Modulators of mitochondrial DNA replication

Abstract

The present disclosure provides compounds of Formula (I), their pharmaceutically acceptable salts, and pharmaceutical compositions thereof, which relate to novel DNA polymerase γ (POLγ) modulators.

Description

MODULATORS OF MITOCHONDRIAL DNA REPLICATION PRIORITY CLAIM

[0001] This application claims the benefit of U.S. provisional application no.63 / 526,814, filed July 14, 2023, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] Embodiments of the invention relate to novel DNA polymerase γ (POLγ) modulators, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. Embodiments of the invention also relate to methods of using such compounds and compositions, including to modulate POLγ. BACKGROUND OF THE INVENTION

[0003] Human mitochondria contain multiple copies of a circular, double-stranded (ds) DNA genome (mtDNA), and a dedicated DNA replication machinery is required for maintaining the mitochondrial genome. POLγ is the replicative polymerase essential for maintaining the mtDNA. POLγ is a heterotrimer in human cells with one catalytic subunit (POLγA) and two accessory subunits (POLγB). POLγA belongs to the family A DNA polymerases. POLγA is 1239 amino acids in length and consists of three distinct regions: an N-terminal exonuclease domain connected by a linker domain to the C-terminal polymerase domain. The accessory POLγB is 485 amino acids in length and the crystal structures of both mouse and human POLγB have revealed the protein as a dimer with high similarities to aminoacyl tRNA synthetases. POLγB acts as a processivity factor, which increases the affinity of the polymerase for DNA and promotes tighter nucleotide binding, thereby increasing the polymerase rate. See, e.g., Gustafsson, C.M., et al., “Maintenance and expression of mammalian mitochondrial DNA,” Annu. Rev. Biochem., 85:133-160 (2016) (Gustafsson 2016) and Farge, G., et al., “The accessory subunit B of DNA polymerase γ is required for mitochondrial replisome function,” Nucleic Acids Res., 35:902-911 (2007).

[0004] A primary biological role of POLγ is to replicate the mitochondrial genome. However, POLγ cannot replicate the ds mtDNA alone. It acts together with a DNA helicase (TWINKLE) and the mitochondrial single-stranded DNA-binding protein (mtSSB). TWINKLE is 684 amino acids in length and forms a hexamer in solution. TWINKLE travelsin front of POLγ during mtDNA replication, unwinding the dsDNA and creating a single- stranded (ss) DNA template that POLγ can utilize. The mtSSB is 148 amino acids in length and is active as a tetramer. It binds to ssDNA, protects this DNA against nucleases, and prevents secondary structure formation so POLγ can use ssDNA as a template to synthesize dsDNA. The mtSSB enhances mtDNA synthesis by increasing the processivity of POLγ and also stimulates TWINKLE’s helicase activity. POLγ cannot initiate DNA synthesis de novo, as it needs a short RNA primer to initiate DNA synthesis. In mitochondria, the mitochondrial RNA polymerase (POLRMT) has a dual function; it acts as an RNA polymerase involved in mtDNA transcription but it also synthesizes the primers needed to initiate mtDNA replication from mitochondrial origins of replication. See, e.g., Gustafsson 2016.

[0005] The mitochondrial genome encodes subunits of the oxidative phosphorylation (OXPHOS) system. The OXPHOS system is composed of four respiratory chain complexes, which are responsible for electron transport and generation of the proton gradient across the mitochondrial inner membrane. ATP synthase uses this proton gradient to produce ATP. See, e.g., id. The biogenesis of the OXPHOS system is under dual genetic control and requires the concerted expression of nuclear DNA and mtDNA encoded genes. Mitochondria contain multiple copies of ds mtDNA, which encodes 2 ribosomal RNAs (mt-rRNAs), 22 transfer RNAs (mt-tRNAs), and 11 messenger RNAs (mt-mRNAs) producing 13 protein subunits of OXPHOS complexes I, III, IV, and ATP synthase (sometime referred to as complex V). The biogenesis of the OXPHOS system is critically dependent on the mtDNA-encoded subunits as they typically have key catalytic roles or are core subunits for OXPHOS assembly. Similar to the nuclear genome, expression of mammalian mtDNA requires several essential steps, including genome maintenance, replication, transcription, RNA maturation, and translation. All proteins involved in these processes are encoded in the nuclear genome, translated in the cytosol, and imported into the mitochondrial network. It is estimated that approximately one quarter of the ~1200 nucleus-encoded mitochondrial proteins are devoted to the control of mtDNA gene expression in mammals. See, e.g., Shokolenko, I.N., et al., “Mitochondrial transcription in mammalian cells,” Front. Biosci. (Landmark Ed.), 22:835-853 (2017). POLγ is required for mtDNA synthesis and is thus essential for biogenesis of the OXPHOS system, resulting in ATP production. ATP production is in turn vital for energy homeostasis in the cell.

[0006] There are over 300 POLγ mutations correlated to a broad clinical spectrum of neurodegenerative and mitochondrial diseases. See, e.g., Rahman, S., et al., “POLG-related disorders and their neurological manifestations,” Nat. Rev. Neurol., 15:40-52 (2019) (Rahman 2019). Many disease-causing variants of POLγ are associated with decreased replication processivity of the mtDNA replication machinery, leading to replication stalling.

[0007] In view of the numerous and varied roles of POLγ, the need exists for potent and specific compounds that increase the processivity of POLγ. SUMMARY OF THE INVENTION

[0008] Provided are compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions comprising the compounds or their salts for increasing the processivity of POLγ.

[0009] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (I): (I)R1is selected from the group consisting of H, C1-C3alkyl, Cl, F, CN, and O-C1-C6alkyl optionally substituted with one or more halogen; R2is H or C1-C3alkyl optionally substituted with OR5; R3is each independently H or C1-C4alkyl optionally substituted with one or more halogen or OH; R4is C-R5or S, wherein one R4is C-R5and the other R4is S;Z is selected from the group consisting of C1-C6alkyl, C1-C6alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl-cycloalkyl, aryl-heterocyclyl, aryl-heteroaryl, and sulfonamide, wherein the C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more halogen, phenyl, OR5, halogen, C(O)NR5R6, NR5R6, NR5-C(O)CH3, SO2R5, NH-SO2R5, heterocyclyl, aryl, heteroaryl, and aryl-heteroaryl, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, C1-C3alkyl-OH, C1-C3alkyl-O-C1-C3alkyl, C(O)OR5, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, keto, C3-C6cycloalkyl, C(O)CH3, C(O)NR5R5, NH- C(O)R5, NH-SO2R5, and C1-C4alkyl that is optionally substituted with one or more F or OH, wherein aryl is optionally substituted with one or more groups selected from the group consisting of: C1-C4alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, and NR5R6, C3-C6cycloalkyl that is substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, NR5R6, SO2R6, SO2NR5R6, SO(NH)R5, S(NR)(NH)R5, P(O)R5R5, and 4- or 5,6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more groupsindependently selected from the group consisting of F, Cl, OR5, CN, C1-C4alkyl, oxo, and NR5R6, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, OR5, NR5R6, oxo, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, OR5, and C(O)NR5R6; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with a group selected from the group consisting of OR5, Cl, and F; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1-C5alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C5alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cycloalkyl optionally substituted with one or more halogens; n is 1-4; p is 1-2; with the proviso that a compound selected from the group consisting of: (S)-1-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea, 1-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and 1-(5-cyclopropylthiazol-4-yl)-3-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

[0010] Further embodiments of the present invention are compounds of formula (I) and their pharmaceutically acceptable salts wherein one or more hydrogen is substituted with a deuterium atom.

[0011] Additional embodiments of the invention are pharmaceutical compositions comprising a compound of the invention, a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0012] The term “alkyl” as used herein refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms in a specified range. For example the term “C1-C7alkyl” means linear or branched chain alkyl groups, including all possible isomers, having 1, 2, 3, 4, 5, 6, or 7 carbon atoms. Furthermore, alkyl groups allow for substituents to be located on any of the carbon atoms. For example, a substituted C3alkyl group allows for the substituent to be located on any one, or more, of the three carbon atoms.

[0013] The term “alkoxy” or “alkoxyl” as used herein refers to an -O-alkyl group. For example, the term “C1-C4alkoxyl” means -O-C1-C4alkyl. In certain embodiments, alkoxy may be represented by “OR” wherein R is an optionally substituted alkyl group. Examples of alkoxyl include methoxyl, ethoxyl, propoxyl (e.g., n-propoxyl and isopropoxyl), and the like.

[0014] The term “azole” as used herein refers to a class of five-membered heterocyclic compounds containing a nitrogen atom and at least one other non-carbon atom (i.e., nitrogen, sulfur, or oxygen) as part of the ring. Examples of azole rings include, but not limited to, pyrrole, furazan, pyrazole, thiazole, oxazole, triazole, thiadiazole, oxadiazole, imidazole, 1,2 pyrazole, 2,3 thiazole, 2,4 thiazole, 2,3 oxazole, 1,2,4 triazole, 1,2,4 thiadiazole, and 1,2,4 oxadiazole.

[0015] The term “halogen” or “halo” as used herein refers any of the six nonmetallic elements that constitute Group 17 (Group VIIa) of the periodic table. The halogen elements include, but are not limited to, fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), and iodine or iodo (I).

[0016] The term “cycloalkyl” as used herein refers to a completely saturated or partially unsaturated cyclic group that includes monocyclic or multicyclic ring system. In certain embodiments, cycloalkyl groups contain 3 to 14 carbon atoms in the ring system (“C4-C14cycloalkyl”) In certain embodiments each of the cycloalkyl rings may contain one or moredouble or triple bonds. Examples of cycloalkyl include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.0]hexane, octahydro-1H-indene, decahydronaphthalene, and tetradecahydroanthracene.

[0017] The term “heterocyclyl” refers to a cycloalkyl group, as described above, in which at least one or more heteroatoms are present in a ring that includes, but is not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms, wherein the heteroatom may be oxidized, e.g., NO, SO, SO2, SO4, and the N may be quaternized. In certain embodiments, heterocyclyl groups contain 3 to 14 atoms in the ring system (“3- to 14-membered heterocyclyl”). Heterocyclyl can be attached to the core structure via a ring carbon atom or a ring heteroatom. Typical monocyclic heterocyclyl rings include, but are not limited to, azetidinyl, pyrrolidyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidyl, piperazinyl, hexahydroazepinyl, 4- piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxanyl, and tetrahydro- 1,1-dioxythienyl.

[0018] The term “aryl” as used herein refers to a monocyclic or multicyclic ring system having the characteristics of a conjugated pi-electron system. In certain embodiments, aryl groups contain 4 to 14 carbon atoms in the ring system (“C4-C14aryl”). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthalenyl, anthracenyl, and phenantherenyl.

[0019] The term “heteroaryl” or “heteroaromatic” as used herein refers to an aryl group, as described above, containing one or more heteroatoms that includes, but is not limited to, N, O, and S atoms, wherein the heteroatom may be oxidized, e.g., NO, SO, SO2, SO4, and the N may be quaternized. In certain embodiments, heteroaryl or heteroaromatic groups contain 4 to 14 atoms in the ring system (“4- to 14-membered heteroaryl”). Examples, without limitation, include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl or 1,2,4-triazolyl), tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl (i.e., 1,2,3-, 1,2,4-, 1,2,5-(furazanyl), or 1,3,4-isomers), oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzofuran, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoxadiazolyl, benzpyrazinyl, indolyl,indazolyl, indolizinyl, pteridinyl, purinyl, phthalazinyl, quinazolinyl, quinolinyl, and quinolizinyl.

[0020] The term “aryl-cycloalkyl” as used herein refers to an aryl group, as defined above, that is fused to a cycloalkyl group, as defined above, by any two or more atoms in the ring. In certain embodiments, aryl-cycloalkyl groups contain 6 to 14 atoms in the ring system (“6- to 14-membered aryl-cycloalkyl”). Aryl-cycloalkyl can be attached to the core structure via a ring carbon atom on the aryl ring or on the cycloalkyl ring. Examples of aryl-cycloalkyl include, but are not limited to, indane, indene, tetrahydronaphthalene, 1,4- dihydronaphthalene, and bicyclo[4.2.0]octa-1,3,5-triene.

[0021] The term “aryl-heteroaryl” as used herein refers to an aryl group, as defined above, that is fused to a heteroaryl group, as defined above. Examples of aryl-heteroaryl include quinoline, quinazoline, quinoxaline, and benzofuran.

[0022] The term “heteroaryl-cycloalkyl” as used herein refers to a heteroaryl group, as defined above, which is fused to a cycloalkyl group, as defined above, by any two or more atoms in the ring. In certain embodiments, heteroaryl-cycloalkyl groups contain 6 to 14 atoms in the ring system (“6- to 14-membered heteroaryl-cycloalkyl”). Heteroaryl-cycloalkyl can be attached to the core structure via a ring carbon atom or heteroatom on the aryl ring or via a carbon atom on the cycloalkyl ring. Examples of heteroaryl-cycloalkyl include, but are not limited to, 1,4,5,6-tetrahydrocyclopenta[b]pyrrole, 4,5,6,7-tetrahydro-1H-indole, 2,3- cyclopentenopyridine, and 5,6,7,8-tetrahydroquinoline.

[0023] The term “aryl-heterocyclyl” as used herein refers to an aryl group, as defined above, which is fused to a heterocyclyl group, as defined above, by any two or more atoms in the ring. In certain embodiments, aryl-heterocyclyl groups contain 6 to 14 atoms in the ring system (“6- to 14-membered aryl-heterocyclyl”). Aryl-heterocyclyl can be attached to the core structure via a ring carbon atom on the aryl ring or a ring carbon atom or heteroatom on the heterocyclyl ring. Examples of aryl-heterocyclyl include, but are not limited to, benzopyran, chromane, 4H-chromene, isochromane, thiochromane, isothiochromane, 1,2,3,4- tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydrobenzofuran, 1,3- dihydroisobenzofuran, 2,3-dihydrobenzo[b]thiophene, 1,3-dihydrobenzo[c]thiophene, indoline, isoindoline, and benzdioxane.

[0024] The term “heteroaryl-heterocyclyl” as used herein refers to a heteroaryl group, as defined above, which is fused to a heterocyclyl group, as defined above, by any two or more atoms in the ring. In certain embodiments, heteroaryl-heterocyclyl groups contain 6 to 14 atoms in the ring system (“6- to 14-membered heteroaryl-heterocyclyl”). Heteroaryl- heterocyclyl can be attached to the core structure via a ring carbon atom or heteroatom on the aryl ring or a ring carbon atom or heteroatom on the heterocyclyl ring. Examples of aryl- heterocyclyl include, but are not limited to 2,3-dihydro-1λ2,6λ2-pyrrolo[2,3-b]pyrrole, 4,7- dihydro-5H-1λ2,6λ2-pyrrolo[2,3-c]pyridine, 5,7-dihydro-6λ2-pyrrolo[3,4-b]pyridine, and 3,4- dihydro-2H-1λ2-1,8-naphthyridine.

[0025] The term “optionally substituted” or “optional substituents” as used herein means that the groups are either unsubstituted or substituted with one or more of the substituents specified. When the groups are substituted with more than one substituent, the substituents may be the same or different. Furthermore, when using the terms “independently,” “independently are,” and “independently selected from” means that the groups may be the same or different.

[0026] The term “deuterium” as used herein refers to an isotope of hydrogen that has one proton and one neutron in its nucleus and that has twice the mass of ordinary hydrogen. Deuterium herein is represented by the symbol “D”.

[0027] The term “deuterated” by itself or used to modify a compound or group as used herein refers to the presence of at least one deuterium atom attached to carbon. For example, the term “deuterated compound” refers to a compound which contains one or more carbon-bound deuterium(s). In a deuterated compound of the present invention, when a particular position is designated as having deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%.

[0028] The term “undeuterated” or “non-deuterated” as used herein refers to the ratio of deuterium atoms of which is not more than the natural isotopic deuterium content, which is about 0.015%; in other words, all hydrogen are present at their natural isotopic percentages. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.

[0029] The term “pharmaceutically acceptable salt” as used herein refers to a salt that is not biologically or otherwise undesirable (e.g., not toxic or otherwise harmful). A salt of a compound of the invention is formed between an acid and a basic group of the compound, or a base and an acidic group of the compound. For example, when the compounds of the invention contain at least one basic group (i.e., groups that can be protonated), the invention includes the compounds in the form of their acid addition salts with organic or inorganic acids such as, for example, but not limited to, salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, acetic acid, citric acid, glutamic acid, lactic acid, and methanesulfonic acid. When compounds of the invention contain one or more acidic groups (e.g., a carboxylic acid), the invention includes the pharmaceutically acceptable salts of the compounds formed with, but not limited to, alkali metal salts, alkaline earth metal salts or ammonium salts. Examples of such salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine, or amino acids. Additional examples of such salts can be found in Stahl, P. H. et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2ndRevised Edition, Wiley, 2011. Compounds

[0030] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (I): (I)wherein:R1is selected from the group consisting of H, C1-C3alkyl, Cl, F, CN, and O-C1-C6alkyl optionally substituted with one or more halogen; R2is H or C1-C3alkyl optionally substituted with OR5; R3is each independently H or C1-C4alkyl optionally substituted with one or more halogen or OH; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is selected from the group consisting of C1-C6alkyl, C1-C6alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl-cycloalkyl, aryl-heterocyclyl, aryl-heteroaryl, and sulfonamide, wherein the C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more halogen, phenyl, OR5, halogen, C(O)NR5R6, NR5R6, NR5-C(O)CH3, SO2R5, NH-SO2R5, heterocyclyl, aryl, heteroaryl, and aryl-heteroaryl, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, C1-C3alkyl-OH, C1-C3alkyl-O-C1-C3alkyl, C(O)OR5, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, keto, C3-C6cycloalkyl, C(O)CH3, C(O)NR5R5, NH- C(O)R5, NH-SO2R5, and C1-C4alkyl that is optionally substituted with one or more F or OH, wherein aryl is optionally substituted with one or more groups selected from the group consisting of: C1-C4alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, and NR5R6, C3-C6cycloalkyl that is substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, NR5R6, SO2R6, SO2NR5R6,SO(NH)R5, S(NR)(NH)R5, P(O)R5R5, and 4- or 5,6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C1-C4 alkyl, oxo, and NR5R6, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, OR5, NR5R6, oxo, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, OR5, and C(O)NR5R6; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with a group selected from the group consisting of OR5, Cl, and F; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1-C5alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C5alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cycloalkyl optionally substituted with one or more halogens; n is 1-4; p is 1-2; with the proviso that a compound selected from the group consisting of: (S)-1-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea, 1-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and 1-(5-cyclopropylthiazol-4-yl)-3-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

[0031] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R1is selected from the group consisting of H, Cl, F, and O-C1alkyl optionally substituted three halogens; R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is selected from the group consisting of C1-C3alkyl, C2alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl- cycloalkyl, and sulfonamide, wherein the C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, cyclobutyl optionally substituted with one or more F, OR5, halogen, NR5R6, and NH-SO2R5, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, CH2-OH, CH2-O-CH3, and C(O)OR5, wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1 alkyl optionally substituted with one or more F, wherein aryl is optionally substituted with one or more groups selected from the group consisting of: C1-C3alkyl that is optionally substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, SO2R6, SO2NR5R6, SO(NH)R5, S(NR)(NH)R5, P(O)R5R5, and 5-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more oxo,wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, cyclobutyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, and OR5; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with one or more groups selected from the group consisting of OR5, Cl, and F; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cyclobutyl optionally substituted with one or more halogens; n is 1; p is 1; with the proviso that a compound selected from the group consisting of: (S)-1-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea, 1-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and 1-(5-cyclopropylthiazol-4-yl)-3-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

[0032] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R1is selected from the group consisting of H, Cl, and F; R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S;Z C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, OR5, halogen, and NR5R6, R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; n is 1; and p is 1.

[0033] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R1is selected from the group consisting of H, Cl, and F; R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl substituted with one or more groups selected from the group consisting of: halogen, C(O)NR5R6, and SO2NR5R6; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; n is 1; and p is 1.

[0034] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R1is selected from the group consisting of H, Cl, and F; R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S;Z heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1alkyl optionally substituted with one or more F, R5is independently H or C1alkyl; n is 1; and p is 1.

[0035] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II): (II) wherein:R2is H or C1-C3alkyl optionally substituted with OR5; R3is each independently H or C1-C4alkyl optionally substituted with one or more halogen or OH; R4is C-R5or S, wherein one R3is C-R5and the other R3is S; Z is selected from the group consisting of C1-C6alkyl, C1-C6alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl-cycloalkyl, aryl-heterocyclyl, and aryl-heteroaryl, wherein the C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more halogen, phenyl, OR5, halogen, C(O)NR5R6, NR5R6, NR5-C(O)CH3, SO2R5, NH-SO2R5, heterocyclyl, aryl, heteroaryl, and aryl-heteroaryl, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, C1-C3alkyl-OH, C1-C3alkyl-O-C1-C3alkyl, C(O)OR5, C(O)NR5R5, NR5R5, and NR5-C(O)CH3,wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, keto, C3-C6cycloalkyl, C(O)CH3, C(O)NR5R5, NH- C(O)R5, NH-SO2R5, and C1-C4alkyl that is optionally substituted with one or more F or OH, wherein aryl is optionally substituted with one or more groups selected from the group consisting of: C1-C4 alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, and NR5R6, C3-C6cycloalkyl that is substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, NR5R6, SO2R6, SO2NR5R6, SO(NH)R5, S(NR)(NH)R5, P(O)R5R5, and 4- or 5,6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C1-C4alkyl, oxo, and NR5R6, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, OR5, NR5R6, oxo, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, OR5, and C(O)NR5R6; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with a group selected from the group consisting of OR5, Cl, and F;wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1-C5alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C5alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cycloalkyl optionally substituted with one or more halogens; p is 1-2; with the proviso that a compound selected from the group consisting of: (S)-1-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea, 1-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and 1-(5-cyclopropylthiazol-4-yl)-3-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

[0036] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is selected from the group consisting of C1-C3alkyl, NR5R6, SR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, OR5, halogen, and NR5R6, wherein cycloalkyl is optionally substituted with one or more F; wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1alkyl optionally substituted with one or more F, wherein aryl is optionally substituted with one or more groups selected from the group consisting of: C1-C3 alkyl that is optionally substituted with NR5R6,halogen, CN, OR5, C(O)NR5R6, SO2R6, SO2NR5R6, SO(NH)R5, S(NR)(NH)R5, P(O)R5R5, and 5-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more oxo, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, CN, C(O)NR5R6, SO2R6, a 4- to 6- membered heterocyclic ring, and C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, and OR5; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with one or more groups selected from the group consisting of OR5, Cl, and F; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; p is 1; with the proviso that a compound selected from the group consisting of: (S)-1-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea, 1-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and 1-(5-cyclopropylthiazol-4-yl)-3-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

[0037] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, OR5, halogen, and NR5R6, R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; and p is 1.

[0038] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl substituted with one or more groups selected from the group consisting of: halogen, C(O)NR5R6, and SO2NR5R6; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; and p is 1.

[0039] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R2is H; R3is H;R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1alkyl optionally substituted with one or more F, R5is independently H or C1alkyl; and p is 1.

[0040] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (III):(III) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is selected from the group consisting of C1-C3alkyl, C1-C6alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl-cycloalkyl, and sulfonamide, wherein the C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more halogen, OR5, halogen, NR5R6, and NH-SO2R5,wherein cycloalkyl is optionally substituted with one or more F, C1-C3alkyl-OH, C1-C3alkyl-O-C1-C3alkyl, C(O)OR5, wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1alkyl optionally substituted with one or more F, wherein aryl is optionally substituted with one or more groups selected from the group consisting of:C1-C3alkyl that is optionally substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, SO2R6, SO2NR5R6, SO(NH)R5, S(NR)(NH)R5, d heterocyclic ring optionally containing one or more additionalheteroatoms that is S or N, and is optionally substituted with one or more oxo, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, and OR5; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with one or more groups selected from the group consisting of OR5, Cl, and F; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cycloalkyl optionally substituted with one or more halogens; with the proviso that a compound selected from the group consisting of: (S)-1-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea, 1-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and1-(5-cyclopropylthiazol-4-yl)-3-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

[0041] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (III) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, OR5, halogen, and NR5R6, R5is independently H or C1alkyl; and R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

[0042] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is NR5R6; R5is independently H or C1alkyl; and R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

[0043] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is C(O)NR5R6; R5is independently H or C1alkyl; and R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

[0044] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein:R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is cycloalkyl is optionally substituted with one or more F; and R5is independently H or C1alkyl.

[0045] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is heterocyclyl that optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1alkyl optionally substituted with one or more F; and R5is independently H or C1 alkyl.

[0046] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl that is optionally substituted with one or more groups selected from the group consisting of: C1-C3alkyl that is optionally substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, SO2R6, SO2NR5R6, SO(NH)R5, S(NR)(NH)R5, P(O)R5R5, and 5-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more oxo; R5is independently H or C1alkyl; andR6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

[0047] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is heteroaryl that is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, CN, C(O)NR5R6, SO2R6, a 4- to 6- membered heterocyclic ring, and C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, and OR5; R5is independently H or C1 alkyl; and R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

[0048] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with one or more groups selected from the group consisting of OR5, Cl, and F; and R5is independently H or C1alkyl.

[0049] In embodiments, the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl-heteroaryl optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; and R5is independently H or C1alkyl.

[0050] In embodiments, R1is H, C1-C3alkyl, Cl, F, CN, and O-C1-C6alkyl optionally substituted with one or more halogen. In embodiments, R1is H. In embodiments, R1is C1-C3alkyl. In embodiments, R1is C1alkyl. In embodiments, R1is C2alkyl. In embodiments, R1is C3alkyl. In embodiments, R1is Cl. In embodiments, R1is Cl. In embodiments, R1is CN. In embodiments, R1is OCH3. In embodiments, R1is OCF3.

[0051] In embodiments, R2is H or C1-C3alkyl substituted with OH or OCH3. In embodiments, R2is H. In embodiments, R2is C1alkyl substituted with OH. In embodiments, R2is C2alkyl substituted with OH. R2is C3alkyl substituted with OH. In embodiments, R2is C1alkyl substituted with OCH3. In embodiments, R2is C2alkyl substituted with OCH3. R2is C3alkyl substituted with OCH3.

[0052] In embodiments, R3is independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH. In embodiments, R3is H. In embodiments, R3is C1alkyl optionally substituted with one or more halogen. In embodiments, R3is C1 alkyl optionally substituted with one or more OH. In embodiments, R3is C2alkyl optionally substituted with one or more halogen. In embodiments, R3is C2alkyl optionally substituted with one or more OH. In embodiments, R3is C3alkyl optionally substituted with one or more halogen. In embodiments, R3is C3alkyl optionally substituted with one or more OH. In embodiments, R3is C4alkyl optionally substituted with one or more halogen. In embodiments, R3is C4alkyl optionally substituted with one or more OH.

[0053] In embodiments, R4is independently H or C1-C4alkyl. In embodiments, R4is H. In embodiments, R4is C1alkyl. In embodiments, R4is H or C2alkyl. In embodiments, R4is C3alkyl. In embodiments, R4is C4alkyl.

[0054] In embodiments, Z is C1-C6alkyl, NR5R6, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-heterocyclyl, or aryl-heteroaryl. In embodiments, Z is C1-C6alkyl optionally substituted with cyclopropyl. In embodiments, Z is C1-C6alkyl optionally substituted with phenyl. In embodiments, Z is C1-C6alkyl optionally substituted with OR5. In embodiments, Z is C1-C6alkyl optionally substituted with halogen. In embodiments, Z is C1-C6alkyl optionally substituted with C(O)NR5R6. In embodiments, Z is C1-C6alkyl optionally substituted with NR5R5. In embodiments, Z is C1-C6alkyl optionally substituted with NR5- C(O)CH3. In embodiments, Z is C1-C6alkyl optionally substituted with SO2R5. In embodiments, Z is C1-C6alkyl optionally substituted with heterocyclyl. In embodiments, Z isC1-C6alkyl optionally substituted with aryl. In embodiments, Z is C1-C6alkyl optionally substituted with heteroaryl. In embodiments, Z is C1-C6alkyl optionally substituted with aryl- heteroaryl.

[0055] In embodiments, Z is NR5R6. In embodiments, Z is C(O)NR5R6.

[0056] In embodiments, Z is cycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of F, C(O)NR5R5, NR5R5, and NR5- C(O)CH3. In embodiments, Z is cycloalkyl optionally substituted with one or more F. In embodiments, Z is cycloalkyl optionally substituted with one or more C(O)NR5R5. In embodiments, Z is cycloalkyl optionally substituted with one or more NR5R5. In embodiments, Z is cycloalkyl optionally substituted with one or more NR5-C(O)CH3.

[0057] In embodiments, Z is heterocyclyl that optionally contains another heteroatom that is N or O and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, keto, C3-C6cycloalkyl, C(O)CH3, C(O)NR5R5, and C1- C4alkyl that is optionally substituted with one or more F or OH. In embodiments, Z is heterocyclyl that contains another heteroatom that is N. In embodiments, Z is heterocyclyl that contains another heteroatom that is O. In embodiments, Z is heterocyclyl that is substituted with one or more F. In embodiments, Z is heterocyclyl that is substituted with one or more OR5. In embodiments, Z is heterocyclyl substituted with one or more keto. In embodiments, Z is heterocyclyl substituted with one or more C3-C6cycloalkyl. In embodiments, Z is heterocyclyl substituted with one or more C(O)CH3. In embodiments, Z is heterocyclyl substituted with one or more C(O)NR5R5. In embodiments, Z is heterocyclyl substituted with one or more C1-C4alkyl that is optionally substituted with one or more OH. In embodiments, Z is heterocyclyl substituted with one or more C1-C4alkyl that is optionally substituted with one or more F.

[0058] In embodiments, Z is aryl that is optionally substituted with one or more C1-C4alkyl that is optionally substituted with one or more F, OH, or NR5R6. In embodiments, Z is aryl that is substituted with one or more C1-C4alkyl that is substituted with one or more F. In embodiments, Z is aryl that is substituted with one or more C1-C4alkyl that is substituted with one or more OH. In embodiments, Z is aryl that is substituted with one or more C1-C3alkyl that is substituted with one or more NR5R6.

[0059] In embodiments, Z is aryl that is optionally substituted with one or more C3-C6cycloalkyl that is substituted with NR5R6.

[0060] In embodiments, Z is aryl that is substituted with one or more halogen. In embodiments, Z is aryl that is substituted with one or more CN. In embodiments, Z is aryl that is substituted with one or more OR5. In embodiments, Z is aryl that is substituted with one or more C(O)NR5R6. In embodiments, Z is aryl that is optionally substituted with one or more NR5R6. In embodiments, Z is aryl that is substituted with one or more SO2R5. In embodiments, Z is aryl that is substituted with one or more SO2NR5R6. In embodiments, Z is aryl that is optionally substituted with one or more SO(NH)R5. In embodiments, Z is aryl that is optionally substituted with one or more S(NR)(NH)R5. In embodiments, Z is aryl that is optionally substituted with one or more P(O)R5R5.

[0061] In embodiments, Z is aryl that is substituted with a 4- or 6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is substituted with one or more F. In embodiments, Z is aryl that is substituted with a 4- or 6- membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is substituted with one or more Cl. In embodiments, Z is aryl that is substituted with a 4- or 6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is substituted with one or more OR5. In embodiments, Z is aryl that is substituted with a 4- or 6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is substituted with one or more CN. In embodiments, Z is aryl that is substituted with a 4- or 6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is substituted with one or more C1-C4alkyl. In embodiments, Z is aryl that is substituted with a 4- or 6- membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, that is substituted with one or more oxo. In embodiments, Z is aryl that is substituted with a 4- or 6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, that is substituted with NR5R5.

[0062] In embodiments, Z is heteroaryl that is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, CN, C(O)NR5R6, OR5, NR5R6, oxo, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C4alkyl optionally substituted with one or more groups independently selected from the group consisting of F,NR5R6,OR5, and C(O)NR5R6. In embodiments, Z is heteroaryl that is optionally substituted with one or more cyclopropyl. In embodiments, Z is heteroaryl that is optionally substituted with one or more CN. In embodiments, Z is heteroaryl that is substituted with one or more C(O)NR5R5. In embodiments, Z is heteroaryl that is substituted with one or more OR5. In embodiments, Z is heteroaryl that is substituted with one or more NR5R5. In embodiments, Z is heteroaryl that is substituted with one or more oxo. In embodiments, Z is heteroaryl that is substituted with one or more SO2R6. In embodiments, Z is heteroaryl that is substituted with one or more 4- to 6-membered heterocyclic ring. In embodiments, Z is heteroaryl that is substituted with one or more C1-C4alkyl optionally substituted with F. In embodiments, Z is heteroaryl that is substituted with one or more C1-C4alkyl optionally substituted with NR5R6. In embodiments, Z is heteroaryl that is substituted with one or more C1-C4alkyl optionally substituted with C(O)NR5R6.

[0063] In embodiments, Z is aryl-heterocyclyl optionally substituted with Cl, F or C1-C4alkyl that is optionally substituted with OR5, Cl or F. In embodiments, Z is aryl-heterocyclyl substituted with one or more Cl. In embodiments, Z is aryl-heterocyclyl substituted with one or more F. In embodiments, Z is aryl-heterocyclyl substituted with one or more C1-C4alkyl that is optionally substituted with OR5. In embodiments, Z is aryl-heterocyclyl substituted with one or more C1-C4 alkyl that is optionally substituted with Cl. In embodiments, Z is aryl- heterocyclyl substituted with one or more C1-C4alkyl that is optionally substituted with F.

[0064] In embodiments, Z is aryl-heteroaryl optionally substituted with C1-C3alkyl that is optionally substituted with OR5.

[0065] In embodiments, R5is H or C1-C5alkyl. In embodiments, R5is H. In embodiments, R5is C1alkyl. In embodiments, R5is C2alkyl. In embodiments, R5is C3alkyl. In embodiments, R5is C4alkyl. In embodiments, R5is C5alkyl.

[0066] In embodiments, R6is H, cyclopropyl, and C1-C5alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen. In embodiments, R6is H. In embodiments, R6is cyclopropyl. In embodiments, R6is C1-C5alkyl optionally substituted with one or more NR5R5. In embodiments, R6is C1-C5alkyl optionally substituted with one or more OR5. In embodiments, R6is C1-C5alkyl optionally substituted with one or more halogen.

[0067] In embodiments, n is 1-4. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.

[0068] In embodiments, p is 1-2. In embodiments, p is 1. In embodiments, p is 2.

[0069] In embodiments, compounds are identified in Table 1. Table 1 No. Chemical Name Structure 1 1-((S)-8-chlorochroman-4-yl)-3-No. Chemical Name Structure 10 (S)-1-(8-chlorochroman-4-yl)-3- 2 idi 4 l hi l4 lNo. Chemical Name Structure 21 5-[4-[[(4S)-8-chlorochroman-4- l b l i hi l2 lNo. Chemical Name Structure 32 1-[(4S)-8-chlorochroman-4-yl]-3- 21222 ifl hlNo. Chemical Name Structure 43 1-((S)-chroman-4-yl)-3-(2-(1- hd hl hi l4 lNo. Chemical Name Structure 54 1-((S)-8-chlorochroman-4-yl)-3- 23hd 3 iflNo. Chemical Name Structure 64 (S)-1-(8-chlorochroman-4-yl)-3- 24 2 hl i hlNo. Chemical Name Structure 75 1-((S)-8-chlorochroman-4-yl)-3- 2222 ifl 1hdNo. Chemical Name Structure 91 1-((R)-8-fluorochroman-4-yl)-3- 21hd hl hi l4No. Chemical Name Structure 102 (S)-1-(8-chlorochroman-4-yl)-3- 2 i l i hi l4No. Chemical Name Structure 117 (S)-1-(2-(acetyl-d3)thiazol-4-yl)-3- 8 hl h 4 l4dNo. Chemical Name Structure 127 (S)-1-(2-(1-acetylazetidin-3- l hi l4 l 38No. Chemical Name Structure 137 1-((S)-8-chlorochroman-4-yl)-3- 21hd hl1222No. Chemical Name Structure 146 1-((S)-8-chloro-6- ifl h h 4 lNo. Chemical Name Structure 154 (S)-1-(2-acetylthiazol-4-yl)-3-(8- hl 6No. Chemical Name Structure 162 (S)-4-(3-(8-chlorochroman-4- l id hi l 2 b liNo. Chemical Name Structure 172 1-(8-chloro-4-methylchroman-4- l 321hd hl hi lNo. Chemical Name Structure 182 1-((S)-8-chlorochroman-4-yl)-3- 21 h hl hi l4No. Chemical Name Structure 191 1-((4S)-8-chloro-2- hlh 4 l 321No. Chemical Name Structure 199 2-(4-(3-((S)-8-chlorochroman-4- l id hi l2 l NNo. Chemical Name Structure 208 N-(1-(4-(3-((S)-8-chlorochroman- 4 l id hi l2No. Chemical Name Structure 218 (S)-4-(3-(8-chlorochroman-4- l id N h l hi l 2

[0070] The compounds of the present invention may contain asymmetric carbon atoms (sometimes as the result of a deuterium atom) and thereby can exist as either individual stereoisomers or mixtures of the enantiomers or mixtures of diastereomers. Accordingly, a compound of the present invention may exist as either a racemic mixture, a mixture of diastereomers, or as individual stereoisomers that are substantially free of other stereoisomers. Synthetic, separation, or purification methods to be used to obtain an enantiomer of a given compound are known in the art and are applicable for obtaining the compounds identified herein.

[0071] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Carbon atoms labelled with * refer to a carbon atom that is chiral but the absolute stereochemistry has not been determined.

[0072] The compounds of the present invention may contain double bonds that may exist in more than one geometric isomer. Examples of such double bonds are carbon-carbon double bonds which form alkenes. In the case of carbon-carbon double bonds, the geometric isomers may be E or Z isomers.

[0073] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the geometric isomerism and has one or more possible geometric isomers, it is understood to represent all possible geometric isomers of the compound.

[0074] Certain compounds of the present invention may be able to exist as tautomers. All tautomeric forms of these compounds, whether isolated individually or in mixtures, are within the scope of the present invention. For example, in instances where an —OH substituent is permitted on a heteroaromatic ring and ketoenol tautomerism is possible, it is understood that the substituent might in fact be present, in whole or in part, in the oxo (═O) form.

[0075] In certain embodiments, hydrogen atoms may be replaced with deuterium. The deuterium isotope content at a the deuterium substituted position may be is greater than the natural isotopic deuterium content (0.015%), more preferably greater than 50%, more preferably greater than 60%, more preferably greater than 75%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%. It will be understood that some variation of natural isotopic abundance may occur in any compound depending upon the source of the reagents used in the synthesis. Thus, a preparation of undeuterated compounds may inherently contain small amounts of deuterated isotopologues, such amounts being insignificant as compared to the degree of stable isotopic substitution of the deuterated compounds of the invention. See, e.g., Gannes, L.Z., et al., Comp Biochem. Physiol. Mol. Integr. Physiol., 119:725 (1998). Replacement of hydrogen with deuterium may affect the activity, toxicity, and pharmacokinetics (e.g., absorption, distribution, metabolism, and excretion ("ADME")) of some drugs. For instance,such replacement may alter the chemical stability and biochemical reactivity of a compound through kinetic isotope effects. Because of the increased mass of deuterium relative to hydrogen, epimerization at stereogenic carbons may be slowed down when hydrogen is replaced with deuterium. See Pirali, T. et al., J. Med. Chem., 62:5276-97 (2019). Additionally, the presence of deuterium may affect how a molecule interacts with enzymes, thereby impacting enzyme kinetics. While in certain cases the increased mass of deuterium as compared to hydrogen can stabilize a compound and thereby improve activity, toxicity, or half-life, such impact is not predictable. In other instances deuteration may have little to no impact on these properties, or may affect them in an undesirable manner. Whether and / or how such replacement will impact drug properties can only be determined if the drug is synthesized, evaluated, and compared to its non-deuterated counterpart. See Fukuto, J.M., et al., J. Med. Chem., 34:2871-76 (1991). Because some drugs have multiple sites of metabolism or more than one active sites for binding to a target, it is unpredictable as to which sites may benefit by deuterium replacement or to what extent isotope enrichment is necessary to produce a beneficial effect. EXAMPLES

[0076] The examples below further illustrate embodiments of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.

[0077] The structures of the compounds are confirmed by mass spectrometry and / or NMR, where peaks assigned to the characteristic protons in the title compound are presented where appropriate.1H NMR shift (δ) are given in parts per million (ppm) down field from an internal reference standard.

[0078] The abbreviations used herein are known to a person of ordinary skill in the art. A partial list of abbreviations that may be used herein include: acetonitrile (CH3CN or MeCN or ACN), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf)Cl2 complex with CH2Cl2), bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium (II) (Pd(amphos)Cl2), calculated (Calcd.), cerium chloride (CeCl3), cesium carbonate (Cs2CO3), cesium fluoride (CsF), copper acetate (Cu(OAc)3), copper bromide (CuBr), copper (I) oxide (Cu2O), degrees Celsius (°C), deuterium (d), dichloromethane (DCM, CH2Cl2), dichloroethane (DCE), N,N-diisopropylethylamine (DIPEA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-disuccinimidylcarbonate (DSC), di-tert-butyl decarbonate (Boc2O), ethyl acetate (EtOAc), ethanol (EtOH), hour (h), iodobenzene diacetate (PhI(OAc)2), N-[(dimethylamino)- 1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), high performance liquid chromatography (HPLC), lithium hydroxide monohydrate (LiOH·H2O), megahertz (MHz), methanol (MeOH, CH3OH), methyl lithium (MeLi), minutes (min), nuclear magnetic resonance (NMR), palladium on carbon (Pd / C), pounds per square inch (PSI), potassium carbonate (K2CO3), potassium hydroxide (KOH), potassium phosphate (K3PO4), pyridine (Pyr), liquid chromatography-mass spectrometry (LCMS), methanesulfonyl chloride (MsCl), room / ambient temperature (RT), sodium bicarbonate (NaHCO3), sodium borohydride (NaBH4), sodium hydride (NaH), sodium hydroxide (NaOH), sodium sulfate (Na2SO3), N- bromosuccinimide (NBS), sodium tert-butoxide (NaOtBu), supercritical fluid chromatography (SFC), tetrabutylammonium tribromide (tBu4NBr3), tetrahydrofuran (THF), thin layer chromatography (TLC), triethylamine (Et3N, TEA), palladium- tetrakis(triphenylphosphine) (Pd(PPh3)4), and water (H2O). Example 1 and Example 2: Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(2-(1- hydroxyethyl)thiazol-4-yl)urea

[0079] Step-1: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(1-ethoxyvinyl)thiazol-4-yl]urea (1- 3): To a stirred solution of 1-(2-bromothiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 1-1 (0.50 g, 1.29 mmol) in 1,4-dioxane (10 mL) was added tributyl(1-ethoxyvinyl)tin 1-2 (0.53 mL, 1.54 mmol) followed by KF (0.22 g, 3.86 mmol) at RT. The reaction mixture was purged with nitrogen for 15 min and then bis(triphenylphosphine)palladium (II) chloride (0.09 g, 0.12 mmol) was added into it. The reaction mixture was heated at 110 °C for 6 h. After completion, reaction mixture was filtered through Celite bed. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash (20% EtOAc / heptane) to afford 1-[(4S)-8-chlorochroman-4-yl]- 3-[2-(1-ethoxyvinyl)thiazol-4-yl]urea 1-3 (0.35 g).1H NMR (400 MHz, DMSO-d6) δ = 9.22 (s, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.26 - 7.20 (m, 2H), 6.90 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 5.07 (s, 1H), 4.98 - 4.90 (m, 1H), 4.44 (br s, 1H), 4.41 - 4.36 (m, 1H), 4.28 - 4.19 (m, 1H), 3.96 (q, J = 6.9 Hz, 2H), 2.13 (dd, J = 5.1, 8.3 Hz, 1H), 2.03 - 1.94 (m, 1H), 1.32 (t, J = 6.9 Hz, 3H); LCMS:[M+H]+= 380.

[0080] Step-2: 1-(2-acetylthiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea (1-4): To a stirred solution of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(1-ethoxyvinyl)thiazol-4-yl]urea 1-3 (0.35 g, 0.82 mmol) in acetone (5 mL) was added concentrated HCl (1.00 mL, 33.30 mmol). Reaction mixture was stirred at RT for 1 h. After completion, reaction mixture was quenched with saturated NaHCO3solution, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1-(2- acetylthiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 1-4 (0.30 g)1H NMR (400 MHz, DMSO-d6) δ = 9.48 (br s, 1H), 7.71 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 4.96 (d, J = 5.5 Hz, 1H), 4.38 (d, J = 7.9 Hz, 1H), 4.24 (t, J = 8.8 Hz, 1H), 2.57 (s, 3H), 2.12 (br s, 1H), 1.98 (br s, 1H); LCMS:[M+H]+= 352.

[0081] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(1-hydroxyethyl)thiazol-4-yl]urea (1- 5): To a stirred solution of 1-(2-acetylthiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 1-4 (0.30 g, 0.76 mmol) in ethanol (8 mL) was added NaBH4(0.13 g, 3.45 mmol) at 0 °C and the reaction mixture was stirred at 40 °C for 4 h. After completion, reaction mixture was concentrated under reduced pressure and product was quenched with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by reverse phase CombiFlash to afford1-[(4S)-8-chlorochroman-4-yl]-3-[2-(1-hydroxyethyl)thiazol-4-yl]urea 1-5 (0.13 g). LCMS: [M+H]+=354.

[0082] Step-4: 1-((S)-8-chlorochroman-4-yl)-3-(2-(1-hydroxyethyl)thiazol-4-yl)urea (Examples 1 and 2): Racemic compound of 1-51-[(4S)-8-chlorochroman-4-yl]-3-[2-(1- hydroxyethyl)thiazol-4-yl]urea (0.13 g) was submitted for chiral-HPLC separation to afford Example 1 (0.04 g) and Example 2 (0.01 g). The absolute stereochemistry of these products was not determined.

[0083] Example 1:1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 7.32 (dd, J = 1.3, 7.9 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.05 (s, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.02 (d, J = 5.3 Hz, 1H), 4.98 - 4.90 (m, 1H), 4.89 - 4.80 (m, 1H), 4.43 - 4.33 (m, 1H), 4.28 - 4.20 (m, 1H), 2.17 - 2.09 (m, 1H), 2.05 - 1.92 (m, 1H), 1.40 (d, J = 6.4 Hz, 3H); LCMS: [M+H]+=354.

[0084] Example 2:1H NMR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 7.32 (dd, J = 1.3, 7.9 Hz, 1H), 7.23 (d, J = 7.1 Hz, 1H), 7.05 (s, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.01 (d, J = 5.3 Hz, 1H), 4.97 - 4.90 (m, 1H), 4.89 - 4.80 (m, 1H), 4.44 - 4.35 (m, 1H), 4.29 - 4.18 (m, 1H), 2.19 - 2.05 (m, 1H), 2.03 - 1.93 (m, 1H), 1.40 (d, J = 6.5 Hz, 3H); LCMS: [M+H]+=354. Example 3: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(dimethylamino)thiazol-4- yl]urea

[0085] Step-1: 2-bromothiazole-4-carbonyl azide (3-2): To a suspension of 2- bromothiazole-4-carboxylic acid 3-1 (2.50 g, 12.00 mmol) in THF (5 mL) was added TEA (2.0 mL, 14.4 mmol) at 0 °C followed by ethyl chloroformate (1.4 mL, 14.4 mmol). Reaction mixture was stirred at RT for 1 h. To the above reaction mixture was added aqueous solution of sodium azide (5.86 g, 90.1 mmol) and stirred at RT for 2 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to obtain 2-bromothiazole-4-carbonyl azide 3-2 (2.40 g). LCMS: [M+H]+= 205.

[0086] Step-2: 1-(2-bromothiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea (3-4): A solution of 2-bromothiazole-4-carbonyl azide 3-2 (2.40 g, 10.3 mmol) in toluene (20 mL) was stirred at 90 °C for 15 min under N2atmosphere. To the above reaction mixture was added (4S)-8-chlorochroman-4-amine hydrochloride 3-3 (2.27 g, 10.3 mmol) and stirred at 90 °C for 12 h. After completion, reaction mixture was concentrated under reduced pressure to obtain a product which was purified by CombiFlash column chromatography to obtain 1-(2- bromothiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 3-4 (2.00 g). LCMS: [M+H]+= 390.

[0087] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(dimethylamino)thiazol-4-yl]urea (Example 3): To a stirred solution of dimethylamine HCl (0.01 g, 0.15 mmol) in DMF (3 mL) was added K2CO3(0.08 g, 0.64 mmol) and stirred for 15 min. To this was added 1-(2- bromothiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 3-4 (0.05 g, 0.12 mmol) and the reaction mixture was stirred at 90 °C for 4 h. After completion, the reaction mixture was quenched with ice cold water, extracted with EtOAc. Combined organic layer was washed with brine solution, dried over anhydrous Na2SO4and evaporated under reduced pressure. The product was purified by CombiFlash (50% EtOAc / n-heptane) to afford Example 3 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 8.74 (s, 1H), 7.32 (dd, J = 1.2, 7.8 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 6.90 (t, J = 1.0 Hz, 2H), 6.21 (s, 1H), 4.95 - 4.85 (m, 1H), 4.43 - 4.34 (m, 1H), 4.26 - 4.17 (m, 1H), 2.95 (s, 6H), 2.18 - 2.06 (m, 1H), 2.01 - 1.90 (m, 1H); LCMS: [M+H]+= 353.Example 4 and Example 5: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[4-[4- [pyrrolidin-2-yl]phenyl]thiazol-2-yl]urea

[0088] Step-1: phenyl N-(4-bromothiazol-2-yl)carbamate (4-2): To a stirred solution of 4- bromothiazol-2-amine 4-1 (0.20 g, 1.12 mmol) in THF (5 mL) was added NaH (60% in mineral oil, 0.04 g, 1.68 mmol) at 0 °C followed by phenyl chloroformate (0.15 mL, 1.23 mmol). The reaction mixture was stirred at 25 °C for 12 h. After completion, reaction was quenched with cold H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by CombiFlash (50% EtOAc / heptane) to afford 4-2 phenyl N-(4-bromothiazol-2- yl)carbamate (0.15 g).1H NMR: (400 MHz, DMSO-d6) δ = 12.60 (br s, 1H), 7.48 - 7.43 (m, 2H), 7.34 - 7.22 (m, 4H); LCMS: [M+H]+ =301.

[0089] Step-2: 1-(4-bromothiazol-2-yl)-3-[(4S)-8-chlorochroman-4-yl]urea (4-4): To a stirred solution of phenyl N-(4-bromothiazol-2-yl)carbamate 4-2 (0.20 g, 0.66 mmol) in MeCN (5 mL) was added DIPEA (0.35 mL, 2.01 mmol) followed by (4S)-8-chlorochroman- 4-amine hydrochloride 4-3 (0.14 g, 0.66 mmol). The reaction mixture was stirred at 80 °C for4 h. After completion, the reaction mixture was diluted with water, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash (30% EtOAc / heptane) to afford 1-(4-bromothiazol-2-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 4-4 (0.26 g).1H NMR (400 MHz, DMSO-d6) δ = 10.51 (br s, 1H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.22 (dd, J = 0.6, 7.8 Hz, 1H), 7.16 - 7.12 (m, 2H), 6.91 (t, J = 7.8 Hz, 1H), 4.98 - 4.93 (m, 1H), 4.40 - 4.34 (m, 1H), 4.30 - 4.23 (m, 1H), 2.17 - 2.10 (m, 1H), 2.08 - 2.01 (m, 1H); LCMS: [M+H]+= 390.

[0090] Step-3: tert-butyl 2-[4-[2-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol- 4-yl]phenyl]pyrrolidine-1-carboxylate (4-6): To a stirred solution of 1-(4-bromothiazol-2- yl)-3-[(4S)-8-chlorochroman-4-yl]urea 4-4 (0.70 g, 1.80 mmol) in 1,4-dioxane (7 mL) and water (3 mL) was added tert-butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]pyrrolidine-1-carboxylate 4-5 (0.84 g, 2.25 mmol) followed by potassium phosphate (1.14 g, 5.40 mmol) at RT and the reaction mixture was purged with N2for 10 min. To this was added Pd(amphos)Cl2(0.25 g, 0.36 mmol) and the reaction mixture was again purged with N2for 5 min. The reaction mixture was heated at 100 °C for 16 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. Combined organic layer was washed with brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash (40% EtOAc / heptane) to afford desired product which was again purified by reverse phase column chromatography to afford tert-butyl 2-[4-[2-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-4- yl]phenyl]pyrrolidine-1-carboxylate 4-6 (0.20 g)1H NMR (400 MHz, DMSO-d6) δ = 10.44 (br s, 1H), 7.77 (d, J = 6.4 Hz, 2H), 7.43 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.18 (d, J = 7.5 Hz, 3H), 6.92 (t, J = 7.8 Hz, 1H), 4.99 (q, J = 6.2 Hz, 1H), 4.86 - 4.68 (m, 1H), 4.45 - 4.35 (m, 1H), 4.27 (t, J = 8.2 Hz, 1H), 3.58 - 3.42 (m, 2H), 2.33 - 2.13 (m, 2H), 2.07 (s, 1H), 1.86 - 1.69 (m, 3H), 1.41 - 1.07 (m, 9H); LCMS: [M+H]+= 555.

[0091] Step-4: 1-[(4S)-8-chlorochroman-4-yl]-3-[4-(4-pyrrolidin-2-ylphenyl)thiazol-2- yl]urea (4-7): To a stirred solution of tert-butyl 2-[4-[2-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-4-yl]phenyl]pyrrolidine-1-carboxylate 4-6 (0.17 g, 0.30 mmol) in 1,4-dioxane (5 mL) was added 4M HCl in 1,4-dioxane (4 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The product was triturated with EtOAc to afford 1-[(4S)-8-chlorochroman- 4-yl]-3-[4-(4-pyrrolidin-2-ylphenyl)thiazol-2-yl]urea 4-7 (0.15 g).1H NMR: (400 MHz,DMSO-d6) δ = 10.55 (br s, 1H), 9.76 (br s, 1H), 8.83 (br s, 1H), 7.91 (d, J = 7.9 Hz, 2H), 7.58 - 7.51 (m, 2H), 7.39 - 7.32 (m, 2H), 7.25 (d, J = 7.7 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 4.99 (d, J = 6.4 Hz, 1H), 4.56 (br s, 1H), 4.44 - 4.36 (m, 1H), 4.33 - 4.24 (m, 1H), 3.57 (s, 1H), 3.40 - 3.27 (m, 2H), 2.38 (d, J = 5.5 Hz, 1H), 2.18 - 2.00 (m, 4H); LCMS: [M+H]+= 455.

[0092] Step-5: 1-[(4S)-8-chlorochroman-4-yl]-3-[4-[4-[pyrrolidin-2-yl]phenyl]thiazol-2- yl]urea (Examples 4 and 5): 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-pyrrolidin-2- ylphenyl)thiazol-4-yl]urea 4-7 (0.15 g) was submitted for chiral-HPLC separation to afford Example 4 (0.04 g) and Example 5 (0.02 g). The absolute stereochemistry of these products was not determined.

[0093] Example 4:1H NMR (400 MHz, DMSO-d6) δ = 7.75 (d, J = 8.3 Hz, 2H), 7.41 (s, 1H), 7.37 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 1.3 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 4.98 (q, J = 6.3 Hz, 1H), 4.45 - 4.35 (m, 1H), 4.33 - 4.22 (m, 1H), 4.04 (t, J = 7.6 Hz, 1H), 3.06 - 2.99 (m, 1H), 2.94 - 2.85 (m, 1H), 2.22 - 2.00 (m, 3H), 1.83 - 1.68 (m, 2H), 1.54 - 1.42 (m, 1H); LCMS: [M+H]+= 456.

[0094] Example 5:1H NMR (400 MHz, DMSO-d6) δ = 8.26 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.46 - 7.39 (m, 3H), 7.34 (dd, J = 1.3, 7.9 Hz, 2H), 7.25 (d, J = 7.1 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 4.99 (q, J = 6.3 Hz, 1H), 4.44 - 4.35 (m, 1H), 4.33 - 4.25 (m, 1H), 4.23 - 4.18 (m, 1H), 3.17 - 3.09 (m, 1H), 3.06 - 2.97 (m, 1H), 2.25 - 2.12 (m, 2H), 2.10 - 2.01 (m, 1H), 1.91 - 1.79 (m, 2H), 1.72 - 1.61 (m, 1H); LCMS: [M+H]+= 456.Example 6 and Example 7: Synthesis of 1-(2-(1-(2-aminopropyl)-1H-pyrazol-3- yl)thiazol-4-yl)-3-((S)-8-chlorochroman-4-yl)urea

[0095] Step-1: tert-butyl (1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol- 1-yl)propan-2-yl)carbamate (6-3): To a stirred solution of tert-butyl N-(2-hydroxy-1- methyl-ethyl)carbamate 6-2 (0.50 g, 2.85 mmol) in toluene (8 mL) was added 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 6-1 (0.66 g, 3.42 mmol) and the reaction mixture was purged with nitrogen for 10 min. To this was added cyanomethylenetributylphosphorane (0.75 mL, 2.85 mmol) and the resulting reaction mixture was stirred at 80 ℃ for 12 h. After completion, the reaction mixture was evaporated under reduced pressure to afford tert-butyl N-[1-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazol-1-yl]ethyl]carbamate 6-3 (1.00 g). LCMS: [M+H]+= 270.

[0096] Step-2: tert-butyl (1-(3-(4-(3-((S)-8-chlorochroman-4-yl)ureido)thiazol-2-yl)-1H- pyrazol-1-yl)propan-2-yl)carbamate (6-5): To a stirred solution of 1-(2-bromothiazol-4- yl)-3-[(4S)-8-chlorochroman-4-yl]urea 6-4 (0.50 g, 1.13 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was added tert-butyl N-[1-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazol-1-yl]ethyl]carbamate 6-3 (1.19 g, 3.40 mmol) followed by K3PO4(0.72 g, 3.40 mmol) at RT and the reaction mixture was purged with N2for 15 min. To thiswas added Pd(dppf)Cl2complex with DCM (0.04 g, 0.05 mmol) and the reaction mixture was stirred at 85 ℃ for 2 h. After completion, reaction mixture was quenched with H2O and filtered through Celite bed. The filtrate was extracted with the EtOAc, combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash to afford tert-butyl (1-(3-(4-(3-((S)-8- chlorochroman-4-yl)ureido)thiazol-2-yl)-1H-pyrazol-1-yl)propan-2-yl)carbamate 6-5 (0.15 g).1H NMR (400 MHz, DMSO-d6) δ = 9.07 (s, 1H), 7.48 (s, 1H), 7.36 - 7.20 (m, 3H), 6.98 (d, J = 7.4 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.72 (br s, 1H), 6.63 (d, J = 8.3 Hz, 1H), 4.98 - 4.91 (m, 1H), 4.57 (dd, J = 4.6, 12.9 Hz, 1H), 4.38 (d, J = 6.5 Hz, 2H), 4.24 (t, J = 9.0 Hz, 1H), 3.97 - 3.90 (m, 1H), 2.17 - 2.10 (m, 1H), 1.97 (s, 1H), 1.26 - 1.13 (m, 9H), 0.97 (d, J = 6.5 Hz, 2H); LCMS: [M+H]+= 533.

[0097] Step-3: 1-(2-(1-(2-aminopropyl)-1H-pyrazol-3-yl)thiazol-4-yl)-3-((S)-8- chlorochroman-4-yl)urea (6-6): To a stirred solution of tert-butyl (1-(3-(4-(3-((S)-8- chlorochroman-4-yl)ureido)thiazol-2-yl)-1H-pyrazol-1-yl)propan-2-yl)carbamate 6-5 (0.15 g, 0.16 mmol) in DCM (1.5 mL), 4.0 M HCl in dioxane (0.006 g, 0.16 mmol) was added at 0 ℃. Reaction mixture was stirred at 25 ℃ for 1 h. After completion, the reaction mixture was evaporated under reduced pressure. The product was washed with EtOAc and concentrated under reduced pressure to afford 1-(2-(1-(2-aminopropyl)-1H-pyrazol-3-yl)thiazol-4-yl)-3- ((S)-8-chlorochroman-4-yl)urea 6-6 (0.11 g). LCMS: [M+H]+ =433.

[0098] Step-4: 1-(2-(1-(2-aminopropyl)-1H-pyrazol-3-yl)thiazol-4-yl)-3-((S)-8- chlorochroman-4-yl)urea (Examples 6 and 7): 1-[2-[1-(2-aminopropyl)pyrazol-3- yl]thiazol-4-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 6-6 (0.11 g) was submitted to chiral- HPLC separation to afford Example 6 (0.01 g) and Example 7. The absolute stereochemistry of these products was not determined.

[0099] Example 6:1H NMR (400 MHz, DMSO-d6) δ = 9.45 (s, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.25 (dd, J = 0.7, 7.7 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 5.87 - 5.63 (m, 2H), 5.01 - 4.92 (m, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.45 - 4.36 (m, 1H), 4.30 - 4.22 (m, 1H), 3.53 - 3.41 (m, 1H), 2.20 - 2.10 (m, 1H), 2.06 - 1.94 (m, 1H), 1.06 (d, J = 6.6 Hz, 3H) LCMS: [M+H]+= 434.

[0100] Example 7:1H NMR (400 MHz, DMSO-d6) δ = 9.21 (s, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.26 (d, J = 7.4 Hz, 1H), 6.97 - 6.89 (m, 2H), 6.78 (d, J = 2.0 Hz,1H), 4.96 (q, J = 6.2 Hz, 1H), 4.40 (d, J = 5.6 Hz, 3H), 4.29 - 4.22 (m, 1H), 3.23 (d, J = 6.4 Hz, 1H), 2.21 - 2.10 (m, 1H), 2.08 - 1.98 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H); LCMS: [M+H]+= 434. Example 8: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(2-(1-ethyl-1H-pyrazol-4- yl)thiazol-4-yl)ureayl]urea (Example 8): To a stirred solution of 1-(2-bromothiazol-4-yl)-3-[(4S)-8- chlorochroman-4-yl]urea 8-1 (0.20 g, 0.51 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added K3PO4(0.32 g, 1.54 mmol) followed by 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole 8-2 (0.13 g, 0.61 mmol) and the reaction mixture was degassed with argon for 30 min. To this was added Pd(dppf)Cl2.DCM (0.02 g, 0.02 mmol) at RT. The reaction mixture was stirred at 90 °C for 4 h. After completion of reaction, the reaction mixture was filtered with Celite bed. The filtrate was diluted with H2O and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to yield the compound which was purified using combi- flash (50% EtOAc / n-heptane) to afford Example 8 (0.06 g).1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 8.26 (s, 1H), 7.82 (s, 1H), 7.33 (dd, J = 1.3, 7.9 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.05 (s, 1H), 6.94 - 6.84 (m, 2H), 4.98 - 4.91 (m, 1H), 4.44 - 4.35 (m, 1H), 4.28 - 4.21 (m, 1H), 4.17 (q, J = 7.3 Hz, 2H), 2.20 - 2.09 (m, 1H), 2.06 - 1.93 (m, 1H), 1.39 (t, J = 7.3 Hz, 3H), LCMS: [M+H]+= 404.Example 9: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(2-pyridyl)thiazol-4-yl]urea

[0102] Step-1: ethyl 2-(2-pyridyl)thiazole-4-carboxylate (9-3): To a stirred solution of ethyl 3-bromo-2-oxo-propanoate 9-2 (1.40 mL, 10.90 mmol) in ethanol (15 mL) was added pyridine-2-carbothioamide 9-1 (1.50 g, 10.90 mmol) at RT. Resulting mixture was stirred at 70 °C for 12 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure. Material was dissolved in ethyl acetate. Organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product was purified by column chromatography (2% MeOH / DCM) to afford ethyl 2-(2- pyridyl)thiazole-4-carboxylate 9-3 (2.20 g).1H NMR (400 MHz, DMSO-d6) δ = 1.33 (t, J = 8.0 Hz, 3H), 4.35 (q, J = 6.8 Hz, 2 H), 7.55 (t, J = 8.0 Hz, 1H), 8.00 (t, J = 7.2 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.60 (s, 1H), 8.66 (d, J = 4.4 Hz 1H); LCMS: [M+H]+= 235.

[0103] Step-2: 2-(2-pyridyl)thiazole-4-carbohydrazide (9-4): To a stirred solution of ethyl 2-(2-pyridyl)thiazole-4-carboxylate 9-3 (2.00 g, 8.45 mmol) in ethanol (35 mL) was added hydrazine hydrate (2.00 mL, 50.70 mmol) at RT. The resulting reaction mixture was stirred at 100 °C for 16 h. After completion of reaction, reaction mixture was diluted in ice water to get the solid which was filtered and dried under reduced pressure to afford 2-(2-pyridyl)thiazole- 4-carbohydrazide 9-4 (1.50 g).1H NMR (400 MHz, DMSO-d6) δ = 9.81 - 9.76 (m, 1H), 8.65(br s, 1H), 8.36 - 8.28 (m, 2H), 8.06 - 8.00 (m, 1H), 7.57 - 7.52 (m, 1H), 4.62 - 4.55 (m, 2H); LCMS: [M+H]+= 221.

[0104] Step-3: 2-(2-pyridyl)thiazole-4-carbonyl azide (9-5): To a stirred solution of 2-(2- pyridyl)thiazole-4-carbohydrazide 9-4 (1.10 g, 4.99 mmol) in acetic acid (15 mL) was added sodium nitrite (0.48 g, 6.99 mmol) at 0 °C for 30 min followed by at RT for 2 h. After completion of reaction, reaction mixture was quenched with ice water to get the solid which was filtered and dried under reduced pressure to afford 2-(2-pyridyl)thiazole-4-carbonyl azide 9-5 (0.80 g).

[0105] Step-4: benzyl N-[2-(2-pyridyl)thiazol-4-yl]carbamate (9-6): A solution of 2-(2- pyridyl)thiazole-4-carbonyl azide 9-5 (0.90 g, 3.89 mmol) in benzyl alcohol (BnOH) (15 mL, 58.40 mmol) was stirred at 110 °C for 12 h. After completion of reaction, reaction mixture was concentrated under the reduced pressure. Product was purified by silica gel flash chromatography using (20% EtOAc / n-heptane) to afford benzyl N-[2-(2-pyridyl)thiazol-4- yl]carbamate 9-6 (0.60 g). LCMS: [M+H]+= 312.

[0106] Step-5: 2-(2-pyridyl)thiazol-4-amine (9-7): A solution of benzyl N-[2-(2- pyridyl)thiazol-4-yl]carbamate 9-6 (0.60 g, 1.93 mmol) in trifluoromethanesulfonic acid (3.00 mL, 34.00 mmol) was stirred at RT for 2 h. After completion of reaction, reaction mixture was quenched with saturated NaHCO3solution and extracted with DCM. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to get 2-(2-pyridyl)thiazol-4-amine 9-7 (0.11 g);1H NMR (400 MHz, DMSO-d6) δ = 8.57 - 8.55 (m, 1H), 7.97 - 7.94 (m, 1H), 7.92 - 7.88 (m, 1H), 7.43 - 7.39 (m, 1H), 3.31 (1H), 5.48 (s, 2H); LCMS: [M+H]+= 178.

[0107] Step-6: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(2-pyridyl)thiazol-4-yl]urea (Example 52): To a stirred solution of 2-(2-pyridyl)thiazol-4-amine 9-7 (0.06 g, 0.33 mmol) in MeCN (3 mL) was added N,N′-disuccinimidyl carbonate (0.04 g, 0.16 mmol) followed by pyridine (0.02 mL, 0.33 mmol) at RT and the resulting reaction mixture was stirred at RT for 20 min. To this was added (4S)-8-chlorochroman-4-amine 9-8 (0.06 g, 0.33 mmol) followed by DIPEA (0.18 mL, 1.02 mmol) at 0 °C. The reaction mixture was stirred at RT for 1 h. After completion of reaction, reaction mixture was diluted with water and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to get a product that was purified by reverse phase flashchromatography to afford 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(2-pyridyl)thiazol-4-yl]urea Example 9 (0.07 g).1H NMR (400 MHz, DMSO-d6) δ = 9.26 (s, 1H), 8.61 (d, J = 3.9 Hz, 1H), 7.99 - 7.93 (m, 2H), 7.51 - 7.46 (m, 1H), 7.38 - 7.25 (m, 3H), 6.95 - 6.88 (m, 2H), 4.97 (d, J = 5.7 Hz, 1H), 4.45 - 4.38 (m, 1H), 4.30 - 4.23 (m, 1H), 2.15 (d, J = 4.4 Hz, 1H), 2.03 (d, J = 4.4 Hz, 1H). LCMS: [M+H]+= 387. Example 10: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-pyridyl)thiazol-4- yl]urea

[0108] Step-1: 2-(4-pyridyl)thiazole-4-carbonyl azide (10-2): To a stirred solution of 2-(4- pyridyl)thiazole-4-carboxylic acid 10-1 (0.50 g, 2.38 mmol) in THF (5 mL) was added TEA (0.67 mL, 4.75 mmol) followed by ethyl chloroformate (0.35 mL, 3.56 mmol) at 0 °C. Reaction mixture was stirred at RT for 2 h. To this was added sodium azide (0.78 g, 11.90 mmol) at RT. The reaction mixture was stirred at RT for 4 h. After completion of the reaction, reaction mixture was diluted with water and was extracted by ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 2-(4-pyridyl)thiazole-4-carbonyl azide 10-2 (0.50 g), which was used as such for the next reaction. LCMS: [M+H]+= 232.

[0109] Step-2: tert-butyl N-[2-(4-pyridyl)thiazol-4-yl]carbamate (10-3): A solution of 2- (4-pyridyl)thiazole-4-carbonyl azide 10-2 (0.33 g, 1.30 mmol) in tert-butanol (6 mL) was stirred at 100 °C for 12 h. After completion of reaction, reaction mixture was concentrated under reduced pressure. The product was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product was purified by the CombiFlash (30%EtOAc / n-Heptane) to afford tert-butyl N-[2-(4-pyridyl)thiazol-4-yl]carbamate 10-3 (0.20 g).1H NMR (400 MHz, DMSO-d6) δ = 10.32 (s, 1H), 9.07 (s, 1H), 8.65 (d, J = 3.2 Hz, 1H), 8.21 (d, J= 8 Hz, 1H) 7.55 - 7.52 (m, 1H), 7.35 (s, 1H), 1.48 (s, 9H); LCMS: [M+H]+= 277.

[0110] Step-3: 2-(4-pyridyl)thiazol-4-amine (10-4): To a stirred solution of tert-butyl N-[2- (4-pyridyl)thiazol-4-yl]carbamate 10-3 (0.38 g, 1.36 mmol) in DCM (5 mL) was added TFA (0.32 mL, 4.07 mmol) at 0 °C. Reaction was stirred at RT for 4 h. After completion of the reaction, reaction mixture was directly concentrated under reduced pressure to afford 2-(4- pyridyl)thiazol-4-amine (0.20 g), which was used such as for the next reaction. LCMS: [M+H]+= 178.

[0111] Step-4: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-pyridyl)thiazol-4-yl]urea (Example 10): To stirred solution of 2-(4-pyridyl)thiazol-4-amine 10-4 (0.18 g, 0.96 mmol) in MeCN (6 mL) was added N,N′-disuccinimidyl carbonate (0.25 g, 0.96 mmol) followed by pyridine (0.08 mL, 0.96 mmol) at RT. The resulting reaction mixture was stirred at RT for 30 min. To this was added DIPEA (0.52 mL, 2.89 mmol) followed by (4S)-8-chlorochroman-4- amine.HCl 10-5 (0.22 g, 0.96 mmol) at 0 °C and reaction was stirred at 0 °C for 4 h. After completion of the reaction, reaction mixture was concentrated under reduced pressure. Material was dissolved in EtOAc. Organic layer was washed with 2N HCl, H2O, brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by CombiFlash (30% EtOAc / hexane) to afford 1-[(4S)-8-chlorochroman-4-yl]-3-[2- (4-pyridyl)thiazol-4-yl]urea Example 10 (0.13 g).1H NMR (400 MHz, DMSO-d6) δ = 9.36 (br s, 1H), 8.71 - 8.67 (m, 2H), 7.81 - 7.78 (m, 2H), 7.46 (s, 1H), 7.34 (d, J = 7.3 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 6.94 - 6.89 (m, 2H), 5.00 - 4.94 (m, 1H), 4.40 (d, J = 5.9 Hz, 1H), 4.27 (d, J = 7.8 Hz, 1H), 2.21 - 2.11 (m, 1H), 2.07 - 1.99 (m, 1H); LCMS: [M+H]+= 387.Example 11: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(2-phenylthiazol-4-yl)urea

[0112] Step-1: To a stirred solution of 2-phenylthiazol-4-amine 11-1 (0.08 g, 0.45 mmol) in MeCN (2 mL) was added pyridine (0.03 mL, 0.45 mmol) followed by N,N′-disuccinimidyl carbonate (0.12 g, 0.45 mmol) and the resulting reaction mixture was stirred at RT for 30 min. To this solution was added (4S)-8-chlorochroman-4-amine 11-2 (0.08 g, 0.45 mmol) followed by DIPEA (0.24 mL, 1.36 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The product was dissolved in EtOAc and washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by preparative HPLC to afford Example 11 (0.02 g).1H NMR (400 MHz, DMSO- d6) δ = 9.25 (s, 1H), 7.89 - 7.82 (m, 2H), 7.52 - 7.46 (m, 3H), 7.37 - 7.32 (m, 1H), 7.26 (br s, 2H), 6.96 - 6.89 (m, 2H), 5.00 - 4.93 (m, 1H), 4.45 - 4.38 (m, 1H), 4.29 - 4.22 (m, 1H), 2.20 - 1.98 (m, 2H); LCMS: [M+H]+= 386. Example 12: Synthesis of (S)-1-(8-fluorochroman-4-yl)-3-(2-phenylthiazol-4-yl)urea

[0113] Step-1: To a stirred solution of 2-phenylthiazol-4-amine 12-1 (0.07 g, 0.40 mmol) in MeCN (2 mL) was added pyridine (0.03 mL, 0.40 mmol) followed by N,N′-disuccinimidyl carbonate (0.10 g, 0.40 mmol) and the resulting reaction mixture was stirred at RT for 30min. To this solution was added (4S)-8-fluorochroman-4-amine 12-2 (0.07 g, 0.40 mmol) followed by DIPEA (0.21 mL, 1.19 mmol) and reaction was stirred at RT for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The product was dissolved in EtOAc and washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by preparative HPLC to afford Example 12 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.26 (br s, 1H), 7.85 (d, 2H), 7.48 (br s, 3H), 7.26 (s, 1H), 7.15 - 7.08 (m, 2H), 6.95 - 6.86 (m, 2H), 4.96 (d, 1H), 4.36 (br s, 1H), 4.22 (t, 1H), 2.15 (d, 1H), 2.02 (d, 1H); LCMS: [M+H]+ = 370. Example 13: Synthesis of (S)-1-(chroman-4-yl)-3-(2-phenylthiazol-4-yl)urea

[0114] Step-1: ethyl 2-phenylthiazole-4-carboxylate (13-2): To a degassed solution of ethyl 2-bromothiazole-4-carboxylate 13-1 (0.50 g, 2.12 mmol), phenylboronic acid (0.39 g, 3.18 mmol) and K2CO3(0.73 g, 5.29 mmol) in toluene (8 mL) and water (2 mL) was added Pd(PPh3)4(0.25 g, 0.21 mmol) and the reaction mixture was stirred at 100 °C for 14 h. After completion, the reaction mixture was quenched with H2O, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product obtained was purified by CombiFlash (20% EtOAc / hexane) to afford 13-2 (0.30 g).1H NMR (400 MHz, DMSO-d6) δ = 8.58 (s, 1H), 7.99 (d, 2H), 7.54 (br s, 3H), 4.39 - 4.32 (m, 2H), 1.34 (t, 3H); LCMS: [M+H]+= 234.

[0115] Step-2: 2-phenylthiazole-4-carboxylic acid (13-3): To a stirred solution of 13-2 (0.20 g, 0.86 mmol) in THF / MeOH / H2O (4:1:1, 6 mL) was added LiOH.H2O (0.11 g, 2.57 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, the reactionmixture was concentrated and diluted with H2O. The pH was adjusted with 2N HCl and the precipitated solid was filtered and dried under reduced pressure to afford 13-3 (0.10 g).1H NMR (400 MHz, DMSO-d6) δ = 13.11 (bs, 1H), 8.49 (s, 1H), 7.98 - 7.97 (m, 2H), 7.53 (br s, 3H); LCMS: [M+H]+= 205.

[0116] Step-3: tert-butyl (2-phenylthiazol-4-yl)carbamate (13-4): To a stirred solution of 13-3 (0.20 g, 0.98 mmol) in tert-butanol (2 mL) was added triethylamine (0.27 mL, 1.95 mmol) followed by diphenylphosphoryl azide (0.27 mL, 1.27 mmol) and the reaction mixture was stirred at 90 °C for 12 h. After completion, the reaction was quenched with H2O and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product obtained was purified by CombiFlash chromatography (20% EtOAc / hexane) to afford 13-4 (0.07 g).1H NMR (400 MHz, DMSO-d6) δ =10.27 (br s, 1H), 7.88 - 7.86 (m, 2H), 7.52 - 7.46 (m, 3H), 7.25 (s, 1H), 1.47 (s, 9H); LCMS: [M-56]+= 221.

[0117] Step-4: 2-phenylthiazol-4-amine (13-5): To a stirred solution of 13-4 (0.40 g, 1.45 mmol) in DCM (2 mL) was added TFA (0.69 g, 5.79 mmol) at 0 °C and the resulting mixture was stirred at RT for 4 h. After completion, the reaction mixture was concentrated under reduced pressure. The product was triturated with diethyl ether and n-pentane to afford 13-5 (0.30 g, TFA salt), which was used directly for the next reaction.

[0118] Step-5: (S)-1-(chroman-4-yl)-3-(2-phenylthiazol-4-yl)urea (Example 13): To a stirred solution of (4S)-chroman-4-amine 13-6 (0.09 g, 0.567 mmol) in MeCN (2 mL) was added pyridine (0.09 mL, 1.13 mmol) followed by N,N′-disuccinimidyl carbonate (0.15 g, 0.57 mmol) and the resulting reaction mixture was stirred at RT for 30 min. To this solution was added 2-phenylthiazol-4-amine 13-5 (0.10 g, 0.57 mmol) followed by DIPEA (0.30 mL, 1.70 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The product was dissolved in EtOAc and washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by preparative HPLC to afford Example 13 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.25 - 9.20 (m, 1H), 7.85 (d, 2H), 7.47 (br s, 3H), 7.30 - 7.24 (m, 2H), 7.20 - 7.14 (m, 1H), 6.93 - 6.87 (m, 2H), 6.83 - 6.78 (m, 1H), 4.94 - 4.87 (m, 1H), 4.31 - 4.24 (m, 1H), 4.17 - 4.10 (m, 1H), 2.17 - 2.07 (m, 1H), 1.99 (br s, 1H); LCMS: [M+H]+= 352.Example 14: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(2-(pyridin-3-yl)thiazol-4- yl)urea

[0119] Step-1: To a stirred solution of 2-(3-pyridyl)thiazol-4-amine 14-1 (0.30 g, 1.69 mmol) in MeCN (10 mL) was added pyridine (0.14 mL, 1.69 mmol), N,N'-disuccinimidyl carbonate (0.43 g, 1.69 mmol) and the reaction mixture was stirred at RT for 45 min. To this solution was added DIPEA (0.89 mL, 5.08 mmol) and (4S)-8-chlorochroman-4-amine hydrochloride 14-2 (0.37 g, 1.69 mmol) and the reaction mixture was stirred at RT for 4 h. After completion, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and evaporated under reduced pressure. The product was purified by preparative HPLC to afford Example 14 (0.04 g).1H NMR (400 MHz, DMSO-d6) δ = 9.34 (br s, 1H), 9.06 (br s, 1H), 8.65 (d, 1H), 8.21 (d, 1H), 7.56 - 7.50 (m, 1H), 7.39 - 7.30 (m, 2H), 7.26 (d, 1H), 6.95 - 6.88 (m, 2H), 4.97 (d, 1H), 4.45 - 4.37 (m, 1H), 4.30 - 4.23 (m, 1H), 2.22 - 2.11 (m, 1H), 2.07 - 1.97 (m, 1H); LCMS: [M+H]+= 387.Example 15: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-(2-cyclopropylthiazol-4- yl)urea

[0120] Step-1: 2-bromothiazole-4-carbonyl azide (15-2): To a suspension of 2- bromothiazole-4-carboxylic acid 15-1 (2.50 g, 12.0 mmol) in THF (5 mL) was added TEA (2.00 mL, 14.40 mmol) at 0 °C followed by ethyl chloroformate (1.40 mL, 14.4 mmol). Reaction mixture was stirred at RT for 1 h. To the above reaction mixture was added aqueous solution of sodium azide (5.86 g, 90.10 mmol) and stirred at RT for 2 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to obtain 2-bromothiazole-4-carbonyl azide 15-2 (2.40 g). LCMS: [M+H]+= 205.

[0121] Step-2: 1-(2-bromothiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea (15-4): A solution of 2-bromothiazole-4-carbonyl azide 15-2 (2.50 g, 10.7 mmol) in toluene (20 mL) was stirred at 90 °C for 15 min. To the above reaction mixture was added (4S)-8- chlorochroman-4-amine hydrochloride 15-3 (2.36 g, 10.70 mmol) and stirred at 90 °C for 12 h. After completion, reaction mixture was concentrated under reduced pressure to obtain a product which was purified by CombiFlash to obtain 15-41-(2-bromothiazol-4-yl)-3-[(4S)-8- chlorochroman-4-yl]urea (1.90 g). LCMS: [M+H]+= 390.

[0122] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-(2-cyclopropylthiazol-4-yl)urea (Example 15): To a stirred solution of 1-(2-bromothiazol-4-yl)-3-[(4S)-8-chlorochroman-4- yl]urea 15-4 (0.18 g, 0.476 mmol) in toluene (3 mL) and water (1 mL) was added cesiumcarbonate (0.31 g, 0.95 mmol) followed by cyclopropylboronic acid 15-5 (0.06 g, 0.71 mmol) at RT. The reaction mixture was purged with argon for 5 min. To this was added Pd(dppf)Cl2(0.07 g, 0.09 mmol) and again purged with argon for 5 min. The reaction mixture was stirred at 80 °C for 12 h. After completion of reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by prep-HPLC to afford Example 15 (0.04 g).1H NMR: (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 7.32 (dd, J = 1.4, 7.9 Hz, 1H), 7.23 - 7.20 (m, 1H), 6.93 - 6.87 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 4.92 (q, J = 1.0 Hz, 1H), 4.42 - 4.35 (m, 1H), 4.26 - 4.19 (m, 1H), 2.34 - 2.25 (m, 1H), 2.17 - 2.07 (m, 1H), 2.01 - 1.93 (m, 1H), 1.10 - 1.03 (m, 2H), 0.89 - 0.84 (m, 2H); LCMS: [M+H]+= 350. Example 16: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(1-methylpyrazol-4- yl)thiazol-4-yl]urea

[0123] Step-1: (tert-butyl N-[2-(1-methylpyrazol-3-yl)thiazol-4-yl]carbamate (16-3): To a degassed solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 16-1 (0.30 g, 1.07 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 16-2 (0.33 g, 1.61 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was added K2CO3(0.44 g, 3.22 mmol) followed by Pd(PPh3)4(0.12 g, 0.10 mmol). Reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction mixture was quenched with H2O and extracted with EtOAc. Combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4andconcentrated under reduced pressure. The product was purified by the CombiFlash column (55% EtOAc / n-heptane) to afford (tert-butyl N-[2-(1-methylpyrazol-3-yl)thiazol-4- yl]carbamate 16-3 (0.27 g). LCMS: (M+H)+= 281.

[0124] Step-2: 2-(1-methylpyrazol-4-yl)thiazol-4-amine (16-4): A mixture of tert-butyl N- [2-(1-methylpyrazol-3-yl)thiazol-4-yl]carbamate 16-3 (0.01 g, 0.03 mmol) and TFA (0.10 mL) was stirred at 0 °C for 15 min followed by at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure to afford 2-(1-methylpyrazol-4-yl)thiazol- 4-amine 16-4 (0.01 g, TFA salt) which was used directly for the next reaction.

[0125] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(1-methylpyrazol-4-yl)thiazol-4- yl]urea (Example 16): To a stirred solution of (4S)-8-chlorochroman-4-amine hydrochloride 16-5 (0.25 g, 1.15 mmol) in MeCN (10 mL) was added pyridine (0.20 mL, 2.31 mmol). The resulting reaction mixture was stirred at RT for 30 min. To this was added 2-(1- methylpyrazol-4-yl)thiazol-4-amine hydrochloride 16-4 (0.17 g, 0.80 mmol) followed by DIPEA (0.85 mL, 4.61 mmol) and the reaction mixture was stirred at 27 °C for 2 h. After completion, reaction mixture was quenched with H2O, extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by prep HPLC to afford Example 16 (0.05 g).1HNMR (400 MHZ, DMSO-d6) δ = 9.15 (s, 1H), 8.22 (s, 1H), 7.81 (d, J = 0.8 Hz, 1H), 7.33 (dd, J = 1.4, 7.9 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.05 (s, 1H), 6.95 - 6.81 (m, 2H), 4.98 - 4.92 (m, 1H), 4.43 - 4.37 (m, 1H), 4.28 - 4.23 (m, 1H), 3.88 (s, 3H), 2.18 - 2.12 (m, 1H), 2.04 - 1.99 (m, 1H); LCMS: [M+H]+= 390.Example 17: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(4- methylsulfonylphenyl)thiazol-4-yl]urea

[0126] Step-1: tert-butyl N-[2-(4-methylsulfonylphenyl)thiazol-4-yl]carbamate (17-3): To a stirred solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 17-1 (0.50 g, 1.79 mmol) in 1,4-dioxane (2 mL) was added (4-methylsulfonylphenyl)boronic acid 17-2 (0.53 g, 2.69 mmol) followed by K3PO4(1.14 g, 5.37 mmol) in water (0.5 mL) at RT. The reaction mixture was purged with argon for 20 min and then added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (0.08 g, 0.10 mmol) at RT. The reaction was stirred at 100 °C for 2 h. After completion, reaction was quenched with H2O, extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash chromatography (40% EtOAc / heptane) to afford tert-butyl N-[2- (4-methylsulfonylphenyl)thiazol-4-yl]carbamate 17-3 (0.40 g).1H NMR (400 MHz, DMSO- d6) δ = 10.38 (br s, 1H), 8.14 - 8.11 (m, 2H), 8.06 - 8.03 (m, 2H), 7.41 (s, 1H), 3.26 (s, 3H), 1.48 (s, 9H); LCMS: [M+H]+= 355.

[0127] Step-2: 2-(4-methylsulfonylphenyl)thiazol-4-amine (17-4): To a stirred solution of tert-butyl N-[2-(4-methylsulfonylphenyl)thiazol-4-yl]carbamate 17-3 (0.20 g, 0.56 mmol) in DCM (2 mL) was added TFA (0.32 g, 2.82 mmol) at 0 °C. Reaction mixture was stirred at RT for 1 h. After completion, the reaction was quenched with saturated NaHCO3and aqueous layer was extracted with EtOAc. Combined organic layer was washed with brine solution,dried over anhydrous Na2SO4and concentrated under reduced pressure. Product was triturated from heptane to afford 2-(4-methylsulfonylphenyl)thiazol-4-amine 17-4 (0.08 g, TFA salt) which was used directly for the next reaction.1H NMR (400 MHz, DMSO-d6) δ = 8.08 - 8.05 (m, 2H), 8.00 - 7.97 (m, 2H), 6.10 (s, 1H), 5.60 (br s, 2H), 3.25 (s, 3H); LCMS: [M+H]+= 255.

[0128] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-methylsulfonylphenyl)thiazol-4- yl]urea (Example 17): To a stirred solution of 2-(4-methylsulfonylphenyl)thiazol-4-amine 17-4 (0.08 g, 0.32 mmol) in MeCN (8 mL) was added N,N′-disuccinimidyl carbonate (0.25 g, 0.98 mmol) followed by pyridine (0.05 g, 0.65 mmol) at RT. The resulting mixture was stirred at RT for 15 min. To this was added (4S)-8-chlorochroman-4-amine 17-5 (0.06 g, 0.32 mmol) followed by DIPEA (0.05 mL, 0.32 mmol) and stirred at RT for 4 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash chromatography (40% EtOAc / heptane) to afford Example 17 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.36 (s, 1H), 8.13 - 8.10 (m, 2H), 8.04 - 8.02 (m, 2H), 7.43 (s, 1H), 7.34 (dd, J = 1.4, 7.9 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 6.94 - 6.90 (m, 2H), 5.00 - 4.94 (m, 1H), 4.44 - 4.38 (m, 1H), 4.29 - 4.23 (m, 1H), 3.26 (s, 3H), 2.20 - 2.12 (m, 1H), 2.06 - 2.00 (m, 1H); LCMS: (M+H)+= 464. Example 18: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[4-(methylsulfamoyl) phenyl] thiazol-4-yl]urea

[0129] Step-1: tert-butyl N-[2-[4-(methylsulfamoyl) phenyl] thiazol-4-yl] carbamate (18- 3): To a stirred solution of [4-(methylsulfamoyl) phenyl] boronic acid 18-2 (0.57 g, 2.69 mmol) in 1, 4 dioxane (8 mL) and water (2 mL) was added tert-butyl N-(2-bromothiazol-4- yl) carbamate 18-1 (0.50 g, 1.79 mmol) followed by K3PO4(1.14 g, 5.37 mmol) and the reaction mixture was degassed for 15 min. To the resulting reaction mixture was added Pd(dppf)Cl2 complex with dichloromethane (0.26 g, 0.35 mmol) and degassed for 10 min. The reaction mixture was stirred at 100 °C for 4 h. After completion, reaction mixture was quenched with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product obtained was purified by CombiFlash (20% EtOAc / hexane) to afford tert-butyl N-[2-[4-(methylsulfamoyl) phenyl] thiazol-4-yl] carbamate 18-3 (0.50 g).1H NMR (400 MHz, DMSO-d6) δ = 10.36 (br s, 1H), 8.08 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 4.4 Hz, 1H), 7.39 (s, 1H), 2.45 (d, J = 3.9 Hz, 3H), 1.48 (s, 9H).

[0130] Step-2: 4-(4-aminothiazol-2-yl)-N-methyl-benzenesulfonamide (18-4): A mixture of tert-butyl N-[2-[4-(methylsulfamoyl) phenyl] thiazol-4-yl] carbamate 18-3 (0.40 g, 1.08 mmol) and TFA (8.00 mL) was stirred at 0 °C for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The product was quenched with saturated NaHCO3solution, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 4-(4-aminothiazol-2-yl)-N-methyl- benzenesulfonamide 18-4 (0.30 g).1H NMR (400 MHz, DMSO-d6) δ = 8.02 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.53- 7.50 (m, 1H), 6.07 (s, 1H), 5.57 (s, 2H), 2.44 (d, J = 85.2 Hz, 3H); LCMS: [M+H]+= 270.

[0131] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[4-(methylsulfamoyl) phenyl] thiazol- 4-yl]urea (Example 18): To a stirred solution of 4-(4-aminothiazol-2-yl)-N-methyl- benzenesulfonamide 18-4 (0.15 g, 0.55 mmol) in MeCN (5 mL) was added N,N- disuccinimidyl carbonate (0.14 g, 0.55 mmol) followed by pyridine (0.04 mL, 0.55 mmol). Reaction mixture was stirred at RT for 45 min. Reaction mixture was cooled to 0 °C, was added DIEPA (0.29 mL, 1.65 mmol) followed by (4S)-8-chlorochroman-4- aminehydrochloride 18-5 (0.12 g, 0.55 mmol) and stirred at 0 °C for 3 h. After completion, reaction mixture was quenched with H2O and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to yield product. The product was purified byCombiFlash (20% EtOAc / n-heptane) to afford Example 18 (0.09 g).1H NMR (400 MHz, DMSO-d6) δ = 9.34 (s, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.57 (q, J = 5.0 Hz, 1H), 7.40 (s, 1H), 7.34 (dd, J = 1.4, 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 2H), 4.97 (q, J = 6.1 Hz, 1H), 4.44 - 4.38 (m, 1H), 4.28 - 4.23 (m, 1H), 2.44 (d, J = 5.0 Hz, 3H), 2.19 - 2.13 (m, 1H), 2.06 - 2.02 (m, 1H); LCMS: [M+H]+= 479. Example 19: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(3- methylsulfonylphenyl)thiazol-4-yl]urea

[0132] Step-1: tert-butyl N-[2-(3-methylsulfonylphenyl)thiazol-4-yl]carbamate (19-3): To a stirred solution of (3-methylsulfonylphenyl)boronic acid 19-2 (0.04 g, 0.21 mmol) in 1,4- dioxane (2 mL) and H2O (0.5 mL) were added tert-butyl N-(2-bromothiazol-4-yl)carbamate 19-1 (0.05 g, 0.17 mmol) and K3PO4(0.11 g, 0.53 mmol) at RT. The reaction mixture was purged with argon gas for 30 min. To the resulting reaction mixture was added (1,1- bis(diphenylphosphino)ferrocene)palladium (II) dichloride (0.03 g, 0.03 mmol) at RT and resulting mixture was degassed for 10 min. The reaction mixture was maintained at 80 °C for 3 h. After completion, the reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford tert-butyl N-[2-(3- methylsulfonylphenyl)thiazol-4-yl]carbamate 19-3 (0.04 g). LCMS: [M+H]+= 299.

[0133] Step-2: 2-(3-methylsulfonylphenyl)thiazol-4-amine (19-4): To a stirred solution of tert-butyl N-[2-(3-methylsulfonylphenyl)thiazol-4-yl]carbamate 19-3 (0.50 g, 1.41 mmol) in DCM (2 mL) was added TFA (1.10 mL, 14.10 mmol) at 0 °C. Reaction mixture was stirred at RT for 4 h. After completion, the reaction mixture was quenched with sodium bicarbonate solution and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 2-(3- methylsulfonylphenyl)thiazol-4-amine 19-4 (0.33 g, TFA salt). LCMS: [M+H]+= 255.

[0134] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(3-methylsulfonylphenyl)thiazol-4- yl]urea (Example 19): To a stirred solution of compound 2-(3- methylsulfonylphenyl)thiazol-4-amine 19-4 (0.10 g, 0.39 mmol) in MeCN (3 mL) was added pyridine (0.03 mL, 0.39 mmol) followed by N,N'-disuccinimidyl carbonate (0.10 g, 0.40 mmol) and reaction mixture was stirred at RT for 15 min. To this was added (4S)-8- chlorochroman-4-amine hydrochloride 19-5 (0.08 g, 0.39 mmol) followed by DIPEA (0.22 mL, 1.18 mmol) and the reaction was stirred at RT for 4 h. After completion, reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to obtain product. The product was purified by prep-HPLC to afford Example 19 (0.06 g).1H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 1H), 8.36 (t, J = 1.6 Hz, 1H), 8.20 - 8.17 (m, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.39 (s, 1H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.97 (q, J = 6.4 Hz, 1H), 4.43 - 4.38 (m, 1H), 4.28 - 4.24 (m, 1H), 3.29 (s, 3H), 2.19 - 2.14 (m, 1H), 2.07 - 2.01 (m, 1H); LCMS: [M+H]+= 464.Example 20: Synthesis of 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2- yl]-N-methyl-benzamide

[0135] Step-1: tert-butyl N-[2-[4-(methylcarbamoyl)phenyl]thiazol-4-yl]carbamate (20- 3): To a stirred solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 20-1 (0.50 g, 1.79 mmol) and [4-(methylcarbamoyl)phenyl]boronic acid 20-2 (0.38 g, 2.15 mmol) in 1,4- dioxane (10 mL), potassium phosphate (1.14 g, 5.37 mmol) was added dissolved in water (2 mL) and the reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, Pd(dppf)Cl2-DCM (0.08 g, 0.107 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by silica gel column chromatography (60% EtOAc / hexane) to afford tert-butyl N-[2-[4- (methylcarbamoyl)phenyl]thiazol-4-yl]carbamate 20-3 (0.55 g). LCMS: [M+H]+= 334.

[0136] Step-2: 4-(4-aminothiazol-2-yl)-N-methyl-benzamide (20-4): A solution of tert- butyl N-[2-[4-(methylcarbamoyl)phenyl]thiazol-4-yl]carbamate 20-3 (0.38 g, 1.14 mmol) in TFA (0.44 mL, 5.70 mmol) was stirred at 30 °C for 1 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure, pH 8 was adjusted with NaHCO3solution and the aqueous layer was extracted with ethyl acetate. Combined organic layer wasdried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by flash column chromatography (80% EtOAc / Heptane) to afford 4-(4-aminothiazol- 2-yl)-N-methyl-benzamide 20-4 (0.20 g). LCMS: [M+H]+= 234.

[0137] Step-3: 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]-N- methyl-benzamide (Example 20): To a stirred solution of 4-(4-aminothiazol-2-yl)-N- methyl-benzamide 20-4 (0.09 g, 0.40 mmol) in MeCN (2 mL) was added pyridine (0.06 mL, 0.81 mmol) followed by N,N'-disuccinimidyl carbonate (0.10 g, 0.40 mmol) at RT and reaction mixture was stirred for 15 min. To this was added (4S)-8-chlorochroman-4-amine hydrochloride 20-5 (0.09 g, 0.40 mmol) followed by DIPEA (0.30 mL, 1.63 mmol) and the resulting reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by prep-HPLC to afford Example 20 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.30 (s, 1H), 8.54 (q, J = 4.2 Hz, 1H), 7.93 (s, 4H), 7.35 - 7.32 (m, 2H), 7.26 (d, J = 7.8 Hz, 1H), 6.94 - 6.90 (m, 2H), 4.99 - 4.94 (m, 1H), 4.43 - 4.38 (m, 1H), 4.28 - 4.23 (m, 1H), 2.80 (d, J = 4.5 Hz, 3H), 2.19 - 2.14 (m, 1H), 2.06 - 2.01 (m, 1H); LCMS: [M+H]+= 443.Example 21: Synthesis of 5-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2- yl]-N-methyl-pyridine-2-carboxamide

[0138] Step-1: methyl 5-[4-(tert-butoxycarbonylamino)thiazol-2-yl]pyridine-2- carboxylate (21-3): To a degassed solution of methyl 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine-2-carboxylate 21-2 (0.14 g, 0.537 mmol), tert-butyl N-(2- bromothiazol-4-yl)carbamate 21-1 (0.10 g, 0.35 mmol) and K3PO4(0.22 g, 1.07 mmol) in 1,4-dioxane (4 mL) and water (1 mL), PdCl2(dppf) complex with dichloromethane (0.05 g, 0.07 mmol) was added and the reaction mixture was stirred at 100 °C for 14 h. Aftercompletion, reaction was quenched with H2O, aqueous layer was extracted with EtOAc.Organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product was purified by CombiFlash to afford methyl 5-[4-(tert- butoxycarbonylamino)thiazol-2-yl]pyridine-2-carboxylate 21-3 (0.03 g).1H NMR (400 MHz, DMSO-d6) δ = 10.44 (br s, 1H), 9.19 (br s, 1H), 8.41 - 8.39 (m, 1H), 8.18 - 8.16 (m, 1H), 7.46 (s, 1H), 3.91 (s, 3H), 1.48 (s, 9H); LCMS: [M+H]+= 336.

[0139] Step-2: 5-[4-(tert-butoxycarbonylamino)thiazol-2-yl]pyridine-2-carboxylic acid (21-4): To a solution of methyl 5-[4-(tert-butoxycarbonylamino)thiazol-2-yl]pyridine-2-carboxylate 21-3 (0.30 g, 0.89 mmol) in THF (6 mL):methanol (2 mL):water (2 mL) was added LiOH.H2O (0.11 g, 2.68 mmol) and the reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was concentrated. The product was diluted with H2O, pH was adjusted with 2N HCl and precipitated solid was filtered, dried under reduced pressure to afford 5-[4-(tert-butoxycarbonylamino)thiazol-2-yl]pyridine-2-carboxylic acid 21-4 (0.20 g). LCMS: [M+H]+= 322.

[0140] Step-3: tert-butyl N-[2-[6-(methylcarbamoyl)-3-pyridyl]thiazol-4-yl]carbamate (21-5): To a stirred solution of 5-[4-(tert-butoxycarbonylamino)thiazol-2-yl]pyridine-2- carboxylic acid 21-4 (0.20 g, 0.62 mmol) in DMF (2 mL) was added methylamine hydrochloride (0.06 g, 0.93 mmol) followed by addition of HATU (0.35 g, 0.93 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, reaction mixture was quenched by addition of water and precipitated solid was filtered, dried under reduced pressure to afford tert-butyl N-[2-[6-(methylcarbamoyl)-3-pyridyl]thiazol-4-yl]carbamate 21- 5 (0.13 g).1H NMR (400 MHz, DMSO-d6) δ = 10.38 (br s, 1H), 9.08 (s, 1H), 8.81 (br s, 1H), 8.40 - 8.38 (m, 1H), 8.14 - 8.12 (m, 1H), 7.46 - 7.42 (m, 1H), 2.84 (m, 3H), 1.48 (s, 9H); LCMS: [M+H]+= 335.

[0141] Step-4: 5-(4-aminothiazol-2-yl)-N-methyl-pyridine-2-carboxamide (21-6): A mixture of tert-butyl N-[2-[6-(methylcarbamoyl)-3-pyridyl]thiazol-4-yl]carbamate 21-5 (0.13 g, 0.38 mmol) and TFA (0.59 mL, 7.78 mmol) was stirred at 0 °C for 10 min followed by at RT for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The product 21-6 was triturated using diethyl ether and used directly for the next reaction. LCMS: [M+H]+= 235.

[0142] Step-5: 5-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]-N- methyl-pyridine-2-carboxamide (Example 21): To a stirred solution of 5-(4-aminothiazol- 2-yl)-N-methyl-pyridine-2-carboxamide 21-6 (0.07 g, 0.299 mmol) in MeCN (2 mL) was added pyridine (0.07 mL, 0.89 mmol) followed by N,N′-disuccinimidyl carbonate (0.07 g, 0.30 mmol). Resulting reaction mixture was stirred at RT for 20 min. To this was added (4S)- 8-chlorochroman-4-amine 21-7 (0.05 g, 0.29 mmol) followed by DIPEA (0.16 mL, 0.89 mmol) and reaction mixture was stirred at 30 °C for 4 h. After completion, reaction mixture was concentrated under reduced pressure and product obtained was dissolved in EtOAc. Organic layer was washed with 2N HCl, H2O, brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by prep-HPLC to afford Example 21 (0.003 g).1H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 1H), 9.08 (d, J = 1.6 Hz, 1H), 8.83 (d, J = 5.1 Hz, 1H), 8.39 (dd, J = 2.2, 8.2 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.45 (s, 1H), 7.34 (dd, J = 1.2, 7.9 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 6.94 - 6.87 (m, 2H), 5.01 - 4.93 (m, 1H), 4.43 - 4.38 (m, 1H), 4.29 - 4.22 (m, 1H), 2.84 (d, J = 4.9 Hz, 3H), 2.19 - 2.15 (m, 1H), 2.07 - 2.03 (m, 1H); LCMS: [M+H]+= 445. Example 22: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[3- (methylsulfamoyl)phenyl]thiazol-4-yl]urea

[0143] Step-1: tert-butyl N-[2-[3-(methylsulfamoyl)phenyl]thiazol-4-yl]carbamate (22- 3): To a stirred solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 22-1 (0.50 g, 1.79 mmol) and [3-(methylsulfamoyl)phenyl]boronic acid 22-2 (0.38 g, 1.79 mmol) in 1,4-dioxane (10 mL), K3PO4(1.14 g, 5.37 mmol) was added dissolved in water (5 mL) and the reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, Pd(dppf)Cl2 complex with dichloromethane (0.29 g, 0.35 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4andconcentrated under reduced pressure to afford tert-butyl N-[2-[3- (methylsulfamoyl)phenyl]thiazol-4-yl]carbamate 22-3 (0.50 g). LCMS: [M+H]+= 370.

[0144] Step-2: 3-(4-aminothiazol-2-yl)-N-methyl-benzenesulfonamide (22-4): To a stirred solution of tert-butyl N-[2-[3-(methylsulfamoyl)phenyl]thiazol-4-yl]carbamate 22-3 (0.10 g, 0.27 mmol) was added TFA (0.21 mL, 2.71 mmol) at 0 °C and the reaction mixture was stirred at that temperature for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The product was quenched with saturated NaHCO3solution, aqueous layer was extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 3-(4-aminothiazol-2-yl)-N-methyl- benzenesulfonamide 22-4 (0.07 g). LCMS: [M+H]+= 270.

[0145] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[3-(methylsulfamoyl)phenyl]thiazol- 4-yl]urea (Example 22): To a stirred solution of 3-(4-aminothiazol-2-yl)-N-methyl- benzenesulfonamide 22-4 (0.07 g, 0.26 mmol) in MeCN (5 mL) was added pyridine (0.04 g, 0.52 mmol) followed by N,N′-disuccinimidyl carbonate (0.06 g, 0.26 mmol). The resulting mixture was stirred at 25 °C for 30 min. To this was added (4S)-8-chlorochroman-4-amine 22-5 (0.04 g, 0.26 mmol) followed by DIPEA (0.10 g, 0.78 mmol) and the reaction mixture was stirred at 25 °C for 12 h. After completion, reaction mixture was concentrated under reduced pressure. The product was diluted with water and solid obtained was filtered, dried under reduced pressure. The product was purified by prep HPLC to afford Example 22 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.39 (s, 1H), 8.26 (t, J = 1.6 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 5.1 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.61 (d, J = 5.0 Hz, 1H), 7.38 (s, 1H), 7.34 (dd, J = 1.4, 7.9 Hz, 1H), 7.25 (d, J = 7.0 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 4.97 (q, J = 6.3 Hz, 1H), 4.43 - 4.38 (m, 1H), 4.29 - 4.23 (m, 1H), 2.44 (d, J = 5.0 Hz, 3H), 2.19 - 2.14 (m, 1H), 2.06 - 2.02 (m, 1H); LCMS: [M+H]+= 479.Example 23: Synthesis of methyl 4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]-2-fluoro-benzoate

[0146] Step-1: methyl 4-[4-(tert-butoxycarbonylamino) thiazol-2-yl]-2-fluoro-benzoate (23-3): To a stirred solution of (3-fluoro-4-methoxycarbonyl-phenyl)boronic acid 23-2 (0.42 g, 2.15 mmol) and tert-butyl N-(2-bromothiazol-4-yl)carbamate 23-1 (0.50 g, 1.79 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added K3PO4(1.14 g, 5.37 mmol) and the reaction mixture was degassed for 30 min. To the resulting reaction mixture was added (1,1'- bis(diphenylphosphino)ferrocene)palladium (II) dichloride (0.29 g, 0.35 mmol) and degassed for another 10 min. The reaction mixture was stirred at 80 °C for 16 h. After completion, reaction was quenched with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by CombiFlash (5-10% EtOAc / Hexane) to afford methyl 4-[4-(tert- butoxycarbonylamino) thiazol-2-yl]-2-fluoro-benzoate 23-3 (0.40 g).1H NMR: (400 MHz, DMSO-d6) δ = 10.37 (br s, 1H), 8.03 - 7.99 (m, 1H), 7.84 - 7.77 (m, 2H), 7.43 (s, 1H), 3.88 (s, 3H), 1.48 (s, 9H). LCMS: [M+H]+= 297.

[0147] Step-2: methyl 4-(4-aminothiazol-2-yl)-2-fluoro-benzoate (23-4): A solution of methyl 4-[4-(tert-butoxycarbonylamino)thiazol-2-yl]-2-fluoro-benzoate 23-3 (1.00 g, 2.84mmol) in TFA (10 mL) was stirred at 0 °C for 2 h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was triturated using pentane to afford methyl 4-(4-aminothiazol-2-yl)-2-fluoro-benzoate 23-4 (0.50 g). LCMS: [M+H]+= 253.

[0148] Step-3: methyl 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]- 2-fluoro-benzoate (23-6): To a stirred solution of methyl 4-(4-aminothiazol-2-yl)-2-fluoro- benzoate 23-4 (0.20 g, 0.79 mmol) in MeCN (5 mL) was added N,N-disuccinimidyl carbonate (0.20 g, 0.793 mmol) followed by pyridine (0.06 mL, 0.79 mmol) and the reaction mixture was stirred at RT for 40 min. Reaction mixture was cooled to 0 °C and DIEPA (0.42 mL, 2.38 mmol) was added followed by (4S)-8-chlorochroman-4-amine hydrochloride 23-5 (0.17 g, 0.793 mmol). The reaction mixture weas stirred at 0 °C for 4 h. After completion, reaction mixture was concentrated under reduced pressure and product was dissolved in EtOAc. Organic layer was washed with 2N HCl, H2O, brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by CombiFlash (20% EtOAc / Hexane) to afford methyl 4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]-2-fluoro-benzoate 23-6 (0.20 g).1H NMR (400 MHz, DMSO-d6) δ = 9.33 (s, 1H), 7.99 (s, 1H), 7.81 - 7.75 (m, 2H), 7.44 (s, 1H), 7.29 (dd, J = 6 Hz, J = 7.6 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 4.96 (s, 1H), 4.39 (s, 1H), 4.25 (s, 1H), 3.87 (s, 3H), 2.14 (s, 1H), 2.03 (s, 1H); LCMS: (M+H)+= 462.

[0149] Step-4: 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]-2-fluoro- N-methyl-benzamide (Example 23): A solution of methyl 4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]-2-fluoro-benzoate 23-6 (0.05 g, 0.12 mmol) in methylamine in methanol (7.00 mL) was stirred at RT for 12 h. After completion, solid was filtered under vacuum. The product solid was purified by prep HPLC to afford Example 23 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.30 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.77 - 7.3H), 7.38 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.94 - 6.91 (m, 2H), 4.96 (q, J = 6.4 Hz, 1H), 4.44 - 4.38 (m, 1H), 4.29 - 4.20 (m, 1H), 2.79 (d, J = 4.4 Hz, 3H), 2.19 - 2.12 (m, 1H), 2.06 - 1.99 (m, 1H); LCMS: [M+H]+= 461.Example 24: Synthesis of 4-[4-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] thiazol- 2-yl]-2-methoxy-benzamide

[0150] Step-1: methyl 4-[4-(tert-butoxycarbonylamino) thiazol-2-yl]-2-methoxy- benzoate (24-3): To a degassed solution of tert-butyl N-(2-bromothiazole-4-yl)carbamate 24- 1 (1.00 g, 3.58 mmol), 24-2 (3-methoxy-4-methoxycarbonyl-phenyl)boronic acid (1.13 g, 5.37 mmol) and K3PO4(2.28 g, 10.7 mmol) in 1,4-dioxane (21 mL):water (7 mL) (3:1) was added Pd(dppf)Cl2(0.16 g, 0.21 mmol) and the reaction mixture was purged with argon for 10 min. Reaction mixture was stirred at 100 °C for 2 h. After completion, the organic layer was separated. The aqueous layer was extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to yield product which was purified by CombiFlash (30% EtOAc / n-heptane) to afford methyl 4- [4-(tert-butoxycarbonylamino) thiazol-2-yl]-2-methoxy-benzoate 24-3 (0.98 g).1H NMR (400 MHz, DMSO-d6) δ = 10.31 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 1.46 (s, 9H); LCMS: [M+H]+= 309.

[0151] Step-2: [2-(3-methoxy-4-methoxycarbonyl-phenyl) thiazol-4-yl]ammonium, 2,2,2- trifluoroacetate (24-4): A solution of methyl 4-[4-(tert-butoxycarbonylamino) thiazol-2-yl]- 2-methoxy-benzoate 24-3 (0.35 g, 0.96 mmol) in TFA (3.5 mL) was stirred at 0 °C for 2 h.After completion, reaction mixture was concentrated under reduced pressure. The product was washed with diethyl ether to afford [2-(3-methoxy-4-methoxycarbonyl-phenyl)thiazol-4- yl]ammonium-2,2,2-trifluoroacetate salt 24-4 (0.30 g).1H NMR (400 MHz, DMSO-d6) δ = 7.73 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 6.26 (s, 1H), 3.89 (s, 3H), 3.79 (s, 3H); LCMS: [M+H]+= 265. Step-3: methyl 4-[4-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] thiazol-2-yl]-2- methoxy-benzoate (24-6): To a stirred solution of N,N′-disuccinimidyl carbonate (0.11 g, 0.46 mmol) in MeCN (8 mL) was added pyridine (0.07 mL, 0.92 mmol) followed by methyl 4-(4-aminothiazol-2-yl)-2-methoxy-benzoate 24-4 (0.12 g, 0.46 mmol) and the reaction mixture was stirred at RT for 1 h. To this was added DIPEA (0.24 mL, 1.39 mmol) followed by (4S)-8-chlorochroman-4-amine 24-5 (0.08 g, 0.46 mmol) and stirred at RT for 45 min. After completion, reaction mixture was concentrated under reduced pressure. The product was dissolved in EtOAc, organic layer was washed with H2O, brine, dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to afford methyl 4-[4- [[(4S)-8-chlorochroman-4-yl] carbamoylamino] thiazol-2-yl]-2-methoxy-benzoate 24-6 (0.22 g). LCMS: [M+H]+= 474.

[0152] Step-4: 4-[4-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] thiazol-2-yl]-2- methoxy-benzamide (Example 24): A solution of methyl 4-[4-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] thiazol-2-yl]-2-methoxy-benzoate 24-6 (0.07 g, 0.14 mmol) in 25% methylamine in methanol (8 mL) was stirred at RT for 16 h. After completion, solid was filtered. The product solid was purified by prep HPLC to afford Example 24 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.39 (s, 1H), 8.19 (d, J = 4.4 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.35 - 7.32 (m, 2H), 7.25 (d, J = 7.3 Hz, 1H), 6.94 - 6.87 (m, 2H), 5.01 - 4.94 (m, 1H), 4.44 - 4.39 (m, 1H), 4.28 - 4.23 (m, 1H), 3.94 (s, 3H), 2.81 (d, J = 4.4 Hz, 3H), 2.18 - 2.13 (m, 1H), 2.05 - 2.01 (m, 1H); LCMS: [M 2H]+= 473.Example 25: Synthesis of 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2- yl]benzamidep- e - u y - - - yp y - -y - o a stirred solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 25-1 (0.60 g, 2.15 mmol) and (4-carbamoylphenyl)boronic acid 25-2 (0.53 g, 3.22 mmol) in 1,4-dioxane (10mL), potassium phosphate (1.37 g, 6.45 mmol) was added dissolved in water (3mL) and the reaction mixture was purged with argon for 30 min. To the resulting reaction mixture, PdCl2 (dppf) (0.09 g, 0.129 mmol) was added and the reaction mixture was again purged with argon for 20 min. The reaction mixture was stirred at 100 °C for 16 h. After completion of reaction, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was diluted with cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine (10 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by silica gel column chromatography (60 % EtOAc / hexane) to afford tert-butyl N-[2-(4-carbamoylphenyl)thiazol-4-yl]carbamate 25-3 (450 mg). LCMS: [M+H]+= 264.

[0154] Step-2: 4-(4-aminothiazol-2-yl)benzamide (25-4): To a stirred solution of tert-butyl N-[2-(4-carbamoylphenyl)thiazol-4-yl]carbamate 25-3 (0.10 g, 0.31 mmol) in DCM (2 mL) maintained at 0 °C was added TFA (0.24 mL, 3.13 mmol). The reaction was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was triturated using diethyl ether and pentane, dried well to afford 4-(4-aminothiazol-2-yl)benzamide 25-4 (0.08 g) which was used directly for the next reaction. LCMS: [M+H]+= 220.

[0155] Step-3: 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2- yl]benzamide (Example 25): To a stirred solution of 4-(4-aminothiazol-2-yl)benzamide 25-4 (0.07 g, 0.35 mmol) in MeCN (3 mL) was added N,N′-disuccinimidyl carbonate (0.09 g, 0.35 mmol) followed by pyridine (0.02 mL, 0.35 mmol). The resulting reaction mixture was stirred at RT for 45 min. To this was added DIPEA (0.19 mL, 1.06 mmol) followed by (4S)- 8-chlorochroman-4-amine hydrochloride 25-5 (0.07 g,0.35 mmol) and the reaction mixture was stirred at 30 °C for 1 h. After completion, reaction mixture was concentrated under reduced pressure and product obtained was dissolved in EtOAc. Organic layer was washed with 2N HCl, H2O, brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by prep-HPLC to afford Example 25 (0.06 g).1HNMR (400 MHz, DMSO-d6) δ = 9.30 (s, 1H), 8.07 (br s, 1H), 7.99 - 7.90 (m, 4H), 7.47 (br s, 1H), 7.36 - 7.32 (m, 2H), 7.26 (d, J = 7.1 Hz, 1H), 6.95 - 6.90 (m, 2H), 4.97 (q, J = 6.1 Hz, 1H), 4.44 - 4.37 (m, 1H), 4.29 - 4.24 (m, 1H), 2.20 - 2.12 (m, 1H), 2.06 - 1.97 (m, 1H); LCMS: [M+H]+= 429.Example 26: Synthesis of 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2- yl]-2-methoxy-benzamide

[0156] Step-1: methyl 4-[4-(tert-butoxycarbonylamino)thiazol-2-yl]-2-methoxy-benzoate (26-3): To a degassed solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 26-1 (1.00 g, 3.58 mmol), 26-2 (3-methoxy-4-methoxycarbonyl-phenyl)boronic acid (1.12 g, 5.37 mmol) and K3PO4(2.5 mL, 10.7 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) (3:1) was added Pd(dppf)Cl2 (0.15 g, 0.21 mmol) and argon was again purged for 10 min. Reaction was stirred at 100 °C for 2 h. After completion, the organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash (30% EtOAc / n-heptane) to afford methyl 4-[4-(tert- butoxycarbonylamino)thiazol-2-yl]-2-methoxy-benzoate 26-3 (0.92 g).1H NMR (400 MHz, DMSO-d6) δ = 10.33 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 1.47 (s, 9H); LCMS: [M+H]+= 365.

[0157] Step-2: methyl 4-(4-aminothiazol-2-yl)-2-methoxybenzoate (26-4): A solution of methyl 4-[4-(tert-butoxycarbonylamino)thiazol-2-yl]-2-methoxy-benzoate 26-3 (092 g 246mmol) in TFA (9.0 mL) was stirred at 0 °C for 1 h. After completion, reaction mass was concentrated under reduced pressure. The product obtained was washed with diethyl ether to afford methyl 4-(4-aminothiazol-2-yl)-2-methoxybenzoate 26-4 (0.75 g, TFA salt). The product was used directly for the next reaction without any further purification.1H NMR (400 MHz, DMSO-d6) δ = 7.73 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 4.61 (br s, 2H), 3.89 (s, 3H), 3.79 (s, 3H); LCMS: [M+H]+= 266.

[0158] Step-3: methyl 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]- 2-methoxy-benzoate (26-6): To a stirred solution of N,N'-disuccinimidyl carbonate (0.06 g, 0.26 mmol) in MeCN (4 mL) were added pyridine (0.04 mL, 0.53 mmol) and methyl 4-(4- aminothiazol-2-yl)-2-methoxybenzoate, TFA salt 26-4 (0.10 g, 0.265 mmol) and stirred at RT for 1 h. To the reaction mixture was added DIPEA (0.19 mL, 1.06 mmol) followed by (4S)-8- chlorochroman-4-amine hydrochloride 26-5 (0.05 g, 0.26 mmol) and stirred at RT for 45 min. After completion, reaction mass was concentrated under reduced pressure. The product was dissolved in EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford methyl 4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]-2-methoxy-benzoate 26-6 (0.08 g)1H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.54 (s, J = 1.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.37 (s, 1H), 7.33 - 7.25 (dd, J = 7.2 Hz, J = 8.0 Hz, 2H), 6.93 - 6.85 (m, 2H), 4.97 (d, J = 8.0 Hz, 1H), 4.42 - 4.25 (m, 2H), 3.89 (s, 3H), 3.80 (m, 3H), 2.17 - 1.98 (m, 2H); LCMS: [M+H]+= 474.

[0159] Step-4: 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]-2- methoxy-benzoic acid (26-7): To a stirred solution of methyl 4-[4-[[(4S)-8-chlorochroman- 4-yl]carbamoylamino]thiazol-2-yl]-2-methoxy-benzoate 26-6 (0.10 g, 0.21 mmol) in methanol (1 mL), THF (3 mL) and water (1 mL) was added LiOH.H2O (0.08 g, 2.11 mmol) at 0 °C and the reaction mixture was stirred at RT for 3 h. After completion, reaction mass was concentrated under reduced pressure. The product obtained was dissolved in H2O. The aqueous layer was acidified with dilute HCl to pH 2-3. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]-2-methoxy-benzoic acid 26-7 (0.06 g). LCMS: [M+H]+= 460.

[0160] Step-5: 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]-2- methoxy-benzamide (Example 26): To a stirred solution of 4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]-2-methoxy-benzoic acid 26-7 (0.16 g, 0.348 mmol) in DMF (3 mL) was added HATU (0.19 g, 0.52 mmol) and DIPEA (0.18 mL, 1.04 mmol) followed by NH4Cl (0.09 g, 1.74 mmol) and the reaction mixture was stirred at RT for 16 h. After completion, reaction mixture was quenched with ice-cold H2O. The precipitated solid was filtered under vacuum to afford Example 26 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.40 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.68 (br s, 1H), 7.61 (br s, 1H), 7.53 - 7.48 (m, 2H), 7.35 - 7.31 (m, 2H), 7.25 (d, J = 7.3 Hz, 1H), 6.94 - 6.85 (m, 2H), 5.01 - 4.94 (m, 1H), 4.44 - 4.38 (m, 1H), 4.29 - 4.24 (m, 1H), 3.95 (s, 3H), 2.19 - 2.12 (m, 1H), 2.06 - 2.00 (m, 1H); LCMS: [M+H]+= 459. Example 27: Synthesis of 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2- yl]-2-fluoro-benzamide

[0161] Step-1: methyl 4-[4-(tert-butoxycarbonylamino)thiazol-2-yl]-2-fluoro-benzoate (27-3): To a degassed solution of tert-butyl N-(2-bromothiazol-4-yl) carbamate 27-1 (1.00 g, 3.58 mmol) was added (3-fluoro-4-methoxycarbonyl-phenyl)boronic acid 27-2 (0.85 g, 4.30mmol) followed by K3PO4(2.28 g, 10.7 mmol) in 1,4-dioxane (10 mL) and water (2 mL). To the resulting reaction mixture was added (1,1'-bis(diphenylphosphino)ferrocene) palladium (II) dichloride (0.17 g, 0.21 mmol) and degassed for 10 min. The reaction mixture was stirred at 80 °C for 2 h. After completion, reaction mixture was passed through Celite bed, the Celite bed was washed with EtOAc. The organic layer was washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by CombiFlash (20% EtOAc / hexane) to afford methyl 4-[4-(tert- butoxycarbonylamino)thiazol-2-yl]-2-fluoro-benzoate 27-3 (0.80 g).1H NMR: (400 MHz, DMSO-d6) δ = 10.38 (br s, 1H), 8.03 - 7.99 (m, 1H), 7.83 - 7.75 (m, 2H), 7.42 (s, 1H), 3.87 (s, 3H), 1.48 (s, 9H); LCMS: [M+H]+= 352.

[0162] Step-2: methyl 4-(4-aminothiazol-2-yl)-2-fluoro-benzoate (27-4): A solution of methyl 4-[4-(tert-butoxycarbonylamino)thiazol-2-yl]-2-fluoro-benzoate 27-3 (1.00 g, 2.84 mmol) in TFA (10 mL) was stirred at 0 °C for 2 h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was triturated with pentane to afford methyl 4-(4-aminothiazol-2-yl)-2-fluoro-benzoate 27-4 (0.50 g) which was used directly for the next reaction. LCMS: [M+H]+= 253.

[0163] Step-3: methyl 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]- 2-fluoro-benzoate (27-6): To a stirred solution of methyl 4-(4-aminothiazol-2-yl)-2-fluoro- benzoate 27-4 (0.20 g, 0.79 mmol) in MeCN (5 mL) was added N,N-disuccinimidyl carbonate (0.20 g, 0.79 mmol) followed by pyridine (0.06 mL, 0.79 mmol). Reaction mixture was stirred at RT for 40 min. Reaction mixture was cooled to 0 °C and was added DIEPA (0.42 mL, 2.38 mmol) followed by (4S)-8-chlorochroman-4-amine hydrochloride 27-5 (0.17 g, 0.79 mmol) and stirred at 0 °C for 4 h. After completion, reaction mixture was concentrated under reduced pressure and product was dissolved in EtOAc. Organic layer was washed with 2N HCl, H2O, brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by CombiFlash (20% EtOAc / hexane) to afford methyl 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]-2-fluoro- benzoate 27-6 (0.20 g).1H NMR (400 MHz, DMSO-d6) δ = 9.33 (s, 1H), 7.99 (s, 1H), 7.81 - 7.75 (m, 2H), 7.44 (s, 1H), 7.29 (dd, J = 6 Hz, J = 7.6 Hz, 2H), 6.92 (d, J = 7.6 Hz, 2H), 4.96 (s, 1H), 4.39 (s, 1H), 4.25 (s, 1H), 3.87(s, 3H), 2.14 (s, 1H), 2.03 (s, 1H); LCMS: [M+H]+= 462.

[0164] Step-4: 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]-2-fluoro- benzoic acid (27-7): To a stirred solution of methyl 4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]-2-fluoro-benzoate 27-6 (0.30 g, 0.64 mmol) in THF (9 mL), methanol (6 mL) and water (3 mL) was added LiOH.H2O (0.27 g, 6.48 mmol). Reaction mixture was stirred at RT for 12 h. After completion, reaction mixture was concentrated, product was diluted with H2O and the pH was adjusted with 2N HCl. Solid obtained was filtered, dried under reduced pressure to afford 4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]-2-fluoro-benzoic acid 27-7 (0.10 g).1H NMR (400 MHz, DMSO-d6) δ = 13.40 (br s, 1H), 9.34 (s, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.75 (dd, J = 8.4, 20.0 Hz, 2H), 7.43 - 7.25 (m, 3H), 6.97 - 6.90 (m, 2H), 4.96 (d, J = 6.0 Hz, 1H), 4.42 - 4.26 (m, 2H), 2.16 - 2.02 (m, 2H); LCMS: [M+H]+= 448.

[0165] Step-5: 4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]-2-fluoro- benzamide (Example 27): To a stirred solution of 4-[4-[[(4S)-8-chlorochroman-4-yl] carbamoylamino]thiazol-2-yl]-2-fluoro-benzoic acid 27-7 (0.16 g, 0.34 mmol) in DMF (6 mL) were added DIPEA (0.18 mL, 1.00 mmol) and HATU (0.19 g, 0.50 mmol) followed by NH4Cl (0.09 g, 1.67 mmol) at 0 °C Reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was quenched with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by prep HPLC to afford Example 27 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.32 (s, 1H), 7.79 - 7.70 (m, 5H), 7.39 (s, 1H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.95 - 6.91 (m, 2H), 4.96 (q, J = 6.3 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.29 - 4.23 (m, 1H), 2.20 - 2.13 (m, 1H), 2.07 - 1.98 (m, 1H); LCMS: [M+H]+= 447.Example 28: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(1-methylpyrazol-3- yl)thiazol-4-yl]urea

[0166] Step-1: tert-butyl N-[2-(1-methylpyrazol-3-yl)thiazol-4-yl]carbamate (28-3): To a degassed solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 28-1 (0.30 g, 1.07 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 28-2 (0.33 g, 1.61 mmol) and K2CO3(0.44 g, 3.22 mmol) in 1,4-dioxane (12 mL) and water (4 mL) was added Pd(PPh3)4(0.12 g, 0.10 mmol) and argon was again purged for 10 min. Reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by CombiFlash (55% EtOAc / n-heptane) to afford (tert-butyl N-[2-(1-methylpyrazol-3- yl)thiazol-4-yl]carbamate 28-3 (0.27 g). LCMS: [M+H]+= 281.

[0167] Step-2: (2-(1-methylpyrazol-3-yl)thiazol-4-amine (28-4): A mixture of tert-butyl N- [2-(1-methylpyrazol-3-yl)thiazol-4-yl]carbamate 28-3 (0.27 g, 0.96 mmol) and TFA (0.80 mL) was stirred at 0 °C for 1 h followed by at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was triturated with pentane to afford (2-(1-methylpyrazol-3-yl) thiazol-4-amine 28-4 (0.20 g, TFA salt) which was used directly for the next reaction. LCMS: [M+H]+= 181.

[0168] Step-3: (1-[(4S)-8-chlorochroman-4-yl]-3-[2-(1-methylpyrazol-3-yl)thiazol-4- yl]urea (Example 28): To a stirred solution of 2-(1-methylpyrazol-3-yl)thiazol-4-amine 28-4 (0.07 g, 0.38 mmol) in MeCN (2 mL) was added pyridine ( 0.14 mL, 1.59 mmol) followed by N,N'-disuccinimidyl carbonate (0.09 g, 0.37 mmol). Resulting reaction mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine 28-5 (0.08 g, 0.37 mmol) followed by DIPEA (0.03 mL, 0.16 mmol) and reaction was stirred at 30 °C for 1 h. After completion, reaction was quenched with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by CombiFlash (30% EtOAc in hexanes) to afford Example 28 (0.38 g).1H NMR (400 MHz, DMSO-d6) δ = 9.22 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.33 (dd, J = 1.4, 7.9 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 4.95 (q, J = 6.3 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.27 - 4.22 (m, 1H), 3.89 (s, 3H), 2.18 - 2.10 (m, 1H), 2.04 - 1.97 (m, 1H); LCMS: [M+H]+=390. Example 29: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-cyanophenyl)thiazol-4- yl]urea

[0169] Step-1: tert-butyl N-[2-(4-cyanophenyl)thiazol-4-yl]carbamate (29-3): To a stirred solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 29-1 (1.00 g, 3.58 mmol) in 1,4- dioxane (20 mL), water (5 mL) were added (4-cyanophenyl)boronic acid 29-2 (0.79 g, 5.37 mmol) and K3PO4(2.28 g, 10.70 mmol) at RT and purged with N2for 15 min. To the abovewas added PdCl2(dppf)2complex with dichloromethane (0.18 g, 0.21 mmol) under same condition and reaction mixture was heated at 100 °C for 2 h. After completion, reaction mixture was quenched with H2O and filtered through Celite bed. The filtrate was extracted with EtOAc and combined organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash (70% EtOAc / Heptane) to afford tert-butyl N-[2-(4-cyanophenyl)thiazol-4-yl]carbamate 29-3 (0.60 g).1H NMR (400 MHz, DMSO-d6) δ = 10.38 (br s, 1H), 8.06 - 8.03 (m, 2H), 7.98 - 7.95 (m, 2H), 7.42 (s, 1H), 1.48 (s, 9H).

[0170] Step-2: 4-(4-aminothiazol-2-yl)benzonitrile (29-4): To a stirred solution of tert- butyl N-[2-(4-cyanophenyl)thiazol-4-yl]carbamate 29-3 (0.18 g, 0.59 mmol) in DCM (4 mL) was added TFA (2 mL) at 0 °C drop wise. Reaction mixture was stirred at RT for 2 h. After completion of reaction, reaction mixture was concentrated under reduced pressure to afford 4-(4-aminothiazol-2-yl)benzonitrile 29-4 (0.12 g). LCMS: [M+H]+= 202.

[0171] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-cyanophenyl)thiazol-4-yl]urea (Example 29): To a stirred solution of 4-(4-aminothiazol-2-yl)benzonitrile 29-4 (0.12 g, 0.53 mmol) in MeCN (2 mL) maintained at 0 °C was added pyridine (0.04 mL, 0.53 mmol) followed by N,N′-disuccinimidyl carbonate (0.13 g, 0.53 mmol). Resulting reaction mixture was stirred at RT for 1 h. To this was added (4S)-8-chlorochroman-4-amine hydrochloride 29-5 (0.11 g, 0.53 mmol) followed by DIPEA (0.29 mL, 1.59 mmol) and reaction mixture was stirred at RT for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The product was quenched with H2O and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified by CombiFlash (40% EtOAc / Heptane) to afford Example 291-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-cyanophenyl)thiazol-4-yl]urea (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.33 (s, 1H), 8.06 - 8.02 (m, 2H), 7.97 - 7.92 (m, 2H), 7.44 (s, 1H), 7.34 (dd, J = 1.2, 7.9 Hz,1H), 7.26 (d, J = 7.1 Hz, 1H), 6.94 - 6.90 (m, 2H), 4.96 (q, J = 6.4 Hz, 1H), 4.44 - 4.36(m, 1H), 4.30 - 4.23 (m, 1H), 2.18 - 2.02 (m,2H); LCMS: [M+H]+= 411.Example 30: Synthesis of 5-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2- yl]pyridine-2-carboxamide

[0172] Step-1: tert-butyl N-[2-(6-cyano-3-pyridyl)thiazol-4-yl]carbamate (30-3): To a stirred solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 30-1 (1.50 g, 5.37 mmol), 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile 30-2 (2.47 g, 10.7 mmol) and Cs2CO3(6.99 g, 21.5 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added Pd(PPh3)4 (0.37 g, 0.322 mmol) at RT. The reaction mixture was stirred at 120 °C for 12 h. After completion of the reaction, the reaction mixture was cooled and quenched with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified with CombiFlash chromatography (45 % EtOAc / n-heptane) to afford tert-butyl N-[2- (6-cyano-3-pyridyl)thiazol-4-yl]carbamate 30-3 (0.23 g). LCMS: [M-H] - = 301.

[0173] Step-2: 5-(4-aminothiazol-2-yl)pyridine-2-carbonitrile (30-4): To a stirred solution of tert-butyl N-[2-(6-cyano-3-pyridyl)thiazol-4-yl]carbamate 30-3 (0.14 g, 0.46 mmol) in DCM (5 mL) was added TFA (0.18 mL, 2.32 mmol) at 0 °C and the resulting reactionmixture was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure. The product was triturated with diethyl ether and n-pentane to afford 5-(4- aminothiazol-2-yl)pyridine-2-carbonitrile 30-4 (0.11 g). LCMS: [M+H]+= 203.

[0174] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(6-cyano-3-pyridyl)thiazol-4-yl]urea (30-6): To a stirred solution of 5-(4-aminothiazol-2-yl)pyridine-2-carbonitrile 30-4 (0.17 g, 0.84 mmol) in MeCN (4 mL) were added pyridine (0.14 mL, 1.68 mmol) and N,N′- disuccinimidyl carbonate (0.21 g, 0.84 mmol) and the reaction mixture was stirred at RT for 1 h. To the resulting reaction mixture (4S)-8-chlorochroman-4-amine hydrochloride 30-5 (0.18 g, 0.84 mmol) was added followed by DIPEA (0.59 mL, 3.36 mmol) and stirred at RT for 45 min. After completion, reaction mixture was concentrated under reduced pressure and product obtained was dissolved in EtOAc. Combined organic layer was washed with 2N HCl solution, water and brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product was purified by column chromatography (40% EtOAc / Heptane) to afford 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(6-cyano-3-pyridyl)thiazol-4-yl]urea 30-6 (0.20 g). LCMS: [M+H]+= 412.

[0175] Step-4: 5-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]pyridine- 2-carboxamide (Example 30): To a stirred solution of 1-[(4S)-8-chlorochroman-4-yl]-3-[2- (6-cyano-3-pyridyl)thiazol-4-yl]urea 30-6 (0.13 g, 0.31 mmol) in DMSO (3 mL) was added 30 % hydrogen peroxide (1.1 mL, 0.94 mmol) solution followed by potassium carbonate (0.17 g, 1.26 mmol) at RT. Reaction mixture was stirred at 30oC for 1 h. After completion of reaction, reaction mixture was diluted with water and the precipitate was filtered out. The solid was washed with methanol and dried under vacuum to afford Example 30 (0.12 g).1H NMR (400 MHz, DMSO-d6) δ = 9.38 (s, 1H), 9.08 (d, J = 1.8 Hz, 1H), 8.38 (dd, J = 2.3, 8.3 Hz, 1H), 8.18 - 8.12 (m, 2H), 7.74 (br s, 1H), 7.45 (s, 1H), 7.34 (dd, J = 1.1, 7.9 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 6.95 - 6.88 (m, 2H), 4.97 (q, J = 6.3 Hz, 1H), 4.44 - 4.37 (m, 1H), 4.29 - 4.25 (m, 1H), 2.20 - 2.12 (m, 1H), 2.07 - 2.01 (m, 1H); LCMS: [M+H]+= 430.Example 31: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[1-(2,2- difluoroethyl)pyrazol-4-yl]thiazol-4-yl]urea

[0176] Step-1: tert-butyl N-[2-[1-(2,2-difluoroethyl)pyrazol-4-yl]thiazol-4-yl]carbamate (31-3): To a stirred solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 31-1 (0.50 g, 1.79 mmol) and 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole 31-2 (0.46 g, 1.79 mmol) in 1,4-dioxane (3 mL) and water (2 mL) was added potassium carbonate (0.74 g, 5.37 mmol). Reaction mixture was degassed with argon for 30 min. To this was added [1,1′-bis (diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (0.07 g, 0.08 mmol) and the reaction mixture was further degassed with argon for 10 min. Reaction mixture was stirred at 90 °C for 9 h. After completion, the reaction mixture was filtered through Celite. The filtrate was diluted with ice- cold water and extracted with EtOAc. Combined organic layer was washed with H2O and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash (30% EtOAc / Hexane) to afford tert-butyl N-[2-[1-(2,2- difluoroethyl)pyrazol-4-yl]thiazol-4-yl]carbamate 31-3 (0.30 g). LCMS: [M+H]+= 275.

[0177] Step-2: 2-[1-(2,2-difluoroethyl)pyrazol-4-yl]thiazol-4-amine (31-4): To a stirred solution of tert-butyl N-[2-[1-(2,2-difluoroethyl)pyrazol-4-yl]thiazol-4-yl]carbamate 31-3 (0.25 g, 0.75 mmol) in DCM (5 mL) maintained at 0 °C was added 2,6-lutidine (0.26 mL, 2.27 mmol) followed by trimethylsilyl trifluoromethanesulfonate (0.28 mL, 1.51 mmol) at RT. Reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was triturated using diethyl ether toafford 2-[1-(2,2-difluoroethyl)pyrazol-4-yl]thiazol-4-amine 31-4 (0.10 g) which was used directly for the next step. LCMS: [M+H]+= 231.

[0178] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[1-(2,2-difluoroethyl)pyrazol-4- yl]thiazol-4-yl]urea (Example 31): To a stirred solution of 2-[1-(2,2-difluoroethyl)pyrazol- 4-yl]thiazol-4-amine 31-4 (0.05 g, 0.22 mmol) in MeCN (3 mL) was added pyridine (0.04 mL, 0.43 mmol) at 0 °C followed by N,N′-disuccinimidyl carbonate (0.06 g, 0.23 mmol) at RT. Resulting reaction mixture was stirred at RT for 30 min. To this was added (4S)-8- chlorochroman-4-amine 31-5 (0.04 g, 0.23 mmol) followed by DIPEA (0.16 mL, 0.86 mmol) and the reaction was stirred at 30 °C for 2 h. After completion, reaction mixture was concentrated under reduced pressure. The product was quenched with H2O and extracted with 10 % MeOH / DCM. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified by CombiFlash (10 % MeOH / DCM) to afford Example 31 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.18 (s, 1H), 8.33 (s, 1H), 7.94 (d, J = 0.6 Hz, 1H), 7.33 (dd, J = 1.3, 7.9 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.10 (s, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.59 - 6.24 (m, 1H), 5.00 - 4.90 (m, 1H), 4.77 - 4.64 (m, 2H), 4.44 - 4.39 (m, 1H), 4.29 - 4.22 (m, 1H), 2.20 - 2.10 (m, 1H), 2.06 - 1.97 (m, 1H); LCMS: [M+H]+= 440. Synthesis of 31-2:

[0179] Step-A: 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole (31-2): To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole 31-A (1.00 g, 5.15 mmol) in MeCN (20 mL) was added cesium carbonate (4.20 g, 12.9 mmol) followed by 2,2-difluoroethyl trifluoromethanesulfonate 31-B (0.80 mL, 5.67 mmol) at RT. Resulting reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was concentrated under reduced pressure, filtered on Celite bed and washed with EtOAc. The product was purified by CombiFlash (30 % EtOAc / Heptane) to afford 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 31-2 (1.00 g). LCMS: [M+H]+= 259. Example 32: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[1-(2,2,2- trifluoroethyl)pyrazol-4-yl]thiazol-4-yl]urea

[0180] Step-1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2- trifluoroethyl)pyrazole (32-2): To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole 32-1 (0.50 g, 2.58 mmol) in DMF (7 mL) was added Cs2CO3(2.09 g, 6.44 mmol) at 0 °C followed by addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.45 mL, 3.09 mmol) and the reaction mixture was stirred at RT for 16 h. After completion of reaction, the reaction mixture was filtered, diluted with water and extracted with ethyl acetate. Organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure. The product obtained was purified by CombiFlash chromatography (50% EtOAc / n-heptane) to afford 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole 32-2 (0.23 g). Step-2: tert-butyl N-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]thiazol-4-yl]carbamate (32- 4): To a stirred solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 32-3 (0.15 g, 0.53 mmol) in 1,4-dioxane (3 mL) and water (0.75 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole 32-2 (0.22 g, 0.80 mmol), tripotassium phosphate (0.34 g, 1.61 mmol) at RT and purged with argon for 15 min. To this was addedPd(dppf)Cl2complex with DCM (0.02 g, 0.03 mmol) and reaction mixture was stirred at 110 °C for 2 h. After completion, reaction mixture was filtered, diluted with water and extracted with ethyl acetate. Organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash (30% EtOAc / heptane) to afford tert-butyl N-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]thiazol-4-yl]carbamate 32-4 (0.15 g). LCMS: [M+H]+= 293 (M-tBu).-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]thiazol-4-amine (32-5): A solution of tert-butyl N-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]thiazol-4-yl]carbamate 32-4 (0.10 g, 0.28 mmol) in TFA (2 mL) was stirred at 0 °C for 15 min followed by at RT for 2 h. After completion, reaction mixture was concentrated, product was quenched with aqueous Na2CO3solution and aqueous layer was extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 2-[1-(2,2,2- trifluoroethyl)pyrazol-4-yl]thiazol-4-amine 32-5 (0.07 g). LCMS: [M+H]+= 249.

[0182] Step-4: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4- yl]thiazol-4-yl]urea (Example 32): To a stirred solution of 2-[1-(2,2,2- trifluoroethyl)pyrazol-4-yl]thiazol-4-amine 32-5 (0.07 g, 0.28 mmol) in MeCN (3 mL) was added pyridine (0.05 mL, 0.56 mmol) followed by N,N′-disuccinimidyl carbonate (0.07 g, 0.28 mmol) at 0 °C. Resulting reaction mixture was stirred at RT for 1 h. To this was added (4S)-8-chlorochroman-4-amine 32-6 (0.06 g, 0.28 mmol) followed by DIPEA (0.15 mL, 0.85 mmol) and reaction mixture was stirred at 25 °C for 1 h. After completion, reaction mixture was quenched with H2O and extracted with ethyl acetate. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified by CombiFlash (60% EtOAc / heptane) to afford Example 32 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.19 (s, 1H), 8.39 (s, 1H), 8.00 (s, 1H), 7.33 (dd, J = 1.1, 7.9 Hz, 1H), 7.24 (d, J = 7.1 Hz, 1H), 7.13 (s, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.20 (q, J = 9.0 Hz, 2H), 4.95 (q, J = 6.2 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.28 - 4.22 (m, 1H), 2.19 - 2.11 (m, 1H), 2.05 - 1.97 (m, 1H); LCMS: [M+H]+= 458.Example 33: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(5-cyano-2- pyridyl)thiazol-4-yl]ureap- - y ypy - - - o a egasse sou on of 6-bromopyridine-3-carbonitrile 33-1 (1.07 g, 5.85 mmol) in 1,2-dimethoxy ethane (10 mL) was added hexamethyl ditin (1.2 mL, 5.85 mmol) and the reaction mixture was purged with argon for 15 min. To the above reaction mixture was added Pd(PPh3)4 (0.33 g, 0.28 mmol) and heated at 100 °C for 48 h. After completion, reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was concentrated under reduced pressure to afford 6- trimethylstannylpyridine-3-carbonitrile 33-2 (0.80 g).

[0184] Step-2: tert-butyl N-[2-(5-cyano-2-pyridyl)thiazol-4-yl]carbamate (33-4): To a degassed solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 33-3 (0.65 g, 2.33 mmol) in toluene (10 mL) was added 6-trimethylstannylpyridine-3-carbonitrile 33-2 (0.75 g, 2.79 mmol) and CuI (0.04 g, 0.23 mmol) followed by Pd(PPh3)4(0.26 g, 0.23 mmol). Reaction mixture was stirred at 110 °C for 16 h. After completion, reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain a product which was purified by CombiFlash (15% EtOAc / n-heptane) to afford tert- butyl N-[2-(5-cyano-2-pyridyl)thiazol-4-yl]carbamate 33-4 (0.05 g). LCMS: [M+H]+= 247. Step-3: 6-(4-aminothiazol-2-yl)pyridine-3-carbonitrile (33-5): To a stirred solution of tert- butyl N-[2-(5-cyano-2-pyridyl)thiazol-4-yl]carbamate 33-4 (0.05 g, 0.16 mmol) in DCM (1 mL) was added TFA (0.5 mL) at 0 °C and the reaction mixture was stirred at RT for 1 h.After completion, reaction mixture was concentrated under reduced pressure. The product was neutralized by NaHCO3solution. The precipitated solid was filtered under reduced pressure to afford 6-(4-aminothiazol-2-yl)pyridine-3-carbonitrile 33-5 (0.03 g). LCMS: [M+H]+= 203.

[0185] Step-4: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(5-cyano-2-pyridyl)thiazol-4-yl]urea (Example 33): To a stirred solution of N,N′-disuccinimidyl carbonate (0.04 g, 0.17 mmol) in MeCN (3 mL) was added pyridine (0.01 mL, 0.17 mmol) followed by 6-(4-aminothiazol-2- yl)pyridine-3-carbonitrile 33-5 (0.03 g, 0.17 mmol) and the reaction mixture was stirred at RT for 45 min. To the above was added DIPEA (0.09 mL, 0.51 mmol) followed by (4S)-8- chlorochroman-4-amine hydrochloride 33-6 (0.03 g, 0.173 mmol) and the reaction mixture was stirred at RT for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The product was washed with ice-cold water and the precipitated solid was filtered under reduced pressure. The solid was triturated with MeOH and hexane to afford Example 33 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.35 (s, 1H), 9.05 (d, J = 1.3 Hz, 1H), 8.42 (dd, J = 2.0, 8.3 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.55 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 6.94 - 6.89 (m, 2H), 5.01 - 4.92 (m, 1H), 4.45 - 4.36 (m, 1H), 4.29 - 4.22 (m, 1H), 2.21 - 2.09 (m, 1H), 2.07 - 1.96 (m, 1H). LCMS: [M+H]+= 412. Preparation of 33-3:

[0186] Step-1: tert-butyl N-(2-bromothiazol-4-yl)carbamate (33-3): To a stirred solution of 2-bromothiazole-4-carboxylic acid 33-A (10.00 g, 48.1 mmol) in tert-butanol (100 mL) was added TEA (7.90 mL, 57.7 mmol) followed by dropwise addition of DPPA (16 mL, 62.5 mmol) at RT. The resulting solution was heated at 80 °C for 12 h. After completion, the reaction mass was concentrated under reduced pressure. The product was diluted with water and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to yield product which was purified by CombiFlash (8% EtOAc / n-heptane) to afford tert-butyl N-(2-bromothiazol-4-yl)carbamate 33-3 (4.20 g).1H NMR (400 MHz, DMSO-d6) δ = 10.31 (s, 1H), 7.20 (s, 1H), 1.45 (s, 9H); LCMS: [M+H]+= 225. Example 34: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[1-(2,2- difluoroethyl)pyrazol-3-yl]thiazol-4-yl]urea

[0187] Step-1: ethyl 2-(1-tert-butoxycarbonylpyrazol-3-yl)thiazole-4-carboxylate (34-3): To a degassed solution of bis(triphenylphosphine)palladium (II) dichloride (0.29 g, 0.42 mmol), cesium carbonate (4.14 g, 12.7 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole-1-carboxylate 34-2 (1.24 g, 4.24 mmol) in 1,4-dioxane (3.5 mL) and water (1.5 mL) was added ethyl 2-bromothiazole-4-carboxylate 34-1 (1.00 g, 4.24 mmol). The reaction mixture was heated at 100 °C for 3 h. After completion, the reaction mixture was filtered through Celite bed. The filtrate was diluted with H2O, aqueous layer was extracted with EtOAc. Combined organic layer was washed with brine solution, dried over anhydrous Na2SO4and evaporated under reduced pressure. The product was purified by CombiFlash (50% EtOAc / n-heptane) to afford ethyl 2-(1-tert-butoxycarbonylpyrazol-3- yl)thiazole-4-carboxylate 34-3 (0.80 g). LCMS: [M+H]+= 224.

[0188] Step-2: ethyl 2-[1-(2,2-difluoroethyl) pyrazol-3-yl] thiazole-4-carboxylate (34-5): To a stirred solution of ethyl 2-(1H-pyrazol-3-yl)thiazole-4-carboxylate 34-3 (0.30 g, 1.34 mmol) in MeCN (6 mL) was added Cs2CO3(0.87 g, 2.69 mmol) followed by 2,2- difluoroethyl trifluoromethanesulfonate 34-4 (0.31 g, 1.47 mmol) and the reaction mixture was stirred at 27 °C for 3 h. After completion, the reaction mixture quenched with H2O, extracted with EtOAc. Combined organic layer was washed with brine solution, dried over anhydrous Na2SO4and evaporated under reduced pressure. The product was purified by CombiFlash (50% EtOAc / n-heptane) to afford ethyl 2-[1-(2,2-difluoroethyl) pyrazol-3-yl] thiazole-4-carboxylate 34-5 (0.24 g). LCMS: [M+H]+= 288.

[0189] Step-3: 2-[1-(2,2-difluoroethyl)pyrazol-3-yl]thiazole-4-carboxylic acid (34-6): To a stirred solution of ethyl 2-[1-(2,2-difluoroethyl)pyrazol-3-yl]thiazole-4-carboxylate 34-5 (0.27 g, 0.96 mmol) in THF (3 mL), methanol (2 mL) and water (1.5 mL) was added lithium hydroxide monohydrate (0.12 g, 2.87 mmol) and the reaction mixture was stirred at 28 °C for 12 h. After completion, reaction mixture was concentrated under reduced pressure. The product was diluted with H2O and washed with EtOAc. Then aqueous layer pH was adjusted with 2N HCl. Precipitated solid was filtered and dried under reduced pressure to afford 2-[1- (2,2-difluoroethyl)pyrazol-3-yl]thiazole-4-carboxylic acid 34-6 (0.21 g).1H NMR (400 MHz, DMSO-d6) δ = 13.18 - 12.85 (m, 1H), 8.42 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 6.88 - 6.83 (m, 1H), 6.58 - 6.28 (m, 1H), 4.79 - 4.70 (m, 2H); LCMS: [M+H]+=260.

[0190] Step-4: tert-butyl N-[2-[1-(2,2-difluoroethyl)pyrazol-3-yl]thiazol-4-yl]carbamate (34-7): To a stirred solution of 2-[1-(2,2-difluoroethyl) pyrazol-3-yl] thiazole-4-carboxylic acid 34-6 (0.20 g, 0.77 mmol) in tert-butanol (3 mL) was added TEA (0.14 mL, 1.00 mmol) followed by dropwise addition of DPPA (0.20 mL, 0.92 mmol) at RT. The resulting mixture was heated at 80 °C for 12 h. After completion, the reaction mass was concentrated under reduced pressure. The product was diluted with water and extracted with EtOAc. Combined organic layer was washed with brine solution, dried over anhydrous Na2SO4and evaporated under reduced pressure. The product was purified via CombiFlash (20% EtOAc / n-heptane) to afford tert-butyl N-[2-[1-(2,2-difluoroethyl)pyrazol-3-yl]thiazol-4-yl]carbamate 34-7 (0.23 g).1H NMR (400 MHz, DMSO-d6) δ = 10.22 (br s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.19 - 7.14 (m, 1H), 6.73 - 6.69 (m, 1H), 6.56 - 6.26 (m, 1H), 4.76 - 4.66 (m, 2H), 1.46 (s, 9H); LCMS: [M+H]+=275.

[0191] Step-5: 2-[1-(2,2-difluoroethyl)pyrazol-3-yl]thiazol-4-amine (34-8): To a stirred solution of tert-butyl N-[2-[1-(2,2-difluoroethyl) pyrazol-3-yl] thiazol-4-yl] carbamate 34-7 (0.10 g, 0.30 mmol) in DCM (3 mL) was added TFA (0.28 mL, 3.63 mmol) at 0 °C and reaction mixture was stirred at 28 °C for 3 h. After completion, the reaction mixture was concentrated under reduced pressure. The product was quenched with H2O, extracted with EtOAc. Combined organic layer was washed with brine solution, dried over anhydrous Na2SO4and evaporated under reduced pressure to yield 2-[1-(2,2-difluoroethyl)pyrazol-3- yl]thiazol-4-amine 34-8 (0.12 g). LCMS: [M+H]+= 231.

[0192] Step-6: 1-[(4S)-8-chlorochrom-[2-[1-(2,2-difluoroethyl)pyrazol-3- yl]thiazol-4-yl]urea (Example 34): To a stirred solution of 2-[1-(2,2-difluoroethyl)pyrazol- 3-yl]thiazol-4-amine 34-8 (0.06 g, 0.28 mmol) in MeCN (3 mL) was added pyridine (0.04 mL, 0.56 mmol) followed by N,N′-disuccinimidyl carbonate (0.07 g, 0.28 mmol) and the reaction mixture was stirred at 27 °C for 45 min. To this was added (4S)-8-chlorochroman-4- amine hydrochloride 34-9 (0.06 g, 0.28 mmol) followed by DIPEA (0.15 mL, 0.84 mmol) and reaction mixture was stirred at 27 °C for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The product was dissolved in EtOAc. Organic layer was washed with H2O and brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by prep HPLC to afford Example 34 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.28 (s, 1H), 7.94 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 6.43 (t, J = 3.0 Hz, 1H), 5.01 - 4.93 (m, 1H), 4.79 - 4.67 (m, 2H), 4.45 - 4.38 (m, 1H), 4.31 - 4.22 (m, 1H), 2.19 - 2.11 (m, 1H), 2.03 (dd, J = 2.4, 6.5 Hz,1H); LCMS: [M+H]+= 440.Example 35: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[1-(2,2,2- trifluoroethyl)pyrazol-3-yl]thiazol-4-yl]ureap , , , y , , y , , trifluoroethyl)pyrazole (35-2): To a stirred solution of 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole 35-1 (2.00 g, 10.3 mmol) in DMF (15 mL) was added Cs2CO3(6.72 g, 20.6 mmol) at RT followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.8 mL, 12.40 mmol) dropwise at 0 °C and the reaction mixture was stirred at RT for 12 h. After completion of starting material, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash chromatography (10% EtOAc / n-heptane) to obtain 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole 35-2 (2.00 g).1H NMR (400 MHz, DMSO-d6) δ = 7.88 (d, J = 2.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 5.19 (q, J = 9.1 Hz, 2H), 1.27 (s, 12H).

[0194] Step-2: tert-butyl N-[2-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]thiazol-4- yl]carbamate (35-4): To a stirred solution of tert-butyl N-(2-bromothiazol-4-yl)carbamate 35-3 (0.70 g, 2.51 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2- trifluoroethyl)pyrazole 35-2 (0.83 g, 3.01 mmol) and Cs2CO3(4.08 g, 12.5 mmol) in DMF (8 mL), nitrogen was purged for 10 min. To the resulting reaction mixture was added PdCl2(dppf)CH2Cl2(0.41 g, 0.50 mmol) and reaction mixture was irradiated under microwave at 100 °C for 30 min. After completion, reaction mixture was filtered throughCelite bed. Cold water was added and aqueous layer was extracted with EtOAc. Organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash (30% EtOAc / Heptane) to afford tert-butyl N-[2-[1- (2,2,2-trifluoroethyl)pyrazol-3-yl]thiazol-4-yl]carbamate 35-4 (0.70 g).1H NMR (400 MHz, DMSO-d6) δ = 10.26 (br s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.19 (s, 1H), 6.75 (d, J = 2.5 Hz, 1H), 5.25 (q, J = 9.1 Hz, 2H), 1.47 (s, 9H). LCMS: [M+H]+= 349.

[0195] Step-3: 2-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]thiazol-4-amine hydrochloride (35- 5): A solution of tert-butyl N-[2-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]thiazol-4-yl]carbamate 35-4 (0.25 g, 0.71 mmol) in HCl in dioxane (4.5 mL, 59.4 mmol) was stirred at 0 °C for 15 min followed by at RT for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The product was triturated with diethyl ether and filtered. The solid was dried under reduced pressure to afford 2-[1-(2,2,2-trifluoroethyl)pyrazol-3-yl]thiazol-4-amine hydrochloride 35-5 (0.20 g). LCMS: [M+H]+= 249.

[0196] Step-4: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[1-(2,2,2-trifluoroethyl)pyrazol-3- yl]thiazol-4-yl]urea (Example 35): To a stirred solution of 2-[1-(2,2,2- trifluoroethyl)pyrazol-3-yl]thiazol-4-amine hydrochloride 35-5 (0.13 g, 0.52 mmol) in MeCN (5 mL) was added N,N′-disuccinimidyl carbonate (0.13 g, 0.52 mmol) followed by pyridine (0.08 mL, 1.05 mmol) and the resulting reaction mixture was stirred at RT for 50 min. To this was added (4S)-8-chlorochroman-4-amine 35-6 (0.09 g, 0.52 mmol) followed by DIPEA (0.27 mL, 1.57 mmol) and reaction mixture was stirred at 0 °C for 2 h. After completion, reaction mixture was concentrated under reduced pressure and product obtained was dissolved in EtOAc. Organic layer was washed with 2N HCl solution, water and brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product was purified by prep-HPLC to afford Example 35 (0.03 g).1H NMR (400 MHz, DMSO-d6) δ = 9.27 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 1.3, 7.9 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.20 (s, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.25 (q, J = 9.1 Hz, 2H), 4.99 - 4.92 (m, 1H), 4.43 - 4.38 (m, 1H), 4.28 - 4.22 (m, 1H), 2.19 - 2.11 (m, 1H), 2.05 - 1.99 (m, 1H); LCMS: [M+H]+= 458.Example 36: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[4-(4-cyanophenyl)thiazol-2- yl]urea

[0197] Step-1: 4-(5-aminothiazol-2-yl)benzonitrile (36-2): To a stirred solution of 4-(2- bromoacetyl)benzonitrile 36-1 (1.12 g, 5.00 mmol) in ethanol (10 mL) was added thiourea (0.57 g, 7.50 mmol) at RT and the reaction mixture was refluxed for 2 h. After completion of reaction, reaction mixture was concentrated under reduced pressure. The product was added into NaHCO3solution and filtered. The solid obtained was dried under vacuum to get 4-(5- aminothiazol-2-yl)benzonitrile 36-2 (0.60 g).1H NMR (400 MHz, DMSO-d6) δ = 7.97 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.33 (s, 1H), 7.18 (s, 2H); LCMS: [M+H]+= 202.

[0198] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[4-(4-cyanophenyl)thiazol-2-yl]urea (Example 36): To a stirred solution of 4-nitro phenyl chloroformate (0.22 g, 1.09 mmol) in THF (5 mL) was added DIPEA (0.40 mL, 2.27 mmol) and the reaction mixture was cooled to 0 °C. To this was added 4-(2-aminothiazol-4-yl)benzonitrile 36-2 (0.36 g, 1.82 mmol) and the reaction mixture was stirred at 0 °C for 30 min. To the resulting reaction mixture was added (4S)-8-chlorochroman-4-amine hydrochloride 36-3 (0.20 g, 0.90 mmol) and stirred at 50 °C for 16 h. After completion, reaction mixture was cooled to RT and quenched with methanol. Reaction mixture was concentrated under reduced pressure. The product was purified by prep HPLC to afford Example 36 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 10.55 (br s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.37 (dd, J = 1.2, 7.8 Hz, 1H), 7.26 (d, J = 7.1 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 5.01 (q, J =6.3 Hz, 1H), 4.44 - 4.38 (m, 1H), 4.32 - 4.26 (m, 1H), 2.22 - 2.13 (m, 1H), 2.11 - 2.04 (m, 1H); LCMS: [M+H]+= 411. Example 37: Synthesis of (1-[(4S)-8-chlorochroman-4-yl]-3-[4-(4- methylsulfonylphenyl)thiazol-2-yl]urea

[0199] Step-1: 2-bromo-1-(4-methylsulfonylphenyl)ethenone (37-2): To a stirred solution of 1-(4-methylsulfonylphenyl)ethanone 37-1 (1.00 g, 5.04 mmol) in chloroform (20 mL) was added bromine (0.26 mL, 5.04 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h. After completion, reaction was quenched with saturated Na2S2O3solution, aqueous layer was extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The compound was purified by CombiFlash (15% EtOAc / hexane) to afford 2-bromo-1-(4-methylsulfonylphenyl)ethanone 37-2 (0.80 g).1H NMR (400 MHz, DMSO-d6) δ = 8.23- 8.21 (m, 2H), 8.11- 8.09 (m, 2H), 5.01 (s, 2H), 3.31 (s, 3H); LCMS: [M+H]+= 277.

[0200] Step-2: 5-(4-methylsulfonylphenyl)thiazol-2-amine (37-4): To a stirred solution of 2-bromo-1-(4-methylsulfonylphenyl)ethanone 37-2 (0.20 g, 0.72 mmol) in MeCN (5 mL) was added thiourea 37-3 (0.54 g, 7.22 mmol) and the reaction mixture was heated at 80 °C for 14 h. After completion, reaction was quenched with H2O, aqueous layer was extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The compound was purified by CombiFlash (40% EtOAc / hexane) to afford 5-(4-methylsulfonylphenyl)thiazol-2-amine 37-4 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 8.23 - 8.21 (m, 2H), 7.98 - 7.96 (m, 2H), 7.53 - 7.49 (m, 1H), 7.18 - 7.16 (m, 1H), 6.51 - 6.49 (m, 1H), 6.11 (br s, 2H), 3.30 (s, 3H).

[0201] Step-3: (1-[(4S)-8-chlorochroman-4-yl]-3-[4-(4-methylsulfonylphenyl)thiazol-2- yl]urea (Example 37): To a stirred solution of 5-(4-methylsulfonylphenyl)thiazol-2-amine 37-4 (0.20 g, 0.78 mmol) in DCE (4 mL) was added DIPEA (0.43 mL, 2.36 mmol) and resulting reaction mixture was stirred at RT for 10 min. The reaction mixture was cooled to 0 °C and was added triphosgene (0.11 g, 0.39 mmol) followed by (4S)-8-chlorochroman-4- amine 37-5 (0.14 g, 0.78 mmol). Resulting reaction mixture was stirred at 80 °C for 2 h. After completion, reaction mixture was concentrated under reduced pressure and product obtained was dissolved in EtOAc. Organic layer was washed with H2O, brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. The compound was purified by prep-HPLC to afford Example 37 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 10.54 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H), 7.78 (s, 1H), 7.35 (dd, J = 1.2, 7.8 Hz, 1H), 7.25 (d, J = 7.1 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 4.99 (q, J = 6.5 Hz, 1H), 4.44 - 4.36 (m, 1H), 4.32 - 4.25 (m, 1H), 3.23 (s, 3H), 2.19 - 2.13 (m, 1H), 2.10 - 2.03 (m, 1H); LCMS: [M+H]+= 464.Example 38: Synthesis of 1-[4-[4-(1-amino-1-methyl-ethyl)phenyl]thiazol-2-yl]-3-[(4S)-8- chlorochroman-4-yl]urea

[0202] Step-1: phenyl N-(4-bromothiazol-2-yl)carbamate (38-2): To a stirred solution of 4-bromothiazol-2-amine 38-1 (2.00 g, 11.20 mmol) in THF (20 mL) was added NaH (60% mineral oil, 0.53 g, 22.30 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 30 min. To the resulting reaction mixture was added phenyl chloroformate (1.60 mL, 13.10 mmol) and stirred at 25 °C for 12 h. After completion, reaction mixture was quenched with ice cold water and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash (20 % EtOAc / heptane) to afford phenyl N-(4- bromothiazol-2-yl)carbamate 38-2 (0.53 g).1H NMR (400 MHz, DMSO-d6) δ = 12.58 (s, 1H), 7.43 - 7.41 (m, 2H), 7.32 - 7.24 (m, 4H); LCMS: [M+H]+= 301.

[0203] Step-2: 1-(4-bromothiazol-2-yl)-3-[(4S)-8-chlorochroman-4-yl]urea (38-4): To a stirred solution of phenyl N-(4-bromothiazol-2-yl)carbamate 38-2 (0.53 g, 1.77 mmol) in MeCN (8 mL) was added DIPEA (0.93 mL, 5.32 mmol) followed by (4S)-8-chlorochroman-4-amine hydrochloride 38-3 (0.39 g, 1.77 mmol) at RT. The reaction mixture was stirred at 80 °C for 4 h. After completion, the reaction mixture was concentrated under reduced pressure. The product was purified by CombiFlash (30 % EtOAc / heptane) to afford 1-(4- bromothiazol-2-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 38-4 (0.50 g).1H NMR (400 MHz, DMSO-d6) δ = 10.50 (br s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.16 - 7.11 (m, 1H), 6.91 (t, J = 7.8 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.42 - 4.34 (m, 1H), 4.30 - 4.23 (m, 1H), 2.19 - 2.10 (m, 1H), 2.09 - 2.01 (m, 1H); LCMS: [M+H]+= 390.

[0204] Step-3: tert-butyl N-[1-[4-[2-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-4-yl]phenyl]-1-methyl-ethyl]carbamate (38-6): To a stirred solution of 1-(4-bromothiazol-2-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 38- 4 (0.25 g, 0.64 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added tert-butyl N-[1-methyl-1-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate 38-5 (0.29 g, 0.80 mmol), tri potassium phosphate (0.40 g, 1.93 mmol) at RT and the reaction mixture was purged with N2for 10 min. To the resulting reaction mixture was added Pd(amphos)Cl2(0.09 g, 0.12 mmol) and again purged with N2for 5 min. Then the reaction mixture was heated at 100 °C for 16 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash (60 % ethyl acetate / heptane) to afford tert-butyl N-[1-[4-[2-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-4-yl]phenyl]-1-methyl-ethyl]carbamate 38-6 (0.15 g).1H NMR (400 MHz, DMSO-d6) δ = 10.43 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.40 (s, 1H), 7.34 - 7.32 (m, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.15 - 7.10 (m, 2H), 6.92 (t, J = 8.0 Hz, 1H), 4.99 - 4.98 (m, 1H), 4.39 - 4.25 (m, 2H), 2.16 - 2.07 (m, 2H), 1.49 (s, 6H), 1.33 (s, 9H); LCMS: [M+H]+= 543.

[0205] Step-4: 1-[4-[4-(1-amino-1-methyl-ethyl)phenyl]thiazol-2-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 38): To a stirred solution of tert-butyl N-[1-[4-[2- [[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-4-yl]phenyl]-1-methyl- ethyl]carbamate 38-6 (0.05 g, 0.09 mmol) in DCM (1 mL) was added 4.0M HCl in 1,4- dioxane (0.83 mL, 24.00 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The product was triturated with EtOAc, pentane and concentrated under reduced pressure to afford Example 38 (0.03 g)1H NMR (400 MHz, DMSO-d6) δ = 10.54 (s, 1H),8.50 (br s, 3H), 7.90 (d, J = 8.5 Hz, 2H), 7.61 - 7.52 (m, 3H), 7.38 -7.30 (m, 2H), 7.28 - 7.21 (m, 1H), 6.92 (t, J = 7.8 Hz, 1H), 4.99 (q, J = 6.6 Hz, 1H), 4.44 - 4.37 (m, 1H), 4.32 - 4.24 (m, 1H), 2.22 -2.12 (m, 1H), 2.09 - 2.01 (m, 1H), 1.64 (s, 6H); LCMS: [M+H]+= 444. Example 39 and Example 40: Synthesis of 1-[2-[1-[2-aminopropyl]pyrazol-4-yl]thiazol- 4-yl]-3-[(4S)-8-chlorochroman-4-yl]urea

[0206] Step-1: tert-butyl N-[1-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazol-1-yl]ethyl]carbamate (39-3): To a stirred solution of tert-butyl N-(2-hydroxy-1- methyl-ethyl)carbamate 39-2 (3.00 g, 17.10 mmol) in toluene (20 mL) was added 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 39-1 (3.99 g, 20.5 mmol) followed by cyanomethylenetributylphosphorane (4.5 mL, 17.1 mmol) at RT and the reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a product which was purified by CombiFlash (80% EtOAc / n-heptane) to afford tert-butyl N-[1-methyl-2-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl]carbamate 39-3 (0.75 g). LCMS: [M+H]+= 352.

[0207] Step-2: tert-butyl N-[2-[4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]pyrazol-1-yl]-1-methyl-ethyl]carbamate (39-5): To a degassed solution of 1-(2-bromothiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 39-4 (0.20 g, 0.50 mmol) and tert-butyl N-[1-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazol-1-yl]ethyl]carbamate 39-3 (0.26 g, 0.61 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added K3PO4 (0.32 g, 1.53 mmol) followed by Pd(dppf)Cl2 complex in DCM (0.02 g, 0.02 mmol). Reaction mixture was stirred at 90 °C for 3 h. After completion, reaction mixture was filtered through Celite, diluted with EtOAc. The organic layer was washed with H2O, brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to yield product which was purified by CombiFlash to afford tert-butyl N-[2-[4-[4-[[(4S)-8- chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]pyrazol-1-yl]-1-methyl-ethyl]carbamate 39-5 (0.05 g). LCMS: [M+H]+= 533.

[0208] Step-3: 1-[2-[1-(2-aminopropyl)pyrazol-4-yl]thiazol-4-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (39-6): A solution of tert-butyl N-[2-[4-[4-[[(4S)-8- chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]pyrazol-1-yl]-1-methyl-ethyl]carbamate 39-5 (0.11 g, 0.20 mmol) in 4M HCl in dioxane (1.0 mL) was stirred at 0 °C for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The product was triturated with Et2O to afford 1-[2-[1-(2-aminopropyl)pyrazol-4-yl]thiazol-4-yl]-3-[(4S)-8- chlorochroman-4-yl]urea 39-6 (0.08 g). LCMS: [M+H]+= 433.

[0209] Step-4: 1-[2-[1-[2-aminopropyl]pyrazol-4-yl]thiazol-4-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Examples 39 and 40): 1-[2-[1-(2-aminopropyl)pyrazol-4- yl]thiazol-4-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 39-6 (0.08 g, 0.19 mmol) was submitted to chiral-HPLC separation to afford Example 39 (0.01 g) and Example 40 (0.01 g). The absolute stereochemistry of these products was not determined.

[0210] Example 39:1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.23 (s, 1H), 7.84 (s, 1H), 7.33 (dd, J = 1.3, 7.9 Hz, 1H), 7.24 (d, J = 7.1 Hz, 1H), 7.05 (s, 1H), 6.94 - 6.85 (m, 2H), 4.95 (q, J = 1.0 Hz, 1H), 4.44 - 4.36 (m, 1H), 4.29 - 4.19 (m, 1H), 3.98 (dd, J = 4.6, 6.1 Hz, 2H), 3.22 (q, J = 1.0 Hz, 1H), 2.19 - 2.10 (m, 1H), 2.04 - 1.97 (m, 1H), 0.95 (d, J = 6.5 Hz, 3H); LCMS: [M+H]+= 433.

[0211] Example 40:1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.23 (s, 1H), 7.84 (s, 1H), 7.33 (dd, J = 1.4, 7.9 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.05 (s, 1H), 6.94 - 6.86 (m, 2H),4.95 (q, J = 1.0 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.28 - 4.20 (m, 1H), 4.07 - 3.92 (m, 2H), 3.22 (q, J = 1.0 Hz, 1H), 2.20 - 2.10 (m, 1H), 2.05 - 1.96 (m, 1H), 0.95 (d, J = 6.4 Hz, 3H); LCMS: [M+H]+= 433. Example 41 and Example 42: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[4- [pyrrolidin-2-yl]phenyl]thiazol-4-yl]urea

[0212] Step-1: tert-butyl 2-[4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol- 2-yl]phenyl]pyrrolidine-1-carboxylate (41-3): To a degassed solution of 1-(2- bromothiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea 41-1 (0.16 g, 0.43 mmol) and tert- butyl 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-1-carboxylate 41- 2 (0.24 g, 0.64 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added K3PO4(0.30 mL, 1.29 mmol) followed by Pd(dppf)Cl2(0.01 g, 0.02mmol) and the reaction mixture was purged with argon for 10 min. Reaction was stirred at 100 °C for 2 h. After completion, the reaction mixture was filtered off through Celite bed. The filtrate was diluted with EtOAc. The organic layer was washed with H2O, brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to obtain a product product which was purified with CombiFlash (20% EtOAc / n-heptane) to afford tert-butyl 2-[4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2-yl]phenyl]pyrrolidine-1-carboxylate 41-3 (0.21 g).1H NMR (400 MHz, DMSO-d6) δ = 9.26 (s, 1H), 7.79 (s, 2H), 7.46 - 7.15 (m, 5H), 6.92 (d, J = 5.5 Hz, 2H), 4.96 (d, J = 4.6 Hz, 1H), 4.87 - 4.71 (m, 1H), 4.40 (s, 1H), 4.26 (d, J = 8.3 Hz, 1H), 3.51 (d, J = 14.8 Hz, 2H), 2.33 (s, 1H), 2.14 (d, J = 4.6 Hz, 1H), 2.03 (s, 1H), 1.83 (s, 2H), 1.71 (s, 1H), 1.48 - 1.04 (m, 9H); LCMS: [M+H]+= 555.

[0213] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-pyrrolidin-2-ylphenyl)thiazol-4- yl]urea hydrochloride (41-4): A solution of tert-butyl 2-[4-[4-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]thiazol-2-yl]phenyl]pyrrolidine-1-carboxylate 41-3 (0.20 g, 0.34 mmol) in 4.0 M HCl in dioxane (2.0 mL) was stirred at 0 °C for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The product was triturated with EtOAc to obtain 41-41-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-pyrrolidin-2-ylphenyl)thiazol-4-yl]urea hydrochloride (0.17 g). LCMS: [M+H]+= 455.

[0214] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[2-[4-[pyrrolidin-2-yl]phenyl]thiazol-4- yl]urea (Examples 41 and 42): 1-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-pyrrolidin-2- ylphenyl)thiazol-4-yl]urea 41-4 (0.21 g) was submitted for chiral-HPLC separation to afford Example 41 (0.05 g) and Example 42 (0.02 g). The absolute stereochemistry of these products was not determined.

[0215] Example 41:1HNMR (400 MHz, DMSO-d6) δ = 9.25 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.21 (s, 1H), 6.96 - 6.85 (m, 2H), 4.96 (q, J = 6.1 Hz, 1H), 4.45 - 4.36 (m, 1H), 4.29 - 4.21 (m, 1H), 4.08 (t, J = 7.6 Hz, 1H), 3.06 - 2.96 (m, 1H), 2.95 - 2.85 (m, 1H), 2.23 - 2.07 (m, 2H), 2.07 - 1.96 (m, 1H), 1.84 - 1.67 (m, 2H), 1.53 - 1.41 (m, 1H); LCMS: [M+H]+= 455.

[0216] Example 42:1H NMR (400 MHz, DMSO-d6) δ = 9.25 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.21 (s, 1H), 6.96 - 6.87 (m, 2H), 5.01 - 4.91 (m, 1H), 4.45 - 4.36 (m, 1H), 4.30 - 4.20 (m, 1H), 4.09 (t, J = 7.6 Hz, 1H), 3.07 - 2.97 (m, 1H), 2.96 - 2.86 (m, 1H), 2.21 - 2.08 (m, 2H), 2.07 - 1.97 (m, 1H), 1.82 - 1.68 (m, 2H), 1.53 - 1.41 (m, 1H); LCMS: [M+H]+= 455.BIOLOGICAL / BIOCHEMICAL EVALUATION DNA polymerization assay to monitor effects on human POLγ and five disease-causing mutant variants of human POLγ.

[0217] The ability of small molecules to stimulate the polymerase activity of POLγ was analyzed in a quantitative fluorescence SYBR Green I assay with fluorescence intensity (FI) readout.

[0218] In the presence of dNTPs, human POLγ and mutant derivatives thereof were incubated with single-stranded, circular M13mp18 ssDNA hybridized to a short DNA oligonucleotide that functions as a primer for initiation of DNA synthesis. POLγ and mutant derivatives thereof will extend the primer and use the M13mp18 molecule as a template to synthesize long stretches of double-stranded DNA. SYBR Green I, which is a double- stranded DNA-binding dye, was used to quantify formation of double-stranded DNA in the reaction. When bound to double-stranded DNA, SYBR Green I fluorescence increases by up to 100-fold.

[0219] The assay was performed in the 384-well plate format. Upon addition of compounds, changes in double-stranded DNA synthesis activity can be monitored by following effects on fluorescent intensity.

[0220] Proteins used in the polymerization assays were wild type POLγA (POLγA:WT) and mutant derivatives thereof in which an Alanine in position 467 of the amino acids sequence had been changed to Threonine (POLγA:A467T), a Glycine in position 848 of the amino acids sequence had been changed to Serine (POLγA:G848S), an Arginine in position 309 of the amino acids sequence had been changed to Cysteine (POLγA:R309C), or a Tyrosine in position 955 of the amino acid sequence had been changed to Cysteine (POLγA:Y955C). W748S substitution arises because of a G to C mutation at position 2243 in exon 13. The W748S mutation is generally found in cis with the E1143G polymorphism, which is caused by an A to G transition at nucleotide 3428 in exon 21 of POLγ. The reactions also contained the accessory POLγB subunit, and the human mitochondrial single stranded DNA binding protein (mtSSB).

[0221] The protein mixture used in the assays contained POLγA or a mutant derivative (1 nM), POLγB (1.3 nM, concentration calculated as a dimer), 25 mM Tris-HCl (pH 8.0), 0.1mg / mL bovine serum albumin, 1 mM Bond-Breaker TCEP solution (pH 7), 25 mM NaCl, and 0.02% Triton X-100.

[0222] The primed circular ssDNA template used in the polymerization assay was generated by hybridizing circular, single-stranded DNA from M13mp18 with a 20 nucleotides long oligonucleotide (5'-GTA AAA CGA CGG CCA GTG CC-3') using a Bio-Rad T100 Thermal Cycler.

[0223] The DNA template mixture used in the assay contained 0.5 nM primed M13 mp18 ssDNA, 400 nM mtSSB, 0.1 mM Tris-HCl (pH 8.0), 0.1 mM dNTP, 10 mM MgCl2, 0.1 mg / mL BSA, 1 mM Bond-Breaker TCEP solution, and 0.02% Triton X-100. The DNA template mixture for the wild type protein contained either 100 μM dNTP or 0.1 μM dNTP, the latter being designated with an * in Table 2.

[0224] Microplates with compounds (0.1μL in each well) to be tested in the assay were prepared from 10 mM compound stocks in 100% DMSO, and equal amounts of DMSO without any compound were added to positive and negative control wells.

[0225] The protein mixture was dispensed (5 μL into each well) into compound plates and incubated at 37 °C for 15 minutes. After incubation, 5 μL of the DNA template mixture was dispensed into each well. The plates were then incubated at 37 °C for 2 hours.

[0226] During incubation, a combined stop buffer and detection reagent solution was prepared. The buffer contained 25 mM EDTA (pH 8.0), 0.02% Triton X-100, and SYBR Green I diluted 10,000 X (for fluorescent readout). EDTA will stop the enzymatic reaction by chelating magnesium ions.

[0227] After the incubation period, SYBR Green I solution was added (10 μL) to the screening plates and the plates were incubated at room temperature in the dark for 20 minutes before the fluorescent signal was read between 485-520 nM on a microtiter plate reader. The compound concentrations for half maximum activity (AC50) are provided in Table 2.Table 2: AC50Values for POLγ Activators on Human POLγ and Human Mutant POLγ. No. A467T G848S W748S+ R309C Y955C WT AC50 AC50 E1143G AC50 AC50 AC50 M M M M M MNo. A467T G848S W748S+ R309C Y955C WT AC50 AC50 E1143G AC50 AC50 AC50 M M M M M MNo. A467T G848S W748S+ R309C Y955C WT AC50 AC50 E1143G AC50 AC50 AC50 M M M M M MNo. A467T G848S W748S+ R309C Y955C WT AC50 AC50 E1143G AC50 AC50 AC50 M M M M M MNo. A467T G848S W748S+ R309C Y955C WT AC50 AC50 E1143G AC50 AC50 AC50 (μM) (μM) (μM) (μM) (μM) (μM)No. A467T G848S W748S+ R309C Y955C WT AC50 AC50 E1143G AC50 AC50 AC50 M M M M M M

Claims

CLAIMS 1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, (I) wherein:R1is selected from the group consisting of H, C1-C3alkyl, Cl, F, CN, and O-C1-C6alkyl optionally substituted with one or more halogen; R2is H or C1-C3alkyl optionally substituted with OR5; R3is each independently H or C1-C4alkyl optionally substituted with one or more halogen or OH; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is selected from the group consisting of C1-C6alkyl, C1-C6alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, , cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl-cycloalkyl, aryl-heterocyclyl, aryl-heteroaryl, and sulfonamide, wherein the C1-C6 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more halogen, phenyl, OR5, halogen, C(O)NR5R6, NR5R6, NR5-C(O)CH3, SO2R5, NH-SO2R5, heterocyclyl, aryl, heteroaryl, and aryl-heteroaryl, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, C1-C3alkyl-OH, C1-C3alkyl-O-C1-C3alkyl, C(O)OR5, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, keto, C3-C6cycloalkyl, C(O)CH3, C(O)NR5R5, NH-C(O)R5, NH-SO2R5, and C1-C4alkyl that is optionally substituted with one or more F or OH, wherein aryl is optionally substituted with one or more groups selected from the group consisting of: C1-C4alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, and NR5R6, C3-C6cycloalkyl that is substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, NR5R6, SO2R6, SO2NR5R6, SO(NH)R, S(NR)(NH)R, P(O)R5R5, and 4- or 5,6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C1-C4alkyl, oxo, and NR5R6, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, OR5, NR5R6, oxo, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, OR5, and C(O)NR5R6; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with a group selected from the group consisting of OR5, Cl, and F; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1-C5alkyl;R6is selected from the group consisting of H, cyclopropyl, and C1-C5alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cycloalkyl optionally substituted with one or more halogens; n is 1-4; p is 1-2; with the proviso that a compound selected from the group consisting of: (S)-1-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea, 1-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and 1-(5-cyclopropylthiazol-4-yl)-3-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

2. The compound according to claim 1, wherein: R1is selected from the group consisting of H, Cl, F and O-C1alkyl optionally substituted three halogens; R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is selected from the group consisting of C1-C3alkyl, C2alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl- cycloalkyl, and sulfonamide, wherein the C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, cyclobutyl optionally substituted with one or more F, OR5, halogen, NR5R6, and NH-SO2R5, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, CH2-OH, CH2-O-CH3, and C(O)OR5, wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1 alkyl optionally substituted with one or more F, wherein aryl is optionally substituted with one or more groups selected from the group consisting of:C1-C3alkyl that is optionally substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, SO2R6, SO2NR5R6, SO(NH)R, S(NR)(NH)R, P(O)R5R5, and 5-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more oxo, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, cyclobutyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, and OR5; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with one or more groups selected from the group consisting of OR5, Cl, and F; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cyclobutyl optionally substituted with one or more halogens; n is 1; and p is 1.

3. The compound according to claim 1, wherein: R1is selected from the group consisting of H, Cl, and F;R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, OR5, halogen, and NR5R6, R5is independently H or C1 alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; n is 1; and p is 1.

4. The compound according to claim 1, wherein: R1is selected from the group consisting of H, Cl, and F; R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl substituted with one or more groups selected from the group consisting of: halogen, C(O)NR5R6, and SO2NR5R6; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; n is 1; and p is 1.

5. The compound according to claim 1, wherein: R1is selected from the group consisting of H, Cl, and F; R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S;Z heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1alkyl optionally substituted with one or more F, R5is independently H or C1alkyl; n is 1; and p is 1.

6. A compound having the structure of formula (II), or a pharmaceutically acceptable salt thereof, (II) wherein:R2is H or C1-C3alkyl optionally substituted with OR5; R3is each independently H or C1-C4alkyl optionally substituted with one or more halogen or OH; R4is C-R5or S, wherein one R3is C-R5and the other R3is S; Z is selected from the group consisting of C1-C6 alkyl, C1-C6 alkene, NR5R6, SR5, C(O)OR5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-heterocyclyl, aryl-heteroaryl, and sulfonamide, wherein the C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more halogen, phenyl, OR5, halogen, heterocyclyl, C(O)NR5R6, NR5R6, NR5-C(O)CH3, SO2R5, NH-SO2R5, aryl, heteroaryl, and aryl-heteroaryl, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, C1-C3alkyl-OH, C1-C3alkyl-O-C1-C3alkyl, C(O)OR5, C(O)NR5R5, NR5R5, and NR5-C(O)CH3,wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, keto, C3-C6cycloalkyl, C(O)CH3, C(O)NR5R5, NH- C(O)R5, NH-SO2R5, and C1-C4alkyl that is optionally substituted with one or more F or OH, wherein aryl is optionally substituted with one or more groups selected from the group consisting of: C1-C4 alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, and NR5R6, C3-C6cycloalkyl that is substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, NR5R6, SO2R6, SO2NR5R6, SO(NH)R, S(NR)(NH)R, P(O)R5R5, and 4- or 5,6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C1-C4alkyl, oxo, and NR5R6, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, OR5, NR5R6, oxo, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, OR5, and C(O)NR5R6; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with a group selected from the group consisting of OR5, Cl, and F;wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1-C5alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C5alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cycloalkyl optionally substituted with one or more halogens; p is 1-2; with the proviso that a compound selected from the group consisting of: (S)-1-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea, 1-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and 1-(5-cyclopropylthiazol-4-yl)-3-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

7. The compound according to claim 6, wherein: R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is selected from the group consisting of C1-C3alkyl, C2alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl- cycloalkyl, and sulfonamide, wherein the C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, cyclobutyl optionally substituted with one or more F, OR5, halogen, NR5R6, and NH-SO2R5, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, CH2-OH, CH2-O-CH3, and C(O)OR5,wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1 alkyl optionally substituted with one or more F, wherein aryl is optionally substituted with one or more groups selected from the group consisting of:C1-C3alkyl that is optionally substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, SO2R6, SO2NR5R6, SO(NH)R, S(NR)(NH)R, P(O)R5R5, and 5-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more oxo, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, cyclobutyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, and OR5; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with one or more groups selected from the group consisting of OR5, Cl, and F; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cyclobutyl optionally substituted with one or more halogens; and p is 1.

8. The compound according to claim 6, wherein: R2is H; R3is H;R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, OR5, halogen, and NR5R6, R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; and p is 1.

9. The compound according to claim 1, wherein: R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl substituted with one or more groups selected from the group consisting of: halogen, C(O)NR5R6, and SO2NR5R6; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; and p is 1.

10. The compound according to claim 1, wherein: R2is H; R3is H; R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1alkyl optionally substituted with one or more F, R5is independently H or C1 alkyl; and p is 1.

11. A compound having the structure of formula (III), or a pharmaceutically acceptable salt thereof,(III) wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is selected from the group consisting of C1-C3alkyl, C1-C6alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl-cycloalkyl, and sulfonamide, wherein the C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more halogen, OR5, halogen, NR5R6, and NH-SO2R5, wherein cycloalkyl is optionally substituted with one or more F, C1-C3alkyl-OH, C1-C3alkyl-O-C1-C3 alkyl, C(O)OR5, wherein heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1alkyl optionally substituted with one or more F, wherein aryl is optionally substituted with one or more groups selected from the group consisting of: C1-C3alkyl that is optionally substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, SO2R6, SO2NR5R6,SO(NH)R, S(NR)(NH)R, P(O)R5R5, and 5-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more oxo, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, and OR5; wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with one or more groups selected from the group consisting of OR5, Cl, and F; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; R5is independently H or C1alkyl; R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen; R7is cycloalkyl optionally substituted with one or more halogens; with the proviso that a compound selected from the group consisting of: (S)-1-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea, 1-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and 1-(5-cyclopropylthiazol-4-yl)-3-((3R,4R)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

12. The compound according to claim 11, wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is C1-C3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, OR5, halogen, and NR5R6,R5is independently H or C1alkyl; and R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

13. The compound according to claim 11, wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is NR5R6; R5is independently H or C1alkyl; and R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

14. The compound according to claim 11, wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is C(O)NR5R6; R5is independently H or C1alkyl; and R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

15. The compound according to claim 11, wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is cycloalkyl is optionally substituted with one or more F; and R5is independently H or C1alkyl.

16. The compound according to claim 11, wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is heterocyclyl that optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, and C1 alkyl optionally substituted with one or more F; and R5is independently H or C1alkyl.

17. The compound according to claim 11, wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl that is optionally substituted with one or more groups selected from the group consisting of: C1-C3 alkyl that is optionally substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, SO2R6, SO2NR5R6, SO(NH)R, S(NR)(NH)R, P(O)R5R5, and 5-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more oxo; R5is independently H or C1alkyl; and R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

18. The compound according to claim 11, wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is heteroaryl that is optionally substituted with one or more groups each independently selected from the group consisting of cyclopropyl, CN, C(O)NR5R6, SO2R6, a 4- to 6- membered heterocyclic ring, and C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, and OR5; R5is independently H or C1 alkyl; and R6is selected from the group consisting of H, cyclopropyl, and C1-C3alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen.

19. The compound according to claim 11, wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with one or more groups selected from the group consisting of OR5, Cl, and F; and R5is independently H or C1alkyl.

20. The compound according to claim 11, wherein: R4is C-R5or S, wherein one R4is C-R5and the other R4is S; Z is aryl-heteroaryl optionally substituted with C1-C3 alkyl that is optionally substituted with OR5; and R5is independently H or C1alkyl.

21. A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:

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