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 (POL γ ) modul ators.

Description

MODULATORS OF MITOCHONDRIAL DNA REPLICATION PRIORITY CLAIM

[0001] This application claims the benefit of U.S. provisional application no.63 / 525,998, filed July 11, 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) wherein: 1R is selected from the group consisting of H, C1-C3 alkyl, Cl, F, and CN; R2is H or C1-C3alkyl substituted with OH or OCH3; R3is each independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH; R4is each independently H or C1-C4 alkyl; Z is selected from the group consisting of C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-heterocyclyl, and aryl-heteroaryl, wherein C1-C6 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR6R7, NR5R5, NR5-C(O)CH3, 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, OH, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of keto, C3-C6 cycloalkyl, C(O)CH3, C(O)O-C1-C3alkyl, C(O)NR5R5, SO2-C1-C3alkyl, and C1-C4alkyl that is optionally substituted with OH, wherein aryl is optionally substituted with one or more groups each independently 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 NR5R5, C3-C6 cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, C(O)OH, C(O)NR6R7, NR6R7, SO2R5, SO2NR5R5, and 4- or 6-membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C1-C4 alkyl, and NR5R5, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C4 alkyl optionally substituted with a group selected from the group consisting of NR5R5, OR5, and C(O)NR5R5, wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of chloro, fluoro, and C1-C4alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of OH, O-C1-C3 alkyl, chloro, and fluoro; wherein the aryl-heteroaryl is optionally substituted with C1-C3alkyl that is optionally substituted with OH; R5is each independently H or C1-C4alkyl;R6is H or C1-C6alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; R7is H or C1-C5alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1-C5alkyl or CN, or R7is C1-C5 alkyl substituted with C3-C6 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1-C5alkyl, CN, NR5R5, and one or more fluoro, or R7is C3-C5cycloalkyl optionally substituted with C1alkyl optionally substituted with OH, or if R6and R7are attached to the same nitrogen atom, R6and R7together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1-C5 alkyl; n is 1-4; p is 1-2; with the proviso that a compound selected from the group consisting of: 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, 1-(8-methylchroman-4-yl)-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)urea, 1-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea, 1-(1-(sec-butyl)-5-methyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, and 1-(8-fluorochroman-4-yl)-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-3-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-C7 alkyl” 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-C4 alkoxyl” means -O-C1-C4 alkyl. 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-C14 cycloalkyl”). In certain embodiments, each of the cycloalkyl rings may contain one or more double 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-C14 aryl”). 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. Incertain 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 thearyl 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 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 inorganicacids 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-C3 alkyl, Cl, F, and CN; R2is H or C1-C3alkyl substituted with OH or OCH3; R3is each independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH; R4is each independently H or C1-C4 alkyl; Z is selected from the group consisting of C1-C6alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-heterocyclyl, and aryl-heteroaryl,wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR6R7, NR5R5, NR5-C(O)CH3, 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, OH, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of keto, C3-C6cycloalkyl, C(O)CH3, C(O)O-C1-C3 alkyl, C(O)NR5R5, SO2-C1-C3 alkyl, and C1-C4 alkyl that is optionally substituted with OH, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: C1-C4 alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3-C6 cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, C(O)OH,C(O)NR6R7, NR6R7, SO2R5, SO2NR5R5, and 4- or 6-membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C1-C4alkyl, and NR5R5, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C4alkyl optionally substituted with a group selected from the group consisting of NR5R5, OR5, and C(O)NR5R5, wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of chloro, fluoro, and C1-C4 alkyl that is optionally substituted with a group selected from the group consisting of OH, O-C1-C3alkyl, chloro, and fluoro; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OH;R5is each independently H or C1-C4alkyl; R6is H or C1-C6 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; R7is H or C1-C5 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1-C5 alkyl or CN, or R7is C1-C5alkyl substituted with C3-C6cycloalkyl optionally substituted with a group selected from the group consisting of O-C1-C5 alkyl, CN, NR5R5, and one or more fluoro, or R7is C3-C5 cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH, or if R6and R7are attached to the same nitrogen atom, R6and R7together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1-C5alkyl; n is 1-4; p is 1-2; with the proviso that a compound selected from the group consisting of: 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, 1-(8-methylchroman-4-yl)-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)urea, 1-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea, 1-(1-(sec-butyl)-5-methyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, and 1-(8-fluorochroman-4-yl)-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-3-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, C1alkyl, Cl, F, and CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is selected from the group consisting of C1-C5alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aryl-heterocyclyl,wherein C1-C5alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR6R7, NR5R5, NR5-C(O)CH3, and SO2R5, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of keto, C3cycloalkyl, C(O)CH3, C(O)O-C1-C3 alkyl, C(O)NR5R5, SO2-C1-C3 alkyl, and C1-C3 alkyl that is optionally substituted with OH, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: C1-C3 alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3 cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, C(O)OH, C(O)NR6R7, NR6R7, SO2R5, SO2NR5R5, and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C1 alkyl, and NR5R5, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C3 alkyl optionally substituted with NR5R5, wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently fluoro or C1 alkyl that is optionally substituted with OH; R5is each independently H or C1-C2 alkyl; R6is H or C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5;R7is H or C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1alkyl or CN, or R7is C1-C3 alkyl substituted with C3 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1alkyl, CN, NR5R5, and one or more fluoro, or R7is C3-C5 cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH, or if R6and R7are attached to the same nitrogen atom, R6and R7together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1 alkyl; n is 1-2; p is 1; with the proviso that a compound selected from the group consisting of: 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, 1-(8-methylchroman-4-yl)-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)urea, 1-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea, 1-(1-(sec-butyl)-5-methyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, and 1-(8-fluorochroman-4-yl)-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-3-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, C1alkyl, Cl, F, and CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is C1-C5alkyl optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)NR6R7, NR5R5, NR5- C(O)CH3, and SO2R5; R5is each independently H or C1-C2 alkyl; n is 1-2; p is 1; with the proviso that a compound selected from the group consisting of: 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea,1-(8-methylchroman-4-yl)-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)urea, 1-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea, 1-(1-(sec-butyl)-5-methyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, and 1-(8-fluorochroman-4-yl)-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-3-yl)urea, is excluded.

[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, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; 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; R5is each independently H or C1-C2 alkyl; n is 1-2; 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, C1alkyl, Cl, F, and CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is heterocyclyl optionally substituted with one or more groups each independently selected from the group consisting of keto, C3 cycloalkyl, C(O)CH3, C(O)NR5R5, and C1-C2alkyl that is optionally substituted with OH; R5is each independently H or C1-C2 alkyl; n is 1-2; p is 1; with the proviso that a compound selected from the group consisting of: 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, 1-(8-methylchroman-4-yl)-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)urea, 1-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea,1-(1-(sec-butyl)-5-methyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, and 1-(8-fluorochroman-4-yl)-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-3-yl)urea, is excluded.

[0035] 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, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl optionally substituted with one or more groups each independently selected from the group consisting of: C1-C3 alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, SO2R5, SO2NR5R5, and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C1alkyl, and NR5R5; R5is each independently H or C1-C2alkyl; n is 1-2; and p is 1.

[0036] 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, C1alkyl, Cl, F, and CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7;R5is each independently H or C1-C2alkyl; R6is H or C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; R7is H, C3-C5 cycloalkyl, or C1-C3 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1 alkyl or CN; n is 1-2; and p is 1.

[0037] 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, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; R5is each independently H or C1-C2alkyl; R6is H or C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; R7is C1-C3 alkyl substituted with C3 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1alkyl, CN, NR5R5, and one or more fluoro; n is 1-2; and p is 1.

[0038] 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, C1alkyl, Cl, F, and CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7;R6and R7together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1alkyl; n is 1-2; and p is 1.

[0039] 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, C1alkyl, Cl, F, CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is heteroaryl optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C3alkyl optionally substituted with NR5R5; R5is each independently H or C1-C2 alkyl; n is 1-2; and p is 1.

[0040] 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, C1alkyl, Cl, F, and CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is aryl-heterocyclyl optionally substituted with one or more groups each independently fluoro or C1 alkyl that is optionally substituted with OH; n is 1-2; and p is 1.

[0041] 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, C1 alkyl, Cl, F, and CN;R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl-heteroaryl optionally substituted with C1-C3 alkyl that is optionally substituted with OH; n is 1-2; and p is 1.

[0042] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II): I) whereinR3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is selected from the group consisting of C1-C2 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aryl-heterocyclyl, wherein C1-C2alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR6R7, NR5R5, NR5-C(O)CH3, and SO2R5, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of keto, C3cycloalkyl, C(O)CH3, C(O)O-C1-C3 alkyl, C(O)NR5R5, SO2-C1-C3 alkyl, and C1-C3 alkyl that is optionally substituted with OH, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of:C1-C3alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3 cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, C(O)OH, C(O)NR6R7, NR6R7, SO2R5, SO2NR5R5, and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C1 alkyl, and NR5R5, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C3alkyl optionally substituted with NR5R5, wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently fluoro or C1alkyl that is optionally substituted with OH; R5is each independently H or C1-C2 alkyl; R6is H or C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; and R7is H or C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1alkyl or CN, or R7is C1-C3 alkyl substituted with C3 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1alkyl, CN, NR5R5, and one or more fluoro, or R7is C3-C5 cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH, or if R6and R7are attached to the same nitrogen atom, R6and R7together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1alkyl.

[0043] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein:R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is C1-C5alkyl optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)NR6R7, NR5R5, NR5- C(O)CH3, and SO2R5; and R5is each independently H or C1-C2 alkyl.

[0044] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; 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; and R5is each independently H or C1-C2 alkyl.

[0045] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1 alkyl; Z is heterocyclyl optionally substituted with one or more groups each independently selected from the group consisting of keto, C3 cycloalkyl, C(O)CH3, C(O)NR5R5, and C1-C2alkyl that is optionally substituted with OH; and R5is each independently H or C1-C2 alkyl.

[0046] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl optionally substituted with one or more groups each independently selected from the group consisting of: C1-C3 alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3cycloalkyl that is substituted with NR5R5, halogen,CN, OR5, SO2R5, SO2NR5R5, and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C1 alkyl, and NR5R5; and R5is each independently H or C1-C2 alkyl.

[0047] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; R5is H or C1-C2 alkyl; R6is H or C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; and R7is H, C3-C5 cycloalkyl, or C1-C3 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1 alkyl or CN.

[0048] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; R5is each independently H or C1-C2 alkyl; R6is H or C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; and R7is C1-C3alkyl substituted with C3cycloalkyl optionally substituted with a group selected from the group consisting of O-C1 alkyl, CN, NR5R5, and one or more fluoro.

[0049] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; and R6and R7together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1alkyl.

[0050] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is heteroaryl optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C3alkyl optionally substituted with NR5R5; and R5is each independently H or C1-C2 alkyl.

[0051] In embodiments, the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl-heterocyclyl optionally substituted with one or more groups each independently fluoro or C1alkyl that is optionally substituted with OH; and R5is each independently H or C1-C2 alkyl.

[0052] In embodiments, R1is H, C1-C3alkyl, Cl, F, or CN. In embodiments, R1is H. In embodiments, R1is C1-C3 alkyl. In embodiments, R1is C1 alkyl. In embodiments, R1is C2 alkyl. In embodiments, R1is C3alkyl. In embodiments, R1is Cl. In embodiments, R1is Cl. In embodiments, R1is CN.

[0053] In embodiments, R2is H or C1-C3alkyl substituted with OH or OCH3. In embodiments, R2is H. In embodiments, R2is C1 alkyl substituted with OH. In embodiments, R2is C2alkyl substituted with OH. R2is C3alkyl substituted with OH. In embodiments, R2is C1 alkyl substituted with OCH3. In embodiments, R2is C2 alkyl substituted with OCH3. R2is C3alkyl substituted with OCH3.

[0054] 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 C2 alkyl optionally substituted with one or more OH. In embodiments, R3is C3alkyl optionally substituted with one or more halogen. In embodiments, R3is C3 alkyl 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.

[0055] In embodiments, R4is independently H or C1-C4 alkyl. In embodiments, R4is H. In embodiments, R4is C1 alkyl. In embodiments, R4is H or C2 alkyl. In embodiments, R4is C3 alkyl. In embodiments, R4is C4alkyl.

[0056] In embodiments, Z is C1-C5alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl- heterocyclyl, or aryl-heteroaryl. In embodiments, Z is C1-C5 alkyl optionally substituted with phenyl. In embodiments, Z is C1-C5alkyl optionally substituted with OH. In embodiments, Z is C1-C5 alkyl optionally substituted with NR5R5. In embodiments, Z is C1-C5 alkyl optionally substituted with C(O)NR5R5. In embodiments, Z is C1-C5alkyl optionally substituted with NR5-C(O)CH3.

[0057] 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.

[0058] In embodiments, Z is heterocyclyl optionally substituted with one or more groups each independently selected from the group consisting of keto, C3 cycloalkyl, C(O)CH3, C(O)NR5R5, and C1-C2alkyl that is optionally substituted with OH. In embodiments, Z is heterocyclyl substituted with one or more keto. In embodiments, Z is heterocyclyl substituted with one or more C3cycloalkyl. 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-C2alkyl that is optionally substituted with OH.

[0059] In embodiments, Z is aryl that is optionally substituted with one or more C1-C3alkyl that is optionally substituted with one or more F, OH, or NR5R5. In embodiments, Z is aryl that is substituted with one or more C1-C3alkyl that is substituted with one or more F. In embodiments, Z is aryl that is substituted with one or more C1-C3 alkyl 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 NR5R5.

[0060] In embodiments, Z is aryl that is optionally substituted with one or more C3 cycloalkyl that is substituted with NR5R5.

[0061] 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)NR6R7. In embodiments, Z is aryl that is optionally substituted with one or more NR6R7. 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 SO2NR5R5. In embodiments, Z is aryl that is substituted with a 4- or 5-membered heterocyclic ring that is substituted with one or more F. In embodiments, Z is aryl that is substituted with a 4- or 5-membered heterocyclic ring that is substituted with one or more C1 alkyl. In embodiments, Z is aryl that is substituted with a 4- or 5-membered heterocyclic ring 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 C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1-C3 alkyl optionally substituted with NR5R5. In embodiments, Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5. In embodiments, Z is heteroaryl that is substituted with one ormore groups each independently selected from the group consisting of OR5. In embodiments, Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of NR5R5. In embodiments, Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of oxo. In embodiments, Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of SO2R5. In embodiments, Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of C1-C3alkyl optionally substituted with NR5R5.

[0063] In embodiments, Z is aryl-heterocyclyl optionally substituted with fluoro or C1alkyl that is optionally substituted with OH. In embodiments, Z is aryl-heterocyclyl substituted with one or more fluoro. In embodiments, Z is aryl-heterocyclyl substituted with one or more C1 alkyl that is optionally substituted with OH.

[0064] In embodiments, R5is H or C1-C4 alkyl. In embodiments, R5is H. In embodiments, R5is C1alkyl. In embodiments, R5is C2alkyl. In embodiments, R5is C3alkyl. In embodiments, R5is C4 alkyl.

[0065] In embodiments, R6is H, C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5. In embodiments, R6is H. In embodiments, R6is C1alkyl substituted with one or more halogen. In embodiments, R6is C1 alkyl substituted with one or more CN. In embodiments, R6is C1 alkyl substituted with one or more NR5R5. In embodiments, R6is C2alkyl substituted with one or more halogen. In embodiments, R6is C2 alkyl substituted with one or more CN. In embodiments, R6is C2alkyl substituted with one or more NR5R5. In embodiments, R6is C3alkyl substituted with one or more halogen. In embodiments, R6is C3 alkyl optionally substituted with one or more CN. In embodiments, R6is C3 alkyl substituted with one or more NR5R5. In embodiments, R6is C4 alkyl substituted with one or more halogen. In embodiments, R6is C4 alkyl substituted with one or more CN. In embodiments, R6is C4 alkyl substituted with one or more NR5R5.

[0066] In embodiments, R7is H or C1-C5alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1-C5alkyl or CN, or R7is C1-C5alkyl substituted with C3-C6 cycloalkyl optionally substituted with a group selected from the group consistingof O-C1-C5alkyl, CN, NR5R5, and one or more fluoro, or R7is C3-C5cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH, or if R6and R7are attached to the same nitrogen atom, R6and R7together with their connecting nitrogen form a 3- to 6- membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1-C5alkyl.

[0067] In embodiments, R7is H. In embodiments, R7is C1-C5 alkyl substituted with one or more hydroxyl. In embodiments, R7is C1-C5alkyl substituted with one or more, NR5R5. In embodiments, R7is C1-C5 alkyl substituted with one or more heteroaryl. In embodiments, R7is C1-C5alkyl substituted with one or more heterocyclyl substituted with C1-C5alkyl. In embodiments, R7is C1-C5 alkyl substituted with one or more heterocyclyl substituted with CN.

[0068] In embodiments, R7is C1-C5alkyl substituted with C3-C6cycloalkyl optionally substituted with a group selected from the group consisting of O-C1-C5 alkyl, CN, NR5R5, and one or more fluoro. In embodiments, R7is C1-C5alkyl substituted with C3-C6cycloalkyl substituted with O-C1-C5 alkyl. In embodiments, R7is C1-C5 alkyl substituted with C3-C6 cycloalkyl substituted with CN. In embodiments, R7is C1-C5 alkyl substituted with C3-C6 cycloalkyl substituted with NR5R5. In embodiments, R7is C1-C5alkyl substituted with C3-C6cycloalkyl substituted with one or more fluoro.

[0069] In embodiments, R7is C3-C5 cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH. In embodiments, or R7is C3cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH. In embodiments, or R7is C3 cycloalkyl substituted with C1alkyl optionally substituted with OH. In embodiments, R7is C4cycloalkyl substituted with C1 alkyl optionally substituted with OH. In embodiments, or R7is C5 cycloalkyl substituted with C1 alkyl optionally substituted with OH.

[0070] In certain embodiments, R6and R7are attached to the same nitrogen atom and together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1-C5 alkyl. In certain embodiments, R6and R7are attached to the same nitrogen atom and together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is O and optionally substituted with C1-C5alkyl. In certain embodiments, R6and R7are attached to the same nitrogen atom and together with theirconnecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is N and optionally substituted with C1-C5 alkyl.

[0071] 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.

[0072] In embodiments, p is 1-2. In embodiments, p is 1. In embodiments, p is 2.

[0073] In embodiments, the compounds are identified in Table 1. Table 1. Example NoChemical Name Structure49Example No.Chemical Name Structure

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] In certain embodiments, hydrogen atoms may be replaced with deuterium. The deuterium isotope content at a substituted position may be 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).EXAMPLES

[0080] 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.

[0081] 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.

[0082] 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)Cl2complex 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), diethylaminosulfur trifluoride (DAST), 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: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-cyanophenyl)pyrazol-3- yl]urea [] p ( py y) ( ) pyrazol-3-amine (0.34 g, 4.13 mmol) in DMF (5 mL) was added cesium carbonate (1.34 g, 4.13 mmol) followed by copper (I) bromide (1.18 g, 0.82 mmol) at RT. To the resulting reaction mixture, 4-fluorobenzonitrile 1-2 (0.50 g, 4.13 mmol) was added and the reaction mixture was stirred at 110 °C for 16 h. After completion of reaction, the reaction mixture was filtered through Celite. 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 compound was purified by silica gel column chromatography (40 % EtOAc / hexane) to afford 4-(3-aminopyrazol-1- yl)benzonitrile 1-3 (0.30 g).1H NMR (400 MHz, DMSO-d6) δ = 8.31 - 8.29 (m, 1H), 7.88 - 7.82 (m, 2H), 7.81 - 7.78 (m, 2H), 5.86 - 5.84 (m, 1H), 5.35 - 5.32 (m, 2H); LCMS: [M+H]+= 185.

[0084] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-cyanophenyl)pyrazol-3-yl]urea (Example 1): To a stirred solution of 4-(3-aminopyrazol-1-yl)benzonitrile 1-3 (0.07g, 0.40 mmol) in MeCN (2 mL) was added pyridine (0.06 g, 0.81 mmol) followed by N,N′- disuccinimidyl carbonate (0.10 g, 0.40 mmol). Reaction mixture was stirred at RT for 30 min.To the resulting reaction mixture were added (4S)-8-chlorochroman-4-amine 1-4 (0.07 g, 0.40 mmol) and N,N-diisopropylethylamine (0.071 mL, 0.407 mmol) and the reaction mixture was stirred at 30 qC for 12 h. After completion, reaction mixture was concentrated under reduced pressure. Residue was diluted with H2O. Precipitated solid was filtered, dried under reduced pressure. Product obtained was purified by prep HPLC to afford 1-[(4S)-8- chlorochroman-4-yl]-3-[1-(4-cyanophenyl)pyrazol-3-yl]urea Example 1 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 9.12 - 9.07 (m, 1H), 8.55 - 8.50 (m, 1H), 7.93 - 7.86 (m, 4H), 7.36 - 7.32 (m, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.12 - 7.08 (m, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.67 - 6.65 (m, 1H), 4.98 - 4.92 (m, 1H), 4.43 - 4.36 (m, 1H), 4.30 - 4.23 (m, 1H), 2.20 - 2.12 (m, 1H), 2.08 - 2.01 (m, 1H); LCMS: [M+H]+= 394. Example 2: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methoxy-4- pyridyl)pyrazol-3-yl]ureabromo-2-methoxy-pyridine 2-1 (1.13 g, 6.02 mmol) in DMF (4 mL) was added copper (I) bromide (0.17 g, 1.20 mmol) and cesium carbonate (2.94 g, 9.03 mmol) followed by 1H- pyrazol-3-amine 2-2 (0.60 g, 7.22 mmol) at RT. Reaction mixture was stirred at 120 °C for 16 h. After completion, reaction mixture was diluted with EtOAc and filtered through Celite bed. Filtrate was washed with H2O, followed by brine. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product was purified by CombiFlash chromatography (30-40% EtOAc / heptane)to afford 1-(2-methoxy-4-pyridyl)pyrazol-3-amine 2-3 (0.75 g).1H NMR (400 MHz, DMSO- d6) δ = 8.28 (br s, 1H), 8.07 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 5.4 Hz, 1H), 6.96 (s, 1H), 5.85 - 5.81 (m, 1H), 5.32 (br s, 2H), 3.85 (s, 3H); LCMS: [M+H]+= 191.

[0086] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methoxy-4-pyridyl)pyrazol-3- yl]urea (Example 2): To a stirred solution of 1-(2-methoxy-4-pyridyl)pyrazol-3-amine 2-3 (0.10 g, 0.54 mmol) in MeCN (3 mL) was added N,N′-disuccinimidyl carbonate (0.13 g, 0.54 mmol) followed by pyridine (0.04 mL, 0.54 mmol) at RT. Reaction mixture was stirred at RT for 15 min. To the resulting reaction mixture, N,N-diisopropylethylamine (0.28 mL, 1.63 mmol) was added followed by (4S)-8-chlorochroman-4-amine 2-4 (0.12 g, 0.54 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 Na2SO4, and concentrated under reduced pressure. Product obtained was purified by CombiFlash chromatography (30-40% EtOAc / heptane) to afford 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2- methoxy-4-pyridyl)pyrazol-3-yl]urea Example 2 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.14 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 6.1 Hz, 1H), 7.36 - 7.25 (m, 3H), 7.10 - 7.04 (m, 2H), 6.94 - 6.90 (m, 1H), 6.64 (d, J = 1.8 Hz, 1H), 4.96 (d, J = 6.1 Hz, 1H), 4.43 - 4.38 (m, 1H), 4.30 - 4.24 (m, 1H), 3.87 (s, 3H), 2.16 - 2.02 (m, 2H); LCMS: [M+H]+= 400. Example 3: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-cyanophenyl)pyrazol-3- yl]urea

[0087] Step-1: 3-(3-aminopyrazol-1-yl)benzonitrile (3-3): To a stirred solution of 1H- pyrazol-3-amine 3-1 (0.10 g, 1.20 mmol) in DMF (2 mL) was added 3-bromobenzonitrile 3-2 (0.50 g, 2.75 mmol) followed by Cs2CO3(0.16 g, 1.20 mmol) and Cu(I)Br (0.01 g, 0.12 mmol). Reaction mixture was stirred at 100 qC for 12 h. After completion, reaction mixture was quenched with H2O, and filtered through Celite pad. Aqueous layer was extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Product obtained was purified by CombiFlash (40 % EtOAc / hexane) to afford 3-(3-aminopyrazol-1-yl)benzonitrile 3-3 (0.15 g).1H NMR (400 MHz, chloroform-d) δ = 7.89 - 7.87 (m, 1H), 7.80 - 7.77 (m, 1H), 7.71 - 7.70 (m, 1H), 7.51 - 7.42 (m, 2H), 5.91 - 5.90 (m, 1H), 3.88 (br s, 2H); LCMS: [M+H]+= 186.

[0088] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-cyanophenyl)pyrazol-3-yl]urea (Example 3): To a stirred solution of 3-(3-aminopyrazol-1-yl)benzonitrile 3-3 (0.10 g, 0.54 mmol) in MeCN (4 mL) was added pyridine (0.04 mL, 0.54 mmol) followed by bis(2,5- dioxopyrrolidin-1-yl) carbonate (0.13 g, 0.54 mmol). Reaction mixture was stirred at RT for 30 min. To the resulting reaction mixture, (4S)-8-chlorochroman-4-amine 3-4 (0.10 g, 0.54 mmol) was added followed by DIPEA (0.28 mL, 1.63 mmol) and the reaction mixture was stirred at 30 qC for 12 h. After completion, reaction mixture was concentrated. Residue was diluted with H2O. Precipitated solid was filtered, dried under reduced pressure to afford product, which was purified by prep-HPLC to afford 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3- cyanophenyl)pyrazol-3-yl]urea Example 3 (0.08 g).1H NMR (400 MHz, DMSO-d6) δ = 9.08 - 9.03 (m, 1H), 8.50 - 8.46 (m, 1H), 8.16 - 8.13 (m, 1H), 8.03 - 7.97 (m, 1H), 7.69 - 7.62 (m, 2H), 7.36 - 7.30 (m, 1H), 7.29 - 7.25 (m, 1H), 7.14 - 7.09 (m, 1H), 6.95 - 6.89 (m, 1H), 6.63 - 6.58 (m, 1H), 4.99 - 4.92 (m, 1H), 4.43 - 4.36 (m, 1H), 4.30 - 4.22 (m, 1H), 2.20 - 2.11 (m, 1H), 2.09 - 2.00 (m, 1H); LCMS: [M+H]+= 394.Example 4: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(1-(2-(dimethylamino)ethyl)- 1H-pyrazol-3-yl)urea

[0089] Step-1: N,N-dimethyl-2-(3-nitro-1H-pyrazol-1-yl) ethane-1-amine (4-3): To a stirred solution of 3-nitro-1H-pyrazole 4-1 (3.00 g, 26.50 mmol) in DMF (50 mL), K2CO3 (11.00 g, 79.6mmol) was added at 0 °C followed by 2-bromo-N,N-dimethylethan-1-amine hydrobromide 4-2 (7.42 g, 31.80 mmol) and the reaction mixture was stirred at 90 °C 8 h. After completion of reaction, the reaction mixture was diluted with water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by silica gel column chromatography (20% EtOAc / hexane) to afford 4-3 (2.2 g).1H NMR (400 MHz, DMSO-d6) δ = 8.06 - 7.99 (m, 1H), 7.02 (s, 1H), 4.32 (t, 2H), 2.68 (t, 2H), 2.16 (s, 6H); LCMS: [M+H]+ = 185.

[0090] Step-2: 1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-amine (4-4): To a stirred solution of N,N-dimethyl-2-(3-nitro-1H-pyrazol-1-yl) ethane-1-amine 4-3 (2.50 g, 13.6 mmol) in a mixture of MeOH (40 mL) and THF (40 mL), 10% Pd / C (1.00 g) was added and the reaction mixture was stirred under 50 psi hydrogen gas pressure at RT for 16 h. After completion of reaction, the reaction mixture was filtered through Celite bed and washed thoroughly with MeOH. The filtrate was concentrated under reduced pressure to afford 4-4 (2.0 g) which was used directly for the next reaction without further purification.1H NMR (400 MHz, DMSO-d6) δ = 7.32 - 7.23 (m, 1H), 5.33 (d, 1H), 4.55 - 4.43 (m, 2H), 3.88 (t, 2H), 2.58 - 2.52 (m, 2H), 2.13 (s, 6H); LCMS: [M+H]+ = 155.

[0091] Step-3: Phenyl (1-(2-(dimethyl amino) ethyl)-1H-pyrazol-3-yl) carbamate (4-5): To a stirred solution of 4-4 (1.0 g, 6.55 mmol) in THF (10 mL), DIPEA (0.26 mL, 1.48 mmol) was added followed by phenyl chloroformate (2.36 g, 15.1 mmol) and the resulting reaction mixture was stirred at RT for 16 h. After completion of reaction, the reaction mixture was diluted with water, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by silica gel column chromatography (20% EtOAc / hexane) to afford 4-5 (1.9 g). This product was used directly for the next reaction.

[0092] Step-4: (S)-1-(8-chlorochroman-4-yl)-3-(1-(2-(dimethylamino)ethyl)-1H-pyrazol- 3-yl)urea (Example 4): To a stirred solution of (S)-8-chlorochroman-4-amine 4-6 (0.1 g, 0.54 mmol) in THF (5 mL), NaH (60% in mineral oil, 0.03 g, 1.09 mmol) was added at 0 °C followed by 4-5 (0.18 g, 0.65 mmol) and the reaction mixture was stirred at 80 °C for 2 h. After completion of reaction, the reaction mixture was diluted with water. The aqueous layer was extracted with 10% MeOH / DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by prep HPLC to afford Example 4 (0.015 g).1H NMR (400 MHz, DMSO-d6) δ = 9.36 - 9.21 (m, 1H), 8.66 (s, 1H), 7.63 (d, 1H), 7.38 - 7.28 (m, 1H), 7.22 (d, 1H), 7.13 - 7.01 (m, 1H), 6.90 (t, 1H), 6.26 (d, 1H), 4.94 (q, 1H), 4.47 - 4.19 (m, 4H), 3.47 - 3.38 (m, 2H), 2.75 (s, 6H), 2.21 - 2.07 (m, 1H), 2.06 - 1.92 (m, 1H);  LCMS: [M+H]+ = 364. Example 5: Synthesis of 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]-N,N-dimethyl-benzamidedimethyl-benzamide (Example 5): To a stirred solution of 4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]benzoic acid (0.05 g, 0.12 mmol) in DMF (1mL) was added DIPEA (0.08 mL, 0.48 mmol) followed by HATU (0.06 g, 0.182 mmol) and N- methylmethanamine hydrochloride (0.01 g, 0.18 mmol) at 0 °C. Reaction 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 underreduced pressure. Product obtained was purified by prep-HPLC to afford 4-[3-[[(4S)-8- chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-N,N-dimethyl-benzamide Example 5 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.35 (dd, J = 1.2, 7.8 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.16 (d, J = 7.0 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 4.99 - 4.94 (m, 1H), 4.44 - 4.38 (m, 1H), 4.30 - 4.24 (m, 1H), 3.00 - 2.94 (m, 6H), 2.22 - 2.13 (m, 1H), 2.08 - 2.01 (m, 1H); LCMS: [M+H]+= 440. Example 6: Synthesis of 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]benzamideyl]benzamide (Example 6): To a stirred solution of 4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]benzoic acid 6-1 (0.05 g, 0.12 mmol) in DMF (1 mL) was added DIPEA (0.08 mL, 0.48 mmol) followed by HATU (0.06 g, 0.182 mmol) and NH4Cl (0.009 g, 0.18 mmol) at 0 ℃ . Reaction mixture was stirred at RT for 16 h. After completion, 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. Product obtained was purified by CombiFlash chromatography (30% EtOAc / hexane) to afford 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]benzamide Example 6 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.09 - 9.07 (m, 1H), 8.47 - 8.46 (m, 1H), 7.98 - 7.93 (m, 3H), 7.75 (s, 2H), 7.37 - 7.34 (m, 2H), 7.29 - 7.26 (m, 1H), 7.17 - 7.13 (m, 1H), 6.95 - 6.91 (m, 1H), 6.58 - 6.57 (m, 1H), 4.99 - 4.96 (m, 1H), 4.43 - 4.39 (m, 1H), 4.29 - 4.25 (m, 1H), 2.19 - 2.14 (m, 1H), 2.05 (td, J = 3.5, 7.0 Hz, 1H); LCMS: [M+H]+= 412.Example 7: Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chloro-5-fluoro-chroman-4-yl]urea

[0095] Step-1: tert-butyl N-[1-[4-[3-[[(4S)-8-chloro-5-fluoro-chroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]carbamate (7-3): To a stirred solution of tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 7-1 (0.20 g, 0.63 mmol) in MeCN (5 mL) was added pyridine (0.10 mL, 1.26 mmol) and N,N′- disuccinimidyl carbonate (0.16 g, 0.63 mmol) at RT. The reaction mixture was stirred at RT for 30 min. To the resulting reaction mixture, N,N-diisopropylethylamine (0.33 mL, 1.90 mmol) and (4S)-8-chloro-5-fluoro-chroman-4-amine 7-2 (0.12 g, 0.63 mmol) were added and stirred at 25 °C for 4 h. After completion, the reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford product which was purified by CombiFlash (30% EtOAc / n-heptane) to afford tert-butyl N-[1-[4-[3-[[(4S)-8- chloro-5-fluoro-chroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl- ethyl]carbamate 7-3 (0.16 g).1H NMR (400 MHz, DMSO-d6) δ = 8.83 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.46 - 7.43 (m, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.18 (s, 1H), 6.84 (t, J = 9.2 Hz, 1H), 6.48 (s, 1H), 5.08 - 5.02 (m, 1H), 4.52 - 4.11 (m, 2H), 2.06 - 2.02 (m, 2H), 1.49 (s, 6H), 1.33 (s, 9H); LCMS: [M+H]+= 544.

[0096] Step-2: 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8-chloro-5- fluoro-chroman-4-yl]urea (Example 7): To a stirred solution of tert-butyl N-[1-[4-[3-[[(4S)-8-chloro-5-fluoro-chroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl- ethyl]carbamate 7-3 (0.13 g, 0.10 mmol) in DCM (3 mL) was added 4M HCl in 1,4-dioxane (2.3 mL, 64.8 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain product. The product was triturated with EtOAc, pentane and was directly lyophilised to afford 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8-chloro-5-fluoro- chroman-4-yl]urea Example 7 (0.04 g).1H NMR (400 MHz, DMSO-d6) δ = 8.86 (s, 1H), 8.39 (d, J = 2.5 Hz, 4H), 7.72 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.46 (dd, J = 5.8, 8.8 Hz, 1H), 7.25 (d, J = 6.8 Hz, 1H), 6.85 (t, J = 8.9 Hz, 1H), 6.57 (d, J = 2.6 Hz, 1H), 5.09 - 4.98 (m, 1H), 4.52 (d, J = 11.0 Hz, 1H), 4.21 - 4.06 (m, 1H), 2.12 - 1.99 (m, 2H), 1.63 (s, 6H); LCMS: [M+H]+= 444. Example 8: Synthesis of 1-(1-ethyl-1H-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea

[0097] Step-1: (E)-8-fluorochroman-4-oneoxime (8-2): To a stirred solution of 8- fluorochroman-4-one 8-1 (2.0 g, 12.0 mmol) in ethanol (100 mL), sodium acetate (2.47 g, 30.1 mmol) was added at 0 °C followed by hydroxylamine hydrochloride (1.67 g, 24.1 mmol) and the reaction mixture was stirred at 90 °C for 5 h. After completion of reaction, the reaction mixture was diluted with water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by silica gel column chromatography (40% EtOAc / hexane) to afford 8-2 (1.8 g).1H NMR (400 MHz, DMSO-d6) δ = 11.43 (s, 1H), 7.59 (d, 1H), 7.25 - 7.15 (m, 1H), 6.98 - 6.85 (m, 1H), 4.26 (t, 2H), 2.86 (t, 2H); LCMS: [M+H]+= 182.

[0098] Step-2: 8-fluorochroman-4-amine (8-3): To a stirred solution of 8-2 (1.80 g, 9.9 mmol) in methanol (25 mL), 10% Pd / C (0.50 g) was added at RT and the reaction mixture was stirred under 50 psi hydrogen gas pressure at RT for 16 h. After completion of reaction, the reaction mixture was filtered through Celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to afford 8-3 (1.5 g).1H NMR (400 MHz, DMSO- d6) δ = 7.19 (d, 1H), 7.07 - 6.97 (m, 1H), 6.87 - 6.76 (m, 1H), 4.36 - 4.17 (m, 2H), 3.90 (br s, 1H), 2.05 - 1.97 (m, 1H), 1.83 - 1.71 (m, 1H).

[0099] Step-3: 1-(1-ethyl-1H-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea (Example 8): To a stirred solution of 8-3 (0.15 g, 0.89 mmol) in DCM (5 mL), TEA (0.37 mL, 2.69 mmol) was added at 0 °C followed by triphosgene (0.16 g, 0.53 mmol) and the reaction mixture was stirred for 15 min. To the resulting reaction mixture 1-ethyl-1H-pyrazol-3-amine 8-4 (0.11 g, 0.98 mmol) was added and the reaction mixture was stirred at RT for 3 h. After completion of reaction, the reaction mixture was diluted with water and aqueous layer was extracted with DCM. The organic layer was washed with saturated sodium bicarbonate solution. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by prep HPLC to afford Example 8 (10 mg).1H NMR (400 MHz, DMSO-d6) δ = 8.65 (s, 1H), 7.52 (d, 1H), 7.23 - 7.03 (m, 4H), 6.89 - 6.83 (m, 1H), 6.10 (d, 1H), 4.96 - 4.89 (m, 1H), 4.40 - 4.29 (m, 1H), 4.24 - 4.16 (m, 1H), 3.94 (q, 2H), 2.21 - 2.07 (m, 1H), 2.06 - 1.93 (m, 1H), 1.27 (t, 3H); LCMS: [M+H]+ = 305.

[0100] Step-1: (E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide (9-3): To a stirred solution of 4-bromobenzaldehyde 9-1 (2.00 g, 10.8 mmol) in THF (25 mL) was added 2-methylpropane-2-sulfinamide 9-2 (1.57 g, 12.97 mmol) at 0 qC followed by titanium (IV) ethoxide (4.93 g, 21.61 mmol). Reaction mixture was stirred at 80 qC for 12 h. After completion, reaction was quenched with H2O and filtered the emulsion through Celite, which was washed with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Product obtained was purified by CombiFlash chromatography (30% EtOAc / hexane) to afford (E)-N-(4- bromobenzylidene)-2-methylpropane-2-sulfinamide 9-3 (2.00 g).1H NMR (400 MHz, DMSO-d6) δ = 8.55 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 1.18 (s, 9H); LCMS: [M+H]+= 290.

[0101] Step-2: N-[1-(4-bromophenyl)but-3-enyl]-2-methyl-propane-2-sulfinamide (9-5): To a stirred solution of (E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide 9-3 (2.00 g, 6.94 mmol) in THF (25 mL) was added ally magnesium bromide 9-4 (1M in THF) (10 mL, 10.41 mmol) at 0 qC. Reaction mixture was stirred at RT for 12 h. After completion, reaction was quenched with aqueous ammonium chloride solution. Aqueous layer was extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated under reduced pressure. Product obtained was purified by CombiFlash chromatography (30% EtOAc / hexane) to afford N-[1-(4-bromophenyl)but-3- enyl]-2-methyl-propane-2-sulfinamide 9-5 (1.50 g). LCMS: [M+H]+= 332.

[0102] Step-3: 1-(4-bromophenyl)but-3-en-1-amine (9-6): To a stirred solution of N-[1-(4- bromophenyl)but-3-enyl]-2-methyl-propane-2-sulfinamide 9-5 (5.00 g, 15.13 mmol) in 1,4- dioxane (25 mL) was added 4.0 M HCl in dioxane (20 mL, 75.70 mmol) at 0 qC. Reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was triturated using diethyl ether to afford 1-(4- bromophenyl)but-3-en-1-amine 9-6 (3.50 g).1H NMR (400 MHz, DMSO-d6) δ = 7.62 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 5.84 - 5.68 (m, 1H), 5.15 - 5.04 (m, 2H), 4.81 (br s, 2H), 4.10 (t, J = 6.8 Hz, 1H), 2.58 - 2.42 (m, 2H).

[0103] Step-4: N-[1-(4-bromophenyl)but-3-enyl]acetamide (9-7): To a stirred solution of 1-(4-bromophenyl)but-3-en-1-amine 9-6 (3.50 g, 15.47 mmol) in chloroform (50 mL) was added triethylamine (3.13 mL, 30.95 mmol) followed by acetic anhydride (1.89 g, 18.57mmol) at 0 qC. Reaction mixture was stirred at RT for 1 h. After completion, reaction was quenched with aqueous sodium bicarbonate solution. Aqueous layer was 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 / hexane) to afford N-[1-(4-bromophenyl)but-3-enyl]acetamide 9-7 (3.00 g). LCMS: [M+H]+= 270.

[0104] Step-5: [5-(4-bromophenyl)pyrrolidin-3-yl] acetate (9-8): To a stirred solution of N-[1-(4-bromophenyl)but-3-enyl]acetamide 9-7 (3.00 g, 11.18 mmol) in THF (20 mL) and water (5 mL) was added iodine (8.51 g, 33.56 mmol) at RT and the reaction mixture was stirred for 16 h. After completion, reaction was quenched with mixture of saturated sodium bicarbonate solution and saturated sodium thiosulfate solution. Aqueous layer was extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford [5-(4-bromophenyl)pyrrolidin-3- yl] acetate 9-8 (3.00 g). Product was used as such for next reaction without purification. LCMS: [M+H]+= 286.

[0105] Step-6: tert-butyl 4-acetoxy-2-(4-bromophenyl)pyrrolidine-1-carboxylate (9-9): To a stirred solution of [5-(4-bromophenyl)pyrrolidin-3-yl] acetate 9-8 (2.80 g, 9.85 mmol) in 1,4-dioxane (25 mL) and water (15 mL) was added BOC anhydride (2.57 g, 11.82 mmol) at 0 qC followed by 1M NaOH solution (0.24 g, 9.85 mmol) to make (pH-8) and reaction was stirred at RT for 1 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 to obtain product. The product was purified by CombiFlash chromatography (55 % EtOAc / n-heptane) to afford tert-butyl 4- acetoxy-2-(4-bromophenyl)pyrrolidine-1-carboxylate 9-9 (2.00 g). LCMS: [M+H]+= 330 [M-tBu].

[0106] Step-7: tert-butyl 2-(4-bromophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (9- 10): To a stirred solution of tert-butyl 4-acetoxy-2-(4-bromophenyl)pyrrolidine-1-carboxylate 9-9 (3.00 g, 7.81 mmol) in methanol (25 mL) was added NaOH (0.34 g, 8.59 mmol) and water (5 mL) at RT. Reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was neutralized with 2N HCl and concentrated under reduced pressure. The product obtained was dissolved in ethyl acetate and washed with water and brine solution. Theorganic layer was dried over anhydrous Na2SO4and concentrated to afford tert-butyl 2-(4- bromophenyl)-4-hydroxy-pyrrolidine-1-carboxylate 9-10 (2.50 g). LCMS: [M+H]+= 286 [M-tBu].

[0107] Step-8: tert-butyl 2-(4-bromophenyl)-4-oxo-pyrrolidine-1-carboxylate (9-11): To a stirred solution of oxalyl chloride (1.1 mL, 13.14 mmol) in dry DCM (10 mL), DMSO (1.86 mL, 26.29 mmol) was added at -78 °C under N2 atmosphere and the reaction mixture was stirred for 10 min. To the resulting reaction mixture, tert-butyl 2-(4-bromophenyl)-4- hydroxy-pyrrolidine-1-carboxylate 9-10 (1.50 g, 4.38 mmol) in DCM (5 mL) was added over a period of 5 min and the reaction mixture was stirred at -78 °C for 15 min. The temperature was raised to -50 ℃. To the resultant solution, triethylamine (5.54 mL, 39.44 mmol) was added and allowed the temperature to warm at RT over 30 min. After completion of reaction, the reaction mixture was quenched with saturated NH4Cl solution at 0 °C and extracted with DCM. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product compound was purified by CombiFlash chromatography to afford tert-butyl 2-(4-bromophenyl)-4-oxo-pyrrolidine-1- carboxylate 9-11 (1.20 g).

[0108] Step-9: tert-butyl 2-(4-bromophenyl)-4,4-difluoro-pyrrolidine-1-carboxylate (9- 12): To a stirred solution of tert-butyl 2-(4-bromophenyl)-4-oxo-pyrrolidine-1-carboxylate 9- 11 (2.00 g, 5.88 mmol) in DCM (25 mL) was added DAST (1.89 g, 11.75 mmol) at 0 ℃. Reaction mixture was stirred at RT for 5 h. After completion, reaction was quenched with saturated sodium bicarbonate solution. Aqueous layer was extracted with DCM. Organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Product obtained was purified by CombiFlash (30% EtOAc / Hexane) to afford tert- butyl 2-(4-bromophenyl)-4,4-difluoro-pyrrolidine-1-carboxylate 9-12 (1.50 g).1H NMR (400 MHz, DMSO-d6) δ = 7.60 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 6.6 Hz, 2H), 5.03 (br s, 1H), 4.09 - 3.91 (m, 2H), 3.09 - 2.93 (m, 1H), 2.36 (d, J = 9.6 Hz, 1H), 1.50 - 1.11 (m, 9H); LCMS: [M+H]+= 308 [M-tBu].

[0109] Step-10: tert-butyl 2-[4-(3-aminopyrazol-1-yl)phenyl]-4,4-difluoro-pyrrolidine-1- carboxylate (9-14): To a stirred solution of tert-butyl 2-(4-bromophenyl)-4,4-difluoro- pyrrolidine-1-carboxylate 9-12 (1.50 g, 4.14 mmol) in DMSO (15 mL) was added 1H- pyrazol-3-amine 9-13 (0.69 g, 8.28 mmol) followed by cesium carbonate (4.05 g, 12.4 mmol)at RT. Argon gas was purged into the reaction mixture for 20 min followed by addition of copper iodide (0.39 g, 2.07 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (0.59 g, 4.14 mmol) at RT. Reaction mixture was stirred at 120 °C for 12 h. After completion, reaction was filtered through celite bed and washed with EtOAc. To this was added 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 tert-butyl 2-[4-(3-aminopyrazol-1-yl)phenyl]-4,4-difluoro-pyrrolidine- 1-carboxylate 9-14 (1.00 g). LCMS: [M+H]+= 365.

[0110] Step-11: tert-butyl 2-[4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1-carboxylate (9-16): To a stirred solution of tert-butyl 2-[4-(3-aminopyrazol-1-yl)phenyl]-4,4-difluoro- pyrrolidine-1-carboxylate 9-14 (0.70 g, 1.92 mmol) in MeCN (10 mL) was added pyridine (0.15 g, 1.92 mmol) followed by N,N′-disuccinimidyl carbonate (0.49 g, 1.92 mmol) at RT. Reaction mixture was stirred at RT for 15 min. To this was added (4S)-8-chlorochroman-4- amine 9-15 (0.35 g, 1.92 mmol) followed by N,N-diisopropylethylamine (1.0 mL, 5.76 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction was quenched with ice cold 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 tert-butyl 2-[4-[3-[[(4S)-8-chlorochroman- 4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1-carboxylate 9-16 (0.70 g). LCMS: [M+H]+= 574.

[0111] Step-12: tert-butyl 2-[4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1-carboxylate (9-17) and tert-butyl 2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]phenyl]-4,4-difluoro-pyrrolidine-1-carboxylate (9-18): 200 mg of tert-butyl 2-[4-[3- [[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine- 1-carboxylate 9-16 was separated by chiral purification method to afford tert-butyl 2-[4-[3- [[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine- 1-carboxylate 9-17 (80 mg) and tert-butyl 2-[4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1-carboxylate 9-18 (20 mg). The absolute stereochemistry of these products was not determined.

[0112] Chiral method: Chiral separation was performed on a Chiral Pack IK column (30 mm x 250 mm), 5μ, with a flow rate of 42 mL / min. Mobile Phase: 50% n-hexane + 50% ethanol / methanol (1:1), held isocratic with detection at a wavelength of 270 nm.

[0113] 9-17:1H NMR (400 MHz, DMSO-d6) δ = 9.05 (br s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.39 - 7.15 (m, 5H), 6.91 (t, J = 7.8 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 4.97 (d, J = 5.1 Hz, 2H), 4.44 - 4.35 (m, 1H), 4.31 - 4.20 (m, 1H), 4.02 - 3.89 (m, 2H), 3.02 - 2.88 (m, 1H), 2.38 - 2.28 (m, 1H), 2.21 - 2.13 (m, 1H), 2.08 - 1.97 (m, 1H), 1.30 - 1.10 (m, 9H); LCMS: [M+H]+= 574.

[0114] 9-18:1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.33 (dd, J = 1.3, 7.9 Hz, 3H), 7.29 - 7.24 (m, 1H), 7.21 (d, J = 7.4 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 5.01 - 4.93 (m, 2H), 4.44 - 4.36 (m, 1H), 4.30 - 4.22 (m, 1H), 4.04 - 3.89 (m, 2H), 3.04 - 2.87 (m, 1H), 2.40 - 2.27 (m, 1H), 2.21 - 2.10 (m, 1H), 2.09 - 1.98 (m, 1H), 1.34 - 1.16 (m, 9H); LCMS: [M+H]+= 574.

[0115] Step-13: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[4,4-difluoropyrrolidin-2- yl]phenyl]pyrazol-3-yl]urea (Example 9): To a stirred solution of tert-butyl 2-[4-[3-[[(4S)- 8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1- carboxylate 9-17 (0.02 g, 0.034 mmol) in ethyl acetate (2 mL) was added 4N HCl in ethyl acetate (5.0 mL) at 0 ℃ and the reaction mixture was stirred at RT for 4h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was triturated using diethyl ether and pentane and dried under vacuum to afford 1-[(4S)-8-chlorochroman- 4-yl]-3-[1-[4-[4,4-difluoropyrrolidin-2-yl]phenyl]pyrazol-3-yl]urea Example 9 (0.007 g).1H NMR (400 MHz, DMSO-d6) δ = 10.67 - 9.82 (m, 1H), 9.09 (s, 1H), 8.43 (d, J = 2.6 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.34 (dd, J = 1.4, 7.9 Hz, 1H), 7.30 - 7.19 (m, 2H), 6.92 (t, J = 7.8 Hz, 1H), 6.57 (d, J = 2.6 Hz, 1H), 5.02 - 4.94 (m, 2H), 4.44 - 4.36 (m, 1H), 4.31 - 4.23 (m, 1H), 3.97 - 3.86 (m, 1H), 3.84 - 3.72 (m, 1H), 3.08 - 2.95 (m, 1H), 2.90 - 2.78 (m, 1H), 2.21 - 2.11 (m, 1H), 2.08 - 1.97 (m, 1H); LCMS: [M+H]+= 474. The absolute stereochemistry of this product was not determined.

[0116] Step-14: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[4,4-difluoropyrrolidin-2- yl]phenyl]pyrazol-3-yl]urea (Example 10): To a stirred solution of tert-butyl 2-[4-[3-[[(4S)- 8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1- carboxylate 9-18 (0.08 g, 0.13 mmol) in ethyl acetate (2 mL) was added 4N HCl in ethylacetate (5.0 mL) at 0 ℃ and the reaction mixture was stirred at RT for 4h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was triturated using diethyl ether and pentane and dried under vacuum to afford 1-[(4S)-8-chlorochroman- 4-yl]-3-[1-[4-[4,4-difluoropyrrolidin-2-yl]phenyl]pyrazol-3-yl]urea Example 10 (0.04 g).1H NMR (400 MHz, DMSO-d6) δ = 10.13 - 9.74 (m, 1H), 9.07 (s, 1H), 8.42 (d, J = 2.6 Hz, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.35 (dd, J = 1.3, 7.9 Hz, 1H), 7.30 - 7.21 (m, 2H), 6.92 (t, J = 7.8 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 5.00 - 4.91 (m, 2H), 4.45 - 4.36 (m, 1H), 4.31 - 4.23 (m, 1H), 3.95 - 3.83 (m, 1H), 3.82 - 3.69 (m, 1H), 3.08 - 2.93 (m, 1H), 2.87 - 2.73 (m, 1H), 2.22 - 2.10 (m, 1H), 2.09 - 1.97 (m, 1H). LCMS: [M+H]+= 474. The absolute stereochemistry of this product was not determined. Example 11: Synthesis of 1-[1-[4-(1-aminocyclopropyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea

[0117] Step-1: tert-butyl N-[1-[4-(3-nitropyrazol-1-yl) phenyl] cyclopropyl]carbamate (11-3): To a stirred solution of 3-nitro-1H-pyrazole 11-1 (0.07 g, 0.61 mmol) in DCM (8 mL) was added [4-[1-(tert-butoxycarbonylamino) cyclopropyl] phenyl] boronic acid 11-2 (0.37 g, 1.36 mmol) followed by copper acetate (0.12 g, 1.24 mmol) and pyridine (0.15 mL, 1.86 mmol). The reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was filtered through Celite bed and the filtrate was washed with brine, dried overanhydrous Na2SO4and concentrated under reduced pressure. Product was purified by flash chromatography (0-70% EtOAc / heptane) to afford tert-butyl N-[1-[4-(3-nitropyrazol-1-yl) phenyl] cyclopropyl] carbamate 11-3 (0.23 g). LCMS: [M+H]+= 289 (M-tBu).

[0118] Step-2: tert-butyl N-[1-[4-(3-aminopyrazol-1-yl) phenyl] cyclopropyl] carbamate (11-4): To a stirred solution of tert-butyl N-[1-[4-(3-nitropyrazol-1- yl)phenyl]cyclopropyl]carbamate 11-3 (0.25 g, 0.72 mmol) in EtOH (8 mL) and water (2 mL) was added NH4Cl (0.50 g, 3.63 mmol) followed by iron powder (0.20 g, 3.63 mmol) at RT and the reaction mixture was stirred under 100 °C for 2 h. After completion, reaction mixture was filtered through Celite. The aqueous layer was extracted with EtOAc. Organic layer was concentrated under reduced pressure. Product obtained was purified by reverse phase column chromatography to afford tert-butyl N-[1-[4-(3-aminopyrazol-1- yl)phenyl]cyclopropyl]carbamate 11-4 (0.15 g).1H NMR (400 MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.68 (br s, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 5.70 (br s, 1H), 5.00 (br s, 2H), 1.43 - 1.25 (m, 9H), 1.09 (br s, 4H); LCMS: [M+H]+= 315.

[0119] Step-3: tert-butyl N-[1-[4-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino]pyrazol-1-yl]phenyl]cyclopropyl]carbamate (11-6): To a stirred solution of tert- butyl N-[1-[4-(3-aminopyrazol-1-yl) phenyl] cyclopropyl] carbamate 11-4 (0.13 g, 0.41 mmol) in MeCN (5 mL) was added pyridine (0.03 mL, 0.41 mmol) and N,N′-disuccinimidyl carbonate (0.10 g, 0.41 mmol) at 0 °C. Reaction mixture was stirred at RT for 50 min. To this were added DIPEA (0.22 mL, 1.24 mmol) and (4S)-8-chlorochroman-4-amine hydrochloride 11-5 (0.09 g, 0.414 mmol) at 0 °C and reaction mixture was stirred at RT 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 Na2SO4 and concentrated under reduced pressure. Product was purified by CombiFlash (30% EtOAc / Hexane) to afford tert-butyl N-[1-[4-[3-[[(4S)-8-chlorochroman-4- yl] carbamoyl amino] pyrazol-1-yl]phenyl]cyclopropyl]carbamate 11-6 (0.15 g).1H NMR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.29 (br s, 1H), 7.70 (br s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.35 - 7.26 (m, 2H), 7.17 (d, J = 7.8 Hz, 3H), 6.91 (t, J = 7.8 Hz, 1H), 6.47 (br s, 1H), 4.39 (d, J = 6.8 Hz, 1H), 4.30 - 4.21 (m, 1H), 4.03 (q, J = 6.8 Hz, 1H), 2.15 (d, J = 3.9 Hz, 1H), 2.07 - 2.00 (m, 1H), 1.38 (br s, 9H), 1.27 (br s, 2H), 1.17 (t, J = 7.3 Hz, 2H); LCMS: [M+H]+= 524.

[0120] Step-4: 1-[1-[4-(1-aminocyclopropyl) phenyl] pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 11): To a stirred solution of tert-butyl N-[1-[4-[3- [[(4S)-8-chlorochroman-4-yl] carbamoyl amino]pyrazol-1-yl]phenyl]cyclopropyl]carbamate 11-6 (0.13 g, 0.248 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (5.0 mL) at 0 °C and the reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was co-distillated with EtOAc and product was purified by prep HPLC to afford Example 11 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.30 (d, J = 2.6 Hz, 1H), 8.21 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.8 Hz, 3H), 7.27 (dd, J = 0.7, 7.8 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 4.99 - 4.94 (m, 1H), 4.44 - 4.37 (m, 1H), 4.30 - 4.23 (m, 1H), 2.20 - 2.11 (m, 1H), 2.07 - 1.98 (m, 1H), 1.01 - 0.97 (m, 2H), 0.96 - 0.90 (m, 2H); LCMS: [M+H]+= 424.Example 12: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2-(dimethylamino)-1,1- difluoro-ethyl]phenyl]pyrazol-3-yl]urea

[0000] Step : , d uoo [ (3 topyao y)p e y]acetc acd ( 3): o a stirred solution of 3-nitro-1H-pyrazole 12-2 (1.00 g, 8.84 mmol) in DMSO (15 mL) were added K2CO3(3.66 g, 26.5 mmol) and CuI (0.34 g, 1.77 mmol) followed by L-proline (0.20 g, 1.77 mmol) and ethyl 2-(4-bromophenyl)-2,2-difluoro-acetate 12-1 (2.96 g, 10.60 mmol) and the reaction mixture was stirred at 120 °C for 12 h. After completion, reaction mixture was quenched with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product was purified by reverse phase column using gradients 0.1% formic acid in H2O and ACN 20-30% as eluent toafford 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]acetic acid 12-3 (0.80 g). LCMS: [M-H]- = 282.

[0122] Step-2: 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanol (12-4): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]acetic acid 12-3 (3.00 g, 10.60 mmol) in THF (5 mL) was added BH3. DMS (0.80 g, 21.2 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 2 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 to afford product 2,2-difluoro-2-[4-(3-nitropyrazol- 1-yl)phenyl]ethanol 12-4 (1.50 g). LCMS: [M+H]+= 270.

[0123] Step-3: [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate (12-5): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1- yl)phenyl]ethanol 12-4 (1.00 g, 2.53 mmol) in DCM (10 mL) was added Et3N (1.1 mL, 7.60 mmol) followed by p-toluene sulphonyl chloride (0.72 g, 3.80 mmol) portion wise and the reaction mixture was stirred at 25 °C for 16 h. After completion, reaction mixture was concentrated under reduced pressure and product was purified by CombiFlash column (50% EtOAc / n-heptane) to afford [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate 12-5 (0.85 g). LCMS: [M+H]+= 424.

[0124] Step-4: 1-[4-(2-azido-1,1-difluoro-ethyl)phenyl]-3-nitro-pyrazole (12-6): To a stirred solution of [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate 12-5 (0.50 g, 1.18 mmol) in DMF (3 mL) was added NaN3(0.15 g, 2.36 mmol) and the resulting reaction mixture was stirred at 100 °C for 16 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1-[4-(2- azido-1,1-difluoro-ethyl)phenyl]-3-nitro-pyrazole 12-6 (0.25 g). LCMS: [M+H]+= 295.

[0125] Step-5: 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine (12-7): To a stirred solution of 1-[4-(2-azido-1,1-difluoro-ethyl)phenyl]-3-nitro-pyrazole (0.60 g, 2.04 mmol) in THF (3 mL) and water (1 mL) was added TPP (1.07 g, 4.08 mmol) at 0 °C. Resulting reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product was purified by reverse phase usinggradients 0.1% formic acid in H2O and ACN 20-30% as eluent to afford 2,2-difluoro-2-[4-(3- nitropyrazol-1-yl)phenyl]ethanamine 12-7 (0.35 g). LCMS: [M+H]+= 269.

[0126] Step-6: 2,2-difluoro-N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine (12-8): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine 12- 7 (0.06 g, 0.22 mmol) in formic acid (0.01 mL, 0.33 mmol) was added formaldehyde (0.01 mL, 0.33 mmol) at 0 °C. Resulting reaction mixture was stirred at 80 °C for 4 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. Organic layer was concentrated under reduced pressure. Product was purified by reverse phase used gradients 0.1% formic acid in H2O and ACN 20-30% as eluent to afford 2,2-difluoro-N,N- dimethyl-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine 12-8 (0.03 g). LCMS: [M+H]+= 297.

[0127] Step-7: 1-[4-[2-(dimethylamino)-1,1-difluoro-ethyl]phenyl]pyrazol-3-amine (12- 9): To a stirred solution of 2,2-difluoro-N,N-dimethyl-2-[4-(3-nitropyrazol-1- yl)phenyl]ethanamine 12-8 (0.20 g, 0.67 mmol) in ethanol (8 mL) and water (2 mL) was added ammonium chloride (0.18 g, 3.38 mmol) followed by iron powder (0.18 g, 3.38 mmol). The reaction was stirred at 80 °C for 4 h. After completion, reaction mixture was filtered and filtrate was concentrated under reduced pressure. Residue obtained was dissolved in EtOAc and filtered. Filtrate was concentrated under reduced pressure to afford product 1- [4-[2-(dimethylamino)-1,1-difluoro-ethyl]phenyl]pyrazol-3-amine 12-9 (0.12 g). LCMS: [M+H]+= 267.

[0128] Step-8: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2-(dimethylamino)-1,1-difluoro- ethyl]phenyl]pyrazol-3-yl]urea (Example 12): To a stirred solution of 1-[4-[2- (dimethylamino)-1,1-difluoro-ethyl]phenyl]pyrazol-3-amine 12-9 (0.15 g, 0.58 mmol) in MeCN (5 mL) was added pyridine (0.06 mL, 0.73 mmol) followed by N,N′-disuccinimidyl carbonate (0.12 g, 0.488 mmol). Resulting reaction mixture was stirred at RT for 15 min. To this was added (4S)-8-chlorochroman-4-amine hydrochloride 12-10 (0.10 g, 0.488 mmol) followed by DIPEA (0.26 mL, 1.46 mmol) and reaction mixture was stirred at RT for 3 h. After completion, the reaction mixture was quenched with ice cold 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 prep-HPLC to afford Example 12 (0.02 g).1H NMR (400 MHz, MeOH-d4) δ = 8.23 (d, J = 2.8 Hz, 1H), 7.73 - 7.69 (m, 2H), 7.64 - 7.60 (m, 2H), 7.31 (d, J = 7.8 Hz, 2H), 6.90 (t, J = 7.8 Hz, 1H), 6.42 (d, J= 2.5 Hz, 1H), 5.07 (t, J = 5.3 Hz, 1H), 4.45 - 4.39 (m, 1H), 4.36 - 4.29 (m, 1H), 3.99 ( t, J = 15.5 Hz, 2H), 3.03 (s, 6H), 2.33 - 2.23 (m, 1H), 2.20 - 2.11 (m, 1H); LCMS: [M+H]+= 476. Example 13 and Example 14: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1- (dimethylamino)ethyl]phenyl]pyrazol-3-yl]urea[ ] p [ ( py y )p y ] ( ) - [4-(3-nitropyrazol-1-yl)phenyl]ethanone 13-1 (0.50 g, 2.16 mmol) in a mixture of methanol (5 mL) and THF (5 mL) was added sodium borohydride (0.12 g, 3.24 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h. After completion, the reaction mixture was quenched with ice cold water and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by flash column chromatography (5% MeOH:DCM) to afford 1-[4-(3- nitropyrazol-1-yl)phenyl]ethanol 13-2 (0.40 g).1H NMR (400 MHz, DMSO-d6) δ = 8.75 (d, J = 2.4 Hz, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 2.4 Hz, 1H), 5.30 (d, J = 4.4 Hz, 1H), 4.82 - 4.79 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H); LCMS: [M+H]+= 234.

[0130] Step-2: 1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate (13-3): To a stirred solution of 1-[4-(3-nitropyrazol-1-yl)phenyl]ethanol 13-2 (0.40 g, 1.72 mmol) in DCM (10 mL) were added triethyl amine (0.35 g, 3.43 mmol) and 4-dimethylaminopyridine(0.04 g, 0.34 mmol) followed by 4-toluenesulfonyl chloride (0.49 g, 2.57 mmol) at 0 °C and the reaction mixture was stirred in a sealed tube at 30 °C for 18 h. After completion, the 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. Product obtained was purified by flash column chromatography (50% EtOAc / heptane) to afford 1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate 13-3 (0.40 g).

[0131] Step-3: N,N-dimethyl-1-[4-(3-nitropyrazol-1-yl) phenyl]ethanamine (13-4): To a stirred solution of 1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate 13-3 (0.40 g, 1.03 mmol) in MeCN (5 mL) was added potassium carbonate (0.42 g, 3.10 mmol) followed by 2M dimethylamine solution in THF (0.76 g, 6.19 mmol) at 0 °C and the reaction mixture was stirred in a sealed tube at 80 °C for 16 h. After completion, the reaction mixture was quenched with ice and extracted with 10% MeOH / DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by flash column chromatography (10% MeOH / DCM) to afford N,N-dimethyl-1-[4-(3-nitropyrazol-1-yl) phenyl] ethanamine 13-4 (0.30 g). LCMS: [M+H]+= 261.

[0132] Step-4: 1-[4-[1-(dimethylamino) ethyl] phenyl] pyrazol-3-amine (13-5): To a stirred solution of N,N-dimethyl-1-[4-(3-nitropyrazol-1-yl) phenyl] ethanamine 13-4 (0.25 g, 0.96 mmol) in ethanol (5 mL) and water (2 mL) was added iron powder (0.32 g, 5.76 mmol) followed by ammonium chloride (0.31g, 5.76 mmol) and the reaction mixture was stirred at 80 °C for 2 h. After completion, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. Product was diluted with H2O and extracted with 20% MeOH / DCM. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by CombiFlash column (10% MeOH / DCM) to afford 1-[4-[1-(dimethylamino) ethyl] phenyl] pyrazol-3-amine 13-5 (0.22 g). LCMS: [M+H]+= 186.

[0133] Step-5: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1- (dimethylamino)ethyl]phenyl]pyrazol-3-yl]urea (Examples 13 and 14): To a stirred solution of 1-[4-[1-(dimethylamino)ethyl]phenyl]pyrazol-3-amine 13-5 (0.20 g, 0.86 mmol) in MeCN (5 mL) maintained at 0 °C was added pyridine (0.09 mL, 1.17 mmol) followed byN,N′-disuccinimidyl carbonate (0.24 g, 0.95 mmol). Resulting mixture was stirred at RT for 30 minutes. To this was added (4S)-8-chlorochroman-4-amine 13-6 (0.19 g, 1.04 mmol) followed by DIPEA (0.61 mL, 3.40 mmol) and reaction was stirred at 30 °C for 16 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 Na2SO4 and concentrated under reduced pressure. The product obtained was purified by Chiral prep HPLC to afford two isomers Example 13 (0.02 g) and Example 14 (0.01 g). The absolute stereochemistry of these products was not determined.

[0134] Example 13:1H NMR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.37 - 7.31 (m, 3H), 7.30 - 7.24 (m, 1H), 7.16 (d, J = 6.6 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H), 4.96 (d, J = 6.4 Hz, 1H), 4.45 - 4.36 (m, 1H), 4.30 - 4.24 (m, 1H), 2.09 (s, 8H), 1.27 (d, J = 6.8 Hz, 3H), 1.24 (br s, 1H); LCMS: [M+H]+= 440.

[0135] Example 14:1H NMR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.31 (d, J = 2.5 Hz, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.36 - 7.31 (m, 3H), 7.29 - 7.25 (m, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H), 5.00 - 4.93 (m, 1H), 4.44 - 4.36 (m, 1H), 4.29 - 4.23 (m, 1H), 3.28 (br s, 1H), 2.17 - 2.14 (m, 1H), 2.09 - 2.08 (m, 6H), 2.06 - 2.03 (m, 1H), 1.26 (s, 3H); LCMS: [M+H]+= 440.Example 15: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-[1-methyl-1- (methylamino)ethyl]phenyl]pyrazol-3-yl]urea

[0136] Step-1: 2-[3-(3-nitropyrazol-1-yl)phenyl]acetonitrile (15-3): To a stirred solution of 3-nitro-1H-pyrazole 15-1 (0.50 g, 4.42 mmol) in DCM (20 mL) were added [3- (cyanomethyl)phenyl]boronic acid 15-2 (1.42 g, 8.84 mmol) and copper (II) acetate (0.87 g, 8.84 mmol) followed by pyridine (0.78 mL, 8.84 mmol) at RT. The reaction mixture was stirred at 25 °C for 16 h. After completion of reaction, the reaction mixture was filtered through Celite bed and filtrate was concentrated under reduced pressure to yield product which was purified by CombiFlash (60% EtOAc / n-heptane) to afford 2-[3-(3-nitropyrazol-1- yl)phenyl]acetonitrile 15-3 (0.30 g).1H NMR (400 MHz, DMSO-d6) δ = 8.81 (d, J = 2.8 Hz, 1H), 7.96 - 7.89 (m, 2H), 7.63 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H), 4.19 (s, 2H).

[0137] Step-2: 2-methyl-2-[3-(3-nitropyrazol-1-yl)phenyl]propanenitrile (15-4): To a stirred solution of 2-[3-(3-nitropyrazol-1-yl)phenyl]acetonitrile (1.00 g, 4.38 mmol) in THF (15 mL) were added sodium hydride (60% in mineral oil, 0.26 g, 11.00 mmol) and iodomethane (0.81 mL, 13.10 mmol) at 0 °C. The reaction mixture was stirred under 25 °C for 16 h. After completion of reaction, reaction mixture was quenched with ice cold water and extracted with ethyl acetate. Combined organic layer and was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to yield product which was purified by CombiFlash column to afford 2-methyl-2-[3-(3-nitropyrazol-1- yl)phenyl]propanenitrile 15-4 (0.75 g). LCMS: [M+H]+= 257.

[0138] Step-3: 2-methyl-2-[3-(3-nitropyrazol-1-yl)phenyl]propanamide (15-5): To a stirred solution of 2-methyl-2-[3-(3-nitropyrazol-1-yl)phenyl]propanenitrile 15-4 (0.80 g, 3.12 mmol) in EtOH (46 mL) were added K2CO3 (0.43 g, 3.12 mmol) and 30% H2O2 (66 mL, 3.12 mmol) at RT. The reaction mixture was stirred at 25 °C for 16 h. After completion of reaction, reaction mixture was diluted with water, aqueous layer was extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to yield the product which was triturated with diethyl ether to afford 2-methyl-2-[3-(3-nitropyrazol-1-yl)phenyl]propanamide 15-5 (0.50 g) which was used directly for the next reaction. LCMS: [M+H]+= 275.

[0139] Step-4: 2-[3-(3-nitropyrazol-1-yl)phenyl]propan-2-amine (15-6): To a stirred solution of 2-methyl-2-[3-(3-nitropyrazol-1-yl)phenyl]propanamide 15-5 (0.50 g, 1.82 mmol) in MeCN (10 mL) and water (10 mL) was added (bis(trifluoroacetoxy)iodo)benzene (0.78 g, 1.82 mmol) at RT. The reaction mixture was stirred under 25 °C for 16 h. After completion of reaction, reaction mixture was diluted with water, aqueous layer was extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield 2-[3-(3-nitropyrazol-1-yl)phenyl]propan-2- amine 15-6 (0.55 g) which was used directly for the next reaction.1H NMR (400 MHz, DMSO-d6) δ = 8.65 (d, J = 2.4 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.62 - 7.55 (m, 1H), 7.32 (d, J = 2.4 Hz, 1H), 3.8 (s, 2H), 1.66 (s, 6H).

[0140] Step-5: tert-butyl N-[1-methyl-1-[3-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate (15-7): To a stirred solution of 2-[3-(3-nitropyrazol-1-yl)phenyl]propan-2-amine 15-6 (0.55 g, 2.23 mmol) in DCM (15 mL) was added triethylamine (0.62 mL, 4.47 mmol) followed bydi-tert-butyl dicarbonate (0.62 mL, 2.68 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. After completion of reaction, reaction mixture was diluted with water, aqueous layer was extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield product which was purified by flash column chromatography (50% EtOAc / n-heptane) to afford tert- butyl N-[1-methyl-1-[3-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 15-6 (0.18 g).1H NMR (400 MHz, DMSO-d6) δ = 8.62 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 5.6 (s, 1H), 1.52 (s, 6H), 1.30 (s, 9H); LCMS: [M+H]+= 291.

[0141] Step-6: tert-butyl N-methyl-N-[1-methyl-1-[3-(3-nitropyrazol-1- yl)phenyl]ethyl]carbamate (15-8): To a stirred solution of tert-butyl N-[1-methyl-1-[3-(3- nitropyrazol-1-yl)phenyl]ethyl]carbamate 15-7 (0.18 g, 0.52 mmol) in THF (5 mL) were added NaH (60% in mineral oil, 0.12 g, 3.12 mmol) and iodomethane (0.19 mL, 3.12 mmol) at 0 °C. The reaction mixture was stirred under 25 °C for 16 h. After completion of reaction, reaction mixture was quenched with ice cold water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield product which was purified by CombiFlash to afford tert-butyl N-methyl-N-[1-methyl-1-[3-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 15- 8 (0.07 g).1H NMR (400 MHz, DMSO-d6) δ = 8.62 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 3.0 (s, 3H), 1.52 (s, 6H), 1.30 (s, 9H); LCMS: [M+H]+= 305.

[0142] Step-7: tert-butyl N-[1-[3-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]-N- methyl-carbamate (15-9): To a stirred solution of tert-butyl N-methyl-N-[1-methyl-1-[3-(3- nitropyrazol-1-yl)phenyl]ethyl]carbamate 15-8 (0.06 g, 0.16 mmol) in ethanol (3 mL) and water (1.5 mL) was added iron powder (0.04 g, 0.83 mmol) followed by ammonium chloride (0.04 g, 0.83 mmol) at RT. The reaction mixture was stirred at 85 °C for 2 h. After completion of reaction, the reaction mixture was filtered with Celite. The filtrate was diluted with water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford tert-butyl N- [1-[3-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]-N-methyl-carbamate 15-9 (0.04 g). LCMS: [M+H]+= 331.

[0143] Step-8: tert-butyl N-[1-[3-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]-N-methyl-carbamate (15-11): To a stirred solution of tert-butyl N-[1-[3-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]-N- methyl-carbamate 15-9 (0.04 g, 0.13 mmol) in MeCN (2 mL) was added pyridine (0.02 mL, 0.27 mmol) followed by N,N′-disuccinimidyl carbonate (0.03 g, 0.13 mmol) at 0 °C. Resulting reaction mixture was stirred at RT for 1 h. To this was added (4S)-8- chlorochroman-4-amine;hydrochloride 15-10 (0.03 g, 0.13 mmol) followed by DIPEA (0.07 mL, 0.40 mmol) at RT and the reaction mixture was stirred at 25 °C for 1 h. After completion of reaction, reaction mixture was quenched with ice cold water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford tert-butyl N-[1-[3-[3-[[(4S)-8-chlorochroman- 4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]-N-methyl-carbamate 15-11 (0.06 g) which was used such as for the next reaction. LCMS: [M+H]+= 540.

[0144] Step-9: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-[1-methyl-1- (methylamino)ethyl]phenyl]pyrazol-3-yl]urea (Example 15): To a stirred solution of tert- butyl N-[1-[3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1- methyl-ethyl]-N-methyl-carbamate 15-11 (1.00 eq, 60 mg, 0.111 mmol) in DCM (1.5 mL), were added 2,6-lutidine (0.07 mL, 0.56 mmol) and trimethylsilyl trifluoromethanesulfonate (0.10 mL, 0.56 mmol) at 0 °C. Reaction mixture was stirred at 25 °C for 2 h. After completion of reaction, the reaction mixture was evaporated, and the residue was dissolved in ethyl acetate. The organic layer was washed with H2O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product was purified by triturating with diethyl ether to afford Example 15 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 1H), 8.99 (s, 2H), 8.41 (s, 1H), 7.81 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.3 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 6.4 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.56 (s, 1H), 4.98 (d, J = 6.4 Hz, 1H), 4.40 (d, J = 6.8 Hz, 1H), 4.26 (s, 1H), 2.32 (s, 3H), 2.15 (d, J = 4.9 Hz, 1H), 2.04 (d, J = 4.4 Hz, 1H), 1.66 (s, 6H); LCMS: [M+H]+= 440.Example 16: Synthesis of 1-[1-[4-(azetidin-3-yl) phenyl] pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]ureaed solution of (4-bromophenyl) boronic acid 16-1 (0.53 g, 2.65 mmol) in IPA (10 mL) was added nickel (II) iodide (0.16 g, 0.53 mmol) followed by (1R,2R)-2-aminocyclohexan-1-ol (0.06 g, 0.53 mmol) and degassed with argon for 10 min. To this was added sodium bis(trimethylsilyl)amide (2M in THF) (0.97 g, 5.30 mmol) and the reaction mixture was further degassed with argon for 20 min. Then to this reaction mixture was added tert-butyl 3- iodoazetidine-1-carboxylate 16-2 (0.75 g, 2.65 mmol) and stirred at 80 °C for 2 h in a sealed tube. After completion, reaction was filtered and filtrate was concentrated under reduced pressure. Product was purified by flash column chromatography (0-50% EtOAc / heptane) to afford tert-butyl 3-(4-bromophenyl) azetidine-1-carboxylate 16-3 (0.27 g). LCMS: [M+H]+= 256.

[0146] Step-2: tert-butyl 3-[4-(3-aminopyrazol-1-yl) phenyl] azetidine-1-carboxylate (16- 5): To a stirred solution of 1H-pyrazol-3-amine 16-4 (0.47 g, 5.66 mmol) in DMF (5 mL) was added tert-butyl 3-(4-bromophenyl) azetidine-1-carboxylate 16-3 (1.94 g, 6.22 mmol) followed by cesium carbonate (4.60 g, 14.10 mmol) and copper (I) bromide (0.24 g, 1.70mmol). The reaction was stirred at 120 °C for 18 h in a sealed tube. After completion, the reaction mixture was quenched with ice water and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by flash column chromatography (5% MeOH / DCM) to afford tert-butyl 3-[4-(3-aminopyrazol-1-yl) phenyl] azetidine-1-carboxylate 16-5 (1.20 g). LCMS: [M+H]+= 316.

[0147] Step-3: tert-butyl 3-[4-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl] phenyl] azetidine-1-carboxylate (16-7): To a stirred solution of tert-butyl 3- [4-(3-aminopyrazol-1-yl) phenyl] azetidine-1-carboxylate 16-5 (0.50g, 1.59 mmol) in MeCN (5 mL) was added pyridine (0.26 mL, 3.18 mmol) followed by N,N′-disuccinimidyl carbonate (0.44 g, 1.75 mmol) at 0 °C. Reaction mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine 16-6 (0.35 g, 1.91 mmol) followed by DIPEA (1.1 mL, 6.36 mmol) and reaction mixture 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. Product was purified by CombiFlash (10% MeOH / DCM) to afford tert-butyl 3-[4-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl] phenyl]azetidine-1-carboxylate 16-7 (0.40 g). LCMS: [M+H]+= 524.

[0148] Step-4: 1-[1-[4-(azetidin-3-yl) phenyl] pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4- yl]urea (Example 16): To a stirred solution of tert-butyl 3-[4-[3-[[(4S)-8-chlorochroman-4- yl] carbamoyl amino] pyrazol-1-yl] phenyl] azetidine-1-carboxylate 16-7 (0.10 g, 0.19 mmol) in DCM (2.5 mL) was added TFA (1.0 mL) at 0 °C and the reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure. The product obtained was purified by prep-HPLC to afford Example 16 (0.003 g).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.17 (d, J = 6.1 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 4.96 (q, J = 6.4 Hz, 1H), 4.44 - 4.36 (m, 1H), 4.30 - 4.23 (m, 1H), 3.86 - 3.75 (m, 3H), 3.58 (t, J = 6.8 Hz, 2H), 2.22 - 2.13 (m, 1H), 2.06 - 1.98 (m, 1H); LCMS: [M+H]+= 424.Example 17: Synthesis of 2-(3-(3-(8-fluorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N,N- dimethylacetamide [ed solution of 3-nitro-1H-pyrazole 17-1 (0.5 g, 4.42 mmol) in MeCN (8 mL) 2-bromo-N,N- dimethyl-acetamide 17-2 (0.5 g, 0.97 mmol) was added and the reaction mixture was cooled to 5-10 °C. To the resulting reaction mixture K2CO3 (0.18 g, 1.00 mmol) was added and the reaction mixture was heated at 85 °C for 2 h. After completion of reaction, the reaction mixture was diluted with water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified by CombiFlash (30% EtOAc / hexane) to afford 17-3 (0.45g). LCMS: [M+H]+= 198.

[0150] Step-2: 2-(3-amino-1H-pyrazol-1-yl)-N,N-dimethylacetamide (17-4): To a stirred solution of 17-3 (0.52 g, 2.63 mmol) in ethanol / water (1:1, 14 mL), NH4Cl (0.14 g, 2.63 mmol) was added followed by iron powder (0.84 g, 15.0 mmol) at RT and stirred for 10 min. The reaction mixture was heated at 80 ºC for 16 h. After completion of reaction, the reaction mixture was diluted with water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified by CombiFlash (30% EtOAc / n-heptane) to afford 17-4 (0.30 g). LCMS: [M+H]+= 169.

[0151] Step-3: 2-(3-(3-(8-fluorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N,N- dimethylacetamide (Example 17): To a stirred solution of N,N'-disuccinimidyl carbonate (0.15 g, 0.60 mmol) in THF (4 mL), pyridine (0.05 mL, 0.60 mmol) was added followed by 17-4 (0.10 g, 0.60 mmol) and the reaction mixture was stirred at RT for 45 min. To the resulting reaction mixture, DIPEA (0.31 mL, 1.78 mmol) was added followed by 8- fluorochroman-4-amine (0.10 g, 0.60 mmol) and the reaction mixture was stirred at RT for 45 min. After completion of reaction, the reaction mixture was diluted with water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 2N HCl and brine solution. The organic layer was dried over anhydrous Na2SO4and evaporated under reduced pressure. The product obtained was purified by CombiFlash (30% EtOAc / n-heptane) to afford Example 17 (0.013 g).1H NMR (400 MHz, DMSO-d6) δ = 8.67 - 8.52 (m, 1H), 7.46 (br s, 1H), 7.21 - 7.04 (m, 3H), 6.86 (d, 1H), 6.19 - 6.07 (m, 1H), 4.97 - 4.86 (m, 3H), 4.42 - 4.27 (m, 1H), 4.25 - 4.16 (m, 1H), 2.96 (s, 3H), 2.81 (s, 3H), 2.13 (d, 1H), 1.98 (d, 1H); LCMS: [M+H]+= 362. Example 18: Synthesis of 1-[1-[4-(3-aminooxetan-3-yl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea

[0152] Step-1: N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide (18- 3): To a stirred solution of 1-bromo-4-iodo-benzene 18-1 (0.10 g, 0.35 mmol) in dry THF ( 3 mL) was added n-BuLi (1.6M in hexane, 0.26 mL, 0.42 mmol) drop wise at -78 °C under argon atmosphere and the reaction mixture was stirred for 10 min. To the resulting reaction mixture was added 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide 18-2 (0.06 g, 0.35 mmol) in THF (2 mL) and the reaction mixture was stirred at -78 °C for 15 min. After completion of reaction, the reaction mixture was quenched with saturated NH4Cl solution at 0 °C and extracted with EtOAc. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure which was purified by CombiFlash (80% EtOAc / heptane) to afford N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl- propane-2-sulfinamide 18-3 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 7.60 (d, J = 7.8 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.33 (br s, 1H), 5.01 - 4.86 (m, 3H), 4.68 (d, J = 5.9 Hz, 1H), 1.11 (s, 9H); LCMS: [M+H]+= 334.

[0153] Step-2: N-[3-[4-(3-aminopyrazol-1-yl)phenyl]oxetan-3-yl]-2-methyl-propane-2- sulfinamide (18-5): To a stirred solution of N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl- propane-2-sulfinamide 18-3 (1.60 g, 4.82 mmol) in DMSO (20 mL) was added 1H-pyrazol-3- amine 18-4 (0.40 g, 4.82 mmol) followed by cesium carbonate (3.14 g, 9.63 mmol). The reaction mixture was purged with argon gas for 20 min and then was added trans-4-hydroxy- D-proline (0.31 g, 2.41 mmol) followed by copper (I) iodide (0.18 g, 0.96 mmol), purged with argon again for 10 min. The reaction was stirred at 120 °C for 12 h. After completion, the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by flash column chromatography (100% EtOAc) to afford N-[3-[4-(3-aminopyrazol-1-yl)phenyl]oxetan-3-yl]-2-methyl-propane-2- sulfinamide 18-5 (0.50 g).1H NMR (400 MHz, DMSO-d6) δ = 8.14 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 6.28 (s, 1H), 5.75 (s, 1H), 5.08 - 4.98 (m, 4H), 4.90 (d, J = 6.4 Hz, 1H), 4.71 (d, J = 6.4 Hz, 1H), 1.16 - 1.05 (m, 9H); LCMS: [M+H]+= 335.

[0154] Step-3: 1-[1-[4-[3-(tert-butylsulfinylamino)oxetan-3-yl]phenyl]pyrazol-3-yl]-3- [(4S)-8-chlorochroman-4-yl]urea (18-7): To a stirred solution of N-[3-[4-(3-aminopyrazol- 1-yl)phenyl]oxetan-3-yl]-2-methyl-propane-2-sulfinamide 18-5 (0.30 g, 0.89 mmol) in MeCN (5 mL) was added pyridine (0.14 mL, 1.79 mmol) followed by N,N′-disuccinimidylcarbonate (0.34 g, 1.35 mmol) and the reaction mixture was stirred at 25 °C for 45 min. To this was added (4S)-8-chlorochroman-4-amine hydrochloride 18-6 (0.19 g, 0.89 mmol) followed by N,N-diisopropylethylamine (0.47 mL, 2.69 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 12 h. After completion, reaction mixture was diluted with H2O, extracted with EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford product (0.40 g). Product obtained was purified by prep HPLC to obtain 1-[1-[4-[3-(tert-butylsulfinylamino)oxetan-3- yl]phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 18-7 (0.14 g). LCMS: [M+H]+= 544.

[0155] Step-4: 1-[1-[4-(3-aminooxetan-3-yl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 18): To a stirred solution of 1-[1-[4-[3-(tert- butylsulfinylamino)oxetan-3-yl]phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 18- 7 (0.05 g, 0.09 mmol) in methanol (1 mL) was added 4M HCl in 1,4 dioxane (0.10 mL, 0.14 mmol) at -10 °C. The reaction mixture was stirred at -5 °C to 0 °C for 20 min. After completion of reaction, the reaction mixture was quenched with aqueous NaHCO3solution at 0 °C and extracted with EtOAc. Combined organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by prep HPLC to afford Example 18 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.21 (s, 1H), 7.71 - 7.57 (m, 4H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.51 (d, J = 2.5 Hz, 1H), 4.97 (q, J = 6.3 Hz, 1H), 4.71 - 4.61 (m, 4H), 4.47 - 4.36 (m, 1H), 4.32 - 4.24 (m, 1H), 2.22 - 2.11 (m, 1H), 2.09 - 1.96 (m, 1H); LCMS: [M+H]+= 440.Example 19 and Example 20: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[(2R)- 1-methylpyrrolidin-2-yl] phenyl] pyrazol-3-yl]urea2- (4-bromophenyl) pyrrolidine 19-1 (0.50 g, 2.21 mmol) in methanol (5 mL) was added formaldehyde (0.66 g, 22.1 mmol). The resulting solution was stirred at RT under nitrogen atmosphere for 2 h. To this was added sodium triacetoxyborohydride (0.93 g, 4.42 mmol) and the reaction mixture was stirred at RT under nitrogen atmosphere for 24 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O and basified using aqueous NaOH solution. Aqueous layer was extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was triturated with n-heptane to afford 2-(4-bromophenyl)-1-methyl-pyrrolidine 19-2 (0.35 g) which was used directly for the next reaction.1H NMR (400 MHz, DMSO-d6) δ = 7.51 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 3.15 (m, 1H), 3.04 (m, 1H), 2.26 (m, 1H), 2.15 (m, 1H), 2.06 (s, 3H), 1.83 (m, 2H), 1.54 (m, 1H); LCMS: [M+H]+= 241.

[0157] Step-2: 1-[4-(1-methylpyrrolidin-2-yl) phenyl] pyrazol-3-amine (19-4): To a stirred solution of 1H-pyrazol-3-amine 19-3 (0.06 g, 0.83 mmol) in DMF (2 mL) was added 2-(4-bromophenyl)-1-methyl-pyrrolidine 19-2 (0.20 g, 0.83 mmol) followed by cesium carbonate (0.54 g, 1.67 mmol) and copper (I) bromide (0.03 g, 0.25 mmol). The reaction mixture was stirred at 140 °C under microwave for 4 h. After completion, the reaction was quenched with ice cold water and extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated under reduced pressure. Product obtained was purified by column chromatography (0-20% MeOH / DCM) to afford 1-[4-(1- methylpyrrolidin-2-yl) phenyl]pyrazol-3-amine 19-4 (0.02 g).1H NMR (400 MHz, DMSO- d6) δ = 8.07 (s, 1H), 7.59 (d, J = 7.2 Hz, 2H), 7.33 (d, J = 7.2 Hz, 2H), 5.71 (s, 1H), 5.01 (s, 2H), 3.14 (m, 1H), 3.01 (m, 1H), 2.22 (m, 2H), 2.07 (s, 3H), 1.85 (m, 2H), 1.58 (m, 1H); LCMS: [M+H]+= 243.

[0158] Step-3: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-(1-methylpyrrolidin-2-yl) phenyl] pyrazol-3-yl]urea (19-6): To a stirred solution of 1-[4-(1-methylpyrrolidin-2-yl) phenyl] pyrazol-3-amine 19-4 (0.10 g, 0.41 mmol) in MeCN (5 mL) was added N,N′-disuccinimidyl carbonate (0.10 g, 0.41 mmol) followed by pyridine (0.06 mL, 0.82 mmol). The resulting reaction mixture was stirred at RT for 45 min. To this was added (4S)-8-chlorochroman-4- amine 19-5 (0.09 g, 0.49 mmol) followed by N,N-disopropylethylamine (0.22 mL, 1.24 mmol). The reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was quenched with H2O and extracted with in DCM. Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by prep-HPLC to afford 1-[1-[4-(1-methylpyrrolidin-2-yl) phenyl] pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea 19-6 (0.12 g).1H NMR (400 MHz, DMSO-d6) δ = 8.99 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.36 - 7.32 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 7.15 - 7.13 (m, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 4.96 (q, J = 6.2 Hz, 1H), 4.40 - 4.37 (m, 1H), 4.27 - 4.22 (m, 1H), 3.13 - 3.12 (m, 1H), 3.06 (d, J = 7.2 Hz, 1H), 2.18 - 2.02 (m, 7H), 1.86 - 1.73 (m, 2H), 1.61 - 1.56 (m, 1H); LCMS: [M+H]+= 453.

[0159] Step-4: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[(2R)-1-methylpyrrolidin-2-yl] phenyl]pyrazol-3-yl]urea (Examples 19 and 20): The purified product of 1-[(4S)-8- chlorochroman-4-yl]-3-[1-[4-(1-methylpyrrolidin-2-yl)phenyl]pyrazol-3-yl]urea 19-6 was submitted for chiral prep HPLC separation to afford Example 19 (0.02 g) and Example 20 (0.02 g). The absolute stereochemistry for these examples was not determined.

[0160] Example 19:1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.38 - 7.32 (m, 3H), 7.27 (d, J = 7.5 Hz, 1H), 7.18 - 7.13 (m, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 2.3 Hz, 1H), 4.96 (q, J = 6.2 Hz, 1H), 4.42 - 4.36 (m, 1H), 4.30 - 4.23 (m, 1H), 3.19 - 3.12 (m, 1H), 3.06 (d, J = 7.2 Hz, 1H), 2.18 - 2.02 (m, 7H), 1.86 - 1.73 (m, 2H), 1.61 - 1.56 (m, 1H); LCMS: [M+H]+= 452.

[0161] Example 20:1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.40 - 7.30 (m, 3H), 7.29 - 7.24 (m, 1H), 7.16 (d, J = 5.7 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 2.3 Hz, 1H), 4.96 (d, J = 6.6 Hz, 1H), 4.46 - 4.35 (m, 1H), 4.30 - 4.23 (m, 1H), 3.15 (d, J = 5.9 Hz, 1H), 3.05 (br s, 1H), 2.24 - 2.02 (m, 7H), 1.86 - 1.72 (m, 2H), 1.57 (dd, J = 3.8, 5.5 Hz, 1H); LCMS: [M+H]+= 452. Example 21: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1-methyl-1- (methylamino) ethyl] phenyl] pyrazol-3-yl]urea

[0162] Step-1: tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl) phenyl]ethyl]carbamate (21-3): To a stirred solution of 3-nitro-1H-pyrazole 21-1 (0.14 g, 1.24 mmol) in DCM (30 mL) were added [4-[1-(tert-butoxycarbonylamino)-1-methyl-ethyl] phenyl] boronic acid 21-2 (1.03 g, 3.71 mmol) and copper acetate (0.24 g, 2.48 mmol) followed by pyridine (0.20 mL, 2.48 mmol) and the reaction mixture was stirred at RT for 16 h. After completion, the reaction mixture was filtered through Celite bed and the filtrate was concentrated underreduced pressure to yield product which was purified by CombiFlash (30% EtOAc / n- heptane) to afford tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 21-3 (0.30 g).1H NMR (400 MHz, DMSO-d6) δ = 8.75 (d, J = 2.4 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 2 H), 7.34 (d, J = 8.8 Hz, 1H), 7.29 (br s, 1H), 1.53 (s, 6H), 1.34 (s, 9H).

[0163] Step-2: tert-butyl N-methyl-N-[1-methyl-1-[4-(3-nitropyrazol-1-yl) phenyl] ethyl]carbamate (21-4): To a stirred solution of tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol- 1-yl) phenyl] ethyl]carbamate 21-3 (0.93 g, 2.68 mmol) in THF (10 mL) was added NaH (60% mineral oil, 0.64 g, 16.1 mmol) at 0 °C followed by MeI (1.0 mL, 16.1 mmol). Reaction mixture was stirred at RT for 24 h. After completion, reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with H2O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield product which was purified by CombiFlash (25% EtOAc / n- heptane) to afford tert-butyl N-methyl-N-[1-methyl-1-[4-(3-nitropyrazol-1-yl) phenyl] ethyl] carbamate 21-4 (0.53 g). LCMS: [M+H]+= 305.

[0164] Step-3: tert-butyl N-[1-[4-(3-aminopyrazol-1-yl) phenyl]-1-methyl-ethyl]-N- methylcarbamate (21-5): To a stirred solution of tert-butyl N-methyl-N-[1-methyl-1-[4-(3- nitropyrazol-1-yl)phenyl]ethyl]carbamate 21-4 (0.26 g, 0.71 mmol) in ethanol (10 mL) and water (2.5 mL) was added NH4Cl (0.19 g, 3.59 mmol) followed by iron powder (0.20 g, 3.59 mmol) at RT and the reaction mixture was stirred under 80 °C for 2 h. After completion, reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc and the combined organic layer was concentrated under reduced pressure to yield product which was purified by CombiFlash (50% EtOAc / n-heptane) to afford tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl- ethyl]-N-methyl-carbamate 21-5 (0.16 g, 0.45 mmol).1H NMR (400 MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.24 (d, J = 7.2 Hz, 2H), 5.70 (s, 1H), 5.00 (s, 2H), 3.00 (s, 3H), 1.56 (s, 6H), 1.06 (s, 9H).

[0165] Step-4: N-[1-[4-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl] phenyl]-1-methyl-ethyl]-N-methyl-carbamate (21-7): To a stirred solution of tert-butyl N- [1-[4-(3-aminopyrazol-1-yl) phenyl]-1-methyl-ethyl]-N-methylcarbamate 21-5 (0.26 g, 0.51 mmol) in MeCN (5 mL) was added N,N′-disuccinimidyl carbonate (0.13 g, 0.514 mmol)followed by pyridine (0.04 mL, 0.51 mmol). To the above reaction mixture was added DIPEA (0.27 mL, 1.54 mmol) followed by (4S)-8-chlorochroman-4-amine hydrochloride 21- 6 (0.11 g, 0.51 mmol). Reaction mixture was stirred at RT for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The residue was washed with ice-cold water and the precipitated solid was filtered under vacuum. The solid was purified by CombiFlash (40% EtOAc / n-heptane) to afford tert-butyl N-[1-[4-[3-[[(4S)-8-chlorochroman- 4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]-N-methyl-carbamate 21-7 (0.11 g).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.26 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.34 - 7.25 (m, 5H), 6.92 - 6.88 (m, 1H), 6.47 (d, J = 2.0 Hz, 1H), 4.97 (m, 1H), 4.40 (m, 1H), 4.25 (m, 1H), 3.01 (s, 3H), 2.25 (m, 1H), 2.21 (m, 1H), 1.56 (s, 6H), 1.05 (s, 9H); LCMS: [M+H]+= 540.

[0166] Step-5: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1-methyl-1-(methylamino) ethyl] phenyl] pyrazol-3-yl]urea (Example 21): To a stirred solution of tert-butyl N-[1-[4-[3- [[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]-N- methyl-carbamate 21-7 (0.02 g, 0.04 mmol) in DCM (0.5 mL) was added 2.6-lutidine (0.05 mL, 0.46 mmol) followed by TMS triflate (0.08 mL, 0.46 mmol) at 0 °C and the reaction mixture was stirred at RT for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, organic layer was washed with H2O, brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product was recrystallized with DCM / diethyl ether (1:3) to afford Example 21 (0.006 g).1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.96 - 8.85 (m, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.61 (d, J = 8.9 Hz, 2H), 7.35 (dd, J = 1.3, 7.8 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 6.9 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 2.5 Hz, 1H), 4.97 (q, J = 6.2 Hz, 1H), 4.45 - 4.34 (m, 1H), 4.31 - 4.20 (m, 1H), 2.34 - 2.28 (m, 3H), 2.23 - 2.12 (m, 1H), 2.08 - 1.99 (m, 1H), 1.67 (s, 6H); LCMS: [M-H]+= 438. Example 22: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-(1-methylazetidin-3- yl)phenyl]pyrazol-3-yl]urea

[0167] Step-1: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-(1-methylazetidin-3- yl)phenyl]pyrazol-3-yl]urea (Example 22): To a stirred solution of 1-[1-[4-(azetidin-3- yl)phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea Example 16 (0.10 g, 0.23 mmol) in methanol (5 mL) was added 37% formaldehyde (1.0 mL, 2.36 mmol) and the reaction mixture was stirred at RT for 2 h. To this was added sodium triacetoxyborohydride (0.17 g, 0.82 mmol) and stirring was continued at RT for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was quenched with ice cold water. Aqueous layer was extracted with 10% MeOH / DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product was purified by prep HPLC to afford Example 22 (0.03 g).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.31 (d, J = 2.5 Hz, 1H), 8.18 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.16 (d, J = 7.1 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 4.96 (q, J = 6.3 Hz, 1H), 4.43 - 4.35 (m, 1H), 4.29 - 4.23 (m, 1H), 3.68 - 3.61 (m, 2H), 3.17 - 3.14 (m, 2H), 2.32 (s, 3H), 2.21 - 2.12 (m, 1H), 2.07 - 2.00 (m, 1H); LCMS: [M+H]+= 438.Example 23: Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)-3-fluoro-phenyl]pyrazol-3- yl]-3-[(4S)-8-chlorochroman-4-yl]urea

[0068] Step : ( bo o uoop e y) et y popa e t e (3 ): o a st ed solution of 2-(4-bromo-2-fluoro-phenyl)acetonitrile 23-1 (2.00 g, 9.34 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 0.93 g, 23.4 mmol) at 0 °C and the reaction mixture was stirred for 1 h. To this was added MeI (1.70 mL, 28.00 mmol) and reaction mixture was stirred at 25 °C for 2 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 was purified by CombiFlash to afford 2-(4- bromo-2-fluoro-phenyl)-2-methyl-propanenitrile 23-2 (0.65 g).1H NMR (400 MHz, CHCl3- d) δ = 7.52 - 7.01 (m, 3H), 1.78 (s, 6H).

[0169] Step-2: [4-(1-cyano-1-methyl-ethyl)-3-fluoro-phenyl]boronic acid (23-3): To a stirred solution of 2-(4-bromo-2-fluoro-phenyl)-2-methyl-propanenitrile 23-2 (8.50 g, 35.1 mmol) in THF (95 mL) was added n-BuLi (23.00 mL, 246 mmol) at -78 °C and reaction mixture was stirred at -78 °C for 1 h. To this was added B(OMe)3 (6.80 mL, 45.60 mmol) and the reaction mixture was warmed to RT for 30 min. After completion of the reaction, THF was removed under reduced pressure. The solid residue was taken up in water and extracted with diethyl ether to remove nonpolar impurities. The aqueous layer was acidified and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford pure [4-(1-cyano-1- methyl-ethyl)-3-fluoro-phenyl]boronic acid 23-3 (2.10 g). LCMS: [M-H]-: 206.

[0170] Step-3: 2-[2-fluoro-4-(3-nitropyrazol-1-yl)phenyl]-2-methyl-propanenitrile (23- 5): To a stirred solution of 3-nitro-1H-pyrazole 23-4 (0.50 g, 4.42 mmol) in DCM (16 mL) was added pyridine (1.1 mL, 13.3 mmol) at 0 °C followed by [4-(1-cyano-1-methyl-ethyl)-3- fluoro-phenyl]boronic acid 23-3 (2.29 g, 11.1 mmol). The reaction mixture was purged with oxygen for 20 min followed by addition of Cu(OAc)2(1.61 g, 8.84 mmol). The resulting reaction mixture was stirred at RT for 12 h. After completion, the reaction mass was concentrated under reduced pressure. The residue 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 CombiFlash (30% EtOAc / n-heptane) to afford 2-[2-fluoro-4-(3-nitropyrazol-1-yl)phenyl]-2-methyl- propanenitrile 23-5 (0.93 g). LCMS: [M+H]+= 275.

[0171] Step-4: 2-[2-fluoro-4-(3-nitropyrazol-1-yl)phenyl]-2-methyl-propanamide (23-6): To a stirred solution of 1-[3-(1,1-dimethylprop-2-ynyl)phenyl]-3-nitro-pyrazole 23-5 (0.93 g, 3.39 mmol) in ethanol (22 mL), saturated K2CO3 (16 mL) was added followed by 30% H2O2 (32 mL). The reaction mixture was stirred at 25 °C for 16 h. After completion, reaction mixture was filtered by Buchner funnel to obtain a white solid which was triturated with diethyl ether to afford 2-[2-fluoro-4-(3-nitropyrazol-1-yl)phenyl]-2-methyl-propanamide 23-6 (0.60 g). LCMS: [M+H]+= 293.

[0172] Step-5: 2-[4-(3-aminopyrazol-1-yl)-2-fluoro-phenyl]-2-methyl-propanamide (23- 7): To a stirred solution of 2-[2-fluoro-4-(3-nitropyrazol-1-yl)phenyl]-2-methyl-propanamide 23-6 (0.60 g, 2.05 mmol) in ethanol (45 mL) and water (15 mL) was added NH4Cl (0.54 g,10.3 mmol) followed by iron powder (0.57 g, 10.3 mmol) at RT. The resulting reaction mixture was stirred at 100 °C for 1 h. After completion, reaction mixture was filtered through Celite bed and washed with 5% MeOH / DCM. Filtrate was dried over anhydrous Na2SO4and concentrated under reduced pressure. Product was purified by column chromatography (100% EtOAc) to afford 2-[4-(3-aminopyrazol-1-yl)-2-fluoro-phenyl]-2-methyl-propanamide 23-7 (0.36 g, 66.86 %). LCMS: [M+H]+= 263.

[0173] Step-6: 2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-2- fluoro-phenyl]-2-methyl-propanamide (23-9): To a stirred solution of 2-[4-(3- aminopyrazol-1-yl)-2-fluoro-phenyl]-2-methyl-propanamide 23-7 (0.18 g, 0.69 mmol) in MeCN (5 mL) was added pyridine (0.05 g, 0.69 mmol) followed by N,N′-disuccinimidyl carbonate (0.17 g,0.69 mmol). The resulting reaction mixture was stirred at RT for 15 min. To this was added (4S)-8-chlorochroman-4-amine hydrochloride 23-8 (0.12 g, 0.69 mmol) followed by DIPEA (0.26 g, 2.06 mmol) and reaction mixture was stirred at 25 °C for 3 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by reverse phase chromatography used gradients 0.1% formic acid in H2O and acetonitrile 50-60% as eluent to afford 2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-2-fluoro-phenyl]- 2-methyl-propanamide 23-9 (0.28 g). LCMS: [M+H]+= 472.

[0174] Step-7: 1-[1-[4-(1-amino-1-methyl-ethyl)-3-fluoro-phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 23): To a stirred solution of 2-[4-[3-[[(4S)-8- chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-2-fluoro-phenyl]-2-methyl-propanamide 23-9 (0.12 g, 0.25 mmol) in MeCN (2 mL) and water (8 mL) was added KOH (0.07 g, 1.16 mmol) followed by 1,3-dibromo-5,5-dimethylhydantoin 23-10 (0.04 g, 0.13 mmol) and the reaction mixture was stirred at RT for 1 h. After completion, the reaction mixture was added into Na2SO3 solution and stirred for 15 min. Then reaction mixture was diluted with aqueous K3PO4solution 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 23 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.38 (d, J = 2.6 Hz, 1H), 8.21 (s, 1H), 7.67 - 7.54 (m, 1H), 7.50 - 7.40 (m, 2H), 7.34 (dd, J = 1.4, 8.0 Hz, 1H), 7.27 (d, J = 7.1 Hz, 1H), 7.13 (d, J = 7.1 Hz, 1H), 6.92 (t,J = 7.8 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 4.96 (q, J = 6.3 Hz, 1H), 4.45 - 4.34 (m, 1H), 4.30 - 4.24 (m, 1H), 2.22 - 2.11 (m, 1H), 2.08 - 1.99 (m, 1H), 1.45 (s, 6H); LCMS: [M+H]+= 445. Example 24: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2- (dimethylamino)acetyl]phenyl]pyrazol-3-yl]urea[ ] p ( [ ( py y )p y] ( ) f 3-nitro-1H-pyrazole 24-1 (3.00 g, 26.5 mmol) in DCM (35 mL) was added (4- acetylphenyl)boronic acid 24-2 (6.53 g, 39.80 mmol) followed by pyridine (7.00 mL, 79.60 mmol) and Cu(OAc)2 (9.60 g, 53.1 mmol). Reaction mixture was stirred at RT for 12 h. After completion, reaction was quenched with H2O, extracted with DCM. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by CombiFlash (30% EtOAc / hexane) to afford product (1- [4-(3-nitropyrazol-1-yl)phenyl]ethanone 24-3 (4.00 g). LCMS: [M+H]+= 232.

[0176] Step-2: 2-bromo-1-[4-(3-nitropyrazol-1-yl)phenyl]ethanone (24-4): To a stirred solution of 1-[4-(3-nitropyrazol-1-yl)phenyl]ethenone 24-3 (1.00 g, 4.33 mmol) in MeCN (15 mL) was added pTSA (0.08 g, 0.43 mmol) followed by NBS (0.76 g, 4.33 mmol). Resulting mixture was stirred at 80 °C for 12 h. After completion, reaction mixture was diluted with ice cold water, extracted with EtOAc. Organic layer was washed with NaHCO3solution, driedover anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified by column chromatography to afford 2-bromo-1-[4-(3-nitropyrazol-1- yl)phenyl]ethanone 24-4 (0.90 g). LCMS: [M+H]+= 312.

[0177] Step-3: 2-(dimethylamino)-1-[4-(3-nitropyrazol-1-yl)phenyl]ethanone (24-5): To a stirred solution of N,N-dimethyl amine (2M in THF, 0.36 g, 8.06 mmol) in MeCN (10 mL) was added K2CO3 (0.22 g, 1.61 mmol) and stirred for 15 min. To this was added 2-bromo-1- [4-(3-nitropyrazol-1-yl)phenyl]ethanone 24-4 (0.50 g, 1.61 mmol) and the reaction mixture was stirred at RT for 90 min. After completion, the obtained product was dissolved in ice cold water, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash (90% EtOAc / heptane) to afford 2-(dimethylamino)-1-[4-(3-nitropyrazol-1- yl)phenyl]ethanone 24-5 (0.18 g). LCMS: [M+H]+= 275.

[0178] Step-4: 1-[4-(3-aminopyrazol-1-yl)phenyl]-2-(dimethylamino)ethanone (24-6): To a stirred solution of 2-(dimethylamino)-1-[4-(3-nitropyrazol-1-yl)phenyl]ethanone 24-5 (0.15 g, 0.54 mmol) in ethanol (3 mL) and water (1 mL) was added NH4Cl (0.14 g, 2.73 mmol) followed by Fe powder (0.15 g, 2.73 mmol). The reaction mixture was stirred at 80 °C for 4 h. After completion, reaction mixture was filtered and filtrate was concentrated under reduced pressure. Residue obtained was dissolved in EtOAc and filtered. Filtrate was concentrated under reduced pressure and purified by reverse phase column chromatography (0.1% formic acid in ACN) to afford 1-[4-(3-aminopyrazol-1-yl)phenyl]-2-(dimethylamino)ethanone 24-6 (0.06 g). LCMS: [M+H]+= 245.

[0179] Step-5: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2- (dimethylamino)acetyl]phenyl]pyrazol-3-yl]urea (Example 24): To a stirred solution of 1- [4-(3-aminopyrazol-1-yl)phenyl]-2-(dimethylamino)ethanone 24-6 (0.06 g, 0.24 mmol) in MeCN (3 mL) was added pyridine (0.03 mL, 0.36 mmol) followed by N,N′-disuccinimidyl carbonate (0.06 g, 0.24 mmol). Resulting mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine;hydrochloride (0.05 g, 0.24 mmol) followed by DIPEA (0.13 mL, 0.73 mmol) and reaction was stirred at RT for 4 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. The product obtained was purified by prep-HPLC to afford Example 24 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ =9.11 (s, 1H), 8.50 (d, J = 2.6 Hz, 1H), 8.15 (s, 1H), 8.05 (d, J = 8.9 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 7.35 (dd, J = 1.1, 7.8 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 4.97 (q, J = 6.3 Hz, 1H), 4.49 - 4.33 (m, 1H), 4.33 - 4.25 (m, 1H), 3.75 (s, 2H), 2.26 (s, 6H), 2.21 - 2.11 (m, 1H), 2.10 - 1.98 (m, 1H); LCMS: [M+H]+= 454. Example 25: Synthesis of 1-[1-[3-fluoro-4-(2-hydroxyethylamino)phenyl]pyrazol-3-yl]-3- [(4S)-8-chlorochroman-4-yl]urea

[0180] Step-1: 2-fluoro-4-(3-nitropyrazol-1-yl)aniline (25-3): To a stirred solution of 3- nitro-1H-pyrazole 25-1 (1.00 g, 8.84 mmol) in THF (10 mL) was added (4-amino-3-fluoro- phenyl) boronic acid 25-2 (2.19 g, 14.2 mmol) followed by copper (I) chloride (0.12 g, 1.33 mmol) and sodium hydroxide (0.42 g, 10.6 mmol). The reaction mixture was stirred at RT for 16 h. After completion, the reaction mixture was filtered through Celite bed and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (0-70% EtOAc / heptane) to afford 2-fluoro-4-(3-nitropyrazol-1-yl)aniline 25-3 (0.75 g). LCMS: [M+H+] = 223.

[0181] Step-2: 2-[2-fluoro-4-(3-nitropyrazol-1-yl)anilino]ethanol (25-4): To a suspension of 2-fluoro-4-(3-nitropyrazol-1-yl)aniline 25-3 (0.30 g, 1.35 mmol) in THF (0.1 mL) was added 2-bromoethanol (0.16 g, 1.35 mmol) and stirred at 90 °C for 12 h. After completion, reaction mixture was diluted with EtOAc and filtered. Filtrate was concentrated under reduced pressure. Product obtained was then purified by flash column chromatography (70%EtOAc / heptane) to afford 2-[2-fluoro-4-(3-nitropyrazol-1-yl)anilino]ethanol 25-4 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 8.61 (d, J = 2.4 Hz, 1H), 7.66 (dd, J = 2.0, 12.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 6.89 (t, J = 9.0 Hz, 1H), 5.71 (br s, 1H), 4.77 (t, J = 5.4 Hz, 1H), 3.59 (q, J = 5.7 Hz, 2H), 3.23 (q, J = 5.5 Hz, 2H); LCMS: [M+H]+= 267.

[0182] Step-3: 2-[4-(3-aminopyrazol-1-yl)-2-fluoro-anilino]ethanol (25-5): To a stirred solution of 2-[2-fluoro-4-(3-nitropyrazol-1-yl)anilino]ethanol 25-4 (0.13 g, 0.48 mmol) in ethanol (4 mL) was added water (1 mL) followed by ammonium chloride (0.12 g, 2.44 mmol) and iron powder (0.13 g, 2.44 mmol) and the reaction mixture was stirred at 100 °C for 2 h. After completion, reaction was filtered and filtrate was concentrated under reduced pressure. Residue was dissolved in EtOAc and filtered. Filtrate was concentrated under reduced pressure to afford 2-[4-(3-aminopyrazol-1-yl)-2-fluoro-anilino]ethanol 25-5 (1.00 g).1H NMR (400 MHz, DMSO-d6) δ = 7.94 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 2.2, 13.4 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.76 (t, J = 9.3 Hz, 1H), 5.64 (d, J = 2.4 Hz, 1H), 5.10 (br s, 1H), 4.92 (br s, 2H), 4.74 (br s, 1H), 3.64 - 3.49 (m, 2H), 3.15 (d, J = 5.4 Hz, 2H); LCMS: [M+H]+= 237.

[0183] Step-4: 1-[1-[3-fluoro-4-(2-hydroxyethylamino)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 25): To a stirred solution of 2-[4-(3-aminopyrazol-1- yl)-2-fluoro-anilino]ethanol 25-5 (0.10 g, 0.45 mmol) in MeCN (8 mL) was added pyridine (0.04 mL, 0.45 mmol) followed by N,N′-disuccinimidyl carbonate (0.11 g, 0.454 mmol). Resulting reaction mixture was stirred at RT for 30 min. To this was added (4S)-8- chlorochroman-4-amine hydrochloride 25-6 (0.10 g, 0.45 mmol) followed by N,N- diisopropylethylamine (0.24 mL, 1.36 mmol) and stirred at RT for 4 h. After completion, the reaction mixture was concentrated under reduced pressure. Product was purified by prep- HPLC to afford Example 25 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 8.91 (s, 1H), 8.15 (s, 1H), 7.39 - 7.30 (m, 2H), 7.29 - 7.23 (m, 2H), 7.15 (d, J = 5.9 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.76 (t, J = 9.0 Hz, 1H), 6.39 (s, 1H), 5.24 (br s, 1H), 4.94 (q, J = 5.9 Hz, 1H), 4.73 (t, J = 5.4 Hz, 1H), 4.44 - 4.33 (m, 1H), 4.30 - 4.18 (m, 1H), 3.56 (q, J = 5.9 Hz, 2H), 3.15 (q, J = 5.7 Hz, 2H), 2.21 - 2.09 (m, 1H), 2.01 (dd, J = 4.4, 6.8 Hz, 1H); LCMS: [M+H]+= 446. Example 26: Synthesis of 1-[1-[6-(1-amino-1-methyl-ethyl)-3-pyridyl]pyrazol-3-yl]-3- [(4S)-8-chlorochroman-4-yl]urea

[0184] Step-1: 2-(5-bromo-2-pyridyl)propan-2-amine (26-2): To a stirred solution of 5- bromopyridine-2-carbonitrile 26-1 (5.00 g, 27.3 mmol) in toluene (5 mL) was drop wise added MeMgI (15.90 g, 95.6 mmol) at 0 °C. Reaction mixture was stirred at 100 °C for 16 h. After completion, reaction mixture was quenched with saturated NH4Cl solution, acidified with 1N HCl, aqueous layer was extracted with EtOAc. Then aqueous layer was basified with saturated NaOH solution, and the aqueous layer was extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 2-(5-bromo-2-pyridyl)propan-2-amine 26-2 (3.80 g). LCMS: [M+H]+= 217.

[0185] Step-2: 2-[1-(5-bromo-2-pyridyl)-1-methyl-ethyl]isoindoline-1,3-dione (26-3): To a stirred solution of 2-(5-bromo-2-pyridyl)propan-2-amine 26-2 (1.50 g, 6.97 mmol) in toluene (10 mL) was added isobenzofuran-1,3-dione (1.08 g, 7.32 mmol) and the reactionmixture was stirred at 110 °C for 16 h. After completion, reaction mixture was concentrated under reduced pressure to obtain product which was purified by flash chromatography (20% EtOAc / heptane) to afford 2-[1-(5-bromo-2-pyridyl)-1-methyl-ethyl]isoindoline-1,3-dione 26- 3 (1.10 g).

[0186] Step-3: 2-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- pyridyl]ethyl]isoindoline-1,3-dione (26-4): To a degassed solution of 2-[1-(5-bromo-2- pyridyl)-1-methyl-ethyl]isoindoline-1,3-dione 26-3 (2.70 g, 7.82 mmol) and bis(pinacolato)diboron (2.98 g, 11.7 mmol) in DMF (10 mL) was added potassium acetate (2.33 g, 23.5 mmol) and Pd(dppf)Cl2(0.57 g, 0.78 mmol) at RT and the resulting solution was stirred at 100 °C for 3 h. After completion, reaction mixture was diluted with water, aqueous layer was extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain product 2- [1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]ethyl]isoindoline-1,3- dione 26-4 (3.80 g). LCMS: [M+H]+= 311 (M-82).

[0187] Step-4: [6-[1-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethyl]-3-pyridyl]boronic acid (26-5): To a stirred solution of 2-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2-pyridyl]ethyl]isoindoline-1,3-dione 26-4 (3.80 g, 9.69 mmol) in THF (5 mL) and water (5 mL) was added sodium metaperiodate (6.19 g, 29.1 mmol) and the reaction mixture was stirred at 25 °C for 30 min. To this was added 1N HCl (4.0 mL) and stirred at same temperature for 16 h. After completion, reaction mixture was quenched with water and extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford [6-[1-(1,3-dioxoisoindolin-2-yl)-1-methyl- ethyl]-3-pyridyl]boronic acid 26-5 (2.42 g). LCMS: [M+H]+= 311.

[0188] Step-5: 2-[1-methyl-1-[5-(3-nitropyrazol-1-yl)-2-pyridyl]ethyl]isoindoline-1,3- dione (26-7): To a stirred solution of 3-nitro-1H-pyrazole 26-6 (0.52 g, 4.60 mmol) in DCM (10 mL) were added [6-[1-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethyl]-3-pyridyl]boronic acid 26-5 (2.42 g, 7.82 mmol), copper acetate (1.66 g, 9.20 mmol) and pyridine (1.1 mL, 13.8 mmol) at RT. Reaction mixture was stirred at RT for 12 h under an oxygen atmosphere. After completion, reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product was purified by flash column chromatography(0-50% EtOAc / heptane) to afford 2-[1-methyl-1-[5-(3-nitropyrazol-1-yl)-2- pyridyl]ethyl]isoindoline-1,3-dione 26-7 (0.52 g). LCMS: [M+H+] = 378.

[0189] Step-6: 2-[1-[5-(3-aminopyrazol-1-yl)-2-pyridyl]-1-methyl-ethyl]isoindoline-1,3- dione (26-8): To a stirred solution of 2-[1-methyl-1-[5-(3-nitropyrazol-1-yl)-2- pyridyl]ethyl]isoindoline-1,3-dione 26-7 (0.14 g, 0.37 mmol) in EtOH (2 mL) and water (2 mL) was added ammonium chloride (0.14 g, 2.60 mmol) followed by iron powder (0.10 g, 1.86 mmol). Reaction mixture was stirred at 60 °C for 16 h. After completion, the reaction mixture 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 to afford 2-[1-[5-(3-aminopyrazol-1-yl)-2-pyridyl]-1-methyl- ethyl]isoindoline-1,3-dione 26-8 (0.12 g). LCMS: [M+H]+= 348.

[0190] Step-7: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[6-[1-(1,3-dioxoisoindolin-2-yl)-1- methyl-ethyl]-3-pyridyl]pyrazol-3-yl]urea (26-10): To a stirred solution of N,N′- disuccinimidyl carbonate (0.13 g, 0.51 mmol) in MeCN (3 mL) were added pyridine (0.04 mL, 0.51 mmol) and 2-[1-[5-(3-aminopyrazol-1-yl)-2-pyridyl]-1-methyl-ethyl]isoindoline- 1,3-dione 26-8 (0.18 g, 0.51 mmol) and the reaction mixture was stirred at RT for 45 min. To this was added DIPEA (0.27 mL, 1.55 mmol) and reaction mixture was stirred for at 25 °C 2 h. After completion, reaction mixture was quenched with H2O, extracted with EtOAc. Combined organic layer was washed with H2O, brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash column to afford 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[6-[1-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethyl]- 3-pyridyl]pyrazol-3-yl]urea 26-10 (0.14 g). LCMS: [M+H]+= 557.

[0191] Step-8: 1-[1-[6-(1-amino-1-methyl-ethyl)-3-pyridyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 26): To a stirred solution of 1-[(4S)-8-chlorochroman- 4-yl]-3-[1-[6-[1-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethyl]-3-pyridyl]pyrazol-3-yl]urea 26- 10 (0.14 g, 0.251 mmol) in ethanol (1 mL) and methanol (1 mL) was added hydrazine hydrate (0.06 mL, 1.26 mmol) at RT. Reaction was stirred at 70 °C for 16 h. After completion, reaction mixture was filtered and washed with MeOH. The filtrate was concentrated under reduced pressure. The product was purified by prep HPLC to afford Example 26 (0.008 g).1H NMR: (400 MHz, DMSO-d6) δ = 9.19 (s, 1H), 8.91 (d, J = 2.4 Hz, 1H), 8.44 (d, J = 2.6 Hz, 1H), 8.33 (br s, 1H), 8.08 (dd, J = 2.6, 8.6 Hz, 1H), 7.72 (d, J = 8.8Hz, 1H), 7.33 (dd, J = 1.3, 7.9 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 4.98 (q, J = 6.2 Hz, 1H), 4.43 - 4.35 (m, 1H), 4.32 - 4.25 (m, 1H), 2.23 - 2.12 (m, 1H), 2.08 - 2.00 (m, 1H), 1.49 (s, 6H); LCMS: [M+H]+= 428. Example 27 and Example 28: Synthesis of 1-[1-[4-[1-amino-2,2,2-trifluoro- ethyl]phenyl]pyrazol 3 yl] 3 [(4S) 8 chlorochroman 4 yl]urea

[0192] Step-1: 2, 2, 2-trifluoro-1-[4-(3-nitropyrazol-1-yl)phenyl]ethanone (27-3): To a stirred solution of 1-(4-bromophenyl)-2,2,2-trifluoro-ethanone 27-2 (0.84 g, 3.32 mmol) in DMF (2 mL) was added 3-nitro-1H-pyrazole 27-1 (0.25 g, 2.21 mmol) followed by addition of K2CO3 (0.76 g, 5.53 mmol), CuI (0.08 g, 0.44 mmol) and trans-N,N′-dimethylcyclohexane- 1,2-diamine (0.13 g, 0.88 mmol). Reaction mixture was stirred at 120 °C for 2 h. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Organic layer was washed with brine and dried over anhydrous Na2SO4. The product obtained was concentrated under reduced pressure to afford 2, 2, 2-trifluoro-1-[4-(3-nitropyrazol-1-yl)phenyl]ethanone 27-3 (0.30 g).1H NMR (400 MHz, DMSO-d6) δ = 9.02 - 8.79 (m, 1H), 8.25 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.47 - 7.34 (m, 1H).

[0193] Step-2: 2-methyl-N-[2,2,2-trifluoro-1-[4-(3-nitropyrazol-1- yl)phenyl]ethyl]propane-2-sulfinamide (27-5): To a stirred solution of 2,2,2-trifluoro-1-[4- (3-nitropyrazol-1-yl)phenyl] ethanone 27-3 (1.70 g, 5.96 mmol) in THF (50 mL) was added 2-methylpropane-2-sulfinamide 27-4 (1.08 g, 8.94 mmol) followed by addition of titanium isopropaoxide (3.6 mL, 11.9 mmol). Reaction mixture was stirred at 80 °C for 16 h. Then the reaction mixture was cooled to RT and was added sodium borohydride (1.13 g, 29.8 mmol) portion wise at RT. The reaction mixture was stirred at RT for 3 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash to afford 2-methyl-N-[2,2,2-trifluoro-1-[4- (3-nitropyrazol-1-yl)phenyl]ethyl]propane-2-sulfinamide 27-5 (0.85 g). LCMS: [M+H]+ = 391.

[0194] Step-3: N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethyl]-2-methyl- propane-2-sulfinamide (27-6): To a stirred solution of 2-methyl-N-[2,2,2-trifluoro-1-[4-(3- nitropyrazol-1-yl)phenyl]ethyl]propane-2-sulfinamide 27-5 (0.65 g, 1.67 mmol) in ethanol (50 mL) was added 10% Pd / C (0.35 g) and the reaction mixture was stirred under 100 psi hydrogen gas pressure at 25 °C for 3 h. After completion, the reaction mixture was filtered over Celite bed. The filtrate was concentrated under reduced pressure. Product was purified by CombiFlash (3-5% MeOH / DCM) to afford N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-2,2,2- trifluoro-ethyl]-2-methyl-propane-2-sulfinamide 27-6 (0.04 g). LCMS: [M+H]+ = 361.

[0195] Step-4: 1-[1-[4-[1-(tert-butylsulfinylamino)-2,2,2-trifluoro-ethyl]phenyl]pyrazol- 3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea (27-8): To a stirred solution of N-[1-[4-(3- aminopyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethyl]-2-methyl-propane-2-sulfinamide 27-6 (0.55 g, 1.53 mmol) in MeCN (20 mL) was added pyridine (0.12 mL, 1.53 mmol) followed by N,N′-disuccinimidyl carbonate (0.39 g, 1.53 mmol). The resulting mixture was stirred at RT for 15 min. To this was added (4S)-8-chlorochroman-4-amine hydrochloride 27-7 (0.33 g, 1.53 mmol) followed by DIPEA (0.55 mL, 3.05 mmol) and reaction mixture was stirred at 25 °C for 3 h. After completion, reaction mixture was diluted with H2O and extracted withEtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by reverse phase chromatography to afford 1-[1-[4-[1-(tert-butylsulfinylamino)-2,2,2-trifluoro- ethyl]phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 27-8 (0.40 g). LCMS: [M+H]+= 70.

[0196] Step-5: 1-[1-[4-(1-amino-2,2,2-trifluoro-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (27-9): To a stirred solution of 1-[1-[4-[1-(tert- butylsulfinylamino)-2,2,2-trifluoro-ethyl]phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4- yl]urea 27-8 (0.40 g, 0.70 mmol) in DCM (15 mL) was added 4 M HCl in dioxane (0.20 mL, 3.51 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 1 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by reverse phase chromatography to afford 1-[1- [4-(1-amino-2,2,2-trifluoro-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 27-9 (0.35 g). LCMS: [M+H]+= 466.

[0197] Step-6: 1-[1-[4-[1-amino-2,2,2-trifluoro-ethyl]phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Examples 27 and 28): 0.35 g of 1-[1-[4-(1-amino-2,2,2- trifluoro-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 27-9 was submitted for chiral-HPLC separation to afford Example 27 (0.06 g) and Example 28 (0.04 g). The absolute stereochemistry of these products was not determined.

[0198] Example 27:1H NMR (400 MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.34 (dd, J = 1.1, 7.9 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.14 (d, J = 7.0 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 4.96 (q, J = 6.2 Hz, 1H), 4.51 (q, J = 8.2 Hz, 1H), 4.45 - 4.35 (m, 1H), 4.31 - 4.21 (m, 1H), 2.70 - 2.52 (m, 2H), 2.21 - 2.10 (m, 1H), 2.09 - 1.99 (m, 1H); LCMS: [M+H]+= 466.

[0199] Example 28:1H NMR (400 MHz, DMSO-d6) δ = 9.04 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.15 (d, J = 7.1 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 4.96 (q, J = 6.4 Hz, 1H), 4.54 (q, J = 8.0 Hz, 1H), 4.44 - 4.37 (m, 1H), 4.30 - 4.23 (m, 1H), 3.12 - 2.59 (m, 2H), 2.22 - 2.11 (m, 1H), 2.09 - 1.98 (m, 1H); LCMS: [M+H]+= 466.Example 29 and Example 30: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4- [pyrrolidin-2-yl] phenyl] pyrazol-3-yl]ureastirred solution of 2-(4-bromophenyl)pyrrolidine 29-1 (0.10 g, 0.44 mmol) in THF (5 mL) was added triethylamine (0.07 mL, 0.53 mmol) followed by (BOC)2(0.11 mL, 0.53 mmol) and stirred at RT for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. Product obtained was purified by flash column chromatography (0-50% EtOAc / heptane) to afford tert-butyl 2-(4-N-bromophenyl)pyrrolidine-1-carboxylate 29-2 (0.10 g, 67.94 %).1H NMR (400 MHz, DMSO-d6) δ = 7.47 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 7.3 Hz, 2H), 4.84 - 4.59 (m, 1H), 3.54 - 3.37 (m, 2H), 2.25 (s, 1H), 1.77 (d, J = 5.9 Hz, 2H), 1.64 (s, 1H), 1.43 - 0.95 (m, 9H); LCMS: [M+H]+= 270.

[0201] Step-2: tert-butyl 2-[4-(3-aminopyrazol-1-yl) phenyl] pyrrolidine-1-carboxylate (29-4): To a stirred solution of 1H-pyrazol-3-amine 29-3 (0.02 g, 0.27 mmol) in DMF (2 mL)was added tert-butyl 2-(4-bromophenyl) pyrrolidine-1-carboxylate 29-2 (0.09 g, 0.30 mmol) followed by cesium carbonate (0.13 g, 0.41 mmol) and copper (I) bromide (0.004 g, 0.02 mmol). The reaction was stirred at 120 °C for 18 h. After completion, the reaction mixture was quenched with ice cold water and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. Product obtained was purified by flash column chromatography (0-70% EtOAc / n-heptane) to afford tert-butyl 2-[4-(3-aminopyrazol-1-yl) phenyl] pyrrolidine-1-carboxylate 29-4 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 8.08 (s, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 5.71 (d, J = 2.5 Hz, 1H), 5.05 (br s, 2H), 4.88 - 4.60 (m, 1H), 3.57 - 3.40 (m, 2H), 2.36 - 2.19 (m, 1H), 1.82 (d, J = 5.5 Hz, 2H), 1.71 (d, J = 5.0 Hz, 1H), 1.48 - 0.99 (m, 9H); LCMS: [M+H]+= 329.

[0202] Step-3: tert-butyl 2-(4-(3-(3-((S)-8-chlorochroman-4-yl)ureido)-1H-pyrazol-1- yl)phenyl)pyrrolidine-1-carboxylate (29-6): To a stirred solution of tert-butyl 2-[4-(3- aminopyrazol-1-yl) phenyl] pyrrolidine-1-carboxylate 29-4 (0.01 g, 0.04 mmol) in MeCN (3 mL) was added N,N′-disuccinimidyl carbonate (0.01 g, 0.04 mmol). The resulting reaction mixture was stirred at RT for 45 min. To this was added (S)-8-chlorochroman-4-amine hydrochloride 29-5 (0.01 g, 0.05 mmol) followed by N,N-diisopropylethylamine (0.02 mL, 0.13 mmol). The reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was quenched with water and extracted with DCM. Combined organic layer were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by CombiFlash column chromatography (90 % EtOAc / n-heptane) to afford tert-butyl 2-(4-(3-(3-((S)-8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)phenyl)pyrrolidine-1- carboxylate 29-6 (0.01 g).1HNMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.31 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 5.3 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 4.97 (q, J = 6.3 Hz, 1H), 4.42 - 4.38 (m, 1H), 4.28 - 4.24 (m, 1H), 3.54 (m, 2H), 2.12 - 2.14 (m, 2H), 2.05 - 2.02 (m, 1H), 1.81 - 1.70 (m, 3H), 1.49 - 1.42 (m, 1H).1.10 (s, 9H); LCMS: [M+H]+= 538.

[0203] Step-4: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-pyrrolidin-2-ylphenyl) pyrazol-3- yl]urea hydrochloride (29-7): To a stirred solution of tert-butyl 2-(4-(3-(3-((S)-8- chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)phenyl)pyrrolidine-1-carboxylate 29-6 (0.15 g, 0.27 mmol) in 1,4-dioxane (2 mL) was added 4N HCl in 1,4-dioxane (2 mL) at 0 °C and theresulting reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure. The residue was triturated with 50% EtOAc / n-heptane to afford 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-pyrrolidin-2-ylphenyl) pyrazol-3-yl]urea hydrochloride 29-7 (0.09 g). LCMS: [M+H]+= 438.

[0204] Step-5: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[pyrrolidin-2-yl] phenyl] pyrazol- 3-yl]urea (Examples 29 and 30): Racemic 29-7 was purified by prep HPLC purification which was submitted for chiral prep HPLC separation to afford Example 29 (0.03 g, 0.07 mmol) and Example 30 (0.03 g, 0.06 mmol). The absolute stereochemistry of these compounds was not determined.

[0205] Example 29:1HNMR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 5.3 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 4.96 (q, J = 6.3 Hz, 1H), 4.43 - 4.38 (m, 1H), 4.29 - 4.24 (m, 1H), 4.03 (t, J = 7.6 Hz, 1H), 3.02 - 2.99 (m, 1H), 2.92 - 2.86 (m, 1H), 2.16 - 2.03 (m, 3H), 1.79 - 1.71 (m, 2H), 1.49 - 1.42 (m, 1H); LCMS: [M+H]+= 438.

[0206] Example 30:1HNMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.34 (dd, J = 1.2, 7.8 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 5.9 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.99 - 4.93 (m, 1H), 4.43 - 4.37 (m, 1H), 4.29 - 4.23 (m, 1H), 4.11 (t, J = 7.7 Hz, 1H), 3.09 - 3.02 (m, 1H), 2.98 - 2.91 (m, 1H), 2.18 - 2.12 (m, 2H), 2.07 - 2.00 (m, 1H), 1.85 - 1.75 (m, 2H), 1.60 - 1.51 (m, 1H); LCMS: [M+H]+= 438.Example 31: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2- (dimethylamino)ethyl]phenyl]pyrazol-3-yl]urea

[0007] Step : et y [ (3 t opy a o y)p e y ]acetate (3 3): o a st ed sout on of 3-nitro-1H-pyrazole 31-2 (1.00 g, 8.84 mmol) in 1,4-dioxane (10 mL) was added potassium carbonate (2.44 g, 17.70 mmol) followed by copper (I) iodide (0.03 g, 0.17 mmol), trans-1,2-diaminocyclohexane (0.02 g, 0.17 mmol) and ethyl 2-(4-iodophenyl)acetate 31-1 (2.56 g, 8.84 mmol) at RT. The resulting reaction mixture was stirred at 110 °C for 12 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue 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 to yield product which was purified by CombiFlash (20% EtOAc / n-heptane) to afford ethyl 2-[4-(3-nitropyrazol-1-yl)phenyl]acetate 31-3 (0.45 g).1H NMR (400 MHz, DMSO-d6) δ = 8.77 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 2.4 Hz, 1H), 4.10 (q, J = 7.3 Hz, 2H), 3.77 (s, 2H), 1.20 (t, J = 7.1 Hz, 3H); LCMS: [M+H]+= 276.

[0208] Step-2: 2-[4-(3-nitropyrazol-1-yl)phenyl]ethanol (31-4): To a stirred solution of ethyl 2-[4-(3-nitropyrazol-1-yl)phenyl]acetate 31-3 (1.50 g, 5.45 mmol) in THF (15 mL) maintained at 0 °C was added lithium borohydride solution 2M in THF (3.30 mL, 6.54 mmol) and reaction mixture was stirred at 26 °C for 4 h. After completion of reaction, reaction mixture was quenched with aqueous ammonium chloride solution, aqueous layer was extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to yield the product which was purified by CombiFlash (50% EtOAc / n-heptane) to afford 2-[4-(3-nitropyrazol-1-yl)phenyl]ethanol 31-4 (0.90 g).1H NMR (400 MHz, DMSO-d6) δ = 8.75 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.34 (s, 1H), 4.69 (t, J = 5.2 Hz, 1H), 3.65 - 3.63 (m, 2H), 2.79 (t, J = 6.8 Hz, 2H); LCMS: [M+H]+= 234.

[0209] Step-3: 2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate (31-5): To a stirred solution of 2-[4-(3-nitropyrazol-1-yl)phenyl]ethanol 31-4 (0.50 g, 2.14 mmol) in DCM (20 mL) was added triethylamine (0.90 mL, 6.43 mmol) followed by p-toluenesulfonyl chloride (0.49 g, 2.57 mmol) at 0 °C. Reaction mixture was stirred at 26 °C for 16 h. After completion, reaction mixture was quenched with H2O, extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated under reduced pressure to yield the product which was purified by CombiFlash (5% EtOAc / n- heptane) to afford 2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate 31-5 (0.65 g).1H NMR (400 MHz, DMSO-d6) δ = 8.76 (d, J = 2.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.66 - 7.63 (m, 2H), 7.38 - 7.33 (m, 5H), 4.30 (t, J = 6.2 Hz, 2H), 2.97 (t, J = 6.2 Hz, 2H), 2.36 (s, 3H); LCMS: [M+H]+= 388.

[0210] Step-4: N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine (31-6): To a stirred solution of 2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate 31-5 (0.60 g, 1.55 mmol) in DMF (10 mL) was added potassium carbonate (0.64 g, 4.65 mmol) followed by dimethyl amine hydrochloride (0.25 g, 3.10 mmol) at RT. The resulting solution was stirred at 110 °C for 12 h. After completion of reaction, the reaction mass was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to yield product which was purified by CombiFlash (5% MeOH / DCM) to afford N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine 31-6 (0.25 g);1H NMR (400 MHz, DMSO-d6) δ = 8.79 (d, J = 2.6 Hz, 1H), 7.92 (d, J = 8.6 Hz,2H), 7.52 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 2.6 Hz, 1H), 3.34 - 3.33 (m, 2H), 3.08 - 3.04 (m, 2H), 2.85 (s, 6H); LCMS: [M+H+] = 261.

[0211] Step-5: 1-[4-[2-(dimethylamino)ethyl]phenyl]pyrazol-3-amine (31-7): To a stirred solution of N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine 31-6 (0.12 g, 0.46 mmol) and ammonium chloride (0.14 g, 2.77 mmol) in ethanol (5 mL) was added water (2 mL) followed by iron powder (0.07 g, 1.38 mmol) at RT. Reaction mixture was stirred at 100 °C for 2 h. After completion of reaction, reaction mixture was quenched with H2O, aqueous layer was extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to get afford 1-[4-[2- (dimethylamino)ethyl]phenyl]pyrazol-3-amine 31-7 (0.10 g) which was used such as for next reaction; LCMS: [M+H]+= 231.

[0212] Step-6: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2- (dimethylamino)ethyl]phenyl]pyrazol-3-yl]urea (Example 31): To a stirred solution of 1- [4-[2-(dimethylamino)ethyl]phenyl]pyrazol-3-amine 31-7 (0.10 g, 0.43 mmol) in MeCN (5 mL) was added pyridine (0.06 g, 0.86 mmol) followed by N,N′-disuccinimidyl carbonate (0.11 g, 0.43 mmol) at RT. Resulting reaction mixture was stirred at 26 °C for 30 min. To this was added (4S)-8-chlorochroman-4-amine 31-8 (0.08 g, 0.43 mmol) followed by DIPEA (0.16 g, 1.30 mmol) and reaction mixture was stirred at 26 °C for 12 h. After completion of reaction, reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O and solid obtained was filtered, dried under reduced pressure. Product was purified by prep HPLC to afford Example 31 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.00 (s, 1H), 8.30 (d, J = 2.6 Hz, 1H), 8.16 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.34 (dd, J = 1.3, 7.9 Hz, 1H), 7.30 - 7.25 (m, 3H), 7.18 (d, J = 6.9 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 4.96 (q, J = 6.3 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.29 - 4.23 (m, 1H), 2.74 (t, J = 1.0 Hz, 2H), 2.62 - 2.56 (m, 2H), 2.28 (s, 6H), 2.20 - 2.13 (m, 1H), 2.07 - 2.00 (m, 1H); LCMS: [M+H]+= 440.Example 32 and Example 33: Synthesis of 1-[1-[4-(1-amino-1-methyl- ethyl)phenyl]pyrazol-3-yl]-3-[(chroman-4-yl]urea[ ] p y [ y [ ( py y )p y ] y ] ate (32-3): To a stirred solution of 3-nitro-1H-pyrazole 32-2 (0.20 g, 1.79 mmol) in DCM (30 mL) were added [4-[1-(tert-butoxycarbonylamino)-1-methyl-ethyl]phenyl]boronic acid 32-1 (1.00 g, 3.58 mmol) and copper acetate (0.35 g, 3.58 mmol) followed by pyridine (0.29 mL, 3.58 mmol) at RT. The reaction mixture was stirred at RT for 16 h. After completion of reaction, the reaction mixture was filtered through Celite bed and the filtrate was concentrated under reduced pressure to get product which was purified by CombiFlash (30% EtOAc / n-heptane) to afford tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1- yl)phenyl]ethyl]carbamate 32-3 (0.40 g).1H NMR (400 MHz, DMSO-d6) δ = 8.88 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 2.8 Hz, 2H), 1.52 (s, 6H), 1.34 (s, 9H). LCMS: [M+H]+= 291.

[0214] Step-2: tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl- ethyl]carbamate (32-4): To a stirred solution of tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol- 1-yl)phenyl]ethyl]carbamate 32-3 (0.40 g, 1.15 mmol) in ethanol (15 mL) and water (10 mL) was added ammonium chloride (0.30 g, 577 mmol) followed by iron powder (0.32 g, 5.77mmol) at RT. The reaction mixture was stirred at 100 °C for 2 h. After completion of reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated, diluted with cold water and extracted with EtOAc. Combined organic layer was washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 32-4 (0.45 g) which was used directly for the next reaction. LCMS: [M+H]+= 318.

[0215] Step-3: tert-butyl N-[1-[4-[3-(chroman-4-ylcarbamoylamino)pyrazol-1- yl]phenyl]-1-methyl-ethyl]carbamate (32-6): To a stirred solution of tert-butyl N-[1-[4-(3- aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 32-4 (0.40 g, 1.26 mmol) in MeCN (10 mL) was added pyridine (0.10 mL, 1.26 mmol) followed by N,N′-disuccinimidyl carbonate (0.32 g, 1.26 mmol) at RT. Resulting mixture was stirred at RT for 15 min. To this was added chroman-4-amine 32-5 (0.18 g, 1.26 mmol) followed by DIPEA (0.91 mL, 5.06 mmol) and reaction mixture was stirred at 30 °C for 12 h. After completion of reaction, 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-[1-[4-[3-(chroman-4-ylcarbamoylamino)pyrazol-1-yl]phenyl]-1-methyl- ethyl]carbamate 32-6 (0.10 g) which was used directly for the next reaction. LCMS: [M+H]+= 492.

[0216] Step-4: 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-chroman-4- yl]urea (Examples 32 and 33): To a stirred solution of tert-butyl N-[1-[4-[3-(chroman-4- ylcarbamoylamino)pyrazol-1-yl]phenyl]-1-methyl-ethyl]carbamate 32-6 (0.10 g, 0.19 mmol) in 1,4-dioxane (1 mL) was added 4M HCl in 1,4-dioxane (0.30 mL) at 0 °C. Reaction mixture was stirred at RT for 4 h. After completion of reaction, reaction mixture was concentrated under reduced pressure to get product which was triturated using diethyl ether and pentane, dried well to afford 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3- chroman-4-yl-urea 32-7 (0.08 g) as the HCl salt. LCMS: [M+H]+= 392. The product (0.08 g) was separated by chiral prep HPLC to afford 1-[1-[4-(1-amino-1-methyl- ethyl)phenyl]pyrazol-3-yl]-3-[chroman-4-yl]urea Example 32 (0.01 g) and 1-[1-[4-(1-amino- 1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[chroman-4-yl]urea Example 33 (0.01 g). The absolute stereochemistry for these products was not determined.

[0217] Example 32:1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.35 - 8.33 (m, 2H), 7.60 (d, J = 13.6 Hz, 4H), 7.28 (d, J = 7.5 Hz, 1H), 7.21 - 7.16 (m, 2H), 6.93 - 6.89 (m, 1H), 6.80 (dd, J = 1.0, 8.3 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 4.94 - 4.88 (m, 1H), 4.26 (dd, J = 3.2, 6.7 Hz, 1H), 4.17 - 4.12 (m, 1H), 2.17 - 2.09 (m, 1H), 2.00 - 1.94 (m, 1H), 1.49 (s, 6H); LCMS: [M+H]+= 392.

[0218] Example 33:1H NMR (400 MHz, DMSO-d6) δ = 8.98 (s, 1H), 8.30 (d, J = 2.5 Hz, 1H), 7.56 (s, 4H), 7.28 (d, J = 7.5 Hz, 1H), 7.21 - 7.13 (m, 2H), 6.93 - 6.89 (m, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.48 (d, J = 2.3 Hz, 1H), 4.93 - 4.88 (m, 1H), 4.30 - 4.23 (m, 1H), 4.17 - 4.11 (m, 1H), 2.49 - 2.46 (m, 2H), 2.18 - 2.09 (m, 1H), 2.02 - 1.94 (m, 1H), 1.38 (s, 6H); LCMS: [M+H]+= 393.

[0219] Preparation of 32-5

[0220] Step-1: chroman-4-one oxime (32-5B): To a stirred solution of chroman-4-one (2.00 g, 13.50 mmol) in EtOH (20 mL), sodium acetate (2.21 g, 27.00 mmol) was added at 0 °C followed by hydroxylamine hydrochloride (1.88 g, 27.00 mmol) at RT and the reaction mixture was stirred at 90 °C for 12 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water to form precipitate. The solid was filtered and dried well to afford chroman-4-one oxime (32-5B, 1.00 g) which was used directly for the next reaction. LCMS: [M+H]+= 164.

[0221] Step-2: chroman-4-amine (32-5): To a stirred solution of chroman-4-one oxime (32- 5B, 1.00 g, 6.13 mmol) in a mixture of methanol (10 mL) and THF (10 mL) was added 10% Pd / C (0.30 g) at RT. The reaction mixture was stirred under 50 psi hydrogen gas pressure in autoclave at RT for 16 h. After completion of reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to afford chroman-4- amine (0.80 g). LCMS: [M-NH2]+= 133.Example 34: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea [0 mmol) inMeCN (3 mL) was added pyridine (0.05 g, 0.69 mmol) followed by bis(2,5-dioxopyrrolidin- 1-yl) carbonate (0.16 g, 0.63 mmol). The resulting mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine 34-2 (0.12 g, 0.69 mmol) followed by DIPEA (0.16 mL, 0.94 mmol) and the reaction was stirred at 30 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the product obtained was dissolved in ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified by prep HPLC to afford Example 34 (0.12 g).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.35 (d, 1H), 7.66 (dd, 2H), 7.46 - 7.40 (m, 2H), 7.34 (dd, 1H), 7.27 (dd, 1H), 7.24 - 7.13 (m, 2H), 6.92 (t, 1H), 6.51 (d, 1H), 5.00 - 4.92 (m, 1H), 4.45 - 4.36 (m, 1H), 4.31 - 4.20 (m, 1H), 2.22 - 2.11 (m, 1H), 2.09 - 1.98 (m, 1H); LCMS: [M+H]+= 369. Example 35: Synthesis of 1-[(4S)-8-fluorochroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea

[0223] Step-1: To a stirred solution of 1-phenylpyrazol-3-amine 35-1 (0.13 g, 0.82 mmol) in DCM (6 mL) was added triphosgene (0.12 g, 0.41 mmol) at RT and the resulting reaction mixture was cooled to 0 °C. To this was added DIPEA (0.43 mL, 2.45 mmol) followed by (4S)-8-fluorochroman-4-amine 35-2 (0.14 g, 0.82 mmol) and reaction was stirred at RT for 3h. After completion, the reaction mixture was quenched with H2O and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by CombiFlash chromatography (30% EtOAc / n-heptane) to afford Example 35 (0.07 g).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.35 (d, 1H), 7.70 - 7.63 (m, 2H), 7.46 - 7.39 (m, 2H), 7.26 - 7.10 (m, 4H), 6.92 - 6.85 (m, 1H), 6.51 (d, 1H), 4.96 (q, 1H), 4.40 - 4.31 (m, 1H), 4.26 - 4.18 (m, 1H), 2.23 - 2.00 (m, 2H); LCMS: [M+H]+= 353. Example 36: Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)- 8-chlorochroman-4-yl]urea

[0224] Step-1: tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate (36-3): To a stirred solution of 3-nitro-1H-pyrazole 36-1 (0.06 g, 0.531 mmol) in DCM (6 mL) was added [4-[1-(tert-butoxycarbonylamino)-1-methyl-ethyl]phenyl]boronic acid 36-2 (0.44 g, 1.59 mmol) followed by copper acetate (0.10 g, 1.06 mmol) and pyridine ( 0.08 mL, 1.06 mmol). The reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was filtered through Celite bed and the filtrate was concentrated under reduced pressure. Product was purified by flash chromatography (0-70% EtOAc / heptane) to afford tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 36-3 (0.12 g). 1H NMR (400 MHz, DMSO-d6) δ = 8.75 (br s, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.38 - 7.23 (m, 2H), 1.52 (s, 6H), 1.34 (s, 9H).

[0225] Step-2: tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl- ethyl]carbamate (36-4): To a stirred solution of tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol- 1-yl)phenyl]ethyl]carbamate 36-3 (0.60 g, 1.56 mmol) in ethanol (8 mL) and water (4 mL) was added NH4Cl ( 1.07 g, 7.78 mmol) followed by iron powder (0.43 g, 7.78 mmol) at RT and the reaction mixture was stirred under 100 °C for 2 h. After completion, reaction was filtered through Celite and filtrate was concentrated. The product was diluted with water and extracted with EtOAc. Organic layer was concentrated under reduced pressure to afford tert- butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 36-4 (0.40 g).1H NMR (400 MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.53 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.3 Hz, 2H), 7.13 (br s, 1H), 5.71 (br s, 1H), 5.04 - 4.89 (m, 2H), 1.49 (s, 6H), 1.33 (br s, 9H); LCMS: [M+H]+= 318.

[0226] Step-3: tert-butyl N-[1-[4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]carbamate (36-6): To a stirred solution of tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 36-4 (0.17 g, 0.53 mmol) in MeCN (5 mL) were added pyridine (0.043 mL, 0.53 mmol) and N,N′- disuccinimidyl carbonate ( 0.13 g, 0.53 mmol) at 0 °C and the reaction mixture was stirred for 10 min. To this was added DIPEA (0.28 mL, 1.61 mmol) followed by (4S)-8- chlorochroman-4-amine 36-5 (0.09 g, 0.53 mmol) at 0 °C and reaction was stirred at RT 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 solution, water, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by CombiFlash (30% EtOAc / hexane) to afford tert-butyl N-[1- [4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl- ethyl]carbamate 36-6 (0.18 g). LCMS: [M+H]+= 526.

[0227] Step-4: 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 36): To a solution of tert-butyl N-[1-[4-[3-[[(4S)-8- chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]carbamate 36-6 (0.17 g, 0.29 mmol) in DCM (1 mL) maintained at 0 °C was added 4M HCl in 1,4-dioxane (0.10 g, 2.91 mmol). Reaction was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure. Product obtained was triturated using EtOAc to afford Example 36 (0.11 g).1H NMR (400 MHz, DMSO-d6) δ = 9.10 (s, 1H), 8.59 (br s, 3H), 8.40 (d, J = 2.6 Hz, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.61 (d, J = 8.9 Hz, 2H), 7.34 (dd, J =1.3, 7.9 Hz, 1H), 7.26 (d, J = 7.1 Hz, 2H), 6.92 (t, J = 7.8 Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H), 4.97 (q, J = 6.3 Hz, 1H), 4.44 - 4.37 (m, 1H), 4.31 - 4.25 (m, 1H), 2.20 - 2.13 (m, 1H), 2.06 - 1.99 (m, 1H), 1.64 (s, 6H) [1H extra for HCl salt]; LCMS: [M+H]+= 427. Example 37: Synthesis of 1-[(4S)-8-methylchroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea[ ] p p ypy ( g, mmol) in MeCN (5 mL) was added pyridine (0.05 mL, 0.69 mmol) followed by N,N′-disuccinimidyl carbonate (0.17 g, 0.69 mmol). The resulting mixture was stirred at RT for 30 min. To this was added (4S)-8-methylchroman-4-amine 37-2 (0.10 g, 0.63 mmol) followed by DIPEA (0.34 mL, 1.88 mmol) and reaction was stirred at 30 °C for 1 h. After completion, reaction mixture was concentrated under reduced pressure and product obtained was dissolved in ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by prep HPLC to afford Example 37 (0.12 g).1H NMR (400 MHz, DMSO-d6) δ = 8.98 - 8.92 (m, 1H), 8.39 (d, 1H), 7.68 - 7.62 (m, 2H), 7.45 - 7.38 (m, 2H), 7.24 - 7.18 (m, 1H), 7.17 - 7.09 (m, 2H), 7.06 (d, 1H), 6.84 - 6.77 (m, 1H), 6.50 (d, 1H), 4.92 - 4.85 (m, 1H), 4.36 - 4.28 (m, 1H), 4.22 - 4.14 (m, 1H), 2.17 - 2.09 (m, 4H), 2.03 - 1.94 (m, 1H); LCMS: [M+H]+= 349. Example 38: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-fluorophenyl) pyrazol- 3-yl]urea

[0229] Step-1: To a stirred solution of 1-(3-fluorophenyl) pyrazol-3-amine 38-1 (0.10 g, 0.56 mmol) in MeCN (5 mL) was added Pyridine (0.05 mL, 0.62 mmol) followed by N,N'- disuccinimidyl carbonate (0.16 g, 0.62 mmol). The resulting mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine 38-2 (0.10 g, 0.56 mmol) followed by DIPEA (0.30 mL, 1.69 mmol) and reaction was stirred at 30 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the product obtained was dissolved in ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by trituration with methanol and hexane, dried under reduced pressure to afford Example 38 (0.09 g).1H NMR (400 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.42 (d, 1H), 7.55 - 7.50 (m, 2H), 7.50 - 7.43 (m, 1H), 7.34 (dd, 1H), 7.29 - 7.25 (m, 1H), 7.16 - 7.11 (m, 1H), 7.07 - 7.01 (m, 1H), 6.94 - 6.89 (m, 1H), 6.56 (d, 1H), 4.99 - 4.93 (m, 1H), 4.43 - 4.37 (m, 1H), 4.30 - 4.23 (m, 1H), 2.20 - 2.12 (m, 1H), 2.08 - 1.99 (m, 1H); LCMS: [M+H]+= 387. Example 39: Synthesis of 1-[1-(3-fluorophenyl) pyrazol-3-yl]-3-[(4S)-8-methylchroman- 4-yl]urea[ ] p ( p y ) py ( ) pyrazol-4-amine 39-1 (1.00 g, 12.00 mmol) in DMSO (10 mL) was added Cu2O (0.17 g, 1.20 mmol) followed by KOH (1.35 g, 24.1 mmol) under Argon. To this was added 1-fluoro-3- iodo-benzene 39-2 (4.10 g, 18.10 mmol) and reaction was stirred at 110 °C for 12 h. After completion, the reaction mixture was quenched with water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by CombiFlash (40% EtOAc / n-heptane) to afford 39-3 (0.31 g).1H NMR (400 MHz, DMSO-d6) δ = 8.18 (d, 1H), 7.51 - 7.38 (m, 3H), 6.92 (t, 1H), 5.78 - 5.74 (m, 1H), 5.15 (s, 2H); LCMS: [M+H]+= 178.

[0231] Step-2: 1-[1-(3-fluorophenyl) pyrazol-3-yl]-3-[(4S)-8-methylchroman-4-yl]urea (Example 39): To a stirred solution of 39-3 (0.11 g, 0.61 mmol) in MeCN (3 mL) was added pyridine (0.54 mL, 0.67 mmol) followed by N,N′-disuccinimidyl carbonate (0.17 g, 0.67 mmol) at RT. The reaction mixture was stirred at RT for 15 min. To this was added (4S)-8- methylchroman-4-amine 39-4 (0.10 g, 0.613 mmol) followed by DIPEA (0.33 mL, 1.84 mmol) and reaction was stirred at 30 °C for 1 h. The resulting reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was quenched with water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to obtain a product. The product was purified by prep HPLC to afford Example 39 (0.04 g).1H NMR (400 MHz, DMSO-d6) δ = 9.05 - 8.95 (m, 1H), 8.41 (d, 1H), 7.56 - 7.39 (m, 3H), 7.15 - 7.00 (m, 4H), 6.80 (t, 1H), 6.55 (d, 1H), 4.93 - 4.84 (m, 1H), 4.36 - 4.28 (m, 1H), 4.21 - 4.14 (m, 1H), 2.18 - 2.08 (m, 4H), 2.03 - 1.95 (m, 1H); LCMS: [M+H]+= 367. Example 40: Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)- 8-fluorochroman-4-yl]urea

[0232] Step-1: tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate (40-3): To a stirred solution of 3-nitro-1H-pyrazole 40-2 (0.14 g, 1.24 mmol) in DCM (30mL) were added [4-[1-(tert-butoxycarbonylamino)-1-methyl-ethyl]phenyl]boronic acid 40-1 (1.03 g, 3.71 mmol) and copper acetate (0.24 g, 2.48 mmol) followed by pyridine (0.20 mL, 2.48 mmol) and the reaction mixture was stirred at RT for 16 h. After completion, the reaction mixture was filtered through Celite bed, the filtrate was concentrated under reduced pressure to afford product which was purified by CombiFlash (30% EtOAc / n-heptane) to afford tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 40-3 (0.30g).1H NMR (400 MHz, DMSO-d6) δ= 8.75 (d, J = 2.4 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 2 H), 7.34 (d, J = 8.8 Hz, 1H), 7.29 (br s, 1H), 1.53 (s, 6H), 1.34 (s, 9H).

[0233] Step-2: tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl- ethyl]carbamate (40-4): To a stirred solution of tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol- 1-yl)phenyl]ethyl]carbamate 40-3 (0.15 g, 0.431 mmol) in ethanol (5 mL) and water (2.5 mL) was added NH4Cl (0.11 g, 2.15 mmol) followed by iron powder (0.12 g, 2.15 mmol) at RT and the reaction mixture was stirred under 80 °C for 2 h. After completion, reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The product was washed with EtOAc and the combined washings were concentrated under reduced pressure to afford tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl- ethyl]carbamate 40-4 (0.10 g). LCMS: [M+H+] = 318.

[0234] Step-3: (4S)-8-fluorochroman-4-amine (40-6): To a stirred solution of tert-butyl N- [1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 40-4 (0.05 g, 0.15 mmol) in MeCN (2 mL) were added N,N′-disuccinimidyl carbonate (0.04 g, 0.15 mmol) and pyridine ( 0.01 mL, 0.158 mmol) and the reaction mixture was stirred at RT for 45 min. To the above was added DIPEA (0.08 mL, 0.47 mmol) followed by (4S)-8-fluorochroman-4-amine 40-5 (0.02 g) and was stirred at RT for 45 min. After completion, reaction mixture was concentrated under reduced pressure. The residue was triturated with H2O and the precipitated solid was filtered to afford tert-butyl N-[1-[4-[3-[[(4S)-8-fluorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]carbamate 40-6 (0.04 g).

[0235] Step-4: 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- fluorochroman-4-yl]urea (Example 40): To a stirred solution of tert-butyl N-[1-[4-[3- [[(4S)-8-fluorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl- ethyl]carbamate 40-6 (0.03 g, 0.0738 mmol) in 1,4-dioxane (1 mL) was added 4M HCl in dioxane (1.0 mL, 0.74 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. Aftercompletion, reaction mixture was concentrated under reduced pressure to afford product which was purified by prep HPLC to afford Example 40 (0.006 g).1H NMR (400 MHz, DMSO-d6) δ = 9.04 (s, 1H), 8.40 (d, J = 2.5 Hz, 1H), 8.36 (br s, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.19 - 7.07 (m, 3H), 6.92 - 6.86 (m, 1H), 6.54 (d, J = 2.3 Hz, 1H), 4.96 (q, J = 6.4 Hz, 1H), 4.39 - 4.33 (m, 1H), 4.27 - 4.21 (m, 1H), 2.21 - 2.14 (m, 1H), 2.06 - 2.01 (m, 1H), 1.63 (s, 6H); LCMS: [M+H]+= 410. Example 41: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(6-methoxy-3- pyridyl)pyrazol-3-yl]urea[ ] p ( y py y )py ( ) 1H-pyrazol-3-amine (0.10 g, 1.20 mmol) in DMF (5 mL) were added CuBr (0.03 g, 0.24 mmol) and Cs2CO3(0.59 g, 1.81 mmol) followed by 5-bromo-2-methoxy-pyridine 41-1 (0.22 g, 1.20 mmol). The reaction was stirred at 120 °C for 16 h. After completion, reaction was quenched with water, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1-(6-methoxy-3- pyridyl)pyrazol-3-amine 41-3 (0.10 g); LCMS: [M+H]+= 191.

[0237] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(6-methoxy-3-pyridyl)pyrazol-3- yl]urea (Example 41): To a stirred solution of 1-(6-methoxy-3-pyridyl)pyrazol-3-amine 41-3 (0.09 g, 0.50 mmol) in MeCN (5 mL) was added pyridine (0.10 mL, 0.50 mmol) followed by N,N’-disuccinimidyl carbonate (0.12 g, 0.50 mmol). The resulting mixture was stirred at RT for 1 h. To this was added (4S)-8-chlorochroman-4-amine 41-4 (0.09 g, 0.50 mmol) followed by DIPEA (0.26 mL, 1.50 mmol) and reaction was stirred at RT for 3 h. After completion, reaction mixture was concentrated under reduced pressure and product obtained was dissolved in EtOAc. The organic layer was washed with 2N HCl solution, water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by reverse phase chromatography (60% ACN in 0.1% formic acid / water) toafford Example 41 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.50 (d, J = 2.6 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 2.6, 8.8 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.94 - 6.89 (m, 2H), 6.53 (s, 1H), 4.99 - 4.94 (m, 1H), 4.43 - 4.37 (m, 1H), 4.27 (d, J = 7.9 Hz, 1H), 3.88 - 3.86 (m, 3H), 2.20 - 2.02 (m, 2H); LCMS: [M+H]+= 400 and 402. Example 42: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-(1-tetrahydropyran-4- ylpyrazol-3-yl)urea[ ] p y py y ( ) tetrahydropyran-4-ol 42-1 (0.67 g, 4.42 mmol) in DCM (10 mL) at 0 °C was added triethylamine (3.20 mL, 23.00 mmol). To this was added methanesulfonyl chloride (1.50 mL, 19.50 mmol) slowly dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was quenched with aqueous NH4Cl solution and extracted with DCM. The combined organic layer was washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford tetrahydropyran-4-yl methanesulfonate 42-2 (0.70 g).1H NMR (400 MHz, DMSO-d6) δ = 4.84 (d, J = 4.3, 8.4 Hz, 1H), 3.87 - 3.73 (m, 2H), 3.45 (t, J = 10.3 Hz, 2H), 3.20 (s, 3H), 1.96 (d, J = 12.3 Hz, 2H), 1.76 - 1.60 (m, 2H).

[0239] Step-2: 3-nitro-1-tetrahydropyran-4-yl-pyrazole (42-4): To a stirred solution of 3- nitro-1H-pyrazole 42-3 (0.30 g, 2.65 mmol) in MeCN (5 mL) was added Cs2CO3 (1.03 g, 3.18 mmol) followed by tetrahydropyran-4-yl methanesulfonate (0.47 g, 2.65 mmol). The reaction mixture was stirred at 80 °C for 2 h. After completion, the reaction was quenched with water and extracted with EtOAc. The combined organic layer was washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography (70% EtOAc / n-hexane) to afford 3-nitro-1- tetrahydropyran-4-yl-pyrazole 42-4 (0.25 g).1H NMR (400 MHz, DMSO-d6) δ = 7.74 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 2.2 Hz, 1H), 5.26 - 5.14 (m, 1H), 4.04 - 3.92 (m, 2H), 3.56 - 3.39 (m, 2H), 2.14 - 1.88 (m, 4H); LCMS: [M+H]+= 198.

[0240] Step-3: 1-tetrahydropyran-4-ylpyrazol-3-amine (42-5): To a stirred solution of 3- nitro-1-tetrahydropyran-4-yl-pyrazole 42-4 (0.20 g, 1.01 mmol) in ethanol (8 mL) and water (2 mL) was added ammonium chloride (0.70 g, 5.07 mmol) and iron powder (0.28 g, 5.07 mmol) at RT. The reaction mixture was stirred at 100 °C for 2 h. After completion, reaction mixture was filtered and washed with EtOAc. Filtrate was concentrated under reduced pressure to afford 1-tetrahydropyran-4-ylpyrazol-3-amine 42-5 (0.20 g).1H NMR (400 MHz, DMSO-d6) δ = 7.35 (d, J = 2.2 Hz, 1H), 5.38 (d, J = 2.2 Hz, 1H), 4.53 (br s, 2H), 4.11 - 3.99 (m, 1H), 3.95 - 3.88 (m, 2H), 3.40 (d, J = 3.4, 11.3 Hz, 2H), 1.90 - 1.78 (m, 4H); LCMS: [M+H]+= 168.

[0241] Step-4: 1-[(4S)-8-chlorochroman-4-yl]-3-(1-tetrahydropyran-4-ylpyrazol-3- yl)urea (Example 42): To a stirred solution of 1-tetrahydropyran-4-ylpyrazol-3-amine 42-5 (0.15 g, 0.79 mmol) in MeCN (3 mL) was added pyridine (0.03 mL, 0.45 mmol) followed by N,N'-disuccinimidyl carbonate (0.11 g, 0.45 mmol) at RT. The reaction mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine hydrochloride 42-6 (0.10 g, 0.45 mmol) followed by DIPEA (0.24 mL, 1.36 mmol). The resulting 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 as sticky solid. The product was purified by flash column chromatography (100% EtOAc in n-hexane) to afford Example 42 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 8.73 (s, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 1.0, 7.9 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.15 (br s, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.12 (d, J = 1.6 Hz, 1H), 4.96 - 4.91 (m, 1H), 4.42 - 4.36 (m, 1H), 4.27 - 4.17 (m, 2H), 3.93 - 3.87 (m,2H), 3.44 - 3.37 (m, 2H), 2.18 - 2.10 (m, 1H), 2.02 - 1.95 (m, 1H), 1.91 - 1.78 (m, 4H); LCMS: [M+H]+= 377. Example 43: Synthesis of : 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol- 1-yl]benzamide

[0000] Step : et y 3 (3 t opy a o y )be oate ( 33): o a st ed sout o o 3- nitro-1H-pyrazole 43-1 (0.50 g, 4.42 mmol) in MeOH (10 mL) was added (4- methoxycarbonylphenyl)boronic acid 43-2 (0.95 g, 5.31 mmol) followed by NaOH (0.35 g, 8.84 mmol) and copper chloride (0.04 g, 0.44 mmol) at RT. The reaction mixture was purged with oxygen gas for 20 min. The reaction was stirred at RT for 12 h. After completion, reaction mixture was concentrated under reduced pressure and was extracted with EtOAc. Organic layer was washed with H2O, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the product. The product was purified by CombiFlash chromatography (25% EtOAc / n-Heptane) to afford methyl 3-(3-nitropyrazol-1-yl)benzoate 43-3 (0.80 g). LCMS: [M+H]+= 248.

[0243] Step-2: methyl 3-(3-aminopyrazol-1-yl)benzoate (43-4): To a stirred solution of iron powder (0.54 g, 9.69 mmol) in THF (12 mL) were added methyl 3-(3-nitropyrazol-1- yl)benzoate 43-3 (0.50 g, 2.02 mmol) and NH4Cl (0.52 g, 9.69 mmol) at RT. The reaction was stirred at 80 °C for 4 h. After completion, reaction mixture was concentrated under reduced pressure and was extracted with EtOAc. Organic layer was washed with H2O, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the product. The product was purified by CombiFlash (25% EtOAc / n-Heptane) to afford methyl 3-(3- aminopyrazol-1-yl)benzoate 43-4 (0.35 g). LCMS: [M+H]+= 218.

[0244] Step-3: methyl 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]benzoate (43-6): To a stirred solution of methyl 3-(3-aminopyrazol-1-yl)benzoate (0.04 g, 0.21 mmol) in MeCN (2 mL) was added pyridine (0.03 mL, 0.43 mmol) followed by bis(2,5- dioxopyrrolidin-1-yl)carbonate (0.05 g, 0.21 mmol). The resulting mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine 43-5 (0.04 g, 0.21 mmol) followed by DIPEA (0.12 mL, 0.65 mmol) and reaction was stirred at 30 °C for 1 h. After completion, reaction mixture was concentrated under reduced pressure and was extracted with EtOAc. Organic layer was washed with H2O, dried over Na2SO4, and evaporated under reduced pressure to get the product. The product was purified by prep-HPLC to afford methyl 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]benzoate 43-6 (0.07 g). LCMS: [M+H]+= 427.

[0245] Step-4: 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]benzoic acid (43-7): To a stirred solution of methyl 3-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]benzoate 43-6 (0.07 g, 0.16 mmol) in methanol (1 mL), THF (4 mL) and water (1 mL) was added LiOH.H2O (0.02 g, 0.49 mmol) at RT. The reaction was stirred at RT for 12 h. After completion, reaction mixture was concentrated and diluted with H2O (2 mL) and pH was adjusted with 2N HCl. Precipitated solid was filtered, dried under reduced pressure to afford 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol- 1-yl]benzoic acid 43-7 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 9.07 - 9.04 (m, 1H), 8.46 - 8.45 (m, 1H), 8.24 - 8.23 (m, 1H), 7.94 - 7.92 (m, 1H), 7.80 - 7.77 (m, 1H), 7.58 - 7.55 (m, 1H), 7.35 - 7.32 (m, 1H), 7.28 - 7.26 (m, 1H), 7.08 - 7.05 (m, 1H), 6.94 - 6.91 (m, 1H), 6.58 - 6.58 (m, 1H), 4.99 - 4.95 (m, 1H), 4.43 - 4.37 (m, 1H), 4.30 - 4.26 (m, 1H), 3.18 - 3.18 (m, 1H), 2.17 - 2.13 (m, 1H), 2.07 - 2.02 (m, 1H); LCMS: [M+H]+= 413.

[0246] Step-5: 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]benzamide (Example 43): To a stirred solution of 3-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]benzoic acid 43-7 (0.07 g, 0.17 mmol) in DMF (1 mL) were added DIPEA ( 0.12 mL, 0.678 mmol), HATU (0.09 g, 0.25mmol) and NH4Cl (0.01 g, 0.25 mmol) maintained at 0 °C. The reaction was stirred at RT for 16 h. After completion, reaction was quenched with H2O, extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to get the product. The product was purified by CombiFlash chromatography (40% EtOAc / n-hexane) to afford Example 43 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.40 (br s, 1H), 8.17 (br s, 1H), 8.04 (br s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.34 (d, J = 7.8 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.58 (br s, 1H), 4.97 (d, J = 5.9 Hz, 1H), 4.39 (d, J = 6.8 Hz, 1H), 4.30 - 4.24 (m, 1H), 2.21 - 2.14 (m, 1H), 2.08 - 2.01 (m, 1H); LCMS: [M+H]+= 412. Example 44: Synthesis of 1-[1-[4-[2-(dimethylamino)ethoxy]phenyl]pyrazol-3-yl]-3- [(4S)-8-chlorochroman-4-yl]urea

[0247] Step-1: (4-(3-nitropyrazol-1-yl)phenol (44-3): To a stirred solution of 3-nitro-1H- pyrazole 44-1 (1.00 g, 8.84 mmol) in DCM (30 mL) were added (4-hydroxyphenyl)boronicacid 44-2 (1.83 g, 13.3 mmol), pyridine (2.3 mL, 26.5 mmol) and Cu(OAc)2(3.20 g, 17.7 mmol) and the reaction mixture was stirred at RT for 12 h under presence of oxygen. After completion, reaction was quenched with H2O, extracted with DCM. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by CombiFlash (30% EtOAc / hexane) to afford (4-(3- nitropyrazol-1-yl)phenol 44-3 (0.50 g). LCMS: [M+H]+= 206.

[0248] Step-2: (N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenoxy]ethanamine (44-5): To a stirred solution of 4-(3-nitropyrazol-1-yl)phenol 44-3 (0.30 g, 1.46 mmol) in DMF (10 mL) were added Cs2CO3(1.18 g, 3.66 mmol) and 2-bromo-N,N-dimethylethanamine hydrobromide 44-4 (0.50 g, 2.19 mmol) and the reaction mixture was stirred at 100 °C for 12 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 / Hexane) to afford (N,N- dimethyl-2-[4-(3-nitropyrazol-1-yl)phenoxy]ethanamine 44-5 (0.13 g). LCMS: [M+H]+= 277.

[0249] Step-3: (1-[4-[2-(dimethylamino)ethoxy]phenyl]pyrazol-3-amine (44-6): To a stirred solution of N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenoxy]ethanamine 44-5 (0.04 g, 0.145 mmol) in ethanol (4 mL) and water (2 mL) was added iron powder (0.02 g, 0.43 mmol) followed by NH4Cl (0.02 g, 0.43 mmol) and the reaction mixture was stirred at 100 °C for 12 h. After completion, reaction mixture was filtered to remove unwanted solid material. Reaction mixture was diluted 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 / hexane) to afford (1-[4-[2- (dimethylamino)ethoxy]phenyl]pyrazol-3-amine 44-6 (0.02 g). LCMS: [M+H]+= 217.

[0250] Step-4: (1-[1-[4-[2-(dimethylamino)ethoxy]phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 44): To a stirred solution of 1-[4-[2- (dimethylamino)ethoxy]phenyl]pyrazol-3-amine 44-6 (0.09 g, 0.38 mmol) in MeCN (2 mL) was added pyridine (0.06 mL, 0.76 mmol) followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (DSC) (0.09 g, 0.38 mmol). Resulting reaction mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine 44-7 (0.07 g, 0.381 mmol) followed by DIPEA (0.28 mL, 1.52 mmol) and reaction mixture was stirred at 30 °C for 1 h. Aftercompletion, 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. Product was purified by CombiFlash (40% EtOAc / hexane) to afford Example 44 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 8.95 (s, 1H), 8.22 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H), 7.34 (dd, J = 1.4, 7.9 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 9.1 Hz, 2H), 6.92 (t, J = 7.8 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 4.96 (q, J = 6.3 Hz, 1H), 4.43 - 4.38 (m, 1H), 4.29 - 4.24 (m, 1H), 4.05 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 5.8 Hz, 2H), 2.21 (s, 6H), 2.16 - 2.12 (m, 1H), 2.07 - 2.01 (m, 1H); LCMS: [M+H]+= 456.Example 45: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1,1-difluoro-2 (methylamino)ethyl] phenyl] pyrazol-3-yl]urea

[0251] Step-1: 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]acetic (45-3): To a stirred solution of 3-nitro-1H-pyrazole 45-2 (1.00 g, 8.84 mmol) in DMSO (15 mL) were added K2CO3(3.66 g, 26.5 mmol), CuI (0.34 g, 1.77 mmol) and L-proline (0.20 g, 1.77 mmol) followed by ethyl 2-(4-bromophenyl)-2,2-difluoro-acetate 45-1 (2.96 g, 10.6 mmol) and the reaction mixture was stirred for at 120 °C for 12 h. After completion, reaction mixture wasdiluted with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Product was purified by reverse phase chromatography to afford 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]acetic acid 45- 3 (0.80 g). LCMS: [M-H] - = 282.

[0252] Step-2: 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanol (45-4): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]acetic acid 45-3 (0.50 g, 1.77 mmol) in THF (5 mL) was added BH3. DMS (0.13 g, 3.53 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 2 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 to afford 2,2-difluoro-2-[4-(3-nitropyrazol-1- yl)phenyl] ethanol 45-4 (0.25 g) which was used directly for the next reaction. LCMS: [M+H]+= 270.

[0253] Step-3: [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate (45-5): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1- yl)phenyl]ethanol 45-4 (0.80 g, 2.97 mmol) in DCM (10 mL) was added triethylamine (1.20 mL, 8.92 mmol) followed by 4-toluenesulfonyl chloride (0.85 g, 4.46 mmol) drop wise at 25 °C. The reaction mixture was stirred for 25 °C at 16 h. After completion, reaction mixture was concentrated under reduced pressure and product was purified by CombiFlash (30-50% EtOAc / heptane) to afford [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate 45-5 (0.90 g). LCMS: [M+H]+= 424.

[0254] Step-4: 1-[4-(2-azido-1,1-difluoro-ethyl)phenyl]-3-nitro-pyrazole (45-6): To a stirred solution of [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate 45-5 (1.10 g, 2.60 mmol) in DMF (5 mL) was added NaN3 (0.33 g, 5.20 mmol). Resulting reaction mixture was stirred at 100 °C for 16 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. Organic layer was concentrated under reduced pressure to affored 1-[4-(2-azido-1,1-difluoro-ethyl)phenyl]-3- nitro-pyrazole 45-6 (0.45 g). LCMS: [M+H]+= 295.

[0255] Step-5: 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine (45-7): To a stirred solution of 1-[4-(2-azido-1,1-difluoro-ethyl)phenyl]-3-nitro-pyrazole 45-6 (0.75 g, 2.55 mmol) in THF (3 mL) and water (1 mL) was added TPP (0.13 g, 5.10 mmol) at 0 °C. Resulting mixture was stirred at RT for 4 h. After completion, reaction mixture was dilutedwith H2O and extracted with EtOAc. Organic layer was concentrated under reduced pressure. Product was purified by reverse phase chromatography to afford 2,2-difluoro-2-[4-(3- nitropyrazol-1-yl)phenyl]ethanamine 45-7 (0.35 g); LCMS: [M+H]+= 269.

[0256] Step-6: tert-butyl N-[2,2-difluoro-2-[4-(3-nitropyrazol-1- yl)phenyl]ethyl]carbamate (45-8): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol- 1-yl)phenyl]ethanamine 45-7 (0.25 g, 0.93 mmol) in DCM (5 mL) were added DIPEA (0.50 mL, 2.80 mmol) and DMAP (0.01 g, 0.09 mmol) followed by (Boc)2O (0.26 mL, 1.12 mmol). The reaction mixture was stirred for 25 °C at 16 h. After completion, the reaction mixture was quenched with ice cold H2O, extracted with DCM and washed with brine solution. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The product residue was purified with CombiFlash to obtain tert- butyl N-[2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 45-8 (0.21 g).1H NMR (400 MHz, DMSO-d6) δ = 8.87 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 2.4 Hz, 2H), 3.77 - 3.59 (m, 2H), 1.31 (s, 9H).

[0257] Step-7: tert-butyl N-[2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]-N- methylcarbamate (45-9): To a stirred solution of tert-butyl N-[2,2-difluoro-2-[4-(3- nitropyrazol-1-yl)phenyl]ethyl]carbamate 45-8 (0.20 g, 0.54 mmol) in DMF (3 mL) were added NaH (60% in mineral oil, 0.02 g, 0.81 mmol) and methyl iodide (0.10 mL, 1.63 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 16 h. After completion, the reaction mixture was quenched with ice cold water, extracted with EtOAc. Organic layer was washed with brine solution, dried over anhydrous Na2SO4and evaporated under reduced pressure. The product residue was purified with CombiFlash (50% EtOAc / n-heptane) to obtain tert- butyl N-[2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]-N-methylcarbamate 45-9 (0.15 g). LCMS: [M+H]+= 283.

[0258] Step-8: tert-butyl N-[2-[4-(3-aminopyrazol-1-yl)phenyl]-2,2-difluoro-ethyl]-N- methylcarbamate (45-10): To a stirred solution of tert-butyl N-[2,2-difluoro-2-[4-(3- nitropyrazol-1-yl)phenyl]ethyl]-N-methylcarbamate 45-9 (0.10 g, 0.26 mmol) in ethanol (5 mL) and water (2 mL) were added NH4Cl (0.07 g, 1.31 mmol) and Fe powder (0.07 g, 1.31 mmol). The reaction was stirred at 80 °C for 4 h. After completion, reaction mixture was filtered and filtrate was concentrated under reduced pressure. Residue obtained was then dissolved in EtOAc and filtered. Filtrate was concentrated under reduced pressure andpurified by reverse phase column chromatography to afford tert-butyl N-[2-[4-(3- aminopyrazol-1-yl)phenyl]-2,2-difluoro-ethyl]-N-methyl-carbamate (0.07 g). LCMS: [M+H]+= 353.

[0259] Step-9: tert-butyl N-[2-[4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-2,2-difluoro-ethyl]-N-methylcarbamate (45- 12): To a stirred solution of tert-butyl N-[2-[4-(3-aminopyrazol-1-yl)phenyl]-2,2-difluoro- ethyl]-N-methylcarbamate 45-10 (0.07 g, 0.19 mmol) in MeCN (3 mL) was added pyridine (0.02 mL, 0.29 mmol) followed by N,N′-disuccinimidyl carbonate (0.05 g, 0.19 mmol). Resulting mixture was stirred at RT for 15 min. To this was added (4S)-8-chlorochroman-4- amine hydrochloride 45-11 (0.04 g, 0.19 mmol) followed by DIPEA (0.10 mL, 0.59 mmol) and reaction mixture was stirred at RT for 3 h. After completion, the reaction was quenched with ice cold water, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated under reduced pressure. The product was purified by column chromatography (5% MeOH / DCM) to afford tert-butyl N-[2,2-difluoro-2-[4-[3- [[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]ethyl]-N- methylcarbamate 45-12 (0.09 g). LCMS: [M+H]+= 562.

[0260] Step-10: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1,1-difluoro-2- (methylamino)ethyl]phenyl]pyrazol-3-yl]urea (Example 45): To a stirred solution of tert- butyl N-[2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-2,2- difluoro-ethyl]-N-methylcarbamate 45-12 (0.10 g, 0.17 mmol) in DCM (3 mL) was added 4M HCl in dioxane (0.20 mL, 0.89 mmol) at 0 °C. Resulting mixture was stirred at RT for 4 h. After completion, the reaction mixture was concentrated under reduced pressure. The product was purified by prep-HPLC to afford Example 45 (0.04 g).1H NMR (400 MHz, DMSO-d6) δ = 9.07 (s, 1H), 8.42 (d, J = 2.6 Hz, 1H), 8.18 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.34 (dd, J = 1.4, 7.9 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.13 (d, J = 7.4 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 4.97 (q, J = 6.3 Hz, 1H), 4.46 - 4.34 (m, 1H), 4.31 - 4.26 (m, 1H), 3.20 - 3.15 (m, 2H), 2.28 (s, 3H), 2.21 - 2.12 (m, 1H), 2.10 - 2.00 (m, 1H); LCMS: [M+H]+= 462.Example 46: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-[2- (methylamino)ethoxy]phenyl]pyrazol-3-yl]urea

[0261] Step-1: 1-(3-methoxyphenyl)-3-nitro-pyrazole (46-3): A stirred solution of (3- methoxyphenyl)boronic acid 46-1 (1.34 g, 8.84 mmol), 3-nitro-1H-pyrazole 46-2 (1.00 g, 8.84 mmol) and NaOH (0.42 g, 10.6 mmol) in methanol (15 mL) was purged with oxygen for 30 min. To this was added CuCl2 (0.24 g, 1.77 mmol) and the reaction mixture was further purged with oxygen for 20 min. The reaction mixture was stirred at 80 °C for 12 h. After completion, the reaction mixture was filtered through Celite. The filtrate was concentrated, the residue was diluted with 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 column chromatography to afford 1-(3- methoxyphenyl)-3-nitro-pyrazole 46-3 (0.80 g).1H NMR (400 MHz, DMSO-d6) δ = 8.81 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 4.9 Hz, 2H), 7.47 (s, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.08 - 7.02 (m, 1H), 3.86 (s, 3H); LCMS: [M+H]+= 220.

[0262] Step-2: 3-(3-nitropyrazol-1-yl)phenol (46-4): A solution of 1-(3-methoxyphenyl)-3- nitro-pyrazole 46-3 (1.00 g, 4.56 mmol) in hydrobromic acid (47-48% in aqueous solution, 15 mL) was stirred at 0 °C and the reaction mixture was stirred at 100 °C for 12 h. After completion of reaction, the reaction mixture was poured into cold water. The aqueous layer was extracted with DCM. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 3-(3-nitropyrazol-1-yl)phenol 46-4 (0.3 g). LCMS: [M-H]- = 205.

[0263] Step-3: N,N-dimethyl-2-[3-(3-nitropyrazol-1-yl)phenoxy]ethanamine (46-6): To a stirred solution of 3-(3-nitropyrazol-1-yl)phenol 46-4 (1.00 g, 4.87 mmol) in DMF (10 mL) was added sodium hydride (60% in mineral oil, 0.39 g, 9.75 mmol) at 0 °C followed by 2- chloro-N,N-dimethyl-ethanamine hydrochloride 46-5 (1.40 g, 9.75 mmol) and the reaction mixture was stirred at RT for 2 h. After completion of reaction, the reaction mixture was poured into cold water. The aqueous layer was extracted with DCM. Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford N,N- dimethyl-2-[3-(3-nitropyrazol-1-yl)phenoxy]ethanamine 46-6 (0.50 g).

[0264] Step-4: 1-[3-[2-(dimethylamino)ethoxy]phenyl]pyrazol-3-amine (46-7): To a stirred solution of N,N-dimethyl-2-[3-(3-nitropyrazol-1-yl)phenoxy]ethanamine 46-6 (0.80 g, 2.90 mmol) in ethanol (6 mL) was added iron powder (1.29 g, 23.2 mmol) followed by ammonium chloride (1.24 g, 23.2 mmol) in water (2 mL). The reaction mixture was stirred at 80 °C for 2 h. After completion, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. Product was diluted with H2O and extracted with 20% MeOH / DCM, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by CombiFlash (10% MeOH / DCM) to afford 1-[3-[2- (dimethylamino)ethoxy]phenyl]pyrazol-3-amine 46-7 (0.70 g). LCMS: [M+H]+= 247.

[0265] Step-5: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-[2-(methylamino)ethoxy]phenyl] pyrazol-3-yl]urea (Example 46): To a stirred solution of 1-[3-[2- (dimethylamino)ethoxy]phenyl]pyrazol-3-amine 46-7 (0.05 g, 0.21 mmol) in MeCN (5 mL) was added pyridine (0.03 mL, 0.43 mmol) at 0 °C followed by N,N′-disuccinimidyl carbonate (0.06 g, 0.23 mmol). Resulting mixture was stirred at RT for 30 min. To this was added (4S)- 8-chlorochroman-4-amine 46-8 (0.04 g, 0.23 mmol) followed by DIPEA (0.16 mL, 0.86 mmol) and reaction was stirred at 30 °C for 2 h. After completion, reaction mixture wasconcentrated under reduced pressure. The product was quenched with H2O and extracted with 10% MeOH / DCM. Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by prep HPLC to afford Example 46 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 9.04 (s, 1H), 8.38 (d, J = 2.5 Hz, 1H), 7.37 - 7.17 (m, 6H), 6.92 (t, J = 7.8 Hz, 1H), 6.80 - 6.77 (m, 1H), 6.49 (d, J = 2.5 Hz, 1H), 4.97 (q, J = 6.3 Hz, 1H), 4.44 - 4.37 (m, 1H), 4.30 - 4.24 (m, 1H), 4.06 (t, J = 5.8 Hz, 2H), 2.64 (t, J = 5.7 Hz, 2H), 2.23 (s, 6H), 2.18 - 2.13 (m, 1H), 2.07 - 1.99 (m, 1H); LCMS: [M+H]+= 456. Example 47 and Example 48: Synthesis of 1-(8-chloro-2-(methoxymethyl)chroman-4- yl)-3-(1-phenyl-1H-pyrazol-3-yl)urea

[0266] Step-1: 8-chlorochromen-4-one (47-3): To a stirred solution of 1-(3-chloro-2- hydroxy-phenyl)ethanone 47-1 (2.00 g, 11.70 mmol) in THF (20 mL) was added ethylformate 47-2 (1.30 g, 17.60 mmol) at 0 °C followed by NaH (60 % in mineral oil, 1.69 g, 70.30 mmol) and the reaction was stirred at RT for 1 h. The reaction mixture was quenched with methanol (3.76 g, 117.00 mmol), concentrated HCl (21.37 g, 0.58 mmol) was added slowly and allowed to stir at RT for 12 h. After completion, the reaction mixture was quenched with NaHCO3and 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 to afford 8-chlorochromen-4-one 47-3 (0.30 g). LCMS: [M+H]+= 181.

[0267] Step-2: 8-chloro-2-(hydroxymethyl)chroman-4-one (47-4): To a stirred solution of 8-chlorochromen-4-one 47-3 (1.00 g, 5.54 mmol) in methanol (10 mL) was added di-tert- butyl peroxide (3.0 mL, 16.60 mmol) at 0 °C. The reaction mixture was stirred at 140 °C in steel bomb for 15 h. Reaction mixture was cooled to RT. After completion, the reaction mixture was evaporated under reduced pressure to afford product. The product was purified by CombiFlash (70 % EtOAc / n-heptane) to afford 8-chloro-2-(hydroxymethyl)chroman-4- one 47-4 (0.50 g).

[0268] Step-3: 8-chloro-2-(methoxymethyl)chroman-4-one (47-5): To a stirred solution of 8-chloro-2-(hydroxymethyl)chroman-4-one 47-4 (2.00 g, 9.41 mmol) in MeCN (20 mL) was added silver carbonate (7.78 g, 28.20 mmol) at 0 °C followed by methyl trifluoromethanesulfonate (5.1 mL, 47.00 mmol). The reaction was stirred at 25 °C for 2 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 evaporated under reduced pressure. The product was purified by CombiFlash to afford 8- chloro-2-(methoxymethyl)chroman-4-one 47-5 (1.10 g). LCMS Purity: [M+H]+= 227.

[0269] Step-4: 8-chloro-2-(methoxymethyl)chroman-4-one (47-6a and 47-6b): After prep- HPLC purification afforded 0.98 g of racemic product, the enantiomers were separated by chiral prep-HPLC purification to afford 8-chloro-2-(methoxymethyl)chroman-4-one 47-6a (0.48 g) and 47-6b 8-chloro-2-(methoxymethyl)chroman-4-one (0.50 g). The absolute stereochemistry of these compounds was not determined.

[0270] 47-6a:1H NMR (400 MHz, DMSO-d6) δ = 7.76 - 7.66 (m, 2H), 7.06 (t, J = 7.8 Hz, 1H), 4.88 - 4.81 (m, 1H), 3.72 - 3.63 (m, 2H), 3.36 (s, 3H), 2.92 (dd, J = 12.2, 17.1 Hz, 1H), 2.72-2.67 (m, 1H); LCMS: [M+H]+= 227.

[0271] 47-6b:1H NMR (400 MHz, DMSO-d6) δ = 7.83 - 7.61 (m, 2H), 7.06 (s, 1H), 4.95 - 4.76 (m, 1H), 3.71 - 3.65 (m, 2H), 3.36 (s, 3H), 2.93 - 2.87 (m, 1H), 2.72-2.67 (m, 1H); LCMS: [M+H]+= 228.

[0272] Step-5: 8-chloro-2-(methoxymethyl)chroman-4-amine (47-7): To a stirred solution of 8-chloro-2-(methoxymethyl)chroman-4-one 47-6a (0.05 g, 0.22 mmol) in methanol (15 mL) was added ammonium acetate (0.25 g, 3.31 mmol) at 0 °C followed by sodium cyanoborohydride (0.04 g, 0.66 mmol) and the reaction mixture was stirred at 80 °C for 16 h. After completion, the reaction mixture was cooled to 0 °C, diluted with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. Then product was dissolved in DCM, was added 4.0M HCl in dioxane to afford 8-chloro-2-(methoxymethyl)chroman-4-amine hydrochloride 47-7 (0.06 g). LCMS: [M+H]+= 228. The absolute stereochemistry of this compound was not determined.

[0273] Step-6: 1-(8-chloro-2-(methoxymethyl)chroman-4-yl)-3-(1-phenyl-1H-pyrazol-3- yl)urea (47-9): To a stirred solution of 1-phenylpyrazol-3-amine 47-8 (0.20 g, 1.26 mmol) in MeCN (15 mL) was added pyridine (0.10 mL, 1.26 mmol) followed by N,N′-disuccinimidyl carbonate (0.32 g, 1.26 mmol). Resulting reaction mixture was stirred at RT for 15 min. Then was added 8-chloro-2-(methoxymethyl)chroman-4-amine 47-7 (0.28 g, 1.26 mmol) followed by DIPEA (0.68 mL, 3.77 mmol) and reaction mixture was stirred at 25 °C for 2 h. After completion, reaction mixture was concentrated under reduced pressure and product was purified by CombiFlash (30-50% EtOAc / n-heptane) to afford 1-(8-chloro-2- (methoxymethyl)chroman-4-yl)-3-(1-phenyl-1H-pyrazol-3-yl)urea 47-9 (0.35 g). LCMS: [M+H]+= 413. The absolute stereochemistry of this compound was not determined.

[0274] Step-7: 1-(8-chloro-2-(methoxymethyl)chroman-4-yl)-3-(1-phenyl-1H-pyrazol-3- yl)urea (Examples 47 and 48): Prep-HPLC afforded 0.08 g of racemic product. The enantiomers were separated by chiral prep-HPLC purification to afford 1-(8-chloro-2- (methoxymethyl)chroman-4-yl)-3-(1-phenyl-1H-pyrazol-3-yl)urea Example 47 (0.08 g) and 1-(8-chloro-2-(methoxymethyl)chroman-4-yl)-3-(1-phenyl-1H-pyrazol-3-yl)urea Example 48 (0.16 g). The absolute stereochemistry of these products was not determined.

[0275] Example 47:1H NMR (400 MHz, DMSO-d6) δ = 8.89 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.45 - 7.37 (m, 3H), 7.31 (d, J = 7.6 Hz, 2H), 7.25 - 7.19 (m,1H), 6.94 (t, J = 7.8 Hz, 1H), 6.50 (d, J = 2.3 Hz, 1H), 4.94 - 4.89 (m, 1H), 4.35 - 4.29 (m, 1H), 3.67 (d, J = 4.6 Hz, 2H), 3.37 (s, 3H), 2.12 (d, J = 14.0 Hz, 1H), 2.01 - 1.89 (m, 1H); LCMS: [M+H]+= 413.

[0276] Example 48:1H NMR (400 MHz, DMSO-d6) δ = 9.19 (s, 1H), 8.36 (d, J = 2.6 Hz, 1H), 7.70 (dd, J = 0.9, 8.6 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 1.1, 7.9 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.91 (t, J = 7.9 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.18 - 5.11 (m, 1H), 4.55 - 4.49 (m, 1H), 3.63 (s, 1H), 3.61 (d, J = 1.4 Hz, 1H), 3.37 (s, 3H), 2.28 - 2.24 (m, 1H), 1.85 - 1.74 (m, 1H). LCMS: [M+H]+= 413.Example 52 and Example 53: Synthesis of 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]- 3-(1-phenylpyrazol-3-yl)urea

[0277] Step-1: ethyl 4-(3-chloro-2-hydroxy-phenyl)-2,4-dioxo-butanoate (49-3): To a stirred solution of 1-(3-chloro-2-hydroxy-phenyl)ethanone 49-1 (8.00 g, 46.90 mmol) in THF (60 mL) was added sodium hydride (60% in mineral oil, 4.50 g, 188.00 mmol) at 0 °C followed by diethyl oxalate 49-2 (16.00 mL, 117.00 mmol). The reaction was stirred at RT for 12 h. After completion, the reaction mixture was quenched with 2N HCl solution andH2O. Aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford ethyl 4-(3-chloro-2-hydroxy-phenyl)-2,4-dioxo-butanoate 49-3 (6.00 g). LCMS: [M-H]- = 269.

[0278] Step-2: ethyl 8-chloro-4-oxo-chromene-2-carboxylate (49-4): To a stirred solution of ethyl 4-(3-chloro-2-hydroxy-phenyl)-2,4-dioxo-butanoate 49-3 (4.00 g, 14.80 mmol) in toluene (35 mL) was added p-toluene sulphonic acid (0.64 g, 3.69 mmol). The reaction mixture was stirred at 120 °C for 12 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 concentrated under reduced pressure. The product was purified by CombiFlash to afford ethyl 8-chloro-4-oxo-chromene-2-carboxylate 49-4 (2.00 g). LCMS: [M+H]+= 253.

[0279] Step-3: 8-chloro-2-(hydroxymethyl)chroman-4-ol (49-5): To a stirred solution of ethyl 8-chloro-4-oxo-chromene-2-carboxylate 49-4 (3.00 g, 11.90 mmol) in methanol (30 mL) was added sodium borohydride (2.25 g, 59.40 mmol) at 0 °C and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was quenched with ice cold H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash to afford 8-chloro-2-(hydroxymethyl) chroman-4-ol 49-5 (2.00 g).

[0280] Step-4: 8-chloro-2-(hydroxymethyl)chroman-4-one (49-6): To a stirred solution of 8-chloro-2-(hydroxymethyl)chroman-4-ol 49-5 (2.00 g, 9.32 mmol) in DCM (20 mL) was added pyridinium chlorochromate (2.01 g, 9.32 mmol) at 0 °C and the reaction mixture was stirred at RT for 3 h. After completion, the reaction mixture was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash to afford 8-chloro-2-(hydroxymethyl)chroman-4-one 49-6 (0.90 g). LCMS: [M- H]- = 213.

[0281] Step-5: 8-chloro-2-(hydroxymethyl)chroman-4-one (49-7a) and 8-chloro-2- (hydroxymethyl)chroman-4-one (49-7b): Chiral prep-HPLC purification of 3 g of racemic 8-chloro-2-(hydroxymethyl)chroman-4-one 49-6 afforded 8-chloro-2-(hydroxymethyl)chroman-4-one (49-7a) (0.45 g) and 8-chloro-2-(hydroxymethyl)chroman-4- one (49-7b) (0.52 g). The absolute stereochemistry of these compounds was not determined.

[0282] 49-7a:1H NMR (400 MHz, DMSO-d6) δ = 7.79 - 7.58 (m, 2H), 7.08 - 7.00 (m, 1H), 5.13 (t, J = 5.6 Hz, 1H), 4.67 (dd, J = 3.7, 12.0 Hz, 1H), 3.77 (br s, 1H), 3.70 (d, J = 4.9 Hz, 1H), 2.93 (dd, J = 12.2, 17.1 Hz, 1H), 2.70 (dd, J = 2.9, 17.1 Hz, 1H).

[0283] 49-7b:1H NMR (400 MHz, DMSO-d6) δ = 7.80 - 7.62 (m, 2H), 7.11 - 6.95 (m, 1H), 5.12 (br s, 1H), 4.74 - 4.60 (m, 1H), 3.77 (d, J = 3.9 Hz, 1H), 3.71 (br s, 1H), 2.93 (dd, J = 12.2, 17.1 Hz, 1H), 2.74 - 2.65 (m, 1H).

[0284] Step-6: [4-amino-8-chloro-chroman-2-yl]methanol (49-8): To a stirred solution of 8-chloro-2-(hydroxymethyl)chroman-4-one 49-7a (0.45 g, 2.12 mmol) in methanol (10 mL) was added ammonium acetate (2.44 g, 31.7 mmol) at 0 °C followed by sodium cyanoborohydride (0.39 g, 6.35 mmol). The reaction mixture was stirred at 80 °C for 16 h. Reaction mixture was cooled to 0 °C, quenched with H2O and pH was adjusted to 13 with 2N NaOH solution. Aqueous layer was extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford [4-amino-8-chloro-chroman-2-yl] methanol (0.30 g). LCMS: [M+H]+= 214. The absolute stereochemistry of this compound was not determined.

[0285] Step-7: [4-amino-8-chloro-chroman-2-yl]methanol hydrochloride (49-9): To a stirred solution of [4-amino-8-chloro-chroman-2-yl]methanol 49-8 (0.30 g, 1.40 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (1.6 mL, 4.21 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was concentrated under reduced pressure. The product was washed with diethyl ether and hexane, dried well to afford [4-amino-8-chloro-chroman-2-yl] methanol hydrochloride 49-9 (0.30 g). LCMS: [M-17]+= 197. The absolute stereochemistry of this compound was not determined.

[0286] Step-8: 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1-phenylpyrazol-3- yl)urea (49-11): To a stirred solution of [4-amino-8-chloro-chroman-2-yl]methanol hydrochloride 49-9 (0.30 g, 1.20 mmol) in MeCN (3 mL) was added pyridine (0.09 mL, 1.20 mmol) followed by N,N′-disuccinimidyl carbonate (0.30 g, 1.20 mmol). Resulting reaction mixture was stirred at RT for 15 min. To this was added 1-phenylpyrazol-3-amine 49-10 (0.19 g, 1.20 mmol) followed by DIPEA (0.86 mL, 4.80 mmol) and reaction mixture wasstirred at 30 °C for 12 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 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1-phenylpyrazol-3- yl)urea 49-11 (0.10 g). LCMS: [M+H]+= 399. The absolute stereochemistry of this compound was not determined.

[0287] 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea (Examples 49 and 50): Chiral prep-HPLC purification of 0.08 g of racemic product afforded 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea, Example 49 (0.01 g) and 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea, Example 50 (0.02 g). The absolute stereochemistry of these products was not determined.

[0288] Example 49:1H NMR (400 MHz, DMSO-d6) δ = 8.90 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.45 - 7.36 (m, 3H), 7.33 - 7.19 (m, 3H), 6.93 (t, J = 7.8 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 5.00 (t, J = 5.6 Hz, 1H), 4.95 - 4.90 (m, 1H), 4.20 - 4.13 (m, 1H), 3.77 - 3.64 (m, 2H), 2.16 (d, J = 14.4 Hz, 1H), 1.98 - 1.89 (m, 1H); LCMS: [M+H]+= 399.

[0289] Example 50:1H NMR (400 MHz, DMSO-d6) δ = 9.18 (s, 1H), 8.36 (d, J = 2.5 Hz, 1H), 7.70 (dd, J = 1.0, 8.6 Hz, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.33 - 7.27 (m, 1H), 7.26 - 7.20 (m, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.90 (t, J = 7.9 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.95 (t, J = 5.7 Hz, 1H), 4.37 - 4.29 (m, 1H), 3.73 - 3.61 (m, 2H), 2.34 - 2.22 (m, 1H), 1.84 - 1.72 (m, 1H); LCMS: [M+H]+= 399. Example 51: Synthesis of 1-[(4S)-8-fluorochroman-4-yl]-3-[1-(3-fluorophenyl) pyrazol- 3-yl]urea

[0290] Step-1: 1-(3-fluorophenyl) pyrazol-3-amine (51-3): To a stirred solution of 1H- pyrazol-3-amine 51-1 (1.00 g, 12.00 mmol), was added Cu2O (0.17 g, 1.20 mmol) followed by KOH (1.35 g, 24.10 mmol) in DMSO (10 mL) under Argon. To this was added 1-fluoro- 3-iodo-benzene 51-2 (4.10 g, 18.10 mmol) and reaction was stirred at 110 °C for 12 h. After completion, the reaction mixture was quenched with H2O, extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by CombiFlash (40% EtOAc / n-heptane) to afford 51-3 (0.31 g).1H NMR (400 MHz, DMSO-d6) δ = 8.18 (d, 1H), 7.51 - 7.38 (m, 3H), 6.92 (t, 1H), 5.78 - 5.74 (m, 1H), 5.15 (s, 2H); LCMS: [M+H]+= 179.

[0291] Step-2: 1-[(4S)-8-fluorochroman-4-yl]-3-[1-(3-fluorophenyl) pyrazol-3-yl]urea (Example 51): To a solution of 1-(3-fluorophenyl) pyrazol-3-amine 51-3 (0.15 g, 0.85 mmol) in DCM (3 mL), was added triphosgene (0.13 g, 0.42 mmol) at 0 °C followed by DIPEA (0.44 mL, 2.54 mmol). The reaction was stirred at RT for 30 min. To this mixture was added (4S)-8-fluorochroman-4-amine 51-4 (0.14 g, 0.85 mmol) and the reaction was stirred at RT for 1 h. After completion, the reaction was quenched with H2O, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product obtained was purified by prep HPLC to afford Example 51 (0.06 g).1H NMR (400 MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.44 - 8.40 (m, 1H), 7.55 - 7.45 (m, 3H), 7.17 - 7.08 (m, 3H), 7.08 - 7.02 (m, 1H), 6.92 - 6.86 (m, 1H), 6.55 (s, 1H), 4.95 (q, 1H), 4.39 - 4.33 (m, 1H), 4.26 - 4.19 (m, 1H), 2.22 - 2.13 (m, 1H), 2.09 - 2.01 (m, 1H); LCMS: [M+H]+= 371.Example 52 and Example 53: Synthesis of 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]- 3-(1-phenylpyrazol-3-yl)urea

[0292] Step-1: [4-amino-8-chloro-chroman-2-yl]methanol (52-2): To a stirred solution of 8-chloro-2-(hydroxymethyl)chroman-4-one 49-7b (0.30 g, 1.41 mmol) in methanol (10 mL) was added ammonium acetate (1.63 g, 21.2 mmol) at 0 °C followed by sodium cyanoborohydride (0.26 g, 4.23 mmol). The reaction was stirred at 80 °C for 16 h. Reaction mixture was cooled to 0 °C, diluted with H2O and pH was adjusted to 13 with 2N NaOH solution. Aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford [4-amino-8-chloro-chroman-2-yl]methanol 52-2 (0.30 g). LCMS: [M+H] + = 214. Theabsolute stereochemistry of this compound was not determined.

[0293] Step-2: [4-amino-8-chloro-chroman-2-yl]methanol hydrochloride (52-3): To a stirred solution of [4-amino-8-chloro-chroman-2-yl]methanol 52-2 (0.30 g, 1.40 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (1.6 mL, 4.21 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was concentrated under reduced pressure. The product was washed with diethyl ether and hexane,dried well to afford [4-amino-8-chloro-chroman-2-yl]methanol hydrochloride 52-3 (0.30 g). LCMS: [M-17]+= 197. The absolute stereochemistry of this compound was not determined.

[0294] Step-3: 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1-phenylpyrazol-3- yl)urea (52-5): To a stirred solution of [4-amino-8-chloro-chroman-2-yl]methanol hydrochloride 52-3 (0.30 g, 1.20 mmol) in MeCN (3 mL) was added pyridine (0.09 mL, 1.20 mmol) followed by N,N′-disuccinimidyl carbonate (0.30 g, 1.20 mmol). Resulting reaction mixture was stirred at RT for 15 min. To this was added 1-phenylpyrazol-3-amine 52-4 (0.19 g, 1.20 mmol) followed by DIPEA (0.86 mL, 4.80 mmol) and reaction mixture was stirred at 30 °C for 12 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 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea 52-5 (0.10 g). LCMS: [M+H]+= 399. The absolute stereochemistry of this compound was not determined.

[0295] Chiral separation: 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1- phenylpyrazol-3-yl)urea (Examples 52 and 53): Chiral prep-HPLC purification of 0.10 g of racemic product 52-5 afforded 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1- phenylpyrazol-3-yl)urea Example 52 (0.01 g) and 1-[8-chloro-2-(hydroxymethyl)chroman-4- yl]-3-(1-phenylpyrazol-3-yl)urea Example 53 (0.02 g). The absolute stereochemistry of these products was not determined.

[0296] Example 52:1H NMR (400 MHz, DMSO-d6) δ = 8.90 (s, 1H), 8.35 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.47 - 7.35 (m, 3H), 7.32 - 7.19 (m, 3H), 6.92 (t, J = 7.8 Hz, 1H), 6.50 (d, J = 2.3 Hz, 1H), 5.00 (t, J = 5.6 Hz, 1H), 4.95 - 4.89 (m, 1H), 4.22 - 4.13 (m, 1H), 3.76 - 3.66 (m, 2H), 2.16 (d, J = 14.3 Hz, 1H), 1.96 - 1.89 (m, 1H); LCMS: [M+H]+= 399.

[0297] Example 53:1H NMR (400 MHz, DMSO-d6) δ = 9.18 (s, 1H), 8.36 (d, J = 2.5 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.44 (t, J = 8.0 Hz, 2H), 7.33 - 7.29 (m, 1H), 7.26 - 7.20 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.90 (t, J = 7.9 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.18 - 5.08 (m, 1H), 4.95 (t, J = 5.6 Hz, 1H), 4.37 - 4.29 (m, 1H), 3.70 - 3.64 (m, 2H), 2.35 - 2.24 (m, 1H), 1.84 - 1.69 (m, 1H); LCMS: [M+H]+= 399.Example 54: Synthesis of 2-(3-amino-1H-pyrazol-1-yl)-N,N-dimethylacetamide

[02] p , y ( py y ) ( ) f 3- nitro-1H-pyrazole 54-1 (0.50 g, 4.42 mmol) in DMF (8 mL) was added K2CO3(1.22 g, 8.84 mmol) at 0 °C followed by 2-chloro-N,N-dimethyl-acetamide 54-2 (0.91 mL, 8.84 mmol). The reaction was stirred at 90 °C for 16 h. After completion, the reaction was quenched with H2O, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product obtained was purified by CombiFlash (40% EtOAc / n-hexane) to afford 54-3 (0.70 g).1H NMR (400 MHz, DMSO-d6) δ = 7.92 (s, 1H), 7.06 (s, 1H), 5.32 (s, 2H), 3.03 (s, 3H), 2.86 (s, 3H); LCMS: [M+H]+= 199.

[0299] Step-2: 2-(3-amino-1H-pyrazol-1-yl)-N,N-dimethylacetamide (54-4): To a stirred solution of 54-3 (0.50 g, 2.01 mmol) in MeOH (10 mL), 10% Pd / C (0.25 g) was added and the reaction mixture was stirred under 50 psi hydrogen pressure at RT for 2 h. After completion, the reaction mixture was filtered through Celite bed. The filtrate was concentrated under reduced pressure to yield 54-4, which was used directly for the next reaction.1H NMR (400 MHz, DMSO-d6) δ = 7.11 (br s, 1H), 5.28 (br s, 1H), 4.60 (s, 2H), 3.03 (s, 2H), 2.84 (s, 3H), 2.67 (s, 3H).

[0300] Step-3: (S)- N,N-dimethyl-2-(3-(3-(8-methylchroman-4-yl) ureido)-1H-pyrazol-1- yl) acetamide (Example 54): To a stirred solution of 54-4 (0.15 g, 0.89 mmol) in ACN (5mL) was added pyridine (0.07 mL, 0.89 mmol) followed by N,N'-disuccinimidyl carbonate (0.23 g, 0.89 mmol). The resulting mixture was stirred at RT for 30 min. To this mixture was added (4S)-8-methylchroman-4-amine 54-5 (0.15 g, 0.89 mmol) followed by DIPEA (0.50 mL, 2.68 mmol) and reaction was stirred at RT for 1 h. After completion, reaction mixture was concentrated under reduced pressure and product obtained was dissolved in ethyl acetate. The organic layer was washed with H2O, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by prep HPLC to afford Example 54 (0.11 g).1H NMR (400 MHz, DMSO-d6) δ = 8.56 (br s, 1H), 7.45 (s, 1H), 7.05 (dd, 3H), 6.78 (t, 1H), 6.15 (br s, 1H), 4.88 (s, 3H), 4.32 - 4.26 (m, 1H), 4.17 - 4.11 (m, 1H), 2.95 (s, 3H), 2.80 (s, 3H), 2.11 (s, 4H), 1.97 - 1.90 (m, 1H); LCMS: [M+H]+= 358. Example 55: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4- [(dimethylamino)methyl]phenyl]pyrazol-3-yl]ureastirred solution of [4-(3-nitropyrazol-1-yl)phenyl]methanol 55-1 (0.18 g, 0.84 mmol) in DCM (2 mL) was added DIPEA (0.59 mL, 3.38 mmol) followed by methanesulfonyl chloride (0.09 mL, 1.27 mmol) at -78oC and the reaction mixture was stirred at -78 °C for 2 h. After completion, the reaction mixture was quenched with NH4Cl solution and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash (5% MeOH / DCM) to afford [4-(3-nitropyrazol-1-yl)phenyl]methyl methane sulfonate 55-2 (0.30 g).

[0302] Step-2: N,N-dimethyl-1-[4-(3-nitropyrazol-1-yl)phenyl]methanamine (55-3): To a stirred solution of [4-(3-nitropyrazol-1-yl)phenyl]methyl methanesulfonate 55-2 (0.33 g, 1.11 mmol) in DMF (3 mL) was added K2CO3(0.94 g, 4.44 mmol) followed by N-methylmethanamine hydrochloride (0.22 g, 2.78 mmol) and the reaction mixture was stirred at 70 °C for 12 h. After completion, the reaction mixture was quenched with H2O, extracted in EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash to afford N,N- dimethyl-1-[4-(3-nitropyrazol-1-yl)phenyl]methanamine 55-3 (0.27 g). LCMS: [M+H]+= 247.

[0303] Step-3: 1-[4-[(dimethylamino)methyl]phenyl]pyrazol-3-amine (55-4): A mixture of N,N-dimethyl-1-[4-(3-nitropyrazol-1-yl)phenyl]methanamine 55-3 (0.25 g, 1.02 mmol) and Pd / C (0.10 g) in methanol (3.5 mL) was stirred at 50 psi H2pressure for 8 h. After completion, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to afford 1-[4-[(dimethylamino)methyl]phenyl]pyrazol-3-amine 55-4 (0.15 g). LCMS: [M+H]+= 217.

[0304] Step-4: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4- [(dimethylamino)methyl]phenyl]pyrazol-3-yl]urea (Example 55): To a stirred solution of 1-[4-[(dimethylamino)methyl]phenyl]pyrazol-3-amine 55-4 (0.14 g, 0.67 mmol) in MeCN (5 mL) was added pyridine (0.11 mL, 1.34 mmol) followed by N,N′-disuccinimidyl carbonate (0.17 g, 0.67 mmol). Resulting reaction mixture was stirred at 27 °C for 30 min. To this was added (4S)-8-chlorochroman-4-amine hydrochloride 55-5 (0.16 g, 0.73 mmol) followed by DIPEA (0.35 mL, 2.01 mmol) and reaction mixture was stirred at 27 °C for 1 h. After completion, the 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 Na2SO4 and concentrated under reduced pressure. Product was purified by CombiFlash (5% DCM / MeOH) to afford Example 55 (0.04 g).1H NMR (400 MHz, DMSO- d6) δ = 9.00 (s, 1H), 8.32 (d, J = 2.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.38 - 7.25 (m, 4H), 7.18 (d, J = 7.4 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.96 (q, J = 6.3 Hz, 1H), 4.44 - 4.37 (m, 1H), 4.31 - 4.25 (m, 1H), 3.38 (s, 3H), 2.14 (s, 6H), 2.08 - 2.00 (m, 1H); LCMS: [M+H]+= 426.Example 56: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methoxypyrimidin-5- yl)pyrazol-3-yl]ureaof 1H-pyrazol-3-amine 56-2 (0.44 g, 5.29 mmol) in DMF (5 mL) was added Cs2CO3 (3.45 g, 10.60 mmol) followed by 5-bromo-2-methoxy-pyrimidine 56-1 (1.00 g, 5.29 mmol) and CuBr (0.07 g, 0.52 mmol) at RT. The reaction was stirred at 120 °C for 16 h. After completion, the reaction mixture was diluted with ice-water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (40% EtOAc / n-Heptane) to afford 1-(2-methoxypyrimidin-5-yl)pyrazol-3-amine 56-3 (0.90 g).1H NMR (400 MHz, DMSO-d6) δ = 8.8 (s, 2H), 8.1 (s, 1H), 5.7 (s, 1H), 5.15 (s, 2H), 3.89 (s, 3H); LCMS: [M+H]+= 192.

[0306] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methoxypyrimidin-5-yl)pyrazol-3- yl]urea (Example 56): To a stirred solution of 1-(2-methoxypyrimidin-5-yl)pyrazol-3-amine 56-3 (0.10 g, 0.52 mmol) in MeCN (5 mL) was added pyridine (0.04 mL, 0.52 mmol) followed by N,N′-disuccinimidyl carbonate (0.13 g, 0.52 mmol) at RT. The resulting reaction mixture was stirred at RT for 30 min. To this was added (S)-8-chlorochroman-4-amine; hydrochloride 56-4 (0.11 g, 0.523 mmol) followed by DIPEA (0.27 mL, 1.57 mmol) at RT and the reaction mixture was stirred at RT for 12 h. After completion, reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with H2O, brine solution and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by prep-HPLC to afford Example 56 (0.005 g).1H NMR (400 MHz, DMSO-d6) δ = 9.09 - 9.05 (m, 1H), 8.95 - 8.92 (m, 2H), 8.37 - 8.34 (m, 1H), 7.33 (dd, J = 1.4, 7.8 Hz, 1H), 7.25 (d, J = 7.1 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.93 - 6.88 (m, 1H), 6.62 - 6.58 (m, 1H), 5.01 - 4.94 (m, 1H), 4.43 - 4.35 (m, 1H), 4.30 - 4.23 (m, 1H), 3.94 (s, 3H), 2.19 - 2.11 (m, 1H), 2.07 - 1.99 (m, 1H); LCMS: [M+H]+= 401.Example 57: Synthesis of 5-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]-N-methyl-pyridine-2-carboxamide:[ ] p y py ( ) f methyl 5-bromopyridine-2-carboxylate 57-1 (0.40 g, 1.85 mmol) in methanol (3 mL) was added methylamine (25% solution in MeOH, 9.30 mL, 9.26 mmol) at 0 °C. The resulting mixture was stirred at 80 °C for 8 h. After completion, reaction was concentrated under reduced pressure to get the product which was washed with diethyl ether and pentane to afford 5-bromo-N-methyl-pyridine-2-carboxamide 57-2 (0.35 g). LCMS: [M+H]+= 217.

[0308] Step-2: 5-(3-aminopyrazol-1-yl)-N-methyl-pyridine-2-carboxamide (57-4): To a stirred solution of 5-bromo-N-methyl-pyridine-2-carboxamide 57-2 (0.30 g, 1.40 mmol) in DMF (7 mL) were added 1H-pyrazol-3-amine 57-3 (0.14 g, 1.67 mmol) and Cs2CO3(0.90 g, 2.79 mmol) followed by copper (II) bromide (0.06 g, 0.27 mmol) at RT. The reaction was stirred in microwave at 180 °C for 30 min. After completion, reaction was quenched with ice cold water , extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the product which was purified by CombiFlash column (5% MeOH / DCM) to afford 5-(3-aminopyrazol-1-yl)-N- methyl-pyridine-2-carboxamide 57-4 (0.13 g). LCMS: [M+H]+= 218.

[0309] Step-3: 5-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-N- methyl-pyridine-2-carboxamide (Example 57): To a stirred solution of product 5-(3-aminopyrazol-1-yl)-N-methyl-pyridine-2-carboxamide 57-4 (0.10 g, 0.46 mmol) in MeCN (5 mL) was added pyridine (0.03 g, 0.46 mmol) followed by N,N′-disuccinimidyl carbonate (0.11 g, 0.46 mmol) at RT. The reaction mixture was stirred at RT for 15 min. To this was added (4S)-8-chlorochroman-4-amine 57-5 (0.08 g, 0.46 mmol) followed by DIPEA (0.24 mL, 1.38 mmol) at RT. 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 to get the product which was purified by prep-HPLC to afford Example 57 (0.005 g).1H NMR (400 MHz, DMSO-d6) δ = 9.17 - 9.15 (m, 1H), 9.00 - 8.99 (m, 1H), 8.74 - 8.69 (m, 1H), 8.60 - 8.57 (m, 1H), 8.25 - 8.20 (m, 1H), 8.10 - 8.06 (m, 1H), 7.35 - 7.32 (m, 1H), 7.27 - 7.24 (m, 1H), 7.07 - 7.04 (m, 1H), 6.94 - 6.89 (m, 1H), 6.69 - 6.66 (m, 1H), 5.01 - 4.94 (m, 1H), 4.43 - 4.37 (m, 1H), 4.32 - 4.23 (m, 1H), 2.84 - 2.81 (m, 3H), 2.21 - 2.12 (m, 1H), 2.08 - 2.00 (m, 1H); LCMS: [M+H]+= 427. Example 58: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-methylsulfonylphenyl) pyrazol-3-yl]urea

[0030] Step : (3 et y su o y p e y ) py a o 3 a e (583): o a st ed so ut o o 1H-pyrazol-3-amine 58-1 (0.20 g, 2.41 mmol) and 1-bromo-3-methylsulfonyl-benzene 58-2 (0.62 g, 2.65 mmol) in DMSO (3 mL) was added cesium carbonate (1.57 g, 4.81 mmol) followed by copper (II) bromide (0.06 g, 0.48 mmol). Reaction mixture was stirred at 150 °C for 30 min in microwave. 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 column (30% EtOAc / hexane) to afford 1-(3-methylsulfonylphenyl) pyrazol-3-amine 58-3. LCMS: [M+H]+= 238.

[0311] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-methylsulf yl]urea (Example 58): To a stirred solution of 1-(3-methylsulfonylphenyl) pyrazol-3-amine 58-3 (0.18 g, 0.75 mmol) in MeCN (5 mL) was added pyridine (0.12 mL, 1.52 mmol) followed by N,N′-disuccinimidyl carbonate (0.21 g, 0.83 mmol). Resulting reaction mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine 58-4 (0.16 g, 0.91 mmol) followed by DIPEA (0.54 mL, 3.03 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 58 (0.04 g).1H NMR (400 MHz, DMSO-d6) δ = 9.14 - 9.11 (m, 1H), 8.55 - 8.53 (m, 1H), 7.99 - 7.91 (m, 4H), 7.35 - 7.32 (m, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.12 - 7.07 (m, 1H), 6.95 - 6.90 (m, 1H), 6.68 - 6.65 (m, 1H), 5.00 - 4.94 (m, 1H), 4.44 - 4.37 (m, 1H), 4.30 - 4.24 (m, 1H), 3.24 - 3.21 (m, 3H), 2.20 - 2.12 (m, 1H), 2.09 - 2.00 (m, 1H); LCMS: [M+H]+= 447. Example 59: Synthesis of 4-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino]pyrazol- 1-yl]-2-fluoro-N-methyl-benzamide

[0312] Step-1: 4-(3-aminopyrazol-1-yl)-2-fluoro-N-methyl-benzamide (59-3): To a stirred solution of 1H-pyrazol-3-amine 59-2 (0.25 g, 3.01 mmol) in DMF (4 mL) were added 2- fluoro-4-iodo-N-methyl-benzamide 59-1 (1.25 g, 4.51 mmol) and CuBr2(0.13 g, 0.60 mmol) followed by cesium carbonate (0.98 g, 3.01 mmol). The reaction mixture was stirred under microwave at 180 °C for 30 min. After completion, reaction mixture was quenched with H2O,extracted with EtOAc. Combined organic layer was washed with H2O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash (0.05% formic acid in H2O:ACN) to afford 4-(3-aminopyrazol-1-yl)-2-fluoro-N- methyl-benzamide 59-3 (0.12 g).1H NMR (400 MHz, DMSO-d6) δ = 8.26 - 8.22 (m, 1H), 8.10 - 8.05 (m, 1H), 7.71 - 7.65 (m, 1H), 7.55 - 7.49 (m, 2H), 5.83 - 5.80 (m, 1H), 5.27 - 5.23 (m, 2H), 2.79 - 2.76 (m, 3H); LCMS: [M+H]+= 235.

[0313] Step-2: 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-2- fluoro-N-methyl-benzamide (Example 59): To a stirred solution of N,N′-disuccinimidyl carbonate (0.13 g, 0.51 mmol) in CH3CN (5 mL) was added pyridine (0.04 mL, 0.51 mmol) and 4-(3-aminopyrazol-1-yl)-2-fluoro-N-methyl-benzamide 59-3 (0.12 g, 0.51 mmol) at RT. Reaction mixture was stirred for 45 min. To this was added, DIPEA (0.25 mL, 1.54 mmol) followed by (4S)-8-chlorochroman-4-amine hydrochloride 59-5 (0.11 g, 0.51 mmol) and reaction mixture was stirred at 25 °C for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The product obtained was diluted with EtOAc and organic layer was washed with 2N HCl, water followed by brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by prep-HPLC to afford Example 59 (0.006 g).1H NMR (400 MHz, DMSO-d6) δ = 9.10 - 9.05 (m, 1H), 8.49 - 8.46 (m, 1H), 8.18 - 8.12 (m, 1H), 7.71 (t, J = 8.3 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.36 - 7.32 (m, 1H), 7.28 - 7.25 (m, 1H), 7.15 - 7.12 (m, 1H), 6.95 - 6.90 (m, 1H), 6.63 - 6.59 (m, 1H), 4.98 - 4.94 (m, 1H), 4.43 - 4.37 (m, 1H), 4.30 - 4.24 (m, 1H), 2.78 (d, J = 4.4 Hz, 3H), 2.16 (dd, J = 5.4, 8.3 Hz, 1H), 2.08 - 2.02 (m, 1H); LCMS: [M+H]+= 444. Example 60: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methyl-4-pyridyl) pyrazol-3-yl]urea

[0314] Step-1: 1-(2-methylpyridin-4-yl)-1H-pyrazol-3-amine (60-3): To a stirred solution of 1H-pyrazol-3-amine 60-1 (0.50 g, 6.02 mmol) in DMF (5 mL) was added copper (I) bromide (0.17 g, 1.20 mmol) and cesium carbonate (2.94 g, 9.03 mmol) followed by 4- bromo-2-methyl-pyridine 60-2 (1.14 g, 6.62 mmol). The reaction was stirred at 110 °C for 16 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 column chromatography (5% MeOH / DCM) to afford 60-3 (0.45 g).1H NMR (400 MHz, CD3OD-d4) δ = 8.31 (d, 1H), 8.12 (d, 1H), 7.52 (d, 1H), 7.46 - 7.43 (m, 1H), 5.97 (d, 1H), 2.53 (s, 3H); LCMS: [M+H]+= 175.

[0315] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methyl-4-pyridyl) pyrazol-3- yl]urea (Example 60): To a stirred solution of 60-3 (0.10 g, 0.57 mmol) in MeCN (5 mL) was added pyridine (0.05 g, 0.69 mmol) followed by N,N’-disuccinimidyl carbonate (0.16 g, 0.63 mmol). The resulting mixture was stirred at RT for 30 min. To this was added (4S)-8- chlorochroman-4-amine 60-4 (0.12 g, 0.63 mmol) followed by DIPEA (0.30 mL, 1.72 mmol) and the reaction was stirred at 30 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the product obtained was dissolved in EtOAc. The organic layer was washed with 2N HCl solution, water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by preparative HPLC to afford Example 60 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 9.29 (br s, 1H), 8.71 (br s, 1H), 8.67 - 8.66 (m, 1H), 7.92 - 7.89 (m, 2H), 7.35 (d, 1H), 7.26 (d, 1H), 7.17 (d, 1H), 6.95 - 6.90 (m, 1H), 6.89 - 6.86 (m, 1H), 5.01 - 4.95 (m, 1H), 4.40 (d, 1H), 4.28 (t, 1H), 2.63 (s, 3H), 2.22 - 2.12 (m, 1H), 2.10 - 2.01 (m, 1H); LCMS: [M+H]+= 384. Example 61: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3,4-dimethoxyphenyl) pyrazol-3-yl]urea

[0316] Step-1: 1-(3,4-dimethoxyphenyl) pyrazol-3-amine (61-3): To a stirred solution of 1H-pyrazol-3-amine 61-1 (0.40 g, 4.81 mmol) in DMSO (8 mL) was added potassium hydroxide (0.27 g, 4.81 mmol) and copper (II) oxide (0.07 g, 0.48 mmol) followed by 4-iodo- 1,2-dimethoxy-benzene 61-2 (1.91 g, 7.22 mmol) at RT. The reaction mixture was degassed under argon atmosphere for 30 min and stirred at 120 °C for 12 h. After completion, the reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4and evaporated under reduced pressure to afford a product. The product was purified by CombiFlash column chromatography to afford 61-3 (0.30 g).1H NMR (400 MHz, DMSO-d6) δ = 8.07 (br s, 1H), 7.27 (br s, 1H), 7.12 (d, 1H), 6.95 (d, 1H), 5.71 (s, 1H), 4.99 (br s, 2H), 3.83 (s, 3H), 3.78 (s, 3H); LCMS: [M+H]+= 220.

[0317] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3,4-dimethoxyphenyl) pyrazol-3- yl]urea (Example 61): To a stirred solution of product (4S)-8-chlorochroman-4-amine 61-4 (0.06 g, 0.30 mmol) in MeCN (3 mL) was added pyridine (0.024 mL, 0.30 mmol) followed by N,N′-disuccinimidyl carbonate (0.04 mL, 0.30 mmol) at RT and the reaction mixture was stirred at RT for 15 min. To this solution was added 1-(3,4-dimethoxyphenyl) pyrazol-3- amine 61-3 (0.07 g, 0.30 mmol) followed by DIPEA (0.16 mL, 0.89 mmol). The resulting reaction was stirred at RT for 4 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 concentrated under reduced pressure to obtain a product. The product was purified by preparative HPLC to afford Example 61 (0.06 g).1H NMR (400 MHz, DMSO-d6) δ = 9.04 (br s, 1H), 8.28 (br s, 1H), 7.35 - 7.33 (m, 1H), 7.27 - 7.15 (m, 4H), 6,99 - 6.97 (m, 1H), 6.93 - 6.89 (m, 1H), 6.42 (br s, 1H), 4.98 - 4.96 (m, 1H), 4.40 - 4.39 (m, 1H), 4.27 - 4.23 (m, 1H), 3.75 (d, 6H), 2.15 - 2.14 (m, 1H), 2.03 - 2.00 (m, 1H); LCMS: [M+H]+= 429.Example 62: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-pyridyl) pyrazol-3- yl]urea -3-amine 62-1 (0.50 g, 6.02 mmol) in DMSO (6 mL) was added KOH (0.68 g, 12.00 mmol), Cu2O (0.09 g, 0.60 mmol) followed by 4-iodopyridine 62-2 (1.48 g, 7.22 mmol) at RT. The reaction mixture was degassed under argon atmosphere for 20 min and stirred at 120 °C for 12 h. After completion, the reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a product. The product was purified using CombiFlash column (55% EtOAc / n-Heptane). The solid obtained was triturated with Et2O to afford 62-3 (0.60 g).1H NMR (400 MHz, DMSO-d6) δ = 8.49 - 8.45 (m, 2H), 8.31 (d, 1H), 7.58 (d, 2H), 5.86 (d, 1H), 5.34 (s, 2H); LCMS: [M+H]+= 161.

[0319] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-pyridyl) pyrazol-3-yl]urea (Example 62): To a stirred solution of 1-(4-pyridyl) pyrazol-3-amine 62-3 (0.50 g, 0.31 mmol) in MeCN (5 mL) was added pyridine (0.025 mL, 0.31 mmol) followed by N,N'- disuccinimidyl carbonate (0.08 g, 0.31 mmol). The resulting mixture was stirred at RT for 30 min. To this solution was added (4S)-8-chlorochroman-4-amine hydrochloride 62-4 (0.07 g, 0.31 mmol) followed by DIPEA (0.16 mL, 0.94 mmol) and the reaction was stirred at 30 °C for 4 h. After completion, the reaction mixture was concentrated under reduced pressure and the product obtained was dissolved in EtOAc. The organic layer was washed with 2N HCl solution, H2O and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified by CombiFlash chromatography (40% EtOAc / hexane) to afford Example 62 (0.02 g).1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.59 - 8.53 (m, 3H), 7.66 (d, 2H), 7.35 (d, 1H), 7.26 (d, 1H), 7.10 (d, 1H), 6.96 - 6.90 (m, 1H), 6.67 (s, 1H), 5.01 - 4.93 (m, 1H), 4.43 - 4.37 (m, 1H), 4.27 (t, 1H), 2.19 - 2.05 (m, 2H); LCMS: [M+H]+= 370.Example 63: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-pyridyl) pyrazol-3- yl]urea 3-1(0.05 g, 0.24 mmol) in MeCN (3 mL) was added pyridine (0.02 mL, 0.24 mmol) and N,N’- disuccinimidyl carbonate (0.06 g, 0.24 mmol) at 0 °C. The reaction mixture was stirred at RT for 10 min. To this solution was added DIPEA (0.13 mL, 0.72 mmol), (4S)-8-chlorochroman- 4-amine hydrochloride 63-2 (0.05 g, 0.24 mmol) and the reaction was stirred at RT for 4 h. After completion of the reaction, the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4and evaporated under reduced pressure to obtain a product. The product was purified by preparative HPLC to afford Example 63 (0.04 g).1H NMR (400 MHz, DMSO-d6) δ = 9.07 (s, 1H), 8.37 (br s, 1H), 7.41 (d, 1H), 7.34 (d, 1H), 7.26 (d, 2H), 7.22 (br s, 1H), 7.14 (d, 1H), 6.91 (t, 1H), 6.50 (br s, 1H), 4.97 (d, 1H), 4.44 - 4.38 (m, 1H), 4.30 - 4.22 (m, 1H), 3.84 (s, 3H), 2.21 - 2.12 (m, 1H), 2.08 - 2.00 (m, 1H); LCMS: [M+H]+= 417.Example 64: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(1-(3-fluoro-4- methoxyphenyl)-1H-pyrazol-3-yl)ureasolution of 3-nitro-1H-pyrazole 64-1 (0.70 g, 6.19 mmol) in MeOH (10 mL) was added (3- fluoro-4-methoxy-phenyl) boronic acid 64-2 (1.05 g, 6.19 mmol) followed by sodium hydroxide (0.74 g, 18.6 mmol). The reaction mixture was purged under oxygen atmosphere for 30 min. To this solution was added copper (II) chloride (0.42 g, 3.10 mmol) and the reaction mixture was further purged under oxygen atmosphere for 20 min. The reaction was stirred at 80 °C for 16 h. After completion, the reaction mixture was filtered through Celite. The filtrate was concentrated and diluted with cold water 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 column chromatography (40% EtOAc / hexane) to afford 64-3 (1.00 g).1H NMR (400 MHz, DMSO-d6) δ = 8.73 (d, 1H), 7.88 (dd, 1H), 7.73 (d, 1H), 7.41 - 7.33 (m, 2H), 3.92 (s, 3H); LCMS: [M+H]+= 238.

[0322] Step-2: 1-(3-fluoro-4-methoxy-phenyl) pyrazol-3-amine (64-4): To a solution of 64-3 (0.50 g, 2.11 mmol) in ethanol (3 mL) and water (2 mL) was added iron powder (0.59 g, 10.5 mmol) followed by NH4Cl (0.50 g, 9.36 mmol). The reaction was stirred at 70 °C for 3 h. After completion, the reaction mixture was filtered and washed with EtOAc. The organic layer was washed with H2O, brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was purified by CombiFlash chromatography (40%EtOAc / Heptane) to afford 64-4 (0.27 g).1H NMR (400 MHz, DMSO-d6) δ = 8.07 (d, 1H), 7.52 (dd, 1H), 7.43 - 7.39 (m, 1H), 7.18 (t, 1H), 5.70 (d, 1H), 5.06 - 4.98 (m, 2H), 3.83 (s, 3H); LCMS: [M+H]+= 208.

[0323] Step-3: (S)-1-(8-chlorochroman-4-yl)-3-(1-(3-fluoro-4-methoxyphenyl)-1H- pyrazol-3-yl)urea (Example 64): To a stirred solution of N,N′-disuccinimidyl carbonate (0.12 g, 0.48 mmol) in CH3CN (2 mL) was added pyridine (0.038 mL, 0.48 mmol) and (4S)- 8-chlorochroman-4-amine 64-5 (0.09 g, 0.48 mmol) at RT. The reaction mixture was stirred for 45 min. To this solution was added DIPEA (0.18 g, 1.45 mmol) followed by 64-4 (0.10 g, 0.48 mmol) and the reaction was stirred for 30 min at RT. After completion, the reaction mixture was concentrated under reduced pressure. The product obtained was diluted with EtOAc and the organic layer was washed with 2N HCL and water followed by brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The product obtained was purified by preparative HPLC to afford Example 64 (0.04 g).1H NMR (400 MHz, DMSO-d6) δ = 8.98 (br s, 1H), 8.29 (br s, 1H), 7.60 - 7.54 (m, 1H), 7.48 - 7.43 (m, 1H), 7.36 - 7.32 (m, 1H), 7.28 - 7.22 (m, 2H), 7.14 - 7.10 (m, 1H), 6.95 - 6.90 (m, 1H), 6.52 - 6.47 (m, 1H), 4.99 - 4.94 (m, 1H), 4.43 - 4.37 (m, 1H), 4.30 - 4.24 (m, 1H), 3.88 - 3.85 (m, 3H), 2.20 - 2.11 (m, 1H), 2.08 - 2.00 (m, 1H); LCMS: [M+H]+= 417.Example 65: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-(1-tetrahydropyran-4- ylpyrazol-3-yl)ureastirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate 65-1 (0.16 g, 0.79 mmol) in DCM (5 mL) at 0 °C was added triethylamine (0.33 mL, 2.38 mmol). To this was added methanesulfonyl chloride (0.1 mL, 1.19 mmol) slowly dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was quenched with aqueous NH4Cl and extracted with DCM. The combined organic layer was washed with H2O and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to afford tert- butyl 4-methylsulfonyloxypiperidine-1-carboxylate 65-2 (0.20 g).1H NMR (400 MHz, DMSO-d6) δ = 4.83 (t, J = 3.9, 8.2 Hz, 1H), 3.65 - 3.56 (m, 2H), 3.25 - 3.12 (m, 5H), 1.97 - 1.85 (m, 2H), 1.68 - 1.54 (m, 2H), 1.40 (s, 9H); LCMS (m / z); [M+NH4]+= 297.

[0325] Step-2: tert-butyl 4-(3-nitropyrazol-1-yl)piperidine-1-carboxylate (65-4): To a stirred solution of 3-nitro-1H-pyrazole 65-3 (1.00 g, 8.84 mmol) in DMF (10 mL) was added Cs2CO3 (4.32 g, 13.30 mmol) followed by tert-butyl 4-methylsulfonyloxypiperidine-1- carboxylate 65-2 (2.47 g, 8.84 mmol) at RT. The reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction was quenched with 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 column chromatography (70% EtOAc / n-hexane) to afford tert-butyl 4-(3-nitropyrazol-1-yl)piperidine-1-carboxylate 65-4 (0.95 g).1H NMR (400 MHz, DMSO-d6) = 8.13 (d, J = 2.0 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 4.63 - 4.43 (m, 1H), 4.06 (d, J = 11.7 Hz, 2H), 3.06 - 2.73 (s, 2H), 2.05 (d, J = 11.7 Hz, 2H), 1.79 (d, J = 4.2, 12.1 Hz, 2H), 1.41 (s, 9H); LCMS (m / z): [M+H]+= 241.

[0326] Step-3: tert-butyl 4-(3-aminopyrazol-1-yl)piperidine-1-carboxylate (65-5): To a stirred solution of tert-butyl 4-(3-nitropyrazol-1-yl)piperidine-1-carboxylate 65-4 (0.50 g, 1.69 mmol) in EtOH (5 mL) and water (3 mL) was added ammonium chloride (0.45 g, 8.44 mmol) followed by iron powder (0.47 g, 8.44 mmol) at RT. The reaction mixture was stirred at 90 °C for 2 h. After completion, reaction mixture was filtered and washed with EtOAc. Filtrate was concentrated under reduced pressure to afford tert-butyl 4-(3-aminopyrazol-1- yl)piperidine-1-carboxylate 65-5 (0.40 g). LCMS (m / z): [M+H]+= 267.

[0327] Step-4: tert-butyl 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]piperidine-1-carboxylate (65-7): To a stirred solution of tert-butyl 4-(3-aminopyrazol-1- yl)piperidine-1-carboxylate 65-5 (0.20 g, 0.75 mmol) in DCM (5 mL) was added triphosgene (0.15 g, 0.52 mmol) at RT. The reaction mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine; hydrochloride 65-6 (0.16 g, 0.75 mmol) followed by DIPEA (0.39 mL, 2.25 mmol). The reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was quenched with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by flash column chromatography (10% MeOH / DCM) to afford tert-butyl 4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]piperidine-1-carboxylate 65-7 (0.20 g). LCMS: [M+H]+= 476.

[0328] Step-5: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-piperidyl)pyrazol-3-yl]urea (Example 65): To a stirred solution of tert-butyl 4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]piperidine-1-carboxylate 65-7 (0.40 g, 0.84 mmol) in DCM (4 mL) was added TFA (0.45 mL, 5.88 mmol) at 0 °C. The reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure. The product was purified by prep-HPLC to afford Example 65 (0.04 g).1H NMR (400 MHz,DMSO-d6) δ = 8.72 - 8.67 (m, 1H), 7.57 - 7.52 (m, 1H), 7.33 - 7.29 (m, 1H), 7.25 - 7.10 (m, 2H), 6.93 - 6.87 (m, 1H), 6.12 - 6.09 (m, 1H), 4.96 - 4.90 (m, 1H), 4.42 - 4.36 (m, 1H), 4.28 - 4.21 (m, 1H), 3.99 (dd, J = 4.2, 7.4, 11.3 Hz, 1H), 3.00 (d, J = 12.5 Hz, 2H), 2.59 - 2.52 (m, 2H), 2.18 - 2.10 (m, 1H), 2.02 - 1.95 (m, 1H), 1.89 - 1.83 (m, 2H), 1.71 - 1.61 (m, 2H); LCMS: [M+H]+= 376. Example 66: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[1-(2-hydroxyethyl)-4- piperidyl]pyrazol-3-yl]ureapiperidyl]pyrazol-3-yl]urea (Example 66): To a stirred solution of 1-[(4S)-8- chlorochroman-4-yl]-3-[1-(4-piperidyl)pyrazol-3-yl]urea Example 65 (0.15 g, 0.39 mmol) in THF (3 mL) was added triethylamine (0.17 mL, 1.20 mmol) followed by 2-bromoethanol (0.10 g, 0.79 mmol) at RT. The reaction mixture was stirred at 70 °C for 5 h. After completion, reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4andconcentrated under reduced pressure to obtain product. The product was purified by prep HPLC to afford Example 66 (0.01 g).1H NMR (400 MHz, DMSO-d6) δ = 8.69 - 8.66 (m, 1H), 7.58 - 7.55 (m, 1H), 7.34 - 7.29 (m, 1H), 7.24 - 7.14 (m, 2H), 6.93 - 6.88 (m, 1H), 6.12 - 6.09 (m, 1H), 4.96 - 4.90 (m, 1H), 4.42 - 4.36 (m, 2H), 4.27 - 4.21 (m, 1H), 3.95 - 3.89 (m, 1H), 3.51 - 3.47 (m, 2H), 2.90 (d, J = 10.6 Hz, 2H), 2.43 - 2.38 (m, 2H), 2.18 - 2.07 (m, 3H), 2.01 - 1.96 (m, 1H), 1.90 - 1.79 (m, 4H); LCMS: [M+H]+= 420.Example 67: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-pyridyl) pyrazol-3- yl]ureapyrazol-3-amine 67-1 (0.05 g, 0.60 mmol) in DMSO (0.5 mL) was added KOH (0.07 g, 1.20 mmol), copper (II) oxide (0.01 g, 0.06 mmol) followed by 3-iodopyridine 67-2 (0.19 g, 0.90 mmol) at RT. The reaction mixture was degassed under argon atmosphere for 20 min. Then, the reaction mixture was stirred at 120 °C for 12 h. After completion, the reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4and evaporated under reduced pressure to obtain a product. The product was purified using CombiFlash chromatography (55% EtOAc / n-heptane). The solid obtained was triturated using Et2O to afford 67-3 (0.07 g).1H NMR (400 MHz, DMSO-d6) δ = 8.92 (br s, 1H), 8.32 (d, 1H), 8.23 (br s, 1H), 7.99 (d, 1H), 7.42 (dd, 1H), 5.80 (br s, 1H), 5.19 (br s, 2H); LCMS: [M+H]+= 161.

[0331] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-pyridyl) pyrazol-3-yl]urea (Example 67): To a stirred solution of 67-3 (0.75 g, 0.47 mmol) in MeCN (2 mL) was added pyridine (0.08 mL, 0.94 mmol) followed by N,N′-disuccinimidyl carbonate (0.12 g, 0.47 mmol) at RT and the reaction mixture was stirred at RT for 45 min. To this solution was added (4S)-8-chlorochroman-4-amine 67-4 (0.09 g, 0.47 mmol) followed by DIPEA (0.35 mL, 1.87 mmol). The resulting reaction mixture was stirred at RT for 4 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 a product. The product was purified by preparative HPLC to afford Example 67 (0.09 g).1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 1H), 8.97 (br s, 1H), 8.46 - 8.42 (m, 2H), 8.06 (d, 1H), 7.48 (dd, 1H), 7.34 (d, 1H), 7.27 (d, 1H), 7.08 (d, 1H), 6.96 - 6.90 (m, 1H), 6.61 (d, 1H), 4.97 (d, 1H), 4.44 - 4.37 (m, 1H), 4.28 (d, 1H), 2.20 - 2.05 (m, 2H); LCMS: [M+H]+= 370.Example 68: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3,4-difluorophenyl) pyrazol-3-yl]urea- pyrazol-3-amine 68-1 (0.50 g, 5.90 mmol) in DMSO (5 mL) was added KOH (0.42 g, 7.31 mmol), Cu2O (0.05 g, 0.35 mmol) followed by 1,2-difluoro-4-iodo-benzene 68-2 (0.86 mL, 8.85 mmol) at RT. The reaction mixture was degassed under argon atmosphere for 30 min and stirred at 120 °C for 14 h. The reaction was dissolved in ice cold water and extracted with ethyl acetate. The organic layer was washed with ice cold brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by CombiFlash column chromatography (30% EtOAc / n-heptane) to afford 68-3 (0.40 g).1H NMR (400 MHz, DMSO-d6) δ = 8.15 (d, 1H), 7.69 (dd, 1H), 7.47 (d, 2H), 5.76 (d, 1H), 5.14 (br s, 2H); LCMS: [M+H]+= 196.

[0333] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3,4-difluorophenyl) pyrazol-3- yl]urea (Example 68): To a stirred solution of 68-3 (0.11 g, 0.51 mmol) in MeCN (4 mL) was added N,N′-disuccinimidyl carbonate (0.13 g, 0.51 mmol) followed by pyridine (0.04 mL, 0.51 mmol). The resulting reaction mixture was stirred at RT for 20 min. To this solution was added DIPEA (0.27 mL, 1.54 mmol) followed by (4S)-8-chlorochroman-4-amine 68-4 (0.10 g, 0.51 mmol) and the reaction was stirred at 30 °C for 3 h. After completion, the reaction mixture was concentrated under reduced pressure and the product obtained was dissolved in EtOAc. The organic layer was washed with 2N HCl solution, H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by CombiFlash column chromatography (30% EtOAc / hexane) to afford Example 68 (0.03 g).1H NMR (400 MHz, DMSO-d6) δ = 9.01 (s, 1H), 8.37 (br s, 1H), 7.76 (dd, 1H), 7.56 - 7.50 (m, 2H), 7.36 - 7.30 (m, 1H), 7.29 - 7.25 (m, 1H), 7.10 (d, 1H), 6.94 - 6.88 (m, 1H), 6.59 - 6.54 (m, 1H), 4.96 (d, 1H), 4.43 - 4.36 (m, 1H), 4.30 - 4.23 (m, 1H), 2.20 - 2.11 (m, 1H), 2.08 - 2.00 (m, 1H); LCMS: [M+H]+= 405.Example 69: Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)-2-fluoro-phenyl]pyrazol-3- yl]-3-[(4S)-8-chlorochroman-4-yl]urea

[0033] Step : ( b o o 3 uo o p e y ) et y p opa e t e (69 ): o a st ed solution of 2-(4-bromo-3-fluoro-phenyl)acetonitrile 69-1 (5.00 g, 23.36 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 2.80 g, 116.81 mmol) at 0 °C and the reaction mixture was stirred for 1 h. To this was added MeI (14.55 mL, 233.61 mmol) and stirred at 25 °C for 2 h. After completion, 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 was purified by CombiFlash to afford 2-(4-bromo-3- fluoro-phenyl)-2-methyl-propanenitrile 69-2 (4.00 g).

[0335] Step-2: 2-[4-(3-aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl-propanenitrile (69- 4): To a stirred solution of 1H-pyrazol-3-amine 69-3 (0.15 g, 1.81 mmol) in DMF (5 mL) was added 2-(4-bromo-3-fluoro-phenyl)-2-methyl-propanenitrile 69-2 (0.43 g, 1.81 mmol) followed by potassium carbonate (0.49 g, 3.61 mmol). The reaction mixture was purged with argon for 20 min and then added trans-N,N'-dimethylcyclohexane-1,2-diamine (0.05 g, 0.36mmol) followed by copper (I) bromide (0.10 g, 0.72 mmol). The reaction mixture was purged with argon for 10 min. The reaction mixture was stirred at 120 °C for 12 h on microwave irradiation. After completion, the reaction mixture was cooled to RT and filtered through Celite. The filtrate was diluted with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by CombiFlash chromatography (30-40% EtOAc / heptane) to afford 2- [4-(3-aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl-propanenitrile 69-4 (0.23 g).1H NMR (400 MHz, DMSO-d6) δ = 7.86 (br s, 1H), 7.78 (t, J = 8.6 Hz, 1H), 7.52 (d, J = 13.6 Hz, 1H), 7.46 – 7.37 (m, 1H), 5.80 (d, J = 2.2 Hz, 1H), 5.16 (s, 2H), 1.70 (s, 6H); LCMS: [M+H]+= 245.

[0336] Step-3: 2-[4-(3-aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl-propanamide (69- 5): To a stirred solution of 2-[4-(3-aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl- propanenitrile 69-4 (0.50 g, 2.05 mmol) in ethanol (4 mL) was added potassium carbonate (0.56 g, 4.09 mmol) in water (2 mL) followed by 30% H2O2 (0.13 g, 4.09 mmol). Reaction mixture was stirred at 25 °C for 12 h. After completion, reaction mixture was diluted with H2O, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product obtained was triturated with n- heptane to afford 2-[4-(3-aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl-propanamide 69-5 (0.03 g).1H NMR (400 MHz, DMSO-d6) δ = 7.82 (t, J = 2.5 Hz, 1H), 7.66 (t, J = 8.8 Hz, 1H), 7.29 – 7.18 (m, 2H), 6.97 (d, J = 13.2 Hz, 2H), 5.76 (d, J = 2.4 Hz, 1H), 5.12 (s, 2H), 1.51 – 1.41 (m, 6H): LCMS: [M+H]+= 263.

[0337] Step-4: 2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-3- fluoro-phenyl]-2-methyl-propanamide (69-7): To a stirred solution of 2-[4-(3- aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl-propanamide 69-5 (0.40 g, 1.53 mmol) in MeCN (8 mL) was added N,N′-disuccinimidyl carbonate (0.39 g, 1.53 mmol) followed by pyridine (0.12 mL, 1.53 mmol). Resulting mixture was stirred at RT for 45 min. To this reaction mixture was added (4S)-8-chlorochroman-4-amine hydrochloride 69-6 (0.40 g, 1.83 mmol) followed by N,N-diisopropylethylamine (0.80 mL, 4.58 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 solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by CombiFlash chromatography (30-40% EtOAc / heptane) to afford 2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-3-fluoro-phenyl]-2-methyl-propanamide 69-7 (0.50 g).1H NMR (400 MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.01 (br s, 1H), 7.58 (t, J = 8.3 Hz, 1H), 7.34 – 7.18 (m, 4H), 7.09 (d, J = 6.8 Hz, 1H), 7.01 – 6.85 (m, 3H), 6.54 (br s, 1H), 4.96 (d, J = 5.9 Hz, 1H), 4.37 (d, J = 6.8 Hz, 1H), 4.29 – 4.18 (m, 1H), 2.13 (d, J = 4.9 Hz, 1H), 2.01 (d, J = 4.4 Hz, 1H), 1.44 (s, 6H); LCMS: [M+H]+= 472.

[0338] Step-5: 1-[1-[4-(1-amino-1-methyl-ethyl)-2-fluoro-phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 69): To a stirred solution of 2-[4-[3-[[(4S)-8- chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-3-fluoro-phenyl]-2-methyl-propanamide 69-7 (0.30 g, 0.63 mmol) in MeCN (2 mL) and water (8 mL) was added potassium hydroxide (0.16 g, 2.86 mmol) followed by 1,3-dibromo-5,5-dimethylhydantoin (0.09 g, 0.31 mmol) and reaction mixture was stirred at RT for 12 h. After completion, sodium sulfite (0.01 g, 0.06 mmol) was added to the reaction mixture and stirred for 15 min. To this was added EtOAc and tripotassium phosphate (0.14 g, 0.69 mmol) for liquid separation, aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The product obtained was purified by prep HPLC to afford Example 69 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 1H), 8.29 (s, 1H), 8.03 (t, J = 2.4 Hz, 1H), 7.65 - 7.52 (m, 2H), 7.42 (dd, J = 1.9, 8.5 Hz, 1H), 7.33 (dd, J = 1.3, 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 5.01 - 4.94 (m, 1H), 4.43 - 4.36 (m, 1H), 4.30 - 4.23 (m, 1H), 2.21 - 2.12 (m, 1H), 2.06 - 2.01 (m, 1H), 1.44 (s, 6H); LCMS: [M+H]+= 444. Example 70: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2- methylsulfonylphenyl)pyrazol-3-yl]urea

[0339] Step-1: 1-(2-methylsulfonylphenyl)pyrazol-3-amine (70-3): To a stirred solution of 1-bromo-2-methylsulfonyl-benzene 70-2 (0.50 g, 2.13 mmol) in DMSO (10 mL) were added 1H-pyrazol-3-amine 70-1 (0.21 g, 2.55 mmol) and Cs2CO3(1.38 g, 4.25 mmol) followed by copper (II) bromide (0.09 g, 0.42 mmol) at RT. The reaction mixture was stirred in microwave at 180 °C for 30 min. After completion, the reaction was quenched with water and extracted with DCM. The combined organic layer was washed with H2O and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by column chromatography (5% MeOH / DCM) to afford 1-(2-methylsulfonylphenyl)pyrazol- 3-amine 70-3 (0.15 g). LCMS: [M+H]+= 238.

[0340] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methylsulfonylphenyl)pyrazol-3- yl]urea (Example 70): To a stirred solution of 1-(2-methylsulfonylphenyl)pyrazol-3-amine 70-3 (0.10 g, 0.42 mmol) in MeCN (5 mL) was added pyridine (0.03 g, 0.42 mmol) followed by N,N′-disuccinimidyl carbonate (0.10 g, 0.42 mmol) at RT. The reaction mixture was stirred at RT for 15 min. To this was added (S)-8-chlorochroman-4-amine 70-4 (0.07 g, 0.42 mmol) followed by DIPEA (0.22 mL, 1.26 mmol) at RT. 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 as sticky solid. The product was purified by prep-HPLC to afford Example 70 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 8.92 - 8.90 (m, 1H), 8.12 - 8.10 (m, 1H), 7.94 (s, 1H), 7.89 - 7.85 (m, 1H), 7.75 - 7.72 (m, 1H), 7.61 - 7.59 (m, 1H), 7.36 - 7.33 (m, 1H), 7.28 - 7.25 (m, 1H), 6.97 - 6.92 (m, 2H), 6.61 - 6.59 (m, 1H), 5.02 - 4.97 (m, 1H), 4.43 - 4.39 (m, 1H), 4.29 - 4.25 (m, 1H), 3.31 (s, 3H), 2.20 - 2.14 (m, 1H), 2.04 (dd, J = 3.4, 6.8, 10.4 Hz, 1H); LCMS (m / z) [M+H]+= 447. Example 71: Synthesis of 1-[(4S)-5-fluorochroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea

[0341] Step-1: To a stirred solution of 1-phenylpyrazol-3-amine 71-1 (0.10 g, 0.59 mmol) in MeCN (3 mL) was added pyridine (0.05 mL, 0.59 mmol) followed by N,N′-disuccinimidyl carbonate (0.15 g, 0.59 mmol) at RT. The reaction mixture was stirred at RT for 15 min. To this solution was added (4S)-5-fluorochroman-4-amine 71-2 (0.10 g, 0.59 mmol) followed by DIPEA (0.67 mL, 3.65 mmol). The resulting reaction mixture was stirred at RT for 12 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 obtain the product. The product was purified by preparative HPLC to afford Example 71 (0.08 g).1H NMR (400 MHz, DMSO-d6) δ = 8.81 (br s, 1H), 8.34 (br s, 1H), 7.63 - 7.60 (m, 2H), 7.41 (t, 2H), 7.30 - 7.20 (m, 3H), 6.79 - 6.71 (m, 2H), 6.51 (br s, 1H), 5.02 (br s, 1H), 4.35 (d, 1H), 4.10 - 4.02 (m, 1H), 2.10 - 1.97 (m, 2H);19FNMR (376 MHz, CDCl3) δ = -112.4; LCMS: [M+H]+= 353. Example 72: Synthesis of 1-[1-[5-(1-amino-1-methyl-ethyl)-2-pyridyl]pyrazol-3-yl]-3- [(4S)-8-chlorochroman-4-yl]urea

[0342] Step-1: 2-(6-chloro-3-pyridyl) propan-2-amine (72-2): To a stirred suspension of anhydrous cerium (III) chloride (7.36 g, 29.9 mmol) in THF (40 mL) was added methyl lithium (1.6 M in diethyl ether) (19.00 mL, 29.9 mmol) at -78 °C and the reaction mixture was stirred at same temperature for 30 min. To the resulting reaction mixture was added 6- chloropyridine-3-carbonitrile 72-1 (1.38 g, 9.96 mmol) in THF (10 mL) and stirred while bringing the temperature to RT in the span of 4 h. Further to this was added aqueous ammonia at -78 °C and stirred at RT for 30 min. After completion, the reaction mixture was filtered through Celite bed and filtrate was concentrated under reduced pressure to afford 2- (6-chloro-3-pyridyl) propan-2-amine 72-2 (1.20 g) which was used directly for the next reaction.1H NMR (400 MHz, DMSO-d6) δ = 8.55 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 2.4, 8.3 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 2.01 (br s, 2H), 1.37 (s, 6H); LCMS: [M+H]+= 171.

[0343] Step-2: tert-butyl (2-(6-chloropyridin-3-yl)propan-2-yl)carbamate (72-3): To a stirred solution of 2-(6-chloro-3-pyridyl) propan-2-amine 72-2 (1.00 g, 5.86 mmol) in THF (10 mL) was added triethylamine (1.6 mL, 11.7 mmol) followed by BOC anhydride (1.6 mL, 7.03 mmol) and stirred at RT for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. Product obtained was purified by flash column chromatography (0-50 % EtOAc / n-heptane) to afford tert-butyl (2-(6-chloropyridin-3- yl)propan-2-yl)carbamate 72-3 (1.20 g).1H NMR (400 MHz, DMSO-d6) δ = 8.34 (s, 1H), 7.75 (dd, J = 2.7, 8.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.35 (br s, 1H), 1.50 (s, 6H), 1.32 (s, 9H).

[0344] Step-3: 2-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3-yl)propan-2-amine (72-5): To a stirred solution of 3-nitro-1H-pyrazole 72-4 (0.20 g, 1.85 mmol) in DMSO (3 mL) was added tert-butyl (2-(6-chloropyridin-3-yl)propan-2-yl)carbamate 72-3 (0.50 g, 1.85 mmol) followed by tripotassium phosphate (0.78 g, 3.69 mmol) and reaction mixture was degassed with argon for 20 min. To this was added trans-N,N'-dimethylcyclohexane-1,2-diamine (0.10 g, 0.74 mmol) followed by copper (I) iodide (0.07 g, 0.36 mmol) and reaction mixture was further degassed with argon for 10 min. Then the reaction mixture was stirred at 125 °C for 16 h. After completion, the reaction mixture was quenched with ice cold water. Aqueous layer was extracted with EtOAc. Combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 2-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3- yl)propan-2-amine 72-5 (0.90 g). LCMS: [M+H]+= 248.

[0345] Step-4: tert-butyl (2-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3-yl)propan-2- yl)carbamate (72-6): To a stirred solution of 2-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3- yl)propan-2-amine 72-5 (0.90 g, 3.64 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.28 mmol) followed by BOC anhydride (1.0 mL, 4.37 mmol) and the reaction mixture was stirred at RT for 4 h. After completion, the reaction mixture was concentrated under reduced pressure. Product obtained was purified by flash column chromatography to afford tert-butyl (2-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3-yl)propan-2-yl)carbamate 72-6 (0.40 g).1H NMR (400 MHz, DMSO-d6) δ = 8.84 (d, J = 2.4 Hz, 1H), 8.50 (s, 1H), 8.07 - 7.98 (m, 1H), 7.97 - 7.91 (m, 1H), 7.41 (br s, 1H), 7.32 (d, J = 2.9 Hz, 1H), 1.56 (s, 6H), 1.33 (br s, 9H); LCMS: [M+H]+= 348.

[0346] Step-5: tert-butyl N-[1-[6-(3-aminopyrazol-1-yl)-3-pyridyl]-1-methyl-ethyl] carbamate (72-7): To a stirred suspension of tert-butyl (2-(6-(3-nitro-1H-pyrazol-1- yl)pyridin-3-yl)propan-2-yl)carbamate 72-6 (0.40 g, 1.15 mmol) in ethanol (12 mL) and water (3 mL) solvent mixture, was added ammonium chloride (0.30 g, 5.76 mmol) followed by iron powder (0.32 g, 5.76 mmol) and the reaction mixture was stirred at 80 °C for 3 h. After completion, the reaction mixture was filtered. Filtrate was concentrated under reduced pressure. Residue obtained was dissolved in EtOAc and filtered. Filtrate was concentrated under reduced pressure to afford tert-butyl N-[1-[6-(3-aminopyrazol-1-yl)-3-pyridyl]-1- methyl-ethyl] carbamate 72-7 (0.25 g).1H NMR (400 MHz, DMSO-d6) δ = 8.27 (s, 1H), 8.22 (s, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.25 (s, 1H), 5.77 (s, 1H), 5.18 (br s, 2H), 1.52 (s, 6H), 1.32 (s, 9H); LCMS: [M+H]+= 318.

[0347] Step-6: tert-butyl N-[1-methyl-1-[6-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl]-3-pyridyl] ethyl]carbamate (72-9): To a stirred solution of tert-butyl N-[1-[6-(3-aminopyrazol-1-yl)-3-pyridyl]-1-methyl-ethyl] carbamate 72-7 (0.20 g, 0.63 mmol) in MeCN (8 mL) was added pyridine (0.05 mL, 0.63 mmol) followed by N,N′- disuccinimidyl carbonate (0.16 g, 0.63 mmol). Resulting reaction mixture was stirred at RT for 30 min. To this reaction mixture was added (4S)-8-chlorochroman-4-amine hydrochloride 72-8 (0.13 g, 0.63 mmol) followed by N,N-diisopropylethylamine (0.33 mL, 1.89 mmol) and stirred at RT for 4 h. After completion, the reaction mixture was quenched with water and extracted with EtOAc. Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by reverse phase column chromatography (gradient method, 0-100% CAN / H2O) to afford tert-butyl N-[1-methyl-1-[6-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl]-3-pyridyl] ethyl]carbamate 72-9 (0.20 g).1H NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.36 (s, 1H), 7.87 - 7.78 (m, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.40 - 7.23 (m, 3H), 7.16 (d, J = 6.8 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 4.99 (d, J = 5.9 Hz, 1H), 4.48 - 4.36 (m, 1H), 4.34 - 4.24 (m, 1H), 2.24 - 2.13 (m, 1H), 2.12 - 2.03 (m, 1H), 1.54 (s, 6H), 1.35 (s, 9H); LCMS: [M+H]+= 527.

[0348] Step-7: 1-[1-[5-(1-amino-1-methyl-ethyl)-2-pyridyl] pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 72): To a stirred solution of tert-butyl N-[1-methyl-1- [6-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl]-3-pyridyl] ethyl]carbamate 72-9 (0.10 g, .19 mmol) in 1,4-dioxane (1 mL) was added 4 N HCl in dioxane (0.40 mL ) and stirred at RT for 1 h. After completion, reaction mixture was concentrated under reduced pressure and residue was triturated with EtOAc to afford product as off-white solid. Product was purified by prep-HPLC to afford Example 72 (0.05 g).1H NMR (400 MHz, DMSO-d6) δ = 9.17 (s, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.44 (d, J = 2.8 Hz, 1H), 8.30 (s, 1H), 8.05 (dd, J = 2.5, 8.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.34 (dd, J = 1.4, 7.9 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 2.8 Hz, 1H), 4.98 (q, J = 6.3 Hz, 1H), 4.43 - 4.36 (m, 1H), 4.31 - 4.24 (m, 1H), 2.19 - 2.12 (m, 1H), 2.09 - 2.01 (m, 1H), 1.48 (s, 6H); LCMS: [M+H]+= 427. Example 73: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-pyridyl) pyrazol-3- yl]urea

[0349] Step-1: 1-(2-pyridyl) pyrazol-3-amine (73-3): To a solution of 1H-pyrazol-3-amine 73-1 (0.60 g, 7.22 mmol) in DMSO (10 mL) was added Cu2O (0.10 g, 0.72 mmol) followed by KOH (0.81 g, 14.4 mmol) at RT. The reaction mixture was degassed under argon atmosphere for 30 min. To this solution was added 2-iodopyridine 73-2 (2.22 g, 10.8 mmol) and the reaction was stirred at 100 °C for 12 h. After completion, the reaction mixture wasquenched with H2O, extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by CombiFlash chromatography (40% EtOAc / heptane) to afford 73-3 (0.35 g).1H NMR (400 MHz, DMSO-d6) δ = 8.33- 8.32 (m, 1H), 8.25 (br s, 1H), 7.85 (t, 1H), 7.59 (d, 1H), 7.16 - 7.10 (m, 1H), 5.80 (d, 1H), 5.24 (s, 2H); LCMS: [M+H]+= 161.

[0350] Step-2: 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-pyridyl) pyrazol-3-yl]urea (Example 73): To a stirred solution of N,N′-disuccinimidyl carbonate (0.16 g, 0.62 mmol) in MeCN (5 mL) was added pyridine (0.05 mL, 0.62 mmol) and 73-3 (0.10 g, 0.62 mmol) at RT. The reaction mixture was stirred for 45 min. To this solution was added, DIPEA (0.32 mL, 1.87 mmol) followed by (4S)-8-chlorochroman-4-amine 73-4 (0.12 g, 0.62 mmol) and the reaction was stirred at RT for 1 h. After completion, the reaction mixture was concentrated under reduced pressure. The product obtained was diluted with EtOAc and organic layer was washed with 2N HCL, water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product obtained was purified by prep HPLC to afford Example 73 (0.02 g).1H NMR: (400 MHz, DMSO-d6) δ = 9.09 (s, 1H), 8.46 (br s, 1H), 8.41 (d, 1H), 7.93 - 7.89 (m, 1H), 7.61 (d, 1H), 7.34 (d, 1H), 7.27 (d, 2H), 7.12 (d, 1H), 6.92 (t, 1H), 6.60 (br s, 1H), 4.97 (d, 1H), 4.39 (d, 1H), 4.27 (t, 1H), 2.15 (br s, 1H), 2.06 (br s, 1H); LCMS: [M+H]+= 370. Example 74: Synthesis of 1-[(4S)-7-fluorochroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea

[0351] Step-1: To a stirred solution of 1-phenylpyrazol-3-amine 74-1 (0.10 g, 0.59 mmol) in MeCN (3 mL) was added pyridine (0.10 mL, 1.19 mmol) followed by N,N′-disuccinimidyl carbonate (0.61 g, 2.39 mmol) at RT and the reaction mixture was stirred at RT for 15 min. To this solution was added (4S)-7-fluorochroman-4-amine 74-2 (0.10 g, 0.60 mmol) followed by DIPEA (0.44 mL, 2.39 mmol). The resulting reaction was stirred at RT for 4 h. Aftercompletion, the reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the product. The product was purified by preparative HPLC to afford Example 74 (0.16 g).1H NMR (400 MHz, DMSO-d6) δ = 8.98 (br s, 1H), 8.34 (br s, 1H), 7.66 (d, 2H), 7.42 (t, 2H), 7.33 (t, 1H), 7.22 (t, 1H), 7.12 (br s, 1H), 6.76 (t, 1H), 6.67 (d, 1H), 6.51 (br s, 1H), 4.89 (d, 1H), 4.30 (br s, 1H), 4.21 - 4.13 (m, 1H), 2.17 - 1.99 (m, 2H); LCMS: [M+H]+= 353. Example 75: Synthesis of (S)-3-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N- methylbenzamide

[0352] Step-1: N-methyl-3-(3-nitro-1H-pyrazol-1-yl)benzamide (75-2): To a stirred solution of 3-(3-nitropyrazol-1-yl)benzoic acid 75-1 (0.30 g, 1.29 mmol) in DMF (5 mL) was added DIPEA (0.92 mL, 5.15 mmol), methylamine hydrochloride (0.13 g, 1.93 mmol) and HATU (0.73 g, 1.93 mmol) and the reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and the precipitated solid was filtered and dried under reduced pressure to afford 75-2 (0.20 g).1H NMR (400 MHz, DMSO-d6) δ = 8.85 - 8.83 (m, 1H), 8.68 - 8.63 (m, 1H), 8.34 (t, 1H), 8.09 - 8.06 (m, 1H), 7.93 - 7.90 (m, 1H), 7.69 (t, 1H), 7.39 (d, 1H), 2.83 (d, 3H); LCMS: [M+H]+= 247.

[0353] Step-2: 3-(3-amino-1H-pyrazol-1-yl)-N-methylbenzamide (75-3): To a solution of 75-2 (0.20 g, 0.81 mmol) in THF / MeOH / water (3:1:1, 10 mL) was added ammoniumchloride (0.13 g, 2.44 mmol) and iron powder (0.14 g, 2.44 mmol) and the reaction mixture was heated at 80 °C for 6 h. After completion, the reaction mixture was quenched with water and filtered through a Celite bed. The aqueous layer was extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash chromatography (50% EtOAc / hexane) to afford 75-3 (0.10 g).1H NMR (400 MHz, DMSO-d6) δ = 8.47 (d, 1H), 8.16 (d, 1H), 8.08 (t, 1H), 7.78 - 7.74 (m, 1H), 7.56 - 7.53 (m, 1H), 7.48 - 7.43 (m, 1H), 5.77 (d, 1H), 5.10 (s, 2H), 2.80 (d, 3H); LCMS: [M+H]+= 217.

[0354] Step-3: (S)-3-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N- methylbenzamide (Example 75): To a solution of 75-3 (0.05 g, 0.23 mmol) in MeCN (2 mL) was added pyridine (0.02 mL, 0.23 mmol) followed by N,N′-disuccinimidyl carbonate (0.06 g, 0.23 mmol) and the resulting reaction mixture was stirred at RT for 30 min. To this solution was added (4S)-8-chlorochroman-4-amine 75-4 (0.04 g, 0.23 mmol) followed by DIPEA (0.12 mL, 0.69 mmol) and reaction mixture was stirred at RT for 1 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and the organic layer was washed with water and brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by preparative HPLC to afford Example 75 (0.03 g).1H NMR (400 MHz, DMSO-d6) δ = 9.04 - 8.98 (m, 1H), 8.54 - 8.48 (m, 1H), 8.42 - 8.37 (m, 1H), 8.16 - 8.11 (m, 1H), 7.84 - 7.77 (m, 1H), 7.69 - 7.62 (m, 1H), 7.55 - 7.48 (m, 1H), 7.37 - 7.25 (m, 2H), 7.14 - 7.06 (m, 1H), 6.96 - 6.89 (m, 1H), 6.61 - 6.56 (m, 1H), 5.01 - 4.94 (m, 1H), 4.45 - 4.38 (m, 1H), 4.32 - 4.24 (m, 1H), 2.85 - 2.79 (m, 3H), 2.23 - 2.12 (m, 1H), 2.10 - 2.00 (m, 1H); LCMS: [M+H]+= 427.Example 76: Synthesis of (S)-4-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N- methylbenzamide

[0355] Step-1: ethyl 4-(3-nitro-1H-pyrazol-1-yl)benzoate (76-3): To a stirred solution of 3- nitro-1H-pyrazole 76-1 (0.10 g, 0.88 mmol) in DMSO (2 mL) was added potassium carbonate (0.15 g, 1.06 mmol) followed by ethyl 4-fluorobenzoate 76-2 (0.16 g, 0.97 mmol) and the reaction mixture was stirred at 90 °C for 12 h. After completion, the reaction mixture was quenched with ice water and extracted in EtOAc. The combined organic layer was washed with brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash column chromatography (40% EtOAc / n- heptane) to afford 76-3 (0.08 g).1H NMR (400 MHz, DMSO-d6) δ = 8.93 (d, 1H), 8.17 - 8.09 (m, 4H), 7.41 (d, 1H), 4.39 - 4.33 (m, 2H), 1.38 - 1.33 (m, 3H); LCMS: [M+H]+= 262.

[0356] Step-2: 4-(3-nitro-1H-pyrazol-1-yl)benzoic acid (76-4): To a stirred solution of 76- 3 (0.40 g, 1.53 mmol) in THF (6 mL) and MeOH (3 mL) was added LiOH.H2O (0.19 g, 4.59 mmol) in water (1 mL) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, pH~3 was adjusted with 2N HCl. The precipitated solid was filtered, dried underreduced pressure to afford 76-4 (0.30).1H NMR (400 MHz, DMSO-d6) δ = 8.90 (d, 1H), 8.16 - 8.12 (m, 2H), 8.09 - 8.06 (m, 2H), 7.42 - 7.39 (m, 1H); LCMS: [M+H]+= 234.

[0357] Step-3: N-methyl-4-(3-nitro-1H-pyrazol-1-yl)benzamide (76-5): To a stirred solution of 76-4 (0.20 g, 0.86 mmol) in DMF (3 mL) was added HATU (0.49 g, 1.29 mmol) and methylamine hydrochloride (0.09 g, 1.29 mmol) followed by DIPEA (0.60 mL, 3.43 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash column chromatography (5% MeOH / DCM) to afford 76-5 (0.19 g). LCMS: [M+H]+= 247.

[0358] Step-4: 4-(3-amino-1H-pyrazol-1-yl)-N-methylbenzamide (76-6): To a stirred solution of 76-5 (0.30 g, 1.22 mmol) in EtOH (3 mL) and water (1 mL) was added iron powder (0.34 g, 6.09 mmol) and ammonium chloride (0.33 g, 6.09 mmol) and the reaction mixture was stirred at 100 °C for 4 h. After completion of the reaction, the mixture was filtered through a Celite bed. The filtrate was concentrated under reduced pressure to afford 76-6 (0.20 g). LCMS: [M+H]+= 217.

[0359] Step-5: (S)-4-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N- methylbenzamide (Example 76): To a stirred solution of 76-6 (0.05 g, 0.23 mmol) in MeCN (2 mL) was added N,N′-Disuccinimidyl carbonate (0.06 g, 0.23 mmol) followed by pyridine (0.02 mL, 0.23 mmol) and the resulting reaction mixture was stirred at RT for 40 min. To this solution was added DIPEA (0.12 mL, 0.69 mmol) and (4S)-8-chlorochroman-4-amine hydrochloride 76-7 (0.05 g, 0.23 mmol) and the reaction mixture was further stirred at RT for 4 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, the aqueous layer was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield a product. The product was purified with preparative HPLC to afford Example 76 (0.03 g).1H NMR (400 MHz, DMSO-d6) δ = 9.10 - 8.97 (m, 1H), 8.49 - 8.34 (m, 2H), 7.90 (d, 2H), 7.74 (d, 2H), 7.38 - 7.25 (m, 2H), 7.16 (d, 1H), 6.96 - 6.90 (m, 1H), 6.57 (br s, 1H), 4.97 (d, 1H), 4.45 - 4.36 (m, 1H), 4.32 - 4.22 (m, 1H), 2.79 (d, 3H), 2.22 - 2.04 (m, 2H); LCMS: [M+H]+= 426.Example 77: Synthesis of (S)-3-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)- N,N-dimethylbenzamide of3-nitro-1H-pyrazole 77-1 (0.50 g, 4.42 mmol) in DCM (10 mL) was added (3- methoxycarbonylphenyl)boronic acid 77-2 (1.19 g, 6.63 mmol), pyridine (1.10 mL, 13.30 mmol) and copper acetate (1.61 g, 8.84 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated under reduced pressure to afford a product. The product was purified by CombiFlash chromatography (50% EtOAc / hexane) to afford 77-3 (0.40 g).1H NMR (400 MHz, DMSO-d6) δ = 8.93 (d, 1H), 8.46 - 8.43 (m, 1H), 8.26 - 8.23 (m, 1H), 8.07 - 8.03 (m, 1H), 7.80 - 7.74 (m, 1H), 7.39 (d, 1H), 3.93 (s, 3H); LCMS: [M+H]+= 248.

[0361] Step-2: 3-(3-nitro-1H-pyrazol-1-yl)benzoic acid (77-4): To a stirred solution of 77- 3 (0.40, 1.62 mmol) in THF / MeOH / water (4:1:1, 12 mL) was added LiOH.H2O (0.20 g, 4.83 mmol) and the reaction mixture was stirred at RT for 4 h. After completion, the reactionmixture was concentrated under reduced pressure. The residue was diluted with water, pH~3 was adjusted with 2N HCl. The precipitated solid was filtered, dried under reduced pressure to afford 77-4 (0.30 g). LCMS: [M+H]+= 234.

[0362] Step-3: N,N-dimethyl-3-(3-nitro-1H-pyrazol-1-yl)benzamide (77-5): To a stirred solution of 77-4 (0.40 g, 1.72 mmol) in DMF (5 mL) was added DIP...

Claims

CLAIMS 1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, whereiR1is selected from the group consisting of H, C1-C3 alkyl, Cl, F, and CN; R2is H or C1-C3alkyl substituted with OH or OCH3; R3is each independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH; R4is each independently H or C1-C4 alkyl; Z is selected from the group consisting of C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-heterocyclyl, and aryl-heteroaryl, wherein C1-C6 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR6R7, NR5R5, NR5-C(O)CH3, 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, OH, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of keto, C3-C6 cycloalkyl, C(O)CH3, C(O)O-C1-C3alkyl, C(O)NR5R5, SO2-C1-C3alkyl, and C1-C4alkyl that is optionally substituted with OH, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: C1-C4alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3-C6 cycloalkyl that is substituted with NR5R5, halogen,CN, OR5, C(O)OH, C(O)NR6R7, NR6R7, SO2R5, SO2NR5R5, and 4- or 6-membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C1-C4alkyl, and NR5R5, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C4 alkyl optionally substituted with a group selected from the group consisting of NR5R5, OR5, and C(O)NR5R5, wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of chloro, fluoro, and C1-C4alkyl that is optionally substituted with a group selected from the group consisting of OH, O-C1-C3alkyl, chloro, and fluoro; wherein the aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OH; R5is each independently H or C1-C4 alkyl; R6is H or C1-C6alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; R7is H or C1-C5alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1-C5alkyl or CN, or R7is C1-C5 alkyl substituted with C3-C6 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1-C5alkyl, CN, NR5R5, and one or more fluoro, or R7is C3 cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH. or if R6and R7are attached to the same nitrogen atom, R6and R7together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1-C5alkyl;n is 1-4; p is 1-2; with the proviso that a compound selected from the group consisting of: 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, 1-(8-methylchroman-4-yl)-3-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl)urea, 1-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea, 1-(1-(sec-butyl)-5-methyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, and 1-(8-fluorochroman-4-yl)-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-3-yl)urea, is excluded.

2. The compound according to claim 1, wherein: R1is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is selected from the group consisting of C1-C5 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aryl-heterocyclyl, wherein C1-C5 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR6R7, NR5R5, NR5-C(O)CH3, and SO2R5, wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of keto, C3cycloalkyl, C(O)CH3, C(O)O-C1-C3 alkyl, , C(O)NR5R5, SO2-C1-C3 alkyl, and C1-C3 alkyl that is optionally substituted with OH, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: C1-C3 alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, C(O)OH, C(O)NR6R7,NR6R7, SO2R5, SO2NR5R5, and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C1alkyl, and NR5R5, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C3alkyl optionally substituted with NR5R5, wherein the aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of fluoro and C1 alkyl that is optionally substituted with OH; R5is each independently H or C1-C2 alkyl; R6is H or C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; R7is H or C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1alkyl or CN, or R7is C1-C3 alkyl substituted with C3 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1alkyl, CN, NR5R5, and one or more fluoro, or R7is C3-C5 cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH, or if R6and R7are attached to the same nitrogen atom, R6and R7together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1 alkyl; n is 1-2; and p is 1.

3. The compound according to claim 2, wherein: R1is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl;Z is C1-C5alkyl optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)NR6R7, NR5R5, NR5- C(O)CH3, and SO2R5; R5is each independently H or C1-C2 alkyl; n is 1-2; and p is 1.

4. The compound according to claim 2, wherein: R1is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; 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; R5is each independently H or C1-C2 alkyl; n is 1-2; and p is 1.

5. The compound according to claim 2, wherein: R1is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is heterocyclyl optionally substituted with one or more groups each independently selected from the group consisting of keto, C3cycloalkyl, C(O)CH3, C(O)NR5R5, and C1-C2 alkyl that is optionally substituted with OH; R5is each independently H or C1-C2alkyl; n is 1-2; and p is 1.

6. The compound according to claim 2, wherein: R1is selected from the group consisting of H, C1alkyl, Cl, F, and CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl;R4is each independently H or C1alkyl; Z is aryl optionally substituted with one or more groups each independently selected from the group consisting of: C1-C3 alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, SO2R5, SO2NR5R5, and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C1 alkyl, and NR5R5; R5is each independently H or C1-C2alkyl; n is 1-2; and p is 1.

7. The compound according to claim 2, wherein: R1is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; R5is each independently H or C1-C2alkyl; R6is H or C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; R7is H, C3-C5 cycloalkyl, or C1-C3 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1 alkyl or CN; n is 1-2; and p is 1.

8. The compound according to claim 2, wherein:R1is selected from the group consisting of H, C1alkyl, Cl, F, and CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; R5is each independently H or C1-C2alkyl; R6is H or C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; R7is C1-C3 alkyl substituted with C3 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1 alkyl, CN, NR5R5, and one or more fluoro; n is 1-2; and p is 1.

9. The compound according to claim 2, wherein: R1is selected from the group consisting of H, C1alkyl, Cl, F, and CN; R2is H or C1 alkyl substituted with OH or OCH3; R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; R5is each independently H or C1-C2 alkyl; R6and R7together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1alkyl; n is 1-2; and p is 1.

10. The compound according to claim 2, wherein: R1is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl;Z is heteroaryl optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C3alkyl optionally substituted with NR5R5; R5is each independently H or C1-C2 alkyl; n is 1-2; and p is 1.

11. The compound according to claim 2, wherein: R1is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R2is H or C1alkyl substituted with OH or OCH3; R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl-heterocyclyl optionally substituted with one or more groups each independently fluoro or C1alkyl that is optionally substituted with OH; n is 1-2; and p is 1.

12. A compound having the structure of formula (II), or a pharmaceutically acceptable salt thereof, (II) wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is selected from the group consisting of C1-C2 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aryl-heterocyclyl, wherein C1-C2 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR6R7, NR5R5, NR5-C(O)CH3, and SO2R5,wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of keto, C3 cycloalkyl, C(O)CH3, C(O)O-C1-C3alkyl, C(O)NR5R5, SO2-C1-C3alkyl, and C1-C3alkyl that is optionally substituted with OH, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: C1-C3alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3 cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, C(O)OH, C(O)NR6R7, NR6R7, SO2R5, SO2NR5R5, and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C1alkyl, and NR5R5, wherein heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C3alkyl optionally substituted with NR5R5, wherein the aryl-heterocyclyl is optionally substituted with one or more fluoro or C1 alkyl that is optionally substituted with OH; R5is each independently H or C1-C2 alkyl; R6is H or C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; and R7is H or C1-C3 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1 alkyl or CN,or R7is C1-C3alkyl substituted with C3cycloalkyl optionally substituted with a group selected from the group consisting of O-C1 alkyl, CN, NR5R5, and one or more fluoro, or R7is C3-C5cycloalkyl optionally substituted with C1alkyl optionally substituted with OH, or if R6and R7are attached to the same nitrogen atom, R6and R7together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1alkyl.

13. The compound according to claim 12, wherein: R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is C1-C5alkyl optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)NR6R7, NR5R5, NR5- C(O)CH3, and SO2R5; and R5is each independently H or C1-C2 alkyl.

14. The compound according to claim 12, wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; 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; and R5is each independently H or C1-C2 alkyl.

15. The compound according to claim 12, wherein: R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is heterocyclyl optionally substituted with one or more groups each independently selected from the group consisting of keto, C3 cycloalkyl, C(O)CH3, C(O)NR5R5, and C1-C2 alkyl that is optionally substituted with OH; and R5is each independently H or C1-C2alkyl.

16. The compound according to claim 12, wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl;Z is aryl optionally substituted with one or more groups each independently selected from the group consisting of: C1-C3alkyl that is optionally substituted with one or more F, OH, or NR5R5, C3 cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, SO2R5, SO2NR5R5, and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C1 alkyl, and NR5R5; and R5is each independently H or C1-C2 alkyl.

17. The compound according to claim 12, wherein: R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; R5is H or C1-C2alkyl; R6is H or C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; and R7is H, C3-C5cycloalkyl, or C1-C3alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1alkyl or CN.

18. The compound according to claim 12, wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; R5is each independently H or C1-C2 alkyl; R6is H or C1-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5; andR7is C1-C3alkyl substituted with C3cycloalkyl optionally substituted with a group selected from the group consisting of O-C1 alkyl, CN, NR5R5, and one or more fluoro.

19. The compound according to claim 12, wherein: R3is each independently H or C1 alkyl; R4is each independently H or C1alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR6R7or NR6R7; and R6and R7together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1 alkyl.

20. The compound according to claim 12, wherein: R3is each independently H or C1alkyl; R4is each independently H or C1 alkyl; Z is heteroaryl optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, oxo, SO2R5, and C1- C3 alkyl optionally substituted with NR5R5, or Z is aryl-heterocyclyl optionally substituted with one or more groups each independently fluoro or C1 alkyl that is optionally substituted with OH; and R5is each independently H or C1-C2alkyl.

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

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