memory function and willingness to explore a novel environment.

[0240] Oligomeric Aβ 25-35 ICV injection of the peptide triggered neurotoxic effects and behavioral deficits in the Y-maze test assessing short-term memory by measuring spontaneous alternation, but no motor changes were observed by measuring locomotion.

[0241] Oligomeric Aβ 25-35 Ten days after ICV injection of the peptide, the hippocampus was dissected, and lipid peroxidation levels were quantified in hippocampal homogenates. 25-35ICV injection of the peptide induced lipid peroxidation, a marker of oxidative stress. Oral administration of 3 mg / kg and 10 mg / kg Example 4 once daily completely inhibited lipid peroxidation, indicating a reduction in oxidative stress (Figure 7).

[0242] Oxidative stress mediates Aβ accumulation via mitochondrial dysfunction. 25-35 This is thought to be the main mechanism of peptide-induced neuronal toxicity (Reference: Meunier et al. Eur J. Pharm 2012), which is successfully inhibited by Example 4.

[0243] This shows that Example 4 very significantly and completely alleviated the deficits in alternation behavior and contextual long-term memory in a dose-response manner, whereas nilotinib only partially alleviated the deficits in spatial working memory or showed no significant effect on the deficits in contextual long-term memory.

[0244] The results are shown in Figures 1 to 7. The results indicate that the compounds have high neuroprotective activity and low cardiovascular events and therefore may be useful in treating or suppressing neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and / or ALS.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R １ is cyclopropyl, wherein said cyclopropyl is substituted with one or more groups selected from the group consisting of halo, alkyl, hydroxyl, hydroxyalkyl, and haloalkyl; R ２ and R ３ are independently -H, halo, alkyl, alkoxy, -CF ３ Or -OCF ３ and R ４ is aryl, monocyclic heteroaryl, cycloalkyl, or heterocyclyl, where the aryl, monocyclic heteroaryl, cycloalkyl, or heterocyclyl is halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, trimethylsilylethoxymethyl, -NO ２ , -NR ａ R ｂ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)NR ａ R ｂ , -NR ａ C(=O)OR ｂ , -OR ａ , -CN, -C(=O)R ａ , -C(=O)OR ａ , -C(=O)NR ａ R ｂ , -OC(=O)R ａ , -OC(=O)OR ａ , -OC(=O)NR ａ R ｂ , -SR ａ , azetidinyl, oxetanyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, phenyl, tetrahydropyranyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; R ａ and R ｂ are independently -H, halo, amino, alkyl, or haloalkyl. or a pharma- ceutically acceptable salt thereof.

2. R １ is cyclopropyl, wherein said cyclopropyl is halo, C １ ~C ３ Alkyl, C １ ~C ３ Hydroxyalkyl and C １ ~C ３ substituted with one or more groups selected from the group consisting of haloalkyl; R ２ and R ３ are independently -H, halo, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, -CF ３ Or -OCF ３ and R ４ is aryl, monocyclic heteroaryl, cycloalkyl, or heterocyclyl, wherein said aryl, monocyclic heteroaryl, cycloalkyl, or heterocyclyl is selected from halo, hydroxyl, C １ ~C ３ Alkyl, C ２ ~C ３ Alkenyl, C ２ ~C ３ Alkynyl, C １ ~C ３ Haloalkyl, -NO ２ , -NR ａ R ｂ , -NR ａ C(=O)R ｂ , -NR ａ C(=O)NR ａ R ｂ , -NR ａ C(=O)OR ｂ , -OR ａ , -CN, -C(=O)R ａ , -C(=O)OR ａ , -C(=O)NR ａ R ｂ , -OC(=O)R ａ , -OC(=O)OR ａ , -OC(=O)NR ａ R ｂ , -SR ａ , azetidinyl, oxetanyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, phenyl, tetrahydropyranyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; R ａ and R ｂ are independently -H, halo, amino, C １ ~C ３ Alkyl or C １ ~C ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

3. R １ But Fluoro, C １ ~C ３ Alkyl, C １ ~C ３ Hydroxyalkyl and C １ ~C ３ cyclopropyl substituted with one or more groups selected from the group consisting of fluoroalkyl; R ２ and R ３ are independently -H, -F, -Br, -Cl, １ ~C ３ Alkyl or -CF ３ and R ４ is phenyl, pyridinyl, thiophenyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, or pyridazinyl, wherein said phenyl, pyridinyl, thiophenyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl, pyrrolyl, or pyridazinyl is selected from the group consisting of halo, hydroxyl, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, -NR ａ R ｂ , -OR ａ , -CN, -C(=O)R ａ , -C(=O)OR ａ , -OC(=O)R ａ , -OC(=O)OR ａ , -SR ａ , pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and pyrrolyl; R ａ and R ｂ are independently -H, halo, amino, C １ ~C ３ Alkyl or C １ ~C ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

4. R １ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is cyclopropyl substituted with one or more groups selected from the group consisting of fluoro, methyl, ethyl, hydroxymethyl, and hydroxyethyl.

5. R １ is fluorocyclopropyl, hydroxymethylcyclopropyl, or difluorocyclopropyl; R ２ and R ３ The compound of claim 1, wherein is independently -H, methyl or fluoro, or a pharma- ceutically acceptable salt thereof.

6. R ４ are fluoro-methylphenyl, chloro-methylphenyl, dimethylphenyl, acetamido-methylphenyl, hydroxy-methylphenyl, hydroxypropanyl-methylphenyl, methyl-propenylphenyl, methyl-pyrrolylphenyl, methyl-thiazolylphenyl, imidazolyl-methylphenyl, cyano-methylphenyl, methyl-pyrazolylphenyl, ethynyl-methylphenyl, methylpyridinyl, fluoro-methyl-methylaminophenyl, dimethylpyridinyl, fluoro-methylpyridinyl, fluoromethyl-methylpyridinyl, cyanopyridinyl, trifluoromethyl-methylpyridinyl, 2. The compound of claim 1, which is ethylpyridinyl, hydroxymethylpyridinyl, hydroxymethyl-methylpyridinyl, hydroxyethyl-methylpyridinyl, chloro-methylpyridinyl, aminopyridinyl, acetyl-methylpyridinyl, amino-dimethylpyridinyl, hydroxyethyl-methylpyridinyl, methylpyrimidinyl, dimethylpyrimidinyl, trifluoromethylpyrimidinyl, pyrazolyl, methylthiazolyl, methyl-tetrahydropyranyl, methylpyrazolyl, methylisothiazolyl, chloro-methylisothiazolyl, or dimethylisothiazolyl,

7. R ４ is fluoro-methylphenyl, chloro-methylphenyl, dimethylphenyl, acetamido-methylphenyl, hydroxy-methylphenyl, methyl-propenylphenyl, ethynyl-methylphenyl, fluoro-methyl-methylaminophenyl, methyl-pyrrolylphenyl, methyl-thiazolylphenyl, cyano-methylphenyl, imidazolyl-methylphenyl, methylpyridinyl, chloro-methylpyridinyl, fluoro-methylpyridinyl, fluoromethyl-methylpyridinyl, dimethylpyridinyl, aminopyridinyl, amino-dimethylpyridinyl, methoxypyridinyl, acetyl-methylpyridinyl, hydroxymethylpyridinyl, hydroxymethyl-methylpyridinyl, hydroxyethyl-methylpyridinyl, cyanopyridinyl, trifluoromethylpyridinyl, methylthiophenyl, methylpyrimidinyl, dimethylpyrimidinyl, pyrazolyl, methylpyrazolyl, methylpyrrolyl, methylisothiazolyl, or dimethylisothiazolyl.

8. R ４ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, thiophenyl, and isothiazolyl, wherein said phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, thiophenyl, or isothiazolyl is optionally substituted with one or more groups selected from the group consisting of halo, alkyl, alkynyl, hydroxyalkyl, amino, cyano, acetyl, hydroxy, and haloalkyl.

9. R ４ is a group represented by the following formula: 【Chemistry 2】 2. The compound of claim 1, selected from the group consisting of:

10. R １ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein is fluorocyclopropyl.

11. 2-fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-chloro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2,6-dimethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-methyl-5-(prop-1-en-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(5-(2-hydroxypropan-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(6-amino-2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylthiophen-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(6-acetyl-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4,6-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(6-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(6-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(6-(1-hydroxyethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-methyl-5-(1H-pyrazol-1-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(5-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(4-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(4-fluoro-6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methylthiazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4,6-dimethylpyrimidin-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(5-ethynyl-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4-chloropyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4-cyanopyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(trifluoromethyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-methyl-5-(1H-pyrrol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-methyl-5-(thiazol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(5-cyano-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(4-methyl-1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-methyl-5-(1H-pyrrol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-methyl-5-(1H-pyrazol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylisothiazol-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-chloro-3-methylisothiazol-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(3,4-dimethylisothiazol-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(5-(1H-imidazol-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(6-(fluoromethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(5-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(6-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylpyridin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylpyridin-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-ethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-vinylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-ethynylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4-bromopyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-(trifluoromethoxy)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(4-(difluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(5-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(4,5-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(o-tolyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-ethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-vinylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-ethynylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2-bromophenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methoxyphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-(trifluoromethoxy)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-(trifluoromethyl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-(difluoromethyl)phenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-(hydroxymethyl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(3-fluoro-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(3-chloro-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(6-(2,3-dimethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; N-(4-chloro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)-4-(trifluoromethyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(4-methoxy-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(4-methyl-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(5-chloro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(4-methylpyridin-3-yl)-5-(trifluoromethyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(5-methoxy-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(5-methyl-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-imidazol-2-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(4-methyl-1H-imidazol-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-imidazol-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-Fluoro-N-(6-(2-methyl-1H-imidazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(3-methylpyrazin-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(4-methyloxazol-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(3-methyl-1H-pyrrol-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-benzo[d]imidazol-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(5-methyl-1H-benzo[d]imidazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(4-methylpyridazin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; and 2-Fluoro-N-(6-(5-methylpyridazin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide 11. The compound of claim 10, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

12. R １ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein: is hydroxymethylcyclopropyl; or a pharma- ceutically acceptable salt thereof.

13. 2-(hydroxymethyl)-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; and N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide 13. The compound of claim 12, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

14. R １ 2. The compound according to claim 1, wherein is hydroxycyclopropyl or difluorocyclopropyl, or a pharma- ceutically acceptable salt thereof.

15. 2-Hydroxy-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2,2-difluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2,2-difluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; and 2,2-difluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide 15. The compound of claim 14, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

16. (1S,2S)-2-fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; and (1S,2S)-2-fluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide 2. The compound of claim 1, selected from the group consisting of:

17. Formula (II): 【Chemistry 3】 [In the formula, R 2 and R 3 are independently -H, halo, alkyl, alkoxy, -CF 3 or -OCF 3 ; R 4 is aryl, monocyclic heteroaryl, cycloalkyl, or heterocyclyl, where said aryl, monocyclic heteroaryl, cycloalkyl, or heterocyclyl is halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, trimethylsilylethoxymethyl, -NO 2 , -NR a R b , -NR a C(═O)R b , -NR a C(═O)NR a R b , -NR a C(═O)OR b , -OR a , -CN, -C(═O)R a , -C(═O)OR a , -C(═O)NR a R b , -OC(═O)R a , -OC(═O)OR a , -OC(═O)NR a R b , -SR a , azetidinyl, oxetanyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, phenyl, tetrahydropyranyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl; R a and R b are independently —H, halo, amino, alkyl, or haloalkyl; R ５ But, Halo, C １ ~C ３ Alkyl, C １ ~C ３ Hydroxyalkyl and C １ ~C ３ haloalkyl] 2. The compound according to claim 1, which is a compound represented by the formula: or a pharma- ceutically acceptable salt thereof.

18. R ４ is fluoro-methylphenyl, chloro-methylphenyl, dimethylphenyl, acetamido-methylphenyl, hydroxy-methylphenyl, methyl-propenylphenyl, ethynyl-methylphenyl, fluoro-methyl-methylaminophenyl, methyl-pyrrolylphenyl, methyl-thiazolylphenyl, cyano-methylphenyl, imidazolyl-methylphenyl, methylpyridinyl, chloro-methylpyridinyl, fluoro-methylpyridinyl, fluoromethyl-methylpyridinyl, dimethylpyridinyl, aminopyridinyl, amino-dimethylpyridinyl, methoxypyridinyl, acetyl-methylpyridinyl, hydroxymethylpyridinyl, hydroxymethyl-methylpyridinyl, hydroxyethyl-methylpyridinyl, cyanopyridinyl, trifluoromethylpyridinyl, methylthiophenyl, methylpyrimidinyl, dimethylpyrimidinyl, pyrazolyl, methylpyrazolyl, methylpyrrolyl, methylisothiazolyl, or dimethylisothiazolyl.

19. (1S,2S)-2-fluoro-N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(2-chloro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(2,6-dimethylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(2-methyl-5-(prop-1-en-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(2-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(5-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(5-(2-hydroxypropan-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(3-hydroxy-2-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(6-amino-2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(3-methylthiophen-2-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-methylpyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(6-acetyl-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(4,6-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(6-chloro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-(hydroxymethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-(1-hydroxyethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(1H-pyrazole-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(2-methyl-5-(1H-pyrazol-1-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(5-(hydroxymethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(4-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(4-fluoro-6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(5-methylthiazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(4,6-dimethylpyrimidin-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-ethynyl-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(4-chloropyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(4-cyanopyridin-3-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(2-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-(trifluoromethyl)pyrimidin-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(2-methyl-5-(1H-pyrrol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(2-methyl-5-(thiazol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-cyano-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(4-methyl-1H-pyrazol-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(2-methyl-5-(1H-pyrrol-2-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(2-methyl-5-(1H-pyrazol-3-yl)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(3-methylisothiazol-5-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(4-chloro-3-methylisothiazol-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(3,4-dimethylisothiazol-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-N-(6-(5-(1H-imidazol-2-yl)-2-methylphenyl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(6-(fluoromethyl)-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(5-fluoro-6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; and (1S,2S)-2-fluoro-N-(6-(6-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide 18. The compound of claim 17, selected from the group consisting of:

20. (2-(2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)boronic acid; 2-Fluoro-N-(6-(7-methyl-2-oxoindolin-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methyl-2-oxoindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(4-methyl-2-oxo-2,3-dihydro-[5,6'-bibenzo[d]thiazol]-2'-yl)cyclopropane-1-carboxamide; N-(6-(4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)cyclopropanecarboxamide; 3-(2-(2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-4-methylpyridine 1-oxide; 2-Fluoro-N-(6-(5-methylindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1-acetyl-5-methylindolin-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(2-fluoro-6-methyl-3-(methylamino)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)-cyclopropane-1-carboxamide; N-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(7-methyl-1H-indazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(7-methyl-1H-indazol-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6'-methyl-[6,7'-bibenzo[d]thiazol]-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(6-fluoro-5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-Fluoro-N-(6-(6-fluoro-5-methylindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(1H-pyrrolo[2,3-b]pyridin-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; 2-fluoro-N-(6-(5-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-fluoro-N-(6-(5-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; 2-(hydroxymethyl)-N-(6-(5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; N-(6-(6-fluoro-5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)-2-(hydroxymethyl)cyclopropane-1-carboxamide; N-(6-(5-fluoro-4-methylpyridin-3-yl)benzo[d]thiazol-2-yl)-2-((methylamino)methyl)cyclopropane-1-carboxamide; and N-(6-(2-fluoro-6-methylphenyl)benzo[d]thiazol-2-yl)-2-((methylamino)methyl)cyclopropane-1-carboxamide or a pharma- ceutically acceptable salt thereof.

21. (2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)boronic acid; (1S,2S)-2-fluoro-N-(6-(7-methyl-2-oxoindolin-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(5-methyl-2-oxoindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(4-methyl-2-oxo-2,3-dihydro-[5,6'-bibenzo[d]thiazole]-2'-yl)cyclopropane-1-carboxamide; 3-(2-((1S,2S)-2-fluorocyclopropane-1-carboxamido)benzo[d]thiazol-6-yl)-4-methylpyridine 1-oxide; (1S,2S)-2-fluoro-N-(6-(5-methylindolin-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(1-acetyl-5-methylindolin-4-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(2-fluoro-6-methyl-3-(methylamino)phenyl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-N-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzo[d]thiazol-2-yl)-2-fluorocyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(7-methyl-1H-indazol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6-(7-methyl-1H-indazol-6-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-fluoro-N-(6'-methyl-[6,7'-bibenzo[d]thiazol]-2-yl)cyclopropane-1-carboxamide; and (1S,2S)-2-Fluoro-N-(6-(6-fluoro-5-methyl-1H-indol-4-yl)benzo[d]thiazol-2-yl)cyclopropane-1-carboxamide 21. The compound of claim 20, which is a stereoisomer selected from the group consisting of:

22. 22. The compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, wherein the salt is a hydrochloride, a formate or a trifluoroacetate.

23. A pharmaceutical composition for treating a neurodegenerative disease, comprising a compound according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof.

24. 24. The pharmaceutical composition of claim 23, further comprising one or more active ingredients useful for treating a neurodegenerative disease.

25. The pharmaceutical composition according to claim 23, wherein the neurodegenerative disease is α-synucleinopathy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy (MSA), Alzheimer's disease or amyotrophic lateral sclerosis (ALS).

26. 24. The pharmaceutical composition according to claim 23, wherein the subject to which it is to be administered is a human.

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