Modulators of mitochondrial DNA replication

Abstract

The present invention provides novel DNA polymerase γ (POL γ) modulators and pharmaceutical compositions thereof.

Description

MODULATORS OF MITOCHONDRIAL DNA REPLICATION CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application 63 / 637,658, filed April 23, 2024, the entire contents of which are incorporated by reference herein. FIELD OF THE INVENTION

[0002] The present disclosure relates to novel DNA polymerase γ (POL γ) modulators, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. 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. DNA polymerase γ (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. The accessory subunit B of DNA polymerase γ is required for mitochondrial replisome function.

[0004] A primary biological role of POLγ is to replicate the mitochondrial genome. However, POLγ cannot replicate the double stranded (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.

[0005] TWINKLE travels in 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 ofPOLγ 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.

[0006] 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. 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. 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.

[0007] Mutations affecting POLγ are among the most frequent causes of mitochondrial disease. More than 300 disease-causing variants have been identified in POLγ, causing a broad clinical spectrum of neurodegenerative and mitochondrial diseases such as Alpers syndrome, stroke- like episodes, and chronic progressive external ophthalmoplegia. Pathogenic variants in the gene encoding POLγA, namely POLG, are now known to cause a spectrum of overlappingphenotypes. These POLγ mutations are linked to the accumulation of damaged mtDNA, including multiple deletions, but can also lead to loss of mtDNA (depletion). Many disease-causing variants of POLγ are associated with decreased replication processivity of the mtDNA replication machinery, leading to replication stalling.

[0008] In view of the numerous and varied roles of POLγ, the need exists for potent and specific modulators of POLγ. SUMMARY OF THE INVENTION

[0009] Other aspects and iterations of the present disclosure are detailed below.

[0010] In some aspects, the present disclosure is directed to a compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein X1 – X3 are independently carbon or nitrogen; R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O- CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6; wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of SO2R6, CCH3CH3NH2, NH2, and C3H6O; wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH; wherein heterocyclodiene is optionally substituted with C1-C6alkyl; R3is absent, hydrogen, C1-C4alkyl, or halogen; wherein C1-C4alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)R6, halogen, or R2and R3are interconnected to form a five-member heteroatom ring; R4and R5are each independently absent or hydrogen; R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3;R7is H, methyl, CH CH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2OR6; n is 1-4; and *denotes a chiral carbon.

[0011] In some aspects, R1is independently selected from the group consisting of hydrogen, halogen, and cyano.

[0012] In some aspects, R1is independently selected from the group consisting of hydrogen, halogen, and O-CH3.

[0013] In some aspects, R1is independently selected from the group consisting of hydrogen and halogen.

[0014] In some aspects, R1is independently selected from the group consisting of hydrogen and chlorine.

[0015] In some aspects, R1is independently selected from the group consisting of hydrogen and cyano.

[0016] In some aspects, R1is independently selected from the group consisting of hydrogen and O-CH3.

[0017] In some aspects, X1– X3comprise one nitrogen and two carbons.

[0018] In some aspects, X1– X3comprise two nitrogens and one carbon.

[0019] In some aspects, X1– X3are carbon.

[0020] In some aspects, R2is selected from the group consisting of hydrogen, halogen, cyano, and methyl.

[0021] In some aspects, when R2is selected from C1-C6alkyl, cycloalkyl, heterocyclyl, and aryl; C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl; C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: SO2R6, CCH3CH3NH2, NH2, and C3H6O; and wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH.

[0022] In some aspects, R2is heterocyclodiene optionally substituted with C1-C6alkyl.

[0023] In some aspects, R2 is selected from C(O)OR6, C(O)NR6R7, cycloalkyl and C(O)R6, OR6,wherein R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, CH2C(O)OCH2CH3; and R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, CH2CH2OR6.

[0024] In some aspects, R3is hydrogen, chlorine, or fluorine.

[0025] In other aspects, the present disclosure is directed to a compound of formula (II), or a pharmaceutically acceptable salt thereof:wherein R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O-CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3; and R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2OR6; *denotes a chiral carbon.

[0026] In some aspect, the halogen of R1is chlorine.

[0027] In yet other aspects, the present disclosure is directed to compound of formula (III) or a pharmaceutically acceptable salt thereof:wherein R2is 2-R6-1,2,3, triazole or C(O)NR6R6; R6is methyl; and *denotes a chiral carbon.

[0028] In yet other aspects, the present disclosure is directed to a compound of formula (IV), or a pharmaceutically acceptable salt thereof:wherein R2is 2-R6-1,2,3, triazole;(R1)1 is chlorine; R6is methyl; and *denotes a chiral carbon.

[0029] In yet other aspects, the present disclosure is directed to a compound of Formula (V) or a pharmaceutically acceptable salt thereof:wherein X1 – X3 are independently carbon or nitrogen; R2is selected from the group consisting of H, CN, SO2R6, pyrolidine, pyrrolidin-3-ol, 2- methyl-1,2,3, triazole, imidazole, C1-3alkyl, C3-6cycloalkyl, heterocyclyl, OR6, C(O)NR6R6, and C(O)R6;wherein C1-3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, F, NHSO2R6, and methyl; wherein C3-6cycloalkyl and C3-6heterocyclyl are independently optionally substituted OH, or C(O)R6; R3is hydrogen or fluorine; or R2and R3are interconnected to form a 5-membered 2,3-dihydro-1H-pyrrole or 5-methyl- 2,3-dihydro-1H-pyrrole; R4and R5are H; (R1)1 is chlorine; and R6is methyl.

[0030] The present disclosure is also directed to a compound of formula (Ia), or a pharmaceutically acceptable salt thereof:wherein X1– X3are independently carbon or nitrogen; R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O- CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, methyl, C1-C6alkyl, C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6; wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: SO2R6, CCH3CH3NH2, NH2, and C3H6O; wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH; wherein heterocyclodiene is optionally substituted with C1-C6alkyl; R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, CH2C(O)OCH2CH3; R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, CH2CH2OR6; R3is absent, hydrogen, C1-C4alkyl, or halogen; wherein C1-C4alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)R6, halogen; or R2and R3are interconnected to form a five-member heteroatom ring; R4 and R5 are each independently absent or hydrogen; and n is 1-4.

[0031] In some aspects, the compound is*denotes a chiral carbon.

[0032] In some aspects, the compound is.

[0033] In some aspects, the compound is *.

[0034] In some aspects, the compound isDETAILED DESCRIPTION OF THE INVENTION

[0035] Provided are compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutical composition comprising the compounds or their salts for increasing the processivity of POLγ. (I) Definitions

[0036] 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-C6alkyl” means linear or branched chain alkyl groups, including all possible isomers, having 1, 2, 3, 4, 5, or 6 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 of the three carbon atoms.

[0037] The term “alkoxy” or “alkoxyl” as used herein refers to an -O-alkyl group. For example, the term “C1-C4alkoxyl” means -O-C1-C4alkyl. Examples of alkoxyl include methoxyl, ethoxyl, propoxyl (e.g., n-propoxyl and isopropoxyl), and the like.

[0038] The term “haloalkoxy” or “haloalkoxyl” as used herein refers to an -O-alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced with a halogen atom. Examples of haloalkoxyl include trifluoromethoxyl, 2,2,2-trifluoroethoxyl, and the like.0027 The term “alkanoyl” or “acyl” as used herein refers to an -C(O)-alkyl group. For example, the term “C1-C6alkanoyl” means -C(O)-C1-C6alkyl. Examples of alkanoyl include acetyl, propionyl, butyryl, and the like.

[0039] The term “bicyclic” as used herein refers to a saturated or unsaturated 6- to 12- membered ring consisting of two joined cyclic substructures, and includes fused, bridged, and spiro bicyclic rings.

[0040] The term “heterobicyclic” as used herein refers to a bicyclic ring that contains 1 or more heteroatom(s) in one or more rings that are optionally substituted or oxidized, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. Examples of heterobicyclic rings include, but are not limited to, 8-azabicyclo[3.2.1]octan-8-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 8-oxa-3- azabicyclo[3.2.1]octan-3-yl, and 5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl.

[0041] The term “cycloalkyl” as used herein refers to a cyclized alkyl ring having the indicated number of carbon atoms in a specified range. Thus, for example, “C3-C6 cycloalkyl” encompasses each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0042] The term “aryl” as used herein refers to a monocyclic or fused bicyclic ring system having the characteristics of aromaticity, wherein at least one ring contains a completely conjugated pi-electron system. Typically, aryl groups contain 6 to 14 carbon atoms (“C6- C14 aryl”) or preferably, 6 to 12 carbon atoms (“C6-C12 aryl”). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring. The point of attachment to the base molecule on such fused aryl ring systems may be a C atom of the aromatic portion or a C or N atom of the non-aromatic portion of the ring system. Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, indanyl, indenyl, and tetrahydronaphthyl.

[0043] The term “cycloaryl” herein refers to a polycyclic group wherein an aryl group is fused to a 5- or 6-membered aliphatic or heterocyclic ring. For example, “ C6-C12cycloaryl” means a C6- C12aryl fused to a 5- or 6-membered aliphatic or heterocyclic ring. One example of C6cycloaryl is 2,3-dihydrobenzo[b][1,4]dioxine.

[0044] The term “heteroaryl” as used herein refers to (i) a 5- or 6-membered ring having the characteristics of aromaticity containing at least one heteroatom selected from N, O and S, wherein each N is optionally in the form of an oxide, and (ii) a 9- or 10- membered bicyclic fused ring system, wherein the fused ring system of (ii) contains at least one heteroatom independently selected from N, O and S, wherein each ring in the fused ring system contains zero, one or more than one heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O)2. Typically, heteroaryl groups contain 5 to 14 ring atoms (“5-14 membered heteroaryl”), and preferably 5 to 12 ring atoms (“5-12 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring, such that aromaticity is maintained. Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, 3-fluroropyridyl, 4-fluoropyridyl, 3- methoxypyridyl, 4-methoxypyridyl, 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., the 1,2,3-, 1,2,4-, 1,2,5- (furazanyl), or 1,3,4- isomer), oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-memberedheterobicyclic, fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, chromenyl, quinolinyl, isoquinolinyl, benzopiperidinyl, benzofuranyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, indazolyl, indolinyl, and isoindolinyl.

[0045] The term “heteroaryloxy” or “heteroaryloxyl” as used herein refers to an -O- heteroaryl group.0035 The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used herein represents a stable 3- to 10-membered monocyclic, non-aromatic ring that is either saturated or unsaturated, and that consists of carbon atoms and from one to two heteroatoms selected from the group consisting of N, O, and S. Examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, and oxazepanyl.0

[0046] The term “oxo” as used herein refers to a group which consists of oxygen which is double bonded to carbon or any other element.

[0047] The term “imine” as used herein refers to a group containing a carbon-nitrogen double bond.

[0048] The term “carboxyl” as used herein refers to a combination of two functional groups attached to a single carbon atom, namely, hydroxyl (OH) and carbonyl (O).

[0049] The term “optionally substituted” or “optional substituents” as used herein means that the groups are either unsubstituted or substituted with one or more of the substituents specified. When the groups are substituted with more than one substituent, the substituents may be the same or different. Furthermore, when using the terms “independently,” “independently are,” and “independently selected from” mean that the groups may be the same or different.

[0050] 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”.

[0051] 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 %.

[0052] 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.

[0053] 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 may be protonated), the invention includes the compounds in the form of their acid addition salts with organic or inorganic acids such as, for example, but not limited to salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, acetic acid, citric acid, glutamic acid, lactic acid, and methanesulfonic acid. When compounds of the invention contain one or more acidic groups (e.g., a carboxylic acid), the invention includes the pharmaceutically acceptable salts of the compounds formed with but not limited to alkali metal salts, alkaline earth metal salts or ammonium salts. Examples of such salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Additional examples of such salts may be found in Stahl, P. H. et al. Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition, Wiley, 2011. (I) Compounds

[0054] In one embodiment, the present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (I):wherein X1 – X3 are independently carbon or nitrogen; R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O-CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6; wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of SO2R6, CCH3CH3NH2, NH2, and C3H6O; wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH; wherein heterocyclodiene is optionally substituted with C1-C6alkyl; R3is absent, hydrogen, C1-C4alkyl, or halogen; wherein C1-C4alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)R6, halogen, or R2and R3are interconnected to form a five-member heteroatom ring; R4and R5are each independently absent or hydrogen; R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3; R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2OR6; n is 1-4; and *denotes a chiral carbon.

[0055] In certain embodiments, R1is hydrogen.

[0056] In certain embodiments, R1is halogen.

[0057] In certain embodiments, R1is cyano.

[0058] In certain embodiments, R1is chlorine.

[0059] In certain embodiments, R1is O-CH3.

[0060] In certain embodiments, R1is independently selected from the group consisting of hydrogen, halogen, and cyano.

[0061] In certain embodiments, R1is independently selected from the group consisting of hydrogen, chlorine, and cyano.

[0062] In certain embodiments, R1is independently selected from the group consisting of hydrogen, chlorine, and O-CH3.

[0063] In certain embodiments, R1is independently selected from the group consisting of hydrogen and halogen.

[0064] In certain embodiments, R1is independently selected from the group consisting of hydrogen and chlorine.

[0065] In certain embodiments, R1is independently selected from the group consisting of hydrogen and cyano.

[0066] In certain embodiments, R1is independently selected from the group consisting of hydrogen and O-CH3.

[0067] In certain embodiments, X1 – X3 is one nitrogen and two carbons.

[0068] In certain embodiments, X1 – X3 is two nitrogens and one carbon.

[0069] In certain embodiments, X1– X3are carbon.

[0070] In certain embodiments, R2is selected from the group consisting of hydrogen, halogen, cyano, and methyl.

[0071] In certain embodiments, R2is selected from C1-C6alkyl, cycloalkyl, heterocyclyl, and aryl; wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl; C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: SO2R6, CCH3CH3NH2, NH2, and C3H6O; and wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH.

[0072] In certain embodiments, R2is heterocyclodiene optionally substituted with C1-C6alkyl.

[0073] In certain embodiments, R2 is selected from C(O)OR6, C(O)NR6R7, cycloalkyl andC(O)R6, OR6; wherein R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, CH2C(O)OCH2CH3; and R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, CH2CH2OR6.

[0074] In certain embodiments, R3is hydrogen, chlorine, or fluorine.

[0075] In some embodiments, the present disclosure is directed to a compound or a pharmaceutically acceptable salt thereof with formula (II):wherein R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O-CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3; R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2OR6;and *denotes a chiral carbon.

[0076] In certain embodiments, R1is chlorine.

[0077] In some embodiments, the present disclosure is directed to a compound or a pharmaceutically acceptable salt thereof with formula (III):wherein R2is 2-R6-1,2,3, triazole or C(O)NR6R6; and R6is methyl; *denotes a chiral carbon.

[0078] In some embodiments, the present disclosure is directed to a compound or a pharmaceutically acceptable salt thereof with formula (IV):wherein R2is 2-R6-1,2,3, triazole; (R1)1is chlorine; and R6is methyl, *denotes a chiral carbon.

[0079] In some embodiments, the present disclosure is directed to a compound or a pharmaceutically acceptable salt thereof with formula (V)wherein X1 – X3 are independently carbon or nitrogen; R2is selected from the group consisting of H, CN, SO2R6, pyrolidine, pyrrolidin-3-ol, 2- methyl-1,2,3, triazole, imidazole, C1-3alkyl, C3-6cycloalkyl, C3-6heterocyclyl, OR6, C(O)NR6R6, and C(O)R6;wherein C1-3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, F, NHSO2R6, and methyl; wherein C3-6cycloalkyl and C3-6heterocyclyl are independently optionally substituted OH, or C(O)R6; R3is hydrogen or fluorine; orR2and R3are interconnected to form a 5-membered 2,3-dihydro-1H-pyrrole or 5-methyl- 2,3-dihydro-1H-pyrrole; R4 and R5 are H; (R1)1 is chlorine; and R6is methyl.

[0080] In some embodiments, the present disclosure is directed to a compound or a pharmaceutically acceptable salt thereof with formula (Ia), or a pharmaceutically acceptable salt thereof:wherein X1 – X3 are independently carbon or nitrogen; R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O-CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, methyl, C1-C6alkyl, C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, andheterocyclodiene; wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6; wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: SO2R6, CCH3CH3NH2, NH2, and C3H6O; wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH; wherein heterocyclodiene is optionally substituted with C1-C6alkyl; R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, CH2C(O)OCH2CH3; R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, CH2CH2OR6; R3is absent, hydrogen, C1-C4alkyl, or halogen;wherein C1-C4alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)R6, halogen; or R2and R3are interconnected to form a five-member heteroatom ring; R4 and R5 are each independently absent or hydrogen; and n is 1-4.

[0081] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(1H- pyrrolo[3,2-b]pyridin-5-yl)urea, Example 1, or a pharmaceutically acceptable salt thereof:.

[0082] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6- methylpyridin-2-yl)urea, Example 2, or a pharmaceutically acceptable salt thereof:.

[0083] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(pyridin-2- yl)urea, Example 3, or a pharmaceutically acceptable salt thereof:.

[0084] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N- methylpicolinamide, Example 4, or a pharmaceutically acceptable salt thereof:.

[0085] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4- yl)ureido)picolinamide, Example 5, or a pharmaceutically acceptable salt thereof:.

[0086] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N- dimethylpicolinamide, Example 6, or a pharmaceutically acceptable salt thereof:.

[0087] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(5- (hydroxymethyl)pyridin-2-yl)urea, Example 7, or a pharmaceutically acceptable salt thereof:.

[0088] In certain embodiments, the compound is, (S)-1-(5-acetylpyridin-2-yl)-3-(8- chlorochroman-4-yl)urea, Example 8, or a pharmaceutically acceptable salt thereof:

[0089] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6- ethoxypyridin-2-yl)urea, Example 9, or a pharmaceutically acceptable salt thereof:

[0090] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6- cyanopyridin-2-yl)urea, Example 10, or a pharmaceutically acceptable salt thereof: .

[0091] In certain embodiments, the compound is (S)-1-(6-(1H-imidazol-2-yl)pyridin-2-yl)-3-(8- chlorochroman-4-yl)urea, Example 11, or a pharmaceutically acceptable salt thereof:.

[0092] In certain embodiments, the compound is methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)- 3-methylpicolinate, Example 12, or a pharmaceutically acceptable salt thereof:.

[0093] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3- methylpicolinic acid, Example 13, or a pharmaceutically acceptable salt thereof:.

[0094] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N,3- trimethylpicolinamide, Example 14, or a pharmaceutically acceptable salt thereof:.

[0095] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6- cyclopropoxypyridin-2-yl)urea, Example 15, or a pharmaceutically acceptable salt thereof:.

[0096] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6-(pyrrolidin- 1-yl)pyridin-2-yl)urea, Example 16, or a pharmaceutically acceptable salt thereof:.

[0097] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(6-(2- hydroxypropyl)pyridin-2-yl)urea or an isomer thereof (e.g. stereoisomer thereof), Example 17 or Example 18, or a pharmaceutically acceptable salt thereof:

[0098] In certain embodiments, the compound is (S)-2-(6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)acetamide, Example 19, or a pharmaceutically acceptable salt thereof:.

[0099] In certain embodiments, the compound is ethyl (S)-2-((6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)oxy)acetate, Example 20, or a pharmaceutically acceptable salt thereof:.

[0100] In certain embodiments, the compound is (S)-2-((6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)oxy)acetamide, Example 21, or a pharmaceutically acceptable salt thereof:.

[0101] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6- cyclopropylpyridin-2-yl)urea, Example 22, or a pharmaceutically acceptable salt thereof: .

[0102] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6- (hydroxymethyl)pyridin-2-yl)urea, Example 23, or a pharmaceutically acceptable salt thereof:.

[0103] In certain embodiments, the compound is (S)-1-(chroman-4-yl)-3-(6- (hydroxymethyl)pyridin-2-yl)urea, Example 24, or a pharmaceutically acceptable salt thereof:.

[0104] In certain embodiments, the compound is (S)-1-(6-acetylpyridin-2-yl)-3-(8- chlorochroman-4-yl)urea, Example 25, or a pharmaceutically acceptable salt thereof:.

[0105] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(6-(1- hydroxyethyl)pyridin-2-yl)urea or an isomer thereof (e.g. stereoisomer thereof), Example 26 or Example 27, or a pharmaceutically acceptable salt thereof:.

[0106] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- hydroxyethyl)-N-methylpicolinamide, Example 28, or a pharmaceutically acceptable salt thereof:.

[0107] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- (dimethylamino)ethyl)picolinamide, Example 29, or a pharmaceutically acceptable salt thereof:.

[0108] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- hydroxyethyl)picolinamide, Example 30, or a pharmaceutically acceptable salt thereof:.

[0109] In certain embodiments, the compound is (S)-N-(2-amino-2-oxoethyl)-6-(3-(8- chlorochroman-4-yl)ureido)-N-methylpicolinamide, Example 31, or a pharmaceutically acceptable salt thereof:.

[0110] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- hydroxy-2-methylpropyl)-N-methylpicolinamide, Example 32, or a pharmaceutically acceptable salt thereof: C.

[0111] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- (dimethylamino)ethyl)-N-methylpicolinamide, Example 33, or a pharmaceutically acceptable salt thereof:.

[0112] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- cyanoethyl)-N-methylpicolinamide, Example 34, or a pharmaceutically acceptable salt thereof:.

[0113] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- methoxyethyl)picolinamide, Example 35, or a pharmaceutically acceptable salt thereof:.

[0114] In certain embodiments, the compound is 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((S)- 1-hydroxypropan-2-yl)picolinamide, Example 36, or a pharmaceutically acceptable salt thereof:.

[0115] In certain embodiments, the compound is 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((S)- 2-hydroxypropyl)picolinamide, Example 37, or a pharmaceutically acceptable salt thereof:.

[0116] In certain embodiments, the compound is 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((R)- 1-hydroxypropan-2-yl)picolinamide, Example 38, or a pharmaceutically acceptable salt thereof:.

[0117] In certain embodiments, the compound is 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((R)- 2-hydroxypropyl)picolinamide, Example 39, or a pharmaceutically acceptable salt thereof:

[0118] In certain embodiments, the compound is (S)-N-(3-amino-3-oxopropyl)-6-(3-(8- chlorochroman-4-yl)ureido)-N-methylpicolinamide, Example 40, or a pharmaceutically acceptable salt thereof:.

[0119] In certain embodiments, the compound is (S)-1-(chroman-4-yl)-3-(1H-pyrrolo[3,2- b]pyridin-5-yl)urea, Example 41, or a pharmaceutically acceptable salt thereof:.

[0120] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(5-(1- hydroxyethyl)pyridin-2-yl)urea, Example 42, or a pharmaceutically acceptable salt thereof:.

[0121] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(6-(2,2,2- trifluoro-1-hydroxyethyl)pyridin-2-yl)urea or an isomer thereof (e.g. stereoisomer thereof), Example 43 or Example 44, or a pharmaceutically acceptable salt thereof:

[0122] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6- ((methylsulfonyl)methyl)pyridin-2-yl)urea, Example 45, or a pharmaceutically acceptable salt thereof:.

[0123] In certain embodiments, the compound is 1-(6-((R)-1-acetylpiperidin-3-yl)pyridin-2-yl)-3- (8-chlorochroman-4-yl)urea or an isomer thereof (e.g. stereoisomer thereof), Example 46 or Example 47, or a pharmaceutically acceptable salt thereof:.

[0124] In certain embodiments, the compound is 6-(3-(7-cyanochroman-4-yl)ureido)-N- methylpicolinamide, Example 48, or a pharmaceutically acceptable salt thereof:.

[0125] In certain embodiments, the compound is (S)-6-(3-(7-cyanochroman-4-yl)ureido)-N- methylpicolinamide, Example 49, or a pharmaceutically acceptable salt thereof:

[0126] In certain embodiments, the compound is (R)-6-(3-(7-cyanochroman-4-yl)ureido)-N- methylpicolinamide, Example 50, or a pharmaceutically acceptable salt thereof:.

[0127] In certain embodiments, the compound is (S)-6-(3-(7-chlorochroman-4-yl)ureido)-N- methylpicolinamide, Example 51, or a pharmaceutically acceptable salt thereof:.

[0128] In certain embodiments, the compound is (R)-6-(3-(7-chlorochroman-4-yl)ureido)-N- methylpicolinamide, Example 52, or a pharmaceutically acceptable salt thereof:.

[0129] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-3- hydroxypyrrolidin-1-yl)pyridin-2-yl)urea, Example 53, or a pharmaceutically acceptable salt thereof:.

[0130] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-3- hydroxypyrrolidin-1-yl)pyridin-2-yl)urea, Example 54, or a pharmaceutically acceptable salt thereof:

[0131] In certain embodiments, the compound is (S)-1-(6-(4-(2-aminopropan-2- yl)phenyl)pyridin-2-yl)-3-(8-chlorochroman-4-yl)urea, Example 55, or a pharmaceutically acceptable salt thereof:.

[0132] In certain embodiments, the compound is 1-(6-((S)-1-aminoethyl)pyridin-2-yl)-3-(-8- chlorochroman-4-yl)urea or an isomer thereof (e.g. stereoisomer thereof), Example 56 or Example 57, or a pharmaceutically acceptable salt thereof:

[0133] In certain embodiments, the compound is N-((R)-1-(6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)ethyl)acetamide or an isomer thereof (e.g. stereoisomer thereof), Example 58 or Example 59, or a pharmaceutically acceptable salt thereof:

[0134] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6-(2-methyl- 2H-1,2,3-triazol-4-yl)pyridin-2-yl)urea, Example 60, or a pharmaceutically acceptable salt thereof:.

[0135] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6-(3- hydroxyoxetan-3-yl)pyridin-2-yl)urea, Example 61, or a pharmaceutically acceptable salt thereof:.

[0136] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6-(1- hydroxycyclopropyl)pyridin-2-yl)urea, Example 62, or a pharmaceutically acceptable salt thereof:.

[0137] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(5-fluoro-6-(1- hydroxyethyl)pyridin-2-yl)urea or an isomer thereof (e.g. stereoisomer thereof), Example 63 or Example 64, or a pharmaceutically acceptable salt thereof:

[0138] In certain embodiments, the compound is (S)-2-(6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)-N,N-dimethylacetamide, Example 65, or a pharmaceutically acceptable salt thereof:.

[0139] In certain embodiments, the compound is (S)-2-(6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)-N-methylacetamide, Example 66, or a pharmaceutically acceptable salt thereof:.

[0140] In certain embodiments, the compound is (S)-6-(3-(8-chloro-6-methoxychroman-4- yl)ureido)-N-methylpicolinamide, Example 67, or a pharmaceutically acceptable salt thereof:.

[0141] In certain embodiments, the compound is, 1-((S)-8-chlorochroman-4-yl)-3-(6-(1-methoxyethyl)pyridin-2-yl)urea or an isomer thereof (e.g. stereoisomer thereof), Example 68 orExample 69, or a pharmaceutically acceptable salt thereof:

[0142] In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3- fluoro-N-methylpicolinamide, Example 70, or a pharmaceutically acceptable salt thereof:.

[0143] In certain embodiments, the compound is N-((S)-1-(6-(3-(-8-chlorochroman-4- yl)ureido)pyridin-2-yl)ethyl)methanesulfonamide or an isomer thereof (e.g. stereoisomer thereof), Example 71 or Example 72, or a pharmaceutically acceptable salt thereof:.

[0144] .In certain embodiments, the compound is (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N- dimethylpyrazine-2-carboxamide, Example 73, or a pharmaceutically acceptable salt thereof:.

[0145] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(2-methyl-1H- pyrrolo[2,3-b]pyridin-6-yl)urea, Example 74, or a pharmaceutically acceptable salt thereof:.

[0146] In certain embodiments, the compound is (S)-1-(6-(4-(3-aminooxetan-3- yl)phenyl)pyridin-2-yl)-3-(8-chlorochroman-4-yl)urea, Example 75, or a pharmaceutically acceptable salt thereof:.

[0147] In certain embodiments, the compound is (S)-1-(2-acetylpyrimidin-4-yl)-3-(8- chlorochroman-4-yl)urea, Example 76, or a pharmaceutically acceptable salt thereof:

[0148] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(2-(1- hydroxyethyl)pyrimidin-4-yl)urea , Example 77, or a pharmaceutically acceptable salt thereof:

[0149] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(2-(1- hydroxyethyl)pyrimidin-4-yl)urea or an isomer thereof (e.g. stereoisomer thereof), Example 78 or Example 79, or a pharmaceutically acceptable salt thereof:

[0150] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(2-methyl-1H- pyrrolo[3,2-b]pyridin-5-yl)urea, Example 80, or a pharmaceutically acceptable salt thereof:

[0151] In certain embodiments, the compound is 1-((S)-8-chlorochroman-4-yl)-3-(2-(2,2,2- trifluoro-1-hydroxyethyl)pyrimidin-4-yl)urea, Example 81, or a pharmaceutically acceptable salt thereof:.

[0152] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(2-(2-methyl- 2H-1,2,3-triazol-4-yl)pyrimidin-4-yl)urea, Example 82, or a pharmaceutically acceptable salt thereof:.

[0153] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6-(2-methyl- 2H-1,2,3-triazol-4-yl)pyrazin-2-yl)urea, Example 83, or a pharmaceutically acceptable salt thereof:.

[0154] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(4-(2-methyl- 2H-1,2,3-triazol-4-yl)pyrimidin-2-yl)urea, Example 84, or a pharmaceutically acceptable salt thereof:.

[0155] In certain embodiments, the compound is (S)-1-(8-chlorochroman-4-yl)-3-(6-(4- (methylsulfonyl)phenyl)pyridin-2-yl)urea, Example 85, or a pharmaceutically acceptable salt thereof:.

[0156] In certain embodiments, the compounds inhibit POL γ.

[0157] In certain embodiments, the compounds promote POL γ.

[0158] The compounds of the present invention may contain asymmetric carbon atoms (sometimes as the result of a deuterium atom) and thereby may 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.

[0159] 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 * or ** refer to a compound that is chiral but the absolute stereochemistry has not been determined.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] In one embodiment, deuterium isotope content at the deuterium substituted position is greater than the natural isotopic deuterium content (0.015%), more preferably greater than 50%, more preferably greater than 60%, more preferably greater than 75%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 97%, morepreferably 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. 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. Additionally, the presence of deuterium may affect how a molecule interacts with enzymes, thereby impacting enzyme kinetics. While in certain cases the increased mass of deuterium as compared to hydrogen may stabilize a compound and thereby improve activity, toxicity, or half-life, such impact is not predictable. In other instances, deuteration may have little to no impact on these properties, or may affect them in an undesirable manner. Whether and / or how such replacement will impact drug properties may only be determined if the drug is synthesized, evaluated, and compared to its non-deuterated counterpart. Because some drugs have multiple sites of metabolism or more than one active sites for binding to a target, it is unpredictable as to which sites may benefit by deuterium replacement or to what extent isotope enrichment is necessary to produce a beneficial effect. EXAMPLES

[0164] The examples and preparations provided below further illustrate and exemplify the compounds 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.

[0165] The structures of the compounds are confirmed by either mass spectrometry or nuclear magnetic resonance spectroscopy (NMR), where peaks assigned to the characteristic protons in the title compound are presented where appropriate.1H NMR shift (δH) are given in parts per million (ppm) down field from an internal reference standard. Acceptable1H NMR shifts and masses are within 5% of the reported values.

[0166] 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: triethylamine (TEA), sodium methoxide (NaOMe), methanol (MeOH), hydrochloric acid (HCl), potassium carbonate (K2CO3), N,N-diisopropylethylamine (DIPEA), dimethylformamide (DMF), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5- b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), lithium hydroxide (LiOH), water (H2O), tetrahydrofuran (THF), dimethylamine (Me2NH), potassium cyanate (KOCN), potassium tert-butoxide (KOtBu), cesium carbonate (Cs2CO3), XPhos-G3- Palladacycle (XPhos Pd G3), lithium diisopropylamide solution (LDA), sodium borohydride (NaBH4), palladium(II) acetate, Pd(OAc)2, 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene(Xantphos), ammonia (NH3), triethylamine (Et3N), palladium(II)bis(triphenylphosphine) dichloride(Pd2(PPh3)2Cl2, tricyclohexylphosphonium tetrafluoroborate (PCy3BF4),trimethyl(trifluoromethyl)silane (TMSCF3), tetrabutylammonium fluoride (TBAF), N- bromosuccinimide (NBS), azobisisobutyronitrile (AIBN), tetrachloromethane (CCl4), sodium thiomethoxide (NaSMe), meta-chloroperoxybenzoic acid (mCPBA), [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), trifluoroacetic acid (TFA), palladium on carbon (Pd-C), sodium cyanoborohydride (NaCNBH3), ammonium acetate (NH4OAc), titanium(IV) ethoxide (Ti(OEt)4), 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine(DBU), tripotassium phosphate (K3PO4), palladium-118 (Pd-118), bis(pinacolato)diboron (B2pin2),potassium acetate (KOAc), n-butyllithium (n-BuLi ), tert-Butyldimethylsilyl trifluoromethanesulfonate (TBSOTF), diethylzinc (Et2Zn), chloroiodomethane, methylamine (MeNH2), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl), 1-Hydroxy-7- azabenzotriazole (HOAt), propylphosphonic anhydride (T3P), phosphorus pentachloride (PCl5), aluminium chloride (AlCl3), iodomethane (CH3I), sodium hydride (NaH), dimethyl ether (DME), hexamethyldisilazane (HMDS), copper iodide (CuI), aqueous (aq.), 1,1’- bis(diphenylphosphino)ferrocene (dppf), butyl lithium (BuLi), calculated (Calcd.), cesium carbonate (Cs2CO3), dichloromethane (DCM, CH2Cl2), dimethyl sulfoxide (DMSO), , 1-ethyl-3- (3- dimethylaminopropyl)carbodiimide (EDC), electrospray ionization (ESI), enantiomeric excess (ee), ethyl acetate (EtOAc), hour (h.), , high performance liquid chromatography (HPLC), , isopropyl alcohol (IPA), lithium hydroxide monohydrate (LiOH HHO), methyl iodide (MeI), minutes (min.), liquid chromatography-mass spectrometry (LCMS), reverse phase (RP), room / ambient temperature (rt, RT), , sodium sulfate (Na2SO3), supercritical fluid chromatography (SFC), triphenylphosphine (PPh3), dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′- biphenyl]-2-yl]phosphane (XPhos).

[0167] The following examples illustrate various non-limiting embodiments of the present disclosure.Chemical Synthesis Example 1: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(1H-pyrrolo[3,2-b]pyridin-5- yl)urea: HScheme 1

[0168] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(1H-pyrrolo[3,2-b]pyridin-5-yl)urea(Example 1) [Step 1]: To a stirred solution of 1H-pyrrolo[3,2-b]pyridin-5-amine hydrochloride (1-1, 96 mg, 0.6) in dichloromethane (8 mL) at -5 °C was added triethylamine (0.32 mL, 2.3 mmol) and triphosgene (60.8 mg, 0.4 mmol). The reaction mixture was stirred at -15 °C for 30 min and (S)-8-chlorochroman-4-amine hydrochloride (1-2), 125 mg, 0.6 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h and volatiles were evaporated. The product was purified by reverse phase preparative HPLC to afford (S)-1-(8-chlorochroman-4-yl)-3-(1H- pyrrolo[3,2-b]pyridin-5-yl)urea (Example 1, 11 mg). LCMS (ESI) Calcd. for C17H15ClN4O2: 342.1, found [M+H]+ = 343.1.1H NMR (400 MHz, DMSO-d6): δH11.19 (s, 1H), 9.50 (brs, 1H), 9.18 (s, 1H), 7.71 (d, 1H), 7.47-7.46 (m, 1H), 7.32 (t, 2H), 7.01 (d, 1H), 6.91 (t, 1H), 6.24-6.22 (m, 1H), 5.11-5.06 (m, 1H), 4.47-4.41 (m, 1H), 4.35-4.29 (m, 1H), 2.25-2.10 (m, 1H), 2.09-2.05 (m, 1H). Example 2: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-methylpyridin-2-yl)urea:

[0169] (S)-1-(8-Chlorochroman-4-yl)-3-(6-methylpyridin-2-yl)urea was synthesized following Scheme 1, step 1 using 6-methylpyridin-2-amine. LCMS (ESI) Calcd. for C16H16ClN3O2: 317.1, found [M+H]+= 318.2.1H NMR (400 MHz, DMSO-d6): δH 9.19 (s, 1H), 8.80 (brs, 1H), 7.57 (t, 1H), 7.33 (d, 1H), 7.28 (d, 1H), 7.19-7.16 (m, 1H), 6.91 (t, 1H), 6.78 (d, 1H), 5.03-4.98 (m, 1H), 4.45-4.39 (m, 1H), 4.29-4.23 (m, 1H), 2.26 (s, 3H), 2.24-2.17 (m, 1H), 2.06-2.00 (m, 1H). Example 3: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(pyridin-2-yl)urea:

[0170] (S)-1-(8-Chlorochroman-4-yl)-3-(pyridin-2-yl)urea was synthesized following Scheme 1, step 1 using pyridin-2-amine hydrochloride. LCMS (ESI) Calcd. for C15H14ClN3O2: 303.1, found [M+H]+= 304.0.1H NMR (400 MHz, DMSO-d6): δH9.18 (s, 1H), 8.50 (d, 1H), 8.13 (d, 1H), 7.69(t, 1H), 7.44 (d, 1H), 7.33 (d, 1H), 7.25 (d, 1H), 6.92-6.88 (m, 2H), 5.04-5.02 (m, 1H), 4.43-4.39 (m, 1H), 4.28-4.24 (m, 1H), 2.19-2.16 (m, 1H), 2.04-2.01 (m, 1H). Example 4: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-methylpicolinamide:

[0171] (S)-6-(3-(8-Chlorochroman-4-yl)ureido)-N-methylpicolinamide was synthesized following Scheme 1, step 1 using 6-amino-N-methyl-pyridine-2-carboxamide. LCMS (ESI) Calcd. for C17H17ClN4O3: 360.1, found [M+H]+= 361.1.1H NMR (400 MHz, DMSO-d6): δH9.03 (s, 1H), 8.15-8.13 (m, 1H), 7.91-7.82 (m, 3H), 7.53 (d, 1H), 7.35-7.27 (m, 2H), 6.91 (t, 1H), 5.01-4.98 (m, 1H), 4.43-4.39 (m, 1H), 4.31-4.26 (m, 1H), 2.75 (d, 3H), 2.19-2.16 (m, 1H), 2.07-2.03 (m, 1H). Example 5: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)picolinamide:

[0172] (S)-6-(3-(8-Chlorochroman-4-yl)ureido)picolinamide was synthesized following Scheme 1, step 1 using 6-aminopicolinamide. LCMS (ESI) Calcd. for C16H15ClN4O33: 346.1, found [M+H]+= 347.1.1H NMR (400 MHz, DMSO-d6): δH 9.04 (s, 1H), 7.89-7.86 (m, 3H), 7.62-7.55 (m, 3H), 7.33-7.26 (m, 2H), 6.92-6.88 (m, 1H), 5.00-4.99 (m, 1H), 4.40-4.27 (m, 2H), 2.16-2.15 (m, 1H), 2.06-2.05 (m, 1H). Example 6: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N- dimethylpicolinamide:

[0173] (S)-6-(3-(8-Chlorochroman-4-yl)ureido)-N,N-dimethylpicolinamide was synthesized following Scheme 1, step 1 using 6-amino-N,N-dimethylpicolinamide. LCMS (ESI) Calcd. for^C18H19ClN4O3: 374.1, found [M+H]+= 375.1.1H NMR (400 MHz, DMSO-d6): δH 9.40 (s, 1H), 8.42 (d, 1H), 7.79 (t, 1H), 7.48 (d, 1H), 7.35 (d, 1H), 7.26 (d, 1H), 7.04 (d, 1H), 6.91 (t, 1H), 5.01-4.98 (m, 1H), 4.46-4.41 (m, 1H), 4.21-4.16 (m, 1H), 2.85 (s, 3H), 2.71 (s, 3H), 2.21-2.13 (m, 1H), 2.05-2.00 (m, 1H). Example 7: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(5-(hydroxymethyl)pyridin-2- yl)urea:

[0174] (S)-1-(8-Chlorochroman-4-yl)-3-(5-(hydroxymethyl)pyridin-2-yl)urea was synthesized following Scheme 1, step 1 using (6-aminopyridin-3-yl)methanol. LCMS (ESI) Calcd. forC16H16ClN3O3: 333.1; found [M+H]+ = 334.2.1H NMR (400 MHz, DMSO-d6): δH 9.15 (s, 1H),8.48 (br, 1H), 8.05 (s, 1H), 7.65-7.62 (m, 1H), 7.42-7.40 (m, 1H), 7.34-7.32 (m, 1H), 7.25-7.24 (m, 1H), 6.92-6.88 (t, 1H), 5.15-5.12 (m, 1H), 5.02-5.01 (m, 1H), 4.39-4.38 (m, 3H), 4.27-4.23 (m, 1H), 2.15 (m, 1H), 2.04 (m, 1H). Example 8: Synthesis of (S)-1-(5-acetylpyridin-2-yl)-3-(8-chlorochroman-4-yl)urea:

[0175] (S)-1-(5-Acetylpyridin-2-yl)-3-(8-chlorochroman-4-yl)urea was synthesized following Scheme 1, step 1 using 1-(6-aminopyridin-3-yl)ethan-1-one. LCMS (ESI) Calcd. for C17H16ClN3O3: 345.1, found [M+H]+= 346.2.1H NMR (400 MHz, DMSO-d6): δH 9.63 (s, 1H), 8.78 (d, 1H), 8.41 (d, 1H), 8.19-8.16 (dd, 1H), 7.60 (d, 1H), 7.34 (d, 1H), 7.26 (d, 1H), 7.91 (t, 1H), 5.03 (q, 1H), 4.42-4.39 (m, 1H), 4.29-4.26 (m, 1H), 2.18-2.16 (m, 1H), 2.06-2.04 (m, 1H). Three methyl protons are merged with solvent residual peak. Example 9: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-ethoxypyridin-2-yl)urea:

[0176] (S)-1-(8-Chlorochroman-4-yl)-3-(6-ethoxypyridin-2-yl)urea was synthesized followingScheme 1, step 1 using 6-ethoxypyridin-2-amine. LCMS (ESI) Calcd. for C17H18ClN3O3: 347.1, [M+H]+= 348.2.1H NMR (400 MHz, DMSO-d6): δH9.25 (s, 1H), 8.58-8.05 (m, 1H), 7.57 (t, 1H), 7.37-7.35 (m, 1H), 7.28-7.26 (m, 1H), 6.91 (t, 1H), 6.83 (d, 1H), 6.27 (d, 1H), 4.97-4.95 (m, 1H), 4.43-4.39 (m, 1H), 4.23-4.17 (m, 1H), 3.83-3.76 (m, 1H), 3.68-3.32 (m, 1H), 2.16-2.03 (m, 2H), 1.07-1.05 (m, 3H). Example 10: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-cyanopyridin-2-yl)urea:

[0177] (S)-1-(8-Chlorochroman-4-yl)-3-(6-cyanopyridin-2-yl)urea was synthesized following Scheme 1, step 1 using 6-aminopicolinonitrile. LCMS (ESI) Calcd. for C16H13ClN4O2: 328.0, [M- H]-= 326.9.1HNMR (400 MHz, DMSO-d6): δH 9.42 (s, 1H), 8.07-8.05 (m, 1H), 7.93 (t, 1H), 7.58 (d, 1H), 7.55-7.53 (m, 1H), 7.35-7.33 (m, 1H), 7.26-7.24 (m, 1H), 6.91 (t, 1H), 5.00-4.95 (m, 1H), 4.43-4.38 (m, 1H), 4.27-4.22 (m, 1H), 2.20-2.14 (m, 1H), 2.05-1.98 (m, 1H). Example 11: Synthesis of (S)-1-(6-(1H-imidazol-2-yl)pyridin-2-yl)-3-(8-chlorochroman-4- yl)urea:Scheme 2.

[0178] To a stirred solution of (S)-1-(8-chlorochroman-4-yl)-3-(6-cyanopyridin-2-yl)urea (Example 10, 130 mg, 0.39 mmol) in methanol (1 mL), 30% sodium methoxide in methanol (2.1mg, 0.04 mmol) was added. The reaction mixture was stirred at 40 °C for 1 h.2,2- Dimethoxyethan-1-amine (2-1, 42 mg, 0.39 mmol) and acetic acid (45 mg, 0.75 mmol) were added and the reaction mixture and was refluxed for 30 min. The reaction mixture was allowed to cool to room temperature and methanol (2 mL) and 6N hydrochloric acid (1.5 mL) were added and refluxed for an additional 12 h. The reaction mixture was concentrated under reduced pressure and pH of solution was adjusted to 3 with the addition of freshly prepared aqueous solution of potassium carbonate, extracted with dichloromethane (70 mL). Combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford (S)-1-(6-(1H-imidazol-2-yl)pyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (Example 11, 92 mg). LCMS(ESI) Calcd. for C18H16ClN5O2: 369.1, [M+H]+= 370.2.1H NMR (400 MHz, DMSO-d6): δH 12.36 (s, 1H), 8.99 (s, 1H), 8.59-8.57 (m, 1H), 7.77 (t, 1H), 7.54-7.52 (m, 1H), 7.49-7.47 (m, 1H), 7.32- 7.28 (m, 2H), 7.23 (s, 1H), 7.03 (s, 1H), 6.87 (t, 1H), 5.05-5.00 (m, 1H), 4.41-4.39 (m, 2H), 2.20-2.06 (m, 2H). Examples 12-14: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N,3- trimethylpicolinamide, (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-methylpicolinic acid, and (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N,3-trimethylpicolinamide:Scheme 3.

[0179] Synthesis of methyl 6-amino-3-methylpicolinate (3-2) [Step 1]: A solution of methyl 6-amino-3-bromo-pyridine-2-carboxylate (3-1, 1.0 g, 4.33 mmol) and potassium carbonate (1.2 g, 8.7 mmol) in dry 1,4-dioxane (10 mL) was degassed with argon for 15 min followed by the addition of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.6 mL, 4.33 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (177 mg, 0.22 mmol).The reaction mixture was heated at 80 °C for 16 h. Reaction mixture was cooled to ambient temperature, filtered through celite and the filtrate was concentrated under reduced pressure. The product was purified by combiflash collumn chromatography to afford methyl 6-amino-3- methyl-pyridine-2-carboxylate (3-2, 600 mg). LCMS (ESI) Calcd. for C8H10N2O2: 166.0, found [M+H]+= 167.0.1H NMR (400 MHz, DMSO-d6): δH 7.59 (d, 1H), 6.72 (d, 1H), 5.29-5.20 (m, 2 H), 3.94 (s, 3H), 2.44 (s, 3 H).

[0180] Synthesis of methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-methylpicolinate (Example 12) [Step 2]: Methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-methylpicolinate (Example 12) was synthesized following Scheme 3, step 2 using 6-amino-3-methyl-pyridine-2- carboxylate. LCMS (ESI) Calcd. for C18H18ClN3O4: 375.1, found [M+H]+= 376.2.1H NMR (DMSO-d6): δH 9.60 (s, 1H), 9.26 (s, 1H), 7.70 (d, 1H), 7.35-7.25 (m, 3H), 6.90 (t, 1H), 5.06-5.01 (m, 1H), 4.47-4.43 (m, 1H), 4.26-4.22 (m, 1H), 3.56 (s, 3H), 2.39 (s, 3H), 2.21-2.14 (m, 1H), 2.02-1.98 (m, 1H).

[0181] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-methylpicolinic acid (Example 13) [Step 3]: To a solution of methyl methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3- methylpicolinate (Example 12, 120 mg, 0.32 mmol) in THF-MeOH-H2O (3:1:1) was added LiOH.H2O (20 mg, 0.48 mmol) at ambient temperature, stirred for 16 h and concentrated under reduced pressure. The aquoues phase was acidified with saturated NaHSO4solution and extracted with 5% THF in ethyl acetate. Combined organic extracts were dried over anhydrous Na2SO4and concentrated to afford (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-methylpicolinic acid (Example 13, 100 mg). LCMS (ESI) Calcd. for C17H16ClN3O4: 361.08, found [M-H]- = 360.2.1H NMR (400 MHz, DMSO-d6): δH13.07 (s, 1H), 9.45 (s, 1H), 9.06 (s, 1H), 7.66 (d, 1H), 7.37-7.26 (m, 3H), 6.88 (t, 1H), 5.07-5.04 (m, 1H), 4.39-4.31 (m, 2H), 2.38 (s, 3H), 2.18-2.12 (m, 1H), 1.99-1.90 (m, 1H).

[0182] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N,3-trimethylpicolinamide (Example 14) [Step 4]: To a solution of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-methylpicolinic acid (Example 13, 120 mg, 0.33 mmol) in dry DMF (4.5 mL) were added HATU (151 mg, 0.398 mmol) and DIPEA (0.24 mL, 1.33 mmol) at 0 °C, followed by the addition of dimethylamine in THF (2M) (0.83 mL, 1.7 mmol) at the same temperature. The reaction mixture was stirred at ambient temperature for 16 h, quenched with ice-cold water and extracted with ethyl acetate (3 x 50 mL). Combined organic extracts were washed with cold brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N,3-trimethylpicolinamide (Example 14, 17 mg). LCMS (ESI) Calcd for C19H21ClN4O3: 388.1, found [M+H]+= 389.2.1H NMR (400 MHz, DMSO-d6): δH 9.28 (s, 1H), 8.36 (s, 1H), 7.63 (d, 1H), 7.39- 7.34 (m, 2H), 7.26 (d, 1H), 6.92-6.89 (m, 1H), 4.96-4.95 (m, 1H), 4.44-4.41 (m, 1H), 4.21-4.14 (m, 1H), 2.87 (s, 3H), 2.59 (s, 3H), 2.16-2.14 (m, 1H), 2.08 (s, 3H), 2.02-1.86 (m, 1H). Example 15: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-cyclopropoxypyridin-2- yl)urea:Scheme 4.

[0183] Synthesis of (S)-1-(8-chlorochroman-4-yl)urea [Step 1]: To a stirred solution of (S)-8- chlorochroman-4-amine.hydrochloric acid salt (4-1, 200 mg, 1.1 mmol) in 20% aqueous HCl (5 mL) was added KOCN (883 mg, 10.9 mmol) in water (5 mL) dropwise at -5 °C and allowed the reaction mixture to stir at ambient temperature for 48 h. The precipitate was filtered and dried under reduced pressure to afford (S)-1-(8-chlorochroman-4-yl)urea (4-2, 200 mg). LCMS (ESI) Calcd. for C10H11ClN2O2: 226.1, found [M+H]+= 227.1.1H NMR (400 MHz, DMSO-d6): δH 7.29 (d, 1H), 7.18 (d, 1H), 6.88 (t, 1H), 6.52 (d, 1H), 5.50 (s, 2H), 4.81-4.79 (m, 1H), 4.34-4.31 (m, 1H), 4.25-4.22 (m, 1H), 2.04-2.02 (m, 2H), 1.91-1.88 (m, 2H).

[0184] Synthesis of 2-bromo-6-cyclopropoxypyridine, 4-5 [Step 2]: To a stirred solution of cyclopropanol (4-3, 860 mg, 14.8 mmol) in THF (25 mL) at 0 °C was added potassium tert- butoxide (1.91 g, 17.0 mmol). After 15 min, 2-bromo-6-fluoro-pyridine (4-4, 2.0 g, 11.4 mmol) was added. The reaction mixture was stirred for at ambient temperature for 14 h, diluted with ethyl acetate and washed with water followed by brine. Combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated. The product was purified bycolumn chromatography to afford 2-bromo-6-(cyclopropoxy)pyridine (4-5, 700 mg). LCMS (ESI) Calcd. for C8H8BrNO: 212.98, found [M+H]+= 214.2.1H NMR (400 MHz, DMSO-d6): δH 7.68 (t, 1H), 7.26 (d, 1H), 6.92 (d, 1H), 4.19-4.15 (m, 1H), 0.81-0.73 (m, 2H), 0.72-0.66 (m, 2H).

[0185] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-cyclopropoxypyridin-2-yl)urea (Example 15) [Step 3]: A stirred solution of (S)-1-(8-chlorochroman-4-yl)urea (4-2, 150 mg, 0.66 mmol), 2-bromo-6-(cyclopropoxy)pyridine (4-5, 184 mg, 0.86 mmol) and cesium carbonate (431 mg, 1.32 mmol) in 1,4-dioxane (12 mL) was purged with argon. After 5 min, Xphos Pd G3 (56 mg, 0.07 mmol) was added. Resulting reaction mixture was stirred at 80oC for 4 h, filtered through a celite bed and evaporated. The residue was diluted with ethyl acetate, washed with water followed by brine. Combined organic extracts were dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford (S)-1-(8-chlorochroman-4-yl)-3-(6-cyclopropoxypyridin-2- yl)urea (Example 15, 73 mg). LCMS (ESI) Calcd. for C18H18ClN3O3: 359.10, found [M+H]+= 360.23.1H NMR (400 MHz, DMSO-d6): δH9.38 (s, 1H), 8.87 (brs, 1H), 7.58 (t, 1H), 7.34 (d, 1H), 7.28 (d, 1H), 6.90 (t, 1H), 6.79 (d, 1H), 6.30 (d, 1H), 5.00-4.98 (m, 1H), 4.43-4.40 (m, 1H), 4.25-4.20 (m, 1H), 3.46-3.43 (m, 1H), 2.18-2.12 (m, 1H), 2.07-2.04 (m, 1H), 0.52-0.46 (m, 2H), 0.27-0.23 (m, 1H), 0.15-0.11 (m, 1H). Example 16: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(pyrrolidin-1-yl)pyridin-2- yl)urea:

[0186] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(pyrrolidin-1-yl)pyridin-2-yl)urea (Example 16): ((S)-1-(8-Chlorochroman-4-yl)-3-(6-(pyrrolidin-1-yl)pyridin-2-yl)urea was synthesized following Scheme 4, step 3 using 2-bromo-6-pyrrolidin-1-yl-pyridine. LCMS (ESI) Calcd. for C19H21ClN4O2: 372.1, found [M+H]+= 373.3.1H NMR (400 MHz, DMSO-d6): δH9.90- 9.89 (m, 1H), 9.19 (s, 1H), 7.36-7.30 (m, 2H), 7.24 (d, 1H), 6.89 (t, 1H), 6.12 (d, 1H), 5.87 (d, 1H), 4.92-4.90 (m, 1H), 4.44-4.42 (m, 1H), 4.21-4.15 (m, 1H) ,2.93-2.92 (m, 2H), 2.75-2.67 (m, 2H), 2.10-2.08 (m, 2H), 1.71-1.68 (m, 4H). Examples 17 & 18: Synthesis of 11-((S)-8-Chlorochroman-4-yl)-3-(6-((S)-2- hydroxypropyl)pyridin-2-yl)urea (isomer 1) and 1-((S)-8-Chlorochroman-4-yl)-3-(6-((R)-2- hydroxypropyl)pyridin-2-yl)urea (isomer 2):Scheme 5.

[0187] Synthesis of 1-(6-bromopyridin-2-yl) propan-2-one (5-3) [Step 1]: To a stirred solution of 2-bromo-6-methyl-pyridine (5-1, 2.5 g, 14.5 mmol) in THF (75 mL) at -78oC under argon atmosphere was added lithium di-isopropyl amide (2M) in THF (15 mL, 29.1 mmol) dropwise and stirred the reaction mixture at -78oC. After 1 h, a solution of N-methoxy-N-methyl- acetamide (5-2, 3.0 g, 29.1 mmol) in THF (10 mL) was added dropwise and allowed the reaction mixture to stir at -78 °C ambient temperature for another 3 h. The reaction mixture was quenched with water and extracted with ethyl acetate. Combined organic extracts were dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure. The product was purified by column chromatography to afford 1-(6-bromopyridin-2-yl) propan-2-one (5-3, 1.0 g). LCMS (ESI) Calcd. for C8H8BrNO: 213.0, found [M+H]+= 214.0.1H NMR (400 MHz, DMSO- d6): δH7.54 (t, 1H), 7.41 (d, 1H), 7.19 (d, 1H), 3.95 (s, 2H), 2.26 (s, 3H).

[0188] Synthesis of 1-(6-bromopyridin-2-yl) propan-2-ol (5-4) [Step 2]: To a stirred solution of 1-(6-bromopyridin-2-yl) propan-2-one (5-3, 1.0 g, 4.7 mmol) in methanol (20 mL) at 0 °C was added sodium borohydride (177 mg, 4.7 mmol) and stirred the reaction mixture at 25 °C for 2 h. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate, and washed with water followed by brine. Combined organic extracts were dried over anhydrous sodium sulphate and concentrated. The product was purified by column chromatography to afford 1-(6-bromopyridin-2-yl) propan-2-ol (5-4, 700 mg). LCMS (ESI) Calcd. for C8H10BrNO: 215.0, found [M+H]+= 215.9.1H NMR (400 MHz, DMSO-d6): δH7.65 (t, 1H), 7.45 (d, 1H), 7.30 (d, 1H), 4.64 (d, 1H), 4.01-3.95 (m, 1H), 2.78-2.69 (m, 2H), 1.08 (d, 3H).

[0189] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-2-hydroxypropyl) pyridin-2-yl) urea (Example 17) and 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-2-hydroxypropyl) pyridin-2-yl) urea (Example 18) [Step 3]: 1-((S)-8-Chlorochroman-4-yl)-3-(6-((S)-2-hydroxypropyl) pyridin-2-yl) urea (Example 17) and 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-2-hydroxypropyl) pyridin-2-yl)urea (Example 18) was synthesized following Scheme 4, step 3 using 1-(6-bromopyridin-2-yl) propan-2-ol (5-4). Both the diastereomers were separated via chiral SFC separation.

[0190] 1-((S)-8-Chlorochroman-4-yl)-3-(6-((S)-2-hydroxypropyl)pyridin-2-yl)urea (Example 17) [Peak-1]: LCMS (ESI) Calcd. for C18H20ClN3O3: 361.1, found [M+H]+= 362.1.1H NMR (400 MHz, DMSO-d6): δH 9.29 (s,1H), 9.13 (brs, 1H), 7.57 (t, 1H), 7.34-7.32 (m, 1H), 7.26 (d, 1H), 7.07 (d, 1H), 6.89 (t, 1H), 6.75 (d, 1H), 5.03-4.98 (m, 1H), 4.50-4.48 (m, 1H), 4.45-4.40 (m, 1H), 4.27-4.21 (m, 1H), 3.72-3.68 (m, 1H), 2.61-2.56 (m, 1H), 2.50-2.43 (m, 1H), 2.19-2.15 (m, 1H), 2.05-2.00 (m, 1H), 0.90 (d, 3H).

[0191] 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-2-hydroxypropyl)pyridin-2-yl)urea (Example 18) [Peak-2]: LCMS (ESI) Calcd. for C18H20ClN3O3: 361.1, found [M+H]+= 362.1.1H NMR (400 MHz, DMSO-d6): δH 9.29 (s, 1H), 9.13 (brs, 1H), 7.57 (t, 1H), 7.35-7.32 (m, 1H), 7.26 (d, 1H), 7.07 (d, 1H), 6.90 (t, 1H), 6.75 (d, 1H), 5.00-4.98 (m, 1H), 4.50-4.48 (m, 1H), 4.45-4.38 (m, 1H), 4.27-4.22 (m, 1H), 3.77-3.74 (m, 1H), 2.62-2.56 (m, 1H), 2.50-2.43 (m, 1H), 2.19-2.15 (m, 1H), 2.05-2.00 (m, 1H), 0.90 (d, 3H).

[0192] Chiral prepataive HPLC method: Chiral separation was performed on Agilent 1200series instrument. Column name: CHIRALPAK IG (250 X 30 mm) 5µ. Operating at ambienttemperature and flow rate was maintained at 27 mL / min. Mobile phase was mixture of 75%Hexane, 25% EtOH, held this isocratic mixture run up to 25 min at 232 nm.Example 19 - Synthesis of 2-[6-[[rac-(4S)-8-chlorochroman-4-yl]carbamoylamino]-2- pyridyl]acetamide:Scheme 6.

[0193] Synthesis of methyl (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)acetate (6-3) [Step 1]: To a solution of (S)-1-(8-chlorochroman-4-yl)urea (6-1, 225 mg, 0.993 mmol) in 1,4-dioxane (3 mL) was added Cs2CO3(807 mg, 2.5 mmol) and the reaction mixture was degassed with argon. After 15 min, methyl 2-(6-bromo-2-pyridyl)acetate (6-2, 297 mg, 1.3 mmol), Xantphos (115 mg, 0.199 mmol) and Pd(OAc)2(22 mg, 0.10 mmol) at the ambient temperature. The reaction mixture was heated at 80 °C for 16 h, filtered through celite and the filtrate was concentrated under reduced pressure. The product was purified by combiflashcolumn chromatography to afford methyl (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2- yl)acetate (6-3, 170 mg). LCMS (ESI) Calcd. for C18H18ClN3O4: 375.10, found [M+H]+= 376.1H NMR (400 MHz, DMSO-d6): δH 9.33 (s, 1H), 8.76 (s,1 H), 7.67-7.63 (m, 1H), 7.33 (d, 1H), 7.25 (d, 2H), 6.91-6.87 (m, 2H), 5.04-5.03 (m, 1H), 4.42-4.38 (m, 1H), 4.29-4.24 (m, 1H), 3.69 (s, 2H), 3.45 (s, 3H), 2.19-2.16 (m, 1H), 2.04-2.01 (m, 1H).

[0194] Synthesis of (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)acetamide (Example 19) [Step 2]: A solution of methyl (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2- yl)acetate (6-3, 70 mg, 0.19 mmol) and NH3 in MeOH (7M) (2.0 mL) in a sealed tube heated at 80 °C for 16 h. The reaction mixture was allowed cool to room temperature and volatiles were evaporated under reduced pressure. The product was purified by revesre phase preparative HPLC to afford (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)acetamide (Example 19, 20 mg). LCMS (ESI) Calcd. for C17H17ClN4O3: 360.1, found [M+H]+= 361.2.1H NMR (400 MHz, DMSO-d6): δH9.23 (s, 1H), 8.65 (s, 1H), 7.62 (t, 1H), 7.39 (s, 1H), 7.32-7.22 (m, 3H), 6.90-6.84 (m, 3H), 5.05-5.02 (m, 1H), 4.40-4.29 (m, 2H), 3.43 (s, 2H), 2.20-2.09 (m, 2H). Examples 20 & 21 - Synthesis of ethyl (S)-2-((6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2- yl)oxy)acetate and (S)-2-((6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)oxy)acetamide:Scheme 7.

[0195] Synthesis of ethyl 2-((6-chloropyridin-2-yl)oxy)acetate (7-3) [Step 1]: To a stirred solution of 6-chloropyridin-2-ol (7-1, 1.0 g, 7.72 mmol) in acetone (15 mL) was added K2CO3(1.6 g, 11.6 mmol) and the reaction mixture was allowed to reflux at 60 °C for 20 min. Ethyl bromo acetate (7-2, 1.0 mL, 9.26 mmol) was added to the reaction mixture and was furtherheated at 60 °C for 5 h. The reaction mixture was allowed to cool, filtered, and concentrated under reduced pressure, diluted with water, and extracted with dichloromethane. Combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get crude. The product was purified by column chromatography to afford ethyl 2-((6-chloropyridin-2-yl)oxy)acetate (7-3, 1.1 g). LCMS (ESI) Calcd. for^C9H10ClNO3: 215.0, found[M+H]+= 216.0.

[0196] Synthesis of ethyl (S)-2-((6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2- yl)oxy)acetate (Example 20) [Step 2]: Ethyl (S)-2-((6-(3-(8-chlorochroman-4-yl)ureido)pyridin- 2-yl)oxy)acetate was synthesized following Scheme 6, step 1. LCMS (ESI) Calcd. for C19H20ClN3O5: 405.1, found [M+H]+= 406.2.1H NMR (400 MHz, DMSO-d6): δH 8.77 (s, 1H), 7.64 (t, 1H), 7.59 (d, 1H), 7.31 (t, 2H), 7.23 (d, 1H), 6.90 (t, 1H), 6.43 (d, 1H), 4.97-4.95 (m, 1H), 4.71 (s, 2H) 4.41-4.37 (m, 1H), 4.26-4.25 (m, 1H), 4.07-4.03 (m, 2H), 2.17-2.13 (m, 1H), 2.02- 1.98 (m, 1H), 1.13 (t, 3H).

[0197] Synthesis of (S)-2-((6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)oxy)acetamide (Example 21) [Step 3]: In a sealed tube, ethyl (S)-2-((6-(3-(8-chlorochroman-4-yl)ureido)pyridin- 2-yl)oxy)acetate (Example 20, 100 mg, 0.246 mmol) and a solution of NH3in methanol (3M, 4.0 mL) was heated at 70 °C for 16 h. Reaction mixture was cooled to ambient temperature and concentrated. The product was purified by reverse phase preparative HPLC to afford (S)-2-((6- (3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)oxy)acetamide (Example 21, 58 mg). LCMS (ESI) Calcd for C17H17ClN4O4= 376.1, found [M+H]+= 377.2.1H NMR (400 MHz, DMSO-d6): δH8.77 (s, 1H), 7.63 (t, 1H), 7.55 (d, 1H), 7.35-7.30 (m, 3H), 7.24-7.22 (m, 2H), 6.89 (t, 1H), 6.42 (d, 1H), 4.96-4.95 (m, 1H), 4.48 (s, 2H), 4.38-4.25 (m, 2H), 2.30-1.90 (m, 2H). Examples 22-27 - Synthesis of substituted pyridinyl chlorochromanyl urea:Scheme 8.

[0198] Synthesis of (S)-1-(6-bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (8-3) [Step 1]: (S)-1-(6-Bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (8-3) was synthesized following Scheme 1, step 1 using 6-bromopyridin-2-amine. LCMS (ESI) Calcd. for^C15H13BrClN3O2: 380.9, found [M+H]+= 382.0.1H NMR (400 MHz, DMSO-d6): δH9.33 (s, 1H), 7.72 (d, 1H), 7.65 (t, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 7.25 (d, 1H), 7.17 (d, 1H), 6.91 (t, 1H), 5.00-4.95 (m, 1H), 4.44-4.39 (m, 1H), 4.27-4.22 (m, 1H), 2.21-2.14 (m, 1H), 2.03-1.96 (m, 1H).

[0199] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-cyclopropylpyridin-2-yl)urea (Example 22) [Step 2]: To a stirred solution of (S)-1-(6-bromopyridin-2-yl)-3-(8-chlorochroman- 4-yl)urea (8-3, 150 mg, 0.4 mmol) in toluene and water (3:1) were added K3PO4(500 mg, 2.4 mmol), PCy3.BF4(45 mg, 0.1 mmol) and purged with nitrogen gas. After 10 min., cyclopropylboronic acid (8-4, 70 mg, 0.8 mmol) and Pd(OAc)2(25 mg, 0.1 mmol) were added and allowed to stir at 110oC for 16 h. The solvents were evaporated under reduced pressure and the residue was diluted with ethyl acetate, washed with 0.2N HCl and brine. Combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated underreduced pressure. The product was purified by reverse phase preparative HPLC to afford (S)-1- (8-chlorochroman-4-yl)-3-(6-cyclopropylpyridin-2-yl)urea (Example 22, 20 mg). LCMS (ESI) Calcd. for^C18H18ClN3O2: 343.1, found [M+H]+= 344.2.1H NMR (400 MHz, DMSO-d6): δH 9.30 (s, 1H), 9.10 (d, 1H), 7.50 (t, 1H), 7.36-7.33 (m, 1H), 7.24 (d, 1H), 6.90 (t, 2H), 6.85 (d, 1H), 4.98-4.96 (m, 1H), 4.42-4.41 (m, 1H), 4.22 (t, 1H), 2.16-2.15 (m, 1H), 2.04-2.03 (m, 1H), 1.88- 1.85 (m, 1H), 0.77-075 (m, 1H), 0.62-0.60 (m, 1H), 0.53-0.52 (m, 1H), 0.24-0.23 (m, 1H).

[0200] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(hydroxymethyl)pyridin-2-yl)urea (Example 23) & (S)-1-(chroman-4-yl)-3-(6-(hydroxymethyl)pyridin-2-yl)urea (Example 24) [Step 3]: A stirred solution of (S)-1-(6-bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (8-3, 200 mg, 0.5 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen. After 10 min., tributylstannylmethanol (8-6, 220 mg, 0.7 mmol), XPhos-Pd-G3 (130 mg, 0.16 mmol) were added and allowed the reaction mixture to stir at 80 °C for 6 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. Combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford the first product (S)-1-(8-chlorochroman-4- yl)-3-(6-(hydroxymethyl)pyridin-2-yl)urea as peak-1 (Example 23, 9.0 mg) and the second product (S)-1-(chroman-4-yl)-3-(6-(hydroxymethyl)pyridin-2-yl)urea as peak-2 (Example 24, 16 mg).

[0201] (S)-1-(8-chlorochroman-4-yl)-3-(6-(hydroxymethyl)pyridin-2-yl)urea (Example 23) [Peak-1]: LCMS (ESI) Calcd. for^C16H16ClN3O3: 333.1, found [M+H]+= 334.2.1H NMR (400 MHz, DMSO-d6): δH9.23 (s, 1H), 8.77 (s, 1H), 7.67 (t, 1H), 7.34-7.31 (m, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 6.98 (d, 1H), 6.90 (t, 1H), 5.31 (t, 1H), 5.03-4.98 (m, 1H), 4.43-4.33 (m, 1H), 4.32 (d, 2H), 4.29-4.24 (m, 1H), 2.22-2.15 (m, 1H), 2.06-2.02 (m, 1H).

[0202] (S)-1-(chroman-4-yl)-3-(6-(hydroxymethyl)pyridin-2-yl)urea (Example 24) [Peak-2]: LCMS (ESI) Calcd. for^C16H17N3O3: 299.1, found [M+H]+= 300.2.1H NMR (400 MHz, DMSO-d6): δH9.19 (s, 1H), 8.69 (s, 1H), 7.67 (t, 1H), 7.29 (d, 1H), 7.23 (d, 1H), 7.16 (t, 1H), 6.98 (d, 1H), 6.88 (t, 1H), 6.80 (d, 1H), 5.30 (t, 1H), 4.97-4.92 (m, 1H), 4.32 (d, 2H), 4.28-4.26 (m, 1H), 4.15 (t, 1H), 2.19-2.13 (m, 1H), 2.00-1.94 (m, 1H).

[0203] Synthesis of (S)-1-(6-acetylpyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (Example 25) [Step 4]: A stirred solution of (S)-1-(6-bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (8-3, 100 mg, 0.3 mmol) in 1,4-dioxane (3 mL) was added tributyl(1-ethoxyvinyl)stannane (8-9, 90 mg, 0.4 mmol) and purged with nitrogen gas. After 10 min., Pd(PPh3)2Cl2 (50 mg, 0.08 mmol) was added and continued stirring at 90 °C for 16 h. The reaction mixture was acidified with 1N HCl(1 mL) at 20 °C and continued stirring for 2 h and filtered through celite pad. Combined filtrates were washed with water, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford (S)-1-(6-acetylpyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (Example 25, 20 mg). LCMS (ESI) Calcd. for^C17H16ClN3O3: 345.1, found [M+H]+= 346.2.1H NMR (400 MHz, DMSO- d6 at 100oC): δH 9.20 (s, 1H), 8.33 (d, 1H), 7.85 (t, 1H), 7.70 (d, 1H), 7.50 (d, 1H), 7.31-7.28 (m, 2H), 6.89 (t, 1H), 5.07-5.02 (m, 1H), 4.49-4.39 (m, 1H), 4.34-4.25 (m, 1H), 2.30 (s, 3H), 2.25- 2.18 (m, 1H), 2.13-2.08 (m, 1H).

[0204] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-(1-hydroxyethyl)pyridin-2-yl)urea (Example 26) & (Example 27) [Step 5]: To a stirred solution of (S)-1-(6-acetylpyridin-2-yl)-3-(8- chlorochroman-4-yl)urea (Example 25, 200 mg, 0.6 mmol) in methanol (6 mL) at 0oC was added NaBH4 (70 mg, 1.7 mmol) potion wise and continued stirring at 0oC for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. Combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The product was initially purified by reverse phase preparative HPLC then by preparative chiral HPLC (SFC) to afford the first product 1-((S)-8- chlorochroman-4-yl)-3-(6-((R)-1-hydroxyethyl)pyridin-2-yl)urea (Example 26, 15 mg) as peak 1 and the second product 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-1-hydroxyethyl)pyridin-2-yl)urea (Example 27, 23 mg) as peak 2.

[0205] 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-1-hydroxyethyl)pyridin-2-yl)urea (11) [Peak- 1]: LCMS (ESI) Calcd. for^C17H18ClN3O3: 347.1, found [M+H]+= 348.2.1H NMR (400 MHz, DMSO-d6): δH9.33 (s, 1H), 9.13 (brs, 1H), 7.65 (t, 1H), 7.34 (d, 1H), 7.28 (d, 1H), 7.11 (d, 1H), 7.00 (d, 1H), 6.89 (t, 1H), 5.26 (d, 1H), 5.01 (d, 1H), 4.42-4.39 (m, 2H), 4.25 (t, 1H), 2.17-2.16 (m, 1H), 2.05-2.03 (m, 1H), 1.12 (d, 3H).

[0206] 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-1-hydroxyethyl)pyridin-2-yl)urea (12) [Peak- 2]: LCMS (ESI) Calcd. for^C17H18ClN3O3: 347.1, found [M+H]+= 348.2.1H NMR (400 MHz, DMSO-d6): δH9.33 (s, 1H), 9.12 (brs, 1H), 7.65 (t, 1H), 7.34 (d, 1H), 7.27 (d, 1H), 7.11 (d, 1H), 7.00 (d, 1H), 6.89 (t, 1H), 5.26 (d, 1H), 5.01 (d, 1H), 4.44-4.42 (m, 2H), 4.25 (t, 1H), 2.17-2.16 (m, 1H), 2.04-2.01 (m, 1H), 1.09 (d, 3H).

[0207] PREP-HPLC (SFC) method: Chiral separation was performed on Waters SFC 80 instruments equipped with Waters 2489 UV / Visible detector by using I-Cellulose-J (30.0 mm x 250mm), 5µ column operating at 35oC temperature, maintaining flow rate of 60 mL / min, using50% CO2 in super critical state and 50% of 100% methanol as mobile phase. Run this isocraticmixture up to 20 min maintaining the isobaric condition of 120 bar at 286 nm wavelength.Example 28: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-hydroxyethyl)-N- methylpicolinamide:Scheme 9.

[0208] Synthesis of methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)picolinate (9-3) [Step 1]: Methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)picolinate (9-3) was synthesized following Scheme 1, step 1 using methyl 6-aminopicolinate (9-2). LCMS (ESI) Calcd. for^C17H16ClN3O4: 361.1, found [M+H]+= 362.1.1H NMR (400 MHz, DMSO-d6): δH 9.75 (s, 1H), 9.25 (s, 1H), 7.87 (t, 1H), 7.59 (d, 1H), 7.45 (d, 1H), 7.34 (d, 1H), 7.27 (d, 1H), 6.90 (t, 1H), 5.07-5.04 (m, 1H), 4.47-4.44 (m, 1H), 4.32-4.28 (m, 1H), 3.68 (s, 3H), 2.22-2.17 (m, 1H), 2.02-2.00 (m, 1H).

[0209] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)picolinic acid (9-4) [Step 2]: To a stirred solution of methyl 6-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyridine-2- carboxylate (9-3, 280 mg, 0.77 mmol) in THF (3 mL), methanol (1 mL) and water (1 mL) was added LiOH.H2O (49 mg, 1.16 mmol). The reaction mixture was stirred at ambient temperature for 16 h and volatiles were evaporated. The aqueous phase was acidified with sodium bisulfate and extracted with 10% methanol in dichloromethane. Combined organic extracts were dried over anhydrous sodium sulphate, filtered and dried under reduced pressure to afford (S)-6-(3- (8-chlorochroman-4-yl)ureido)picolinic acid (9-4, 220 mg). LCMS (ESI) Calcd. for C16H14ClN3O4: 347.1, found [M+H]+= 348.0.1H NMR (400 MHz, DMSO-d6): δH 13.20 (s, 1H), 9.66 (s, 1H),9.29 (s, 1H), 7.85 (t, 1H), 7.57 (d, 1H), 7.47 (d, 1H), 7.29 (t, 2H), 6.88 (t, 1H), 5.10-5.05 (m, 1H), 4.43-4.34 (m, 2H), 2.24-2.18 (m, 1H), 2.01-1.98 (m, 1H).

[0210] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-hydroxyethyl)-N- methylpicolinamide (Example 28) [Step 3]: To a solution of (S)-6-(3-(8-chlorochroman-4- yl)ureido)picolinic acid (9-4, 110 mg, 0.32 mmol) in dry DMF (4 mL) under inert atmosphere at room temperature, HATU (180 mg, 0.47 mmol) and DIPEA (0.14 mL, 0.79 mmol) were added. The reaction mixture was stirred for 5 min and reaction mixture 2-(methylamino)ethan-1-ol (9-5, 29 mg, 0.38 mmol) was added and stirred at ambient temperature for additional 4 h, diluted with extracted with ethyl acetate (50 mL), and washed with ice-cold water and brine. Combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford (S)-6-(3-(8- chlorochroman-4-yl)ureido)-N-(2-hydroxyethyl)-N-methylpicolinamide (Example 28, 50 mg). LCMS (ESI) calcd. for C19H21ClN4O4 = 404.1, found [M+H]+= 405.2.1H NMR (400 MHz, DMSO- d6 at 100 °C): δH 9.01 (s, 1H), 8.04 (d, 1H), 7.76 (t, 1H), 7.58 (d, 1H), 7.31-7.25 (m, 2H), 7.03 (d, 1H), 6.88 (m, 1H), 5.03- 4.98 (m, 1H), 4.44-4.39 (m, 1H), 4.33 (s, 1H), 4.28-4.23 (m, 1H), 3.50 (s, 2H), 3.33 (s, 2H), 2.97-2.90 (m, 3H), 2.19–2.14 (m, 1H), 2.03-2.00 (m, 1H). Example 29: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- (dimethylamino)ethyl)picolinamide:

[0211] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- (dimethylamino)ethyl)picolinamide (Example 29): (S)-6-(3-(8-Chlorochroman-4-yl)ureido)-N-(2-(dimethylamino)ethyl)picolinamide was synthesized following Scheme 9, step 3 using N1,N1-dimethylethane-1,2-diamine. LCMS (ESI) Calcd. for C20H24ClN5O3: 417.1, found [M+H]+= 418.3.1H NMR (400 MHz, DMSO-d6): δH9.03 (s, 1H), 8.08-8.05 (m, 1H), 7.96 (d, 1H), 7.87 (t, 1H), 7.63 (d, 1H), 7.57 (d, 1H), 7.33 (d, 1H), 7.26 (d, 1H), 6.90 (t, 1H), 5.01-4.96 (m, 1H), 4.43- 4.38 (m, 1H), 4.30-4.24 (m, 1H), 3.36-3.32 (m ,2H), 2.35-2.32 (m, 2H), 2.18-2.14 (m, 7H), 2.06- 2.02 (m, 1H). Example 30: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- hydroxyethyl)picolinamide

[0212] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- hydroxyethyl)picolinamide (Example 30): (S)-6-(3-(8-Chlorochroman-4-yl)ureido)-N-(2- hydroxyethyl)picolinamide was synthesized following Scheme 9, step 3 using 2-aminoethan-1- ol. LCMS (ESI) Calcd. for C18H19ClN4O4: 390.1, found [M+H]+= 391.1.1H NMR (400 MHz, DMSO-d6): δH9.06 (s, 1H), 8.17 (t, 1H), 7.98 (d,1H), 7.88 (t, 1H), 7.58-7.54 (m, 1H), 7.53-7.52 (m, 1H), 7.34-7.32 (m, 1H), 7.27-7.24 (m,1H), 6.90 (t, 1H), 5.00-4.96 (m, 1H), 4.82 (t, 1H), 4.43-4.38 (m, 1H), 4.29-4.23 (m, 1H), 3.50-3.46 (m, 2H), 3.35-3.30 (m, 2H), 2.182.06 (m, 1H), 2.03- 1.98 (m, 1H). Example 31: Synthesis of (S)-N-(2-amino-2-oxoethyl)-6-(3-(8-chlorochroman-4-yl)ureido)- N-methylpicolinamide

[0213] Synthesis of (S)-N-(2-amino-2-oxoethyl)-6-(3-(8-chlorochroman-4-yl)ureido)-N-methylpicolinamide (Example 31): (S)-N-(2-Amino-2-oxoethyl)-6-(3-(8-chlorochroman-4-yl)ureido)-N-methylpicolinamide was synthesized following Scheme 9, step 3 using 2- (methylamino)acetamide hydrochloride. LCMS (ESI) Calcd for C19H20ClN5O4: 417.12, found [M+H]+= 418.2.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 8.99 (s, 1H), 7.94 (d, 1H), 7.77 (t, 1H), 7.62 (d, 1H), 7.28 (t, 2H), 7.06 (d, 1H), 6.91-6.83 (m, 3H), 5.01-5.00 (m, 1H), 4.43-4.38 (m, 1H), 4.30-4.24 (m, 1H), 3.92 (s, 2H), 2.90 (s, 3H), 2.22-2.17 (m, 1H), 2.10-2.04 (m, 1H). Example 32: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-hydroxy-2- methylpropyl)-N-methylpicolinamide

[0214] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-hydroxy-2-methylpropyl)-N-methylpicolinamide (Example 32): (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-hydroxy-2-methylpropyl)-N-methylpicolinamide was synthesized following Scheme 9, step 3 using 2-methyl-1-(methylamino)propan-2-ol. LCMS (ESI) Calcd. for C21H25ClN4O4: 432.1, found [M+H]+ = 433.2.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 9.06 (s, 1H), 8.09 (s, 1H), 7.76 (t, 1H), 7.55 (d, 1H), 7.31-7.24 (m, 2H), 7.00 (d, 1H), 6.88 (t, 1H), 5.02 (d, 1H), 4.45-4.41 (m, 1H), 4.25 (m, 1H), 4.17 (s, 1H), 3.34 (s, 2H), 2.95 (s, 3H), 2.22-2.19 (m, 1H), 2.06-2.04 (m, 1H), 1.07 (s, 6H). Example 33: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- (dimethylamino)ethyl)-N-methylpicolinamide methylpicolinamide

[0215] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-(dimethylamino)ethyl)-N- methylpicolinamide methylpicolinamide (Example 33): (S)-6-(3-(8-chlorochroman-4- yl)ureido)-N-(2-(dimethylamino)ethyl)-N-methylpicolinamide methylpicolinamide wassynthesized following Scheme 9, step 3 using N,N,N′-trimethylethylenediamine. LCMS (ESI)Calcd. for C21H26ClN5O3: 431.2 found [M+H]+= 432.3.1H NMR (400 MHz, DMSO-d60at 100 °C): δH9.07 (s, 1H), 8.17-8.16 (m, 1H), 7.76 (t, 1H), 7.53 (d, 1H), 7.31-7.25 (m, 2H), 7.01 (d, 1H), 6.88 (t, 1H), 5.03-5.01 (m, 1H), 4.45-4.40 (m, 1H), 4.27-4.23 (m, 1H), 3.31 (s, 2H), 2.85 (s, 3H), 2.34-2.32 (m, 2H), 2.22-2.19 (m, 2H), 2.08 (s, 6H).Example 34: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-cyanoethyl)-N- methylpicolinamide

[0216] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-cyanoethyl)-N- methylpicolinamide (Example 34): (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-cyanoethyl)-N-methylpicolinamide was synthesized following Scheme 9, step 3 using 3-(methylamino)propanenitrile. LCMS (ESI) Calcd. for C20H20ClN5O3: 413.1; found [M+H]+= 414.2.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 9.01 (s, 1H), 7.86-7.78 (m, 2H), 7.68-7.66 (m, 1H), 7.31-7.26 (m, 2H), 7.09 (d, 1H), 6.89 (t, 1H), 5.03-4.98 (m, 1H), 4.44–4.38 (m, 1H), 4.29-4.28 (m, 1H), 3.59 (s, 2H), 2.93 (s, 3H), 2.75 (t, 2H), 2.23–2.16 (m, 1H), 2.08-2.04 (m, 1H). Example 35: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- methoxyethyl)picolinamide

[0217] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2- methoxyethyl)picolinamide (Example 35): (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-(2-methoxyethyl)picolinamide was synthesized following Scheme 9, step 3 using 2-methoxyethan-1-amine. LCMS (ESI) Calcd. for C19H21ClN4O4: 404.13; found [M+H]+= 405.2.1H NMR (400 MHz, DMSO-d6): δH 9.07 (s, 1H), 8.14 (s, 1H), 7.96-7.94 (m, 1H), 7.89-7.86 (m, 1H), 7.61-7.55 (m, 2H), 7.33 (d, 1H), 7.26 (d, 1H), 6.90 (m, 1H), 4.99 (s,1H), 4.42-4.40 (m, 1H), 4.29-4.27 (m, 1H), 3.41 (s, 4H), 3.25 (s, 3H), 2.18-2.16 (m, 1H), 2.07-2.05 (m, 1H). Example 36: Synthesis of 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((S)-1-hydroxypropan- 2-yl)picolinamide

[0218] Synthesis of 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((S)-1-hydroxypropan-2-yl)picolinamide (Example 36): (6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((S)-1-hydroxypropan-2-yl)picolinamide was synthesized following Scheme 9, step 3 using (S)-2-aminopropan-1-ol. LCMS (ESI) Calcd for C19H21ClN4O4: 404.1; found [M+H]+= 405.2.1H NMR (400 MHz, DMSO-d6): δH 9.12 (s, 1H), 7.95 (t, 2H), 7.88 (t, 1H), 7.56 (d, 1H), 7.51 (d, 1H), 7.32 (d, 1H), 7.24 (d, 1H), 6.90 (t, 1H), 4.99-4.98 (m,1H), 4.87 (t, 1H), 4.42-4.38 (m, 1H), 4.29-4.24 (m, 1H), 3.98-3.95 (m, 1H), 3.39 (t, 2H), 2.33-2.15 (m, 1H), 2.10-2.03 (m, 1H), 1.06 (d, 3H). Example 37: Synthesis of 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((S)-2- hydroxypropyl)picolinamide

[0219] Synthesis of 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((S)-2-hydroxypropyl)picolinamide (Example 37): 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((S)-2-hydroxypropyl)picolinamide was synthesized following Scheme 9, step 3 using (S)-(+)-1-Amino-2-propanol. LCMS (ESI) Calcd. for C19H21ClN4O4 = 404.1; found [M+H]+: 405.2.1H NMR (400 MHz, DMSO-d6 at 100 °C): δH 8.89 (s, 1H), 7.98-7.94 (m, 2H), 7.85 (t, 1H), 7.59 (d, 1H), 7.38 (d, 1H), 7.29 (t, 2H), 6.89 (t, 1H), 5.09-4.98 (m, 1H), 4.50 (s, 1H), 4.43-4.38 (m, 1H), 4.32- 4.28 (m, 1H), 3.78-3.76 (m, 1H), 3.36-3.30 (m, 1H), 3.21-3.14 (m, 1H), 2.22-2.19 (m, 1H), 2.08- 2.05 (m, 1H), 1.08 (d, 3H). Example 38: Synthesis of 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((R)-1-hydroxypropan- 2-yl)picolinamide

[0220] Synthesis of 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((R)-1-hydroxypropan-2-yl)picolinamide (Example 38): 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((R)-1-hydroxypropan-2-yl)picolinamide was synthesized following Scheme 9, step 3 using (R)-2-aminopropan-1-ol. LCMS (ESI) Calcd. for C19H21ClN4O4 = 404.1 found [M+H]+: 405.2.1H NMR (400 MHz, DMSO-d6): δH 9.10 (s, 1H), 8.01-7.96 (m, 2H), 7.88 (t, 1H), 7.56 (d, 1H), 7.44 (d, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 6.90(t, 1H), 4.99-4.97 (m, 1H), 4.88 (s, 1H), 4.42-4.37 (m, 1H), 4.28- 4.24 (m, 1H), 3.98-3.94 (m, 1H), 3.92-3.39 (m, 2H), 2.16-2.13 (m, 1H), 2.02-1.99 (m, 1H), 1.10 (d, 3H). Example 39: Synthesis of 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((R)-2- hydroxypropyl)picolinamide

[0221] Synthesis of 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((R)-2- hydroxypropyl)picolinamide (Example 39): 6-(3-((S)-8-chlorochroman-4-yl)ureido)-N-((R)-2-hydroxypropyl)picolinamide was synthesized following Scheme 9, step 3 using (R)-1-aminopropan-2-ol. LCMS (ESI) Calcd. for C19H21ClN4O4: 404.1, found [M+H]+: 405.2.1H NMR (400 MHz, DMSO-d6): δH 9.07 (s, 1H), 8.13 (t, 1H), 8.01 (d, 1H), 7.88 (t, 1H), 7.58 (d, 1H), 7.48 (d, 1H), 7.33 (d, 1H), 7.26 (d, 1H), 6.90 (t, 1H), 5.00-4.95 (m, 1H), 4.86 (d, 1H), 4.42-4.38 (m, 1H), 4.28-4.24 (m, 1H), 3.73 (t, 1H), 3.13-3.07 (m, 1H), 2.18-2.14 (m, 1H), 2.03-1.98 (m, 1H), 1.04 (d,3H). One proton is exchangeable. Example 40: Synthesis of (S)-N-(3-amino-3-oxopropyl)-6-(3-(8-chlorochroman-4- yl)ureido)-N-methylpicolinamide

[0222] Synthesis of (S)-N-(3-amino-3-oxopropyl)-6-(3-(8-chlorochroman-4-yl)ureido)-N- methylpicolinamide (Example 40): (S)-N-(3-amino-3-oxopropyl)-6-(3-(8-chlorochroman-4-yl)ureido)-N-methylpicolinamide was synthesized following Scheme 9, step 3. LCMS (ESI)Calcd for C19H21ClN4O4= 431.1, found [M+H]+= 432.1.1H NMR (400 MHz, DMSO-d6at 100 °C): δH9.01 (s, 1H), 7.95 (d, 1H), 7.76 (t, 1H), 7.61 (d, 1H), 7.31-7.25 (m, 2H), 7.02 (d, 1H),6.89 (t, 3H), 6.72 (brs, 2H), 5.01-4.99 (m,1H), 4.41-4.39 (m, 1H), 4.25 (t, 1H), 3.48 (s, 2H), 2.86 (s, 3H), 2.32 (s, 2H), 2.20-2.19 (m, 1H), 2.07-2.04 (m, 1H). Example 41: Synthesis of (S)-1-(chroman-4-yl)-3-(1H-pyrrolo[3,2-b]pyridin-5-yl)urea

[0223] Synthesis of (S)-1-(chroman-4-yl)-3-(1H-pyrrolo[3,2-b]pyridin-5-yl)urea (Example 41): (S)-1-(Chroman-4-yl)-3-(1H-pyrrolo[3,2-b]pyridin-5-yl)urea was synthesized following Scheme 4, step 3. LCMS (ESI) Calcd. for C17H16N4O2: 308.33, found [M+H]+= 309.2.1H NMR (400 MHz, DMSO-d6): δH11.18 (s, 1H), 9.43 (bs, 1H), 9.14 (s, 1H), 7.70 (d, 1H), 7.45 (t, 1H), 7.30 (d, 1H), 7.16 (t, 1H),7.00 (d, 1H), 6.89 (t, 1H), 6.80 (d, 1H), 6.19 (s, 1H), 5.05- 5.00 (m, 1H), 4.84-4.03 (m, 2H), 2.32-2.19 (m, 1H), 2.08-2.00 (m, 1H). Example 42: Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(5-(1-hydroxyethyl)pyridin-2- yl)urea:Scheme 10.

[0224] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(5-(1-hydroxyethyl)pyridin-2-yl)urea (Example 42) [Step 1]: To a stirred solution of (S)-1-(5-acetylpyridin-2-yl)-3-(8-chlorochroman-4- yl)urea (10-1, 40 mg, 0.1 mmol) in methanol (2 mL) was added sodium borohydride (8.8 mg, 0.2 mmol) at 0oC and stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with 30% isopropanol in chloroform. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford product which was purified by reverse phase preparative HPLC, lyophilized to afford 1-((S)-8-chlorochroman- 4-yl)-3-(5-(1-hydroxyethyl)pyridin-2-yl)urea (Example 42, 15 mg). LCMS (ESI) Calcd. for C17H18ClN3O3: 347.10, found [M+H]+= 348.17.1H NMR (400 MHz, DMSO-d6): δH 9.17 (s, 1H), 8.62-8.50 (m, 1H), 8.07 (d, 1H), 7.66 (dd, 1H), 7.38-7.32 (m, 2H), 7.24 (d, 1H), 6.90 (t, 1H), 5.16 (d, 1H), 5.02 (q, 1H), 4.67-4.65 (m, 1H), 4.40-4.39 (m, 1H), 4.27-4.25 (q, 1H), 2.32-2.15 (m, 1H), 2.03-1.85 (m, 1H), 1.29-1.28 (m, 3H).Examples 43 & 44: Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (isomer 1) and 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-2,2,2- trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (isomer 2):Scheme 11.

[0225] Synthesis of 1-(6-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-ol, 11-2 [Step 1]: To astirred solution of 6-chloropicolinaldehyde (11-1, 1 g, 7.1 mmol) in THF (20 mL) was added trimethyl(trifluoromethyl)silane (1.3 mL, 8.5 mmol) at 0oC, followed by tetrabutylammonium fluoride, 1M in THF (8.5 mL, 8.5 mmol) and stirred the reaction mixture at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by combi flash chromatography to afford 1-(6-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-ol (11-2, 1 g). LCMS (ESI) Calcd. for C7H5ClF3NO: 211.0, found [M+H]+= 212.1.

[0226] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea, 11-4 [Step 2]: To a stirred solution of (S)-1-(8-chlorochroman- 4-yl)urea (11-3, 112 mg, 0.5 mmol), 1-(6-chloropyridin-2-yl)-2,2,2-trifluoroethan-1-ol (11-2, 70 mg, 0.3 mmol) and Cs2CO3(269 mg, 0.8 mmol) in 1,4-dioxane (10 mL) was degassed with argon for 10 min. To this reaction mixture were added Xantphos (57 mg, 0.1 mmol) and palladium(II) acetate (15 mg, 0.06 mmol) and stirred the reaction mixture at 80oC for 16 h. The reaction mixture was cooled to ambient temperature and filtered through celite bed. The filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC and lyophilized to afford 1-((S)-8-chlorochroman-4-yl)-3-(6-(2,2,2-trifluoro-1- hydroxyethyl)pyridin-2-yl)urea (11-4, 89 mg). LCMS (ESI) Calcd. for C17H15ClF3N3O3: 401.08, [M+H]+= 402.1.

[0227] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (Example 43) and 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)- 2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (Example 44) [Step 3]: 1-((S)-8- chlorochroman-4-yl)-3-(6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (11-4, 89 mg, 0.2 mmol) were separated by SFC and lyophilized to afford the first product 1-((S)-8- chlorochroman-4-yl)-3-(6-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (Example 43, 43 mg) as peak 1 and the second product 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyridin-2-yl)urea (Example 44, 40 mg) as peak 2. Absolute stereochemistry was arbitrarily assigned.

[0228] 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-2- yl)urea (Example 43): LCMS (ESI) Calcd. for C17H15ClF3N3O3: 401.08, found [M+H]+= 402.1.1H NMR (400 MHz, DMSO-d6): δH 9.44 (s, 1H), 8.74 (bs, 1H), 7.77 (t, 1H), 7.34-7.31 (m, 2H), 7.25 (d, 1H), 7.14 (d, 1H), 6.93-6.91 (m, 1H), 6.89-6.87 (m, 1H), 5.05-5.01 (m, 1H), 4.86 (t, 1H),4.42- 4.38 (m, 1H), 4.28-4.23 (m, 1H), 2.18-2.14 (m, 1H), 2.07-1.99 (m, 1H).

[0229] 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-2- yl)urea (Example 44): LCMS (ESI) Calcd. for C17H15ClF3N3O3: 401.08, found [M+H]+= 402.1.1H NMR (400 MHz, DMSO-d6): δH9.42 (s, 1H), 8.67 (bs, 1H), 7.77 (t, 1H), 7.36-7.31 (m, 2H), 7.24 (d, 1H), 7.14 (d, 1H), 6.91-6.85 (m, 2H), 5.05-5.02 (m, 1H), 4.92 (t, 1H),4.42-4.38 (m, 1H), 4.30- 4.29 (m, 1H), 2.19-2.16 (m, 1H), 2.03-2.02 (m, 1H).

[0230] SFC method: Separation was performed on instrument Thar SFC-80 equipped with UV detector 2489 by using I-Cellulose J Column (21.1 nm x 250 nm), 5µ Column operating at 35 °C temperature, maintaining flow rate of 70 mL / min, using 50% CO2 in super critical state and 50% of (10% methanol) as mobile phase, run this isocratic mixture up to 10 min and maintained isobaric condition of 100 bar at 230 nm. Example 45: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6- ((methylsulfonyl)methyl)pyridin-2-yl)urea:Scheme 12.

[0231] Synthesis of 2-(bromomethyl)-6-chloropyridine (12-2) [Step 1]: To a stirred solution of 2-chloro-6-methylpyridine (12-1, 500 mg, 3.9 mmol) in carbon tetrachloride (11 mL) was added N-Bromo succinimide (767 mg, 4.3 mmol) and benzoyl peroxide (127 mg, 0.4 mmol) at ambient temperature. The reaction mixture was heated at 90oC for 16 h. The reaction mixture was diluted with dichloromethane, washed with water and brine. The organic extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by combi flash chromatography to afford 2-(bromomethyl)-6-chloropyridine (12-2, 150 mg). LCMS (ESI) Calcd. for C6H5BrClN: 204.9, found [M+H]+= 205.8.

[0232] Synthesis of 2-chloro-6-((methylthio)methyl)pyridine (12-3) [Step 2]: To a stirred solution of 2-(bromomethyl)-6-chloropyridine (12-2, 300 mg, 1.5 mmol) in N,N dimethyl formamide (3 mL) was added sodium methane thionate (122 mg, 1.7 mmol) and the reaction mixture was heated at 90oC for 16 h. The reaction mixture was diluted with ethyl acetate, washed with cold water and brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by combi flash chromatography to afford 2-chloro-6-((methylthio)methyl)pyridine (12-3, 100 mg). LCMS (ESI) Calcd. for C7H8ClNS: 173.0, found [M+H]+= 173.8.

[0233] Synthesis of 2-chloro-6-((methylsulfonyl)methyl)pyridine (12-4) [Step 3]: To the solution of 2-chloro-6-((methylthio)methyl)pyridine (12-3, 200 mg, 1.2 mmol) in dichloromethane (8 mL) was added meta-Chloroperbenzoic acid (568 mg, 2.3 mmol) at 0 °C and stirred at ambient temperature for 3 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane, and washed with aqueous sodium bicarbonate solution followed by brine. Organic extract was dried over anhydrous sodium sulfate, evaporated under reduced pressure.The crude product was purified by combi flash chromatography to afford 2-chloro-6- ((methylsulfonyl)methyl)pyridine (12-4, 160 mg). LCMS (ESI) Calcd. for C7H8ClNO2S: 205, found [M+H]+= 206.

[0234] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-((methylsulfonyl)methyl)pyridin-2- yl)urea (Example 45) [Step 4]: (S)-1-(8-Chlorochroman-4-yl)-3-(6- ((methylsulfonyl)methyl)pyridin-2-yl)urea was synthesized following Scheme 4, step 3. LCMS (ESI) Calcd. for C17H18ClN3O4S: 395.1, found [M+H]+= 396.2.1H NMR (400 MHz, DMSO-d6): δH 9.33 (s, 1H), 8.43-8.41 (m, 1H), 7.75-7.71 (m, 1H), 7.42-7.40 (m, 1H), 7.32-7.24 (m, 2H), 7.03- 7.01 (m, 1H), 6.90-6.86 (m, 1H), 5.05-5.04 (m, 1H), 4.53-4.31 (m, 4H), 2.87 (s, 3H), 2.12 (m, 2H). Examples 46 & 47: Synthesis of 1-(6-((R)-1-acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8- chlorochroman-4-yl)urea and 1-(6-((S)-1-acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8- chlorochroman-4-yl)urea:

[0235] Synthesis of tert-butyl 6-nitro-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate (13- 3) [Step 1]: A 100 mL seal tube was charged with 2-chloro-6-nitropyridine (13-1, 500 mg, 3.15 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (13-2, 1.17 g, 3.78 mmol), K2CO3 (1.3 g, 9.46 mmol), 1,4-Dioxane (8 mL) and water (2 mL). The mixture was degassed and purged with argon for 10 min. The reaction mixture was treated with Pd(dppf)Cl2.DCM (129 mg, 0.15 mmol), purged with argon for 5 min. It was heated at 100oC for 3h. The reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was collected, and the aqueous phase was extracted with ethyl acetate (thrice). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using column chromatography to afford tert-butyl 6-nitro-5',6'-dihydro-[2,3'- bipyridine]-1'(2'H)-carboxylate (13-3, 750 mg). LCMS (ESI) Calcd. for C15H19N3O4: 305.14, found [M+H]+= 306.1.

[0236] Synthesis of 6-nitro-1',2',5',6'-tetrahydro-2,3'-bipyridine (13-4) [Step 2]: To a solutionof tert-butyl 6-nitro-5',6'-dihydro-[2,3'-bipyridine]-1'(2'H)-carboxylate (13-3, 400 mg, 1.31 mmol) in dichloromethane (10 mL) was added TFA (1.3 mL, 17.0 mmol) dropwise at 0oC and stirred at ambient temperature for 1 h. The reaction mixture quenched with saturated sodium bicarbonate solution and extracted with 5% MeOH in dichloromethane (thrice). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 6-nitro-1',2',5',6'-tetrahydro-2,3'-bipyridine (13-4, 220 mg). The product was used for the next step without further purification. LCMS (ESI) Calcd. for C10H11N3O2: 205.1, found [M+H]+= 206.2.

[0237] Synthesis of 1-(6-nitro-5',6'-dihydro-[2,3'-bipyridin]-1'(2'H)-yl)ethan-1-one (13-5)[Step 3]: To a stirred solution of 6-nitro-1',2',5',6'-tetrahydro-2,3'-bipyridine (13-4, 194 mg, 0.94 mmol) in dichloromethane (15 mL) was added triethylamine (0.3 mL, 2.08 mmol) at 0 °C. Acetyl chloride (0.07 mL, 1.04 mmol) was added to the reaction mixture at 0 °C and stirred at ambient temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with water followed by brine. Organic extract was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by column chromatography to give 1-(6-nitro- 5',6'-dihydro-[2,3'-bipyridin]-1'(2'H)-yl)ethan-1-one (13-5, 190 mg). LCMS (ESI) Calcd. for C12H13N3O3: 247.1, found [M+H]+= 248.1.

[0238] Synthesis of 1-(3-(6-aminopyridin-2-yl)piperidin-1-yl)ethan-1-one (13-6) [Step 4]: Ina 50 mL round bottom flask containing a solution of 1-(6-nitro-5',6'-dihydro-[2,3'-bipyridin]-1'(2'H)-yl)ethan-1-one (13-5, 190 mg, 0.76 mmol) in methanol (10mL) and Ethyl acetate (20mL) was added 10% Pd-C ( 100 mg) under nitrogen atmosphere. The flask was evacuated then filled with hydrogen gas balloon and stirred at ambient temperature for 3 h. The reaction was monitored by TLC. The reaction mixture was then diluted with ethyl acetate and filtered through a bed of celite by methanol. The filtrate was dried under vaccum to give 1-(3-(6-aminopyridin-2- yl)piperidin-1-yl)ethan-1-one (13-6, 165 mg). LCMS (ESI) Calcd. for C12H17N3O: 219.1, found [M+H]+= 220.5,

[0239] Synthesis of 1-(6-(1-acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (13-8) [Step 5]: 1-(6-(1-Acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (13-8) was synthesized following Scheme 1, step 1. LCMS (ESI) Calcd. forC22H25ClN4O3: 428.16, found [M+H]+= 429.1.

[0240] Synthesis of 1-(6-((R)-1-acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (Example 46) and 1-(6-((S)-1-acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8- chlorochroman-4-yl)urea (Example 47) [Step 6]: Diastereomers of 1-(6-(1-acetylpiperidin-3- yl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (13-8, 140 mg, 0.32 mmol) were separated by chiral SFC HPLC to afford the first product 1-(6-((R)-1-acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8- chlorochroman-4-yl)urea (Example 46, 50 mg) as peak 1 and the second product 1-(6-((S)-1- acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (Example 47, 55 mg) as peak 2. Absolute stereochemistry was not determined and arbitrarily assigned.

[0241] 1-(6-((R)-1-acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (Example 46): LCMS (ESI) Calcd. for C22H25ClN4O3: 428.2, found [M+H]+= 429.3.1H NMR (400 MHz, DMSO-d6at 100 °C): δH9.06-9.02 (m, 2H), 7.62-7.58 (m, 1H), 7.32-7.26 (m, 2H), 7.11- 7.09 (m, 1H), 6.91-6.81 (m, 2H), 5.01 (bs, 1H), 4.42 (bs, 1H), 4.28-4.23 (m, 1H), 4.07-3.76 (m, 2H), 2.50 (s, 2H), 2.32-2.04 (m, 2H), 1.95 (s, 3H), 1.76-1.50 (m, 2H), 1.31-1.21 (m, 3H).

[0242] 1-(6-((S)-1-acetylpiperidin-3-yl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (Example 47): LCMS (ESI) Calcd. for C22H25ClN4O3: 428.16, found [M+H]+= 429.2.1H NMR (400 MHz, DMSO-d6): δH9.52-9.47 (m, 2H), 7.64-7.58 (m, 1H), 7.32-7.27 (m, 2H), 6.97-6.78 (m, 3H), 4.97 (m, 1H), 4.47-4.44 (m, 1H), 4.30-4.15 (m, 2H), 3.72-3.59 (m, 1H), 2.66-4.49 (m, 2H), 2.14-1.91 (m, 3H), 1.86 (s, 3H), 1.78-1.76 (m, 1H), 1.55-1.49 (m, 1H), 1.38-1.34 (m, 2H).

[0243] SFC method: Separation was performed Pic Solution 175 instrument equipped withKnauer UV Detector 40D by using I Cellulose J (30.0 mm x 250mm), 5µ Column operating at 35°C temperature, maintaining flow rate of 100 mL / min, using 80% CO2 in super critical state and 20% of 100% Methanol as mobile phase, run this isocratic mixture for 8 min and maintained theisobaric condition of 100 bar at 220 nm wavelength. Absolute stereochemistry was not determined and arbitrarily assigned. Examples 48-50: Synthesis of 6-(3-(7-cyanochroman-4-yl)ureido)-N-methylpicolinamide, (S)-6-(3-(7-cyanochroman-4-yl)ureido)-N-methylpicolinamide and (R)-6-(3-(7- cyanochroman-4-yl)ureido)-N-methylpicolinamideScheme 14.

[0244] Synthesis of 4-aminochromane-7-carbonitrile (14-2) [Step 1]: A 100 mL round bottom flask was charged with 4-oxochromane-7-carbonitrile (14-1, 400 mg, 2.31 mmol), ammonium acetate (1.78 g, 23.1 mmol) and sodium cyanoborohydride (435 mg, 6.93 mmol). The flask was then purged with argon, and methanol (20 mL) was added by syringe. The solution was stirred at ambient temperature for 48 h. All the volatiles were evaporated. The reaction mixture was dissolved in water and extracted by 5% methanol in dichloromethane. The organic part was dried over anhydrous Na2SO4and evaporated to give crude product. The product was purified by combi-flash column chromatography to afford 4-aminochromane-7-carbonitrile (14-2, 250 mg). LCMS (ESI) Calcd. for C10H10N2O: 174.08, found [M+H]+= 174.9.

[0245] Synthesis of 6-(3-(7-cyanochroman-4-yl)ureido)-N-methylpicolinamide (Example 48) [Step 2]: 6-(3-(7-Cyanochroman-4-yl)ureido)-N-methylpicolinamide (Example 48) was synthesized following Scheme 1, step 1. LCMS (ESI) Calcd. for C18H17N5O3: 351.13, found [M+H]+= 352.2.1H NMR (400 MHz, DMSO-d6): δH9.01 (s, 1H), 8.20 (d, 1H), 7.96 (d, 1H), 7.88- 7.79 (m, 2H), 7.53-7.47 (m, 2H), 7.33-7.31 (m, 2H), 5.05-5.00 (m, 1H), 4.37-4.33 (m, 1H), 4.29- 4.24 (m, 1H), 2.75 (d, 3H), 2.19-2.16 (m, 1H), 2.08-2.00 (m, 1H).

[0246] Synthesis of (S)-6-(3-(7-cyanochroman-4-yl)ureido)-N-methylpicolinamide (Example 49) and (R)-6-(3-(7-cyanochroman-4-yl)ureido)-N-methylpicolinamide (Example 50) [Step 3]: 6-(3- (7-cyanochroman-4-yl)ureido)-N-methylpicolinamide (Example 48, 29 mg, 0.08 mmol) were separated by SFC HPLC and lyophilized to afford the first product (S)-6-(3-(7-cyanochroman-4- yl)ureido)-N-methylpicolinamide (Example 49, 6 mg) as peak 1 and the second product (R)-6- (3-(7-cyanochroman-4-yl)ureido)-N-methylpicolinamide (Example 50, 8 mg) as peak 2.

[0247] (S)-6-(3-(7-cyanochroman-4-yl)ureido)-N-methylpicolinamide (Example 49) [Peak 1]: LCMS (ESI) Calcd. for C18H17N5O3: 351.13, found [M+H]+= 352.2.1H NMR (400 MHz, DMSO-d6): δH 9.19 (s, 1H), 8.20 (brs, 1H), 8.02 (d, 1H), 7.88-7.80 (m, 2H), 7.53-7.47 (m, 2H), 7.33-7.31 (m, 2H), 5.03 (d, 1H), 4.34-4.27 (m, 2H), 2.76-2.75 (m, 3H), 2.16-2.06 (m, 2H).

[0248] (R)-6-(3-(7-cyanochroman-4-yl)ureido)-N-methylpicolinamide (Example 50) [Peak 2]: LCMS (ESI) Calcd. for C18H17N5O3: 351.13, found [M+H]+= 352.2.1H NMR (400 MHz, DMSO-d6): δH9.22 (s, 1H), 8.22 (d, 1H), 8.04 (d, 1H), 7.88-7.81 (m, 2H), 7.53-7.47 (m, 2H), 7.34-7.31 (m, 2H), 5.03-5.02 (m, 1H), 4.37-4.25 (m, 2H), 2.76-2.75 (m, 3H), 2.19-2.03 (m, 2H).

[0249] SFC method: Separation was performed Waters SFC Prep 80 instrument equipped with Waters 2489 UV / Visible Detector CHIRALPAK IC (30mm x 250mm), 5µ Column operating at 35 °C temperature, maintaining flow rate of 70 mL / min, using 65% CO2in super critical state and 35% of 100% Methanol as mobile phase, run this isocratic mixture for 12 min and maintained the isobaric condition of 110 bar at 244 nm wavelength. Examples 51-52: Synthesis of (S)-6-(3-(7-chlorochroman-4-yl)ureido)-N- methylpicolinamide and (R)-6-(3-(7-chlorochroman-4-yl)ureido)-N-methylpicolinamide:

[0250] Synthesis of (R,E)-N-(7-chlorochroman-4-ylidene)-2-methylpropane-2-sulfinamide (15-2) [Step 1]: To a solution of 7-chlorochroman-4-one (15-1, 600 mg, 3.29 mmol) and (R)-2- methylpropane-2-sulfinamide (0.60 g, 4.93 mmol) in THF (15 mL) was added Ti(OEt)4 (1.9 mL, 8.21 mmol) at ambient temperature. The reaction mixture was heated at reflux and stirred for 16 h. The reaction mixture was allowed to cool to ambient temperature and quenched with ice cold water. The resulting white precipitate was filtered through a celite pad and the filter cake was washed with EtOAc. The combined filtrate was washed with brine and dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by Combi-flash column chromatography to afford (R,E)-N-(7-chlorochroman-4-ylidene)-2-methylpropane-2-sulfinamide (15-2, 800 mg). LCMS Calcd. for C13H16ClNO2S: 285.79, found [M+H]+= 286.1.

[0251] Synthesis of (R)-N-((S)-7-chlorochroman-4-yl)-2-methylpropane-2-sulfinamide (15- 3) [Step 2]: To a stirred solution of (R,E)-N-(7-chlorochroman-4-ylidene)-2-methylpropane-2- sulfinamide (15-2, 800 mg, 2.80 mmol) in methanol (10 mL) was added NaBH4(106 mg, 2.80 mmol) and stirred at 0C for 15 min. The reaction mixture was quenched with ice cold water and extracted with EtOAc (twice). Combined organic extract was washed with brine, dried over anhydrous Na2SO4,and concentrated under reduced pressure. The crude product was purified by combiflash chromatography to afford (R)-N-((S)-7-chlorochroman-4-yl)-2-methylpropane-2- sulfinamide (15-3, 600 mg) as major and (R)-N-((R)-7-chlorochroman-4-yl)-2-methylpropane-2- sulfinamide (15-4, 80 mg) as minor.

[0252] (R)-N-((S)-7-chlorochroman-4-yl)-2-methylpropane-2-sulfinamide (15-3): LCMS Calcd. for C13H18ClNO2S: 287.2; found [M+H]+= 288.2.1H NMR (400 MHz, CDCl3): δH7.18-7.16 (m, 1H), 6.89-6.82 (m, 2H), 4.48 (m, 1H), 4.24-4.21 (m, 2H), 3.25 (br, 1H), 2.43-2.38 (m, 1H), 2.19-2.14 (m, 1H).

[0253] (R)-N-((R)-7-chlorochroman-4-yl)-2-methylpropane-2-sulfinamide (15-4): LCMS Calcd. for C13H18ClNO2S: 287.2; found [M+H]+: 288.1.1H NMR (400 MHz, CDCl3): δH7.26 (s, 1H), 6.90-6.84 (m, 2H), 4.53 (m, 1H), 4.26-4.15 (m, 2H), 3.25 (br, 1H), 2.09-2.07 (m, 2H).

[0254] Synthesis of (S)-7-chlorochroman-4-amine hydrochloride (15-5) [Step 3]: To the solution of (R)-N-((S)-7-chlorochroman-4-yl)-2-methylpropane-2-sulfinamide (15-3, 500 mg, 1.73 mmol) in 1,4-Dioxane (10 mL) was added MeOH (0.70 mL, 17.3 mmol) and 4M HCl in Dioxane (0.45 mL, 1.82 mmol) at 0 °C and stirred at ambient temperature for 2.5 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with hexane and dried to afford (S)-7-chlorochroman-4-amine hydrochloride (15-5, 375 mg).1H NMR (400 MHz, DMSO-d6): δH 8.56 (br, 2H), 7.51-7.49 (d, 1H), 7.07-7.04 (m, 1H), 6.97 (d, 1H), 4.49 (m, 1H), 4.28-4.26(m, 2H), 2.27-2.202(m, 1H), 2.12-2.07 (m, 1H).

[0255] Synthesis of (S)-6-(3-(7-chlorochroman-4-yl)ureido)-N-methylpicolinamide (Example 51) [Step 4]: (S)-7-chlorochroman-4-amine hydrochloride (15-5, 200 mg, 0.909 mmol) was taken in MeOH and neutralized with solid NaHCO3, filtered the solution and concentrated under reduced pressure. To this were added a solution of 6-amino-N-methylpicolinamide (15-6, 137 mg, 0.91 mmol) in dichloromethane (25 mL). This solution suspension was cooled to -10 °C and was added triphosgene (270 mg, 0.91 mmol) followed by triethylamine (0.51 mL, 3.63 mmol) at -10 °C and stirred at ambient temperature for 16 h. The reaction mixture was dilute with dichloromethane and washed with brine. Organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC and lyophilized to afford (S)-6-(3-(7-chlorochroman-4-yl)ureido)-N- methylpicolinamide (Example 51, 20 mg). LCMS Calcd. for C17H17ClN4O3:360.2, found [M+H]+= 361.2.1H NMR (400 MHz, DMSO-d6): δH9.05 (s, 1H), 8.15-8.14 (m, 1H), 7.89-7.81 (m, 3H), 7.53-7.51 (m, 1H), 7.32-7.30 (d, 1H), 6.96-6.94 (m, 1H), 6.90-6.89 (d, 1H), 4.95-4.90 (m, 1H), 4.33-4.17 (m, 2H), 2.75-2.74 (d, 3H), 2.15-2.02 (m, 2H).

[0256] Synthesis of (R)-6-(3-(7-chlorochroman-4-yl)ureido)-N-methylpicolinamide (Example 52): (R)-6-(3-(7-chlorochroman-4-yl)ureido)-N-methylpicolinamide was synthesized following Scheme 15, step 3 and 4. LCMS (ESI) Calcd. for C17H17ClN4O3: 360.1, found [M+H]+= 361.1.1H NMR (400 MHz, DMSO-d6): δH9.05 (s, 1H), 8.14 (s, 1H), 7.88-7.81 (m, 3H), 7.53-7.51 (m, 1H), 7.32-7.30 (m, 1H), 6.96-6.89 (m, 2H), 4.94-4.92 (m, 1H), 4.30-4.28 (m, 1H), 4.200-4.20 (m, 1H), 2.75-2.74 (m, 3H), 2.12-1.99 (m, 2H). Examples 53-54: Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-3-hydroxypyrrolidin- 1-yl)pyridin-2-yl)urea (Example 53) and 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-3- hydroxypyrrolidin-1-yl)pyridin-2-yl)urea (Example 54):Scheme 16.

[0257] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-3-hydroxypyrrolidin-1- yl)pyridin-2-yl)urea (Example 53) [Step 1]: To a stirred solution of (S)-1-(6-bromopyridin-2-yl)- 3-(8-chlorochroman-4-yl)urea (16-1, 100 mg, 0.26 mmol) in THF (3 mL) was added (R)- pyrrolidin-3-ol (16-2, 68 mg, 0.78 mmol) and DBU (0.23 mL, 1.57 mmol) and the reaction mixture was heated at 70°C for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by reverse phase prep HPLC and lyophilized to afford 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-3- hydroxypyrrolidin-1-yl)pyridin-2-yl)urea (Example 53, 26 mg,). LCMS (ESI) Calcd. for C19H21ClN4O3: 388.2, found [M+H]+= 389.2.1H NMR (400 MHz, DMSO-d6): δH 9.81 (brs, 1H), 9.19 (s, 1H), 7.35-7.26 (m, 2H), 7.24 (d, 1H), 6.89 (t, 1H), 6.15-7.13 (m, 1H), 5.86-5.84 (m, 1H), 4.94-4.90 (m, 1H), 4.84-4.83 (m, 1H), 4.45-4.40 (m, 1H), 4.21-4.15 (m, 2H), 3.13-3.10 (m, 1H), 2.99-2.97 (m, 1H), 2.85 (d, 1H), 2.67-2.66 (m, 1H), 2.12-2.07 (m, 2H), 1.70-1.64 (m, 2H).

[0258] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-3-hydroxypyrrolidin-1- yl)pyridin-2-yl)urea (Example 54) [Step 2]: 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-3- hydroxypyrrolidin-1-yl)pyridin-2-yl)urea was synthesized following Scheme 16, step 2 using (S)- pyrrolidin-3-ol. LCMS (ESI) Calcd. for C19H21ClN4O3: 388.2, found [M+H]+= 389.2.1H NMR (400 MHz, DMSO-d6): δH9.76 (brs, 1H), 9.17 (s, 1H), 7.35-7.31 (m, 2H), 7.23 (d, 1H), 6.89 (t, 1H), 6.15 (d, 1H), 5.86 (d, 1H), 4.94-4.92 (m, 1H), 4.83 (s, 1H), 4.43-4.41 (m, 1H), 4.23-4.16 (m, 2H), 2.98-2.91 (m, 3H), 2.67-2.66 (m, 1H), 2.07 (s, 2H), 1.70-1.60 (m, 2H). Examples 55: Synthesis of (S)-1-(6-(4-(2-aminopropan-2-yl)phenyl)pyridin-2-yl)-3-(8- chlorochroman-4-yl)urea (Example 55):

[0259] Synthesis of (S)-1-(6-bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (16-1) [Step 1]: (S)-1-(6-Bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea was synthesized following Scheme 1, step 1. LCMS (ESI) Calcd. for C15H13BrClN3O2: 382.2, found [M+H]+= 383.2.1H NMR (400 MHz, DMSO-d6): δH9.32 (s, 1H), 7.72-7.70 (m, 1H), 7.64 (t, 1H), 7.48(d, 1H), 7.33 (d, 1H), 7.26 (t, 1H), 7.14 (d, 1H), 6.91 (t, 1H), 4.98-4.96 (m, 1H), 4.40-4.39 (m, 1H), 4.24 (t, 1H), 2.16-2.15 (m, 1H), 2.01-1.99 (m, 1H).

[0260] Synthesis of tert-butyl (S)-(2-(4-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2- yl)phenyl)propan-2-yl)carbamate (17-5) [Step 2]: To a stirred solution of (S)-1-(6- bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (16-1, 150 mg, 0.4 mmol) in 1,4-Dioxane (8 mL) and water (2 mL), (4-(2-((tert-butoxycarbonyl)amino)propan-2-yl)phenyl)boronic acid (17-4, 110 mg, 0.4 mmol) and K3PO4 (166 mg, 0.8 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min. Pd-118 (25 mg, 0.04 mmol) was added and the whole reaction mixture was heated to 90oC for 16h. The reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The crude mixture was diluted with water and extracted with ethyl acetate. Combined organic extract was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to afford crude compound. The product was purified by column chromatography to afford tert-butyl (S)-(2-(4-(6-(3-(8- chlorochroman-4-yl)ureido)pyridin-2-yl)phenyl)propan-2-yl)carbamate (17-5, 120 mg). LCMS(ESI) Calcd. for C29H33ClN4O4: 537.05, found [M+H]+= 538.3.1H NMR (400 MHz, DMSO- d6): δH 9.56 (s, 2H), 7.75 (t, 1H), 7.48-7.40 (m, 4H), 7.33 (d, 1H), 7.18-7.15 (m, 2H), 7.09-7.07 (m, 1H), 6.92 (t, 1H), 5.03-5.49 (m, 1H), 4.43-4.40 (m, 1H), 4.16-4.15 (m, 1H), 2.15-2.09 (m, 2H), 1.51-0.85 (m, 15H).

[0261] Synthesis of (S)-1-(6-(4-(2-aminopropan-2-yl)phenyl)pyridin-2-yl)-3-(8- chlorochroman-4-yl)urea (Example 55) [Step 3]: To a stirred solution of tert-butyl (S)-(2-(4-(6- (3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)phenyl)propan-2-yl)carbamate (17-5, 140 mg, 0.26 mmol) in dichloromethane (8 mL) , 4N HCl in Dioxane (1.10 mL) was added and the reaction mixture was stirred at 25oC for 16 h. The reaction mixture was concentrated under reduced pressure. The product was purified by reverse phase prep-HPLC to afford (S)-1-(6-(4-(2- aminopropan-2-yl)phenyl)pyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (Example 55, 60 mg). LCMS (ESI) Calcd. for C24H25ClN4O2: 436.1, found [M+H]+= 437.2.1H NMR (400 MHz, DMSO- d6): δH 9.64 (bs, 1H), 9.56 (s, 1H), 7.74 (t, 1H), 7.47-7.41 (m, 4H), 7.37-7.32 (m, 3H), 7.07 (d, 1H), 6.93 (t, 1H), 5.03-5.49 (m, 1H), 4.44-4.41 (m, 1H), 4.16-4.10 (m, 1H), 2.18-1.96 (m, 4H), 1.36 (m, 6H). Examples 56 & 57: Synthesis of 1-(6-((S)-1-aminoethyl)pyridin-2-yl)-3-((S)-8- chlorochroman-4-yl)urea (isomer 1) & 1-(6-((R)-1-aminoethyl)pyridin-2-yl)-3-((S)-8- chlorochroman-4-yl)urea (isomer 2):Scheme 18.

[0262] Synthesis of (S)-1-(6-acetylpyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (18-3) [Step 1]: (S)-1-(6-Acetylpyridin-2-yl)-3-(8-chlorochroman-4-yl)urea was synthesized following Scheme 6, step 1. LCMS (ESI) Calcd. for C17H16ClN3O3: 345.78, found [M+H]+= 346.2.

[0263] Synthesis of 1-(6-(1-aminoethyl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (18- 4) [Step 2]: To a stirred solution of (S)-1-(6-acetylpyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (18- 3, 120 mg, 0.35 mmol) in methanol (10 mL), Ammonium acetate (267 mg, 3.47 mmol), and Sodium cyanoborohydride (44 mg, 0.694 mmol) were added at 0°C The reaction mixture was then heated at reflux for 16 h. All the volatiles were evaporated. The reaction mixture was dissolved in ethyl acetate and washed by water (twice). Combined organic extract was driedover anhydrous Na2SO4and evaporated under reduced pressure. The crude product was purified by reverse phase preparative HPLC to afford 1-(6-(1-aminoethyl)pyridin-2-yl)-3-((S)-8- chlorochroman-4-yl)urea (18-4, 62 mg). LCMS (ESI) Calcd. for C17H19ClN4O2: 346.81, found [M+H]+= 347.2.

[0264] Synthesis of 1-(6-((S)-1-aminoethyl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (Example 56) & 1-(6-((R)-1-aminoethyl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (Example 57) [Step 3]: 1-(6-(1-aminoethyl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (18-4, 55 mg, 0.16 mmol) was separated by SFC chiral and lyophilized to afford the first product 1-(6- ((S)-1-aminoethyl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (Example 56, 12 mg) as peak 1 and the second product 1-(6-((R)-1-aminoethyl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (Example 57, 12 mg) as peak 2. Absolute stereochemistry was not determined and assigned arbitrarily.

[0265] 1-(6-((S)-1-aminoethyl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea, (Example 56) [Peak 1]: LCMS (ESI) Calcd. for C17H19ClN4O2: 346.1, found [M+H]+= 347.1.1H NMR (400 MHz, DMSO-d6): δH9.32 (s, 1H), 9.21 (brs, 1H), 7.62 (t, 1H), 7.34 - 7.32 (m, 1H), 7.25 (d, 1H), 7.07 (d, 1H), 6.96 (d, 1H), 6.89 (t, 1H), 5.00-4.98 (m, 1H), 4.44 -4.22 (m, 2H), 3.75 -3.73 (m, 1H), 2.18- 2.02 (m, 2H), 1.02 (d, 1H) .

[0266] 1-(6-((R)-1-aminoethyl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (Example 57) [Peak 2]: LCMS (ESI) Calcd. for C17H19ClN4O2: 346.81, found [M+H]+= 347.21.1H NMR (400 MHz, DMSO-d6): δH9.32 (s, 1H), 9.21 (brs, 1H), 7.62 (t, 1H), 7.34 - 7.32 (m, 1H), 7.27 (d, 1H), 7.07 (d, 1H), 6.95 (d, 1H), 6.89 (t, 1H), 5.00-4.99 (m, 1H), 4.44 -4.22 (m, 2H), 3.73 -3.71 (m, 1H), 2.19- 2.02 (m, 1H),1.02 (d, 1H).

[0267] SFC method: SFC prep purification has been done in Waters SFC 80 instrument equipped with Knauer 2489 UV / Visible Detector by using C Amylose A (30.0 mm x 250mm), 5µ Column operating at 35 ºC temperature, maintaining flow rate of 70 mL / min, using 50% CO2 in super critical state & 50% of 0.1% IPAmine in isopropanol as mobile phase. Run this isocratic mixture up to 12.0 minutes and maintained the isobaric condition of 100 bar at 240 nm wavelength. Examples 58 & 59: Synthesis of N-((R)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2- yl)ethyl)acetamide (isomer 1) and N-((S)-1-(6-(3-((S)-8-chlorochroman-4- yl)ureido)pyridin-2-yl)ethyl)acetamide (isomer 2):Scheme 19.

[0268] Synthesis of N-(1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2- yl)ethyl)acetamide (19-3) [Step 1]: To a stirred solution of 1-(6-(1-aminoethyl)pyridin-2-yl)-3- ((S)-8-chlorochroman-4-yl)urea (18-4, 50 mg, 0.14 mmol) in dichloromethane (10 mL), acetic anhydride (0.02 mL, 0.14 mmol), and pyridine (0.015 mg, 0.17 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. All the volatiles were evaporated. The crude product was purified by reverse phase preparative HPLC to afford N-(1-(6-(3-((S)-8- chlorochroman-4-yl)ureido)pyridin-2-yl)ethyl)acetamide (19-3, 30 mg). LCMS (ESI) Calcd. for C19H21ClN4O3: 388.1, found [M+H]+= 389.2.

[0269] N-((R)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2-yl)ethyl)acetamide (Example 58) and N-((S)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2-yl)ethyl)acetamide (Example 59) [Step 2]: N-(1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2-yl)ethyl)acetamide (19-3, 48 mg, 0.12 mmol) was separated by SFC chiral and lyophilized to afford the first product N-((R)-1- (6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2-yl)ethyl)acetamide (Example 58, 22 mg) as peak 1 and the second product N-((S)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2- yl)ethyl)acetamide (Example 59, 18 mg) as peak 2. The absolute stereochemistry of both the diastereomers were arbitrarily assigned.

[0270] N-((R)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2-yl)ethyl)acetamide (Example 58) [Peak 1]: LCMS (ESI) Calcd. for C19H21ClN4O3: 388.1, found [M+H]+= 389.24.1H NMR (400 MHz, DMSO-d6): δH9.31 (s, 1H), 8.89 (bs, 1H), 8.14 (d, 1H), 7.63 (t, 1H), 7.33-7.31 (m, 1H), 7.25 (d, 1H), 7.13 (d, 1H), 6.88 (t, 1H), 6.81 (d, 1H), 5.03-4.98 (m, 1H), 4.69-4.27 (m, 3H), 2.33-2.32 (m, 2H), 1.76 (s, 1H), 1.10 (d, 1H). The absolute stereochemistry was unknown.

[0271] N-((S)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2-yl)ethyl)acetamide (Example 59) [Peak 2]: LCMS (ESI) Calcd. for C19H21ClN4O3: 388.1, found [M+H]+= 389.24.1H NMR (400 MHz, DMSO-d6): δH 9.32 (s, 1H), 8.93 (bs, 1H), 8.13 (d, 1H), 7.63 (t, 1H), 7.33-7.31 (m, 1H), 7.25 (d, 1H), 7.14 (d, 1H), 6.89 (t, 1H), 6.83 (d, 1H), 5.03-4.98 (m, 1H), 4.69-4.27 (m, 3H), 2.33-2.32 (m, 2H), 1.77 (s, 1H), 1.11 (d, 1H). The absolute stereochemistry was unknown.

[0272] SFC method: SFC prep purification has been done in Waters SFC 80 instrument equipped with Waters 2489 UV / Visible Detector by using (R,R)-Whelk-O-1 (21.1 mm x 250mm ), 5µ Column operating at 35 ºC temperature, maintaining flow rate of 70 mL / min, using 60% CO2 in super critical state & 40% of 100% methanol as mobile phase. Run this isocratic mixture up to 10.0 minutes and maintained the isobaric condition of 100 bar at 230 nm wavelength. Example 60: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(2-methyl-2H-1,2,3-triazol-4- yl)pyridin-2-yl)urea (Example 60):Scheme 20.

[0273] Synthesis of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3- triazole, 20-2 [Step 1]: To a stirred solution of 4-bromo-2-methyl-2H-1,2,3-triazole (20-1, 200 mg, 1.2 mmol) in 1,4-Dioxane (8 mL) was added potassium acetate (364 mg, 3.7 mmol), bis(pinacolato)diboron (345 mg, 1.4 mmol) and the reaction mixture was degassed with argon for 10 min. Pd(dppf)Cl2 (45 mg, 0.06 mmol) was added to the reaction mixture and heated at 80oC for 3 h. The reaction mixture was cooled to ambient temperature and filtered through celite bed. Filtrate was evaporated under reduced pressure. The crude product was purified by combi flash chromatography to afford 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H- 1,2,3-triazole (20-2, 50 mg);1H NMR (400 MHz, DMSO-d6): δH 8.07 (s, 1H), 4.20-4.18 (m, 3H), 1.07 (s, 12H).

[0274] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(2-methyl-2H-1,2,3-triazol-4- yl)pyridin-2-yl)urea (Example 60) [Step 2]: To a stirred solution of (S)-1-(6-bromopyridin-2-yl)- 3-(8-chlorochroman-4-yl)urea (17-3, 220 mg, 0.6 mmol) in acetonitrile (15 mL) was added 2- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (20-2, 180 mg, 0.9mmol) and cesium carbonate (562 mg, 1.7 mmol). The reaction mixture was degassed with argon for 10 min, Xphos Pd G3 (49 mg, 0.06 mmol) was added, and the reaction mixture was heated at 80oC for 16 h. The reaction mixture was cooled to ambient temperature, filtered through celite bed, diluted with ethyl acetate, washed with water. The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The productwas purified by reverse phase preparative HPLC and lyophilized to afford (S)-1-(8-chlorochroman-4-yl)-3-(6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)urea (Example 60, 37 mg) LCMS (ESI) Calcd. for C18H17ClN6O2: 384.1, found [M+H]+= 385.2.1H NMR (400 MHz, DMSO- d6 ): δH 9.52 (s, 1H), 9.24 (brs, 1H), 7.77 (t, 1H), 7.60 (s, 1H), 7.43-7.21 (m, 4H), 6.92-6.88 (m, 1H), 5.07-5.02 (m, 1H), 4.47-4.42 (m, 1H), 4.34-4.29 (m, 1H), 4.14 (s, 3H), 2.32-2.05 (m, 2H). Example 61: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(3-hydroxyoxetan-3- yl)pyridin-2-yl)urea (Example 61):Scheme 21.

[0275] Synthesis of 3-(6-bromopyridin-2-yl)oxetan-3-ol (21-3) [Step 1]: To a solution of 2,6- dibromopyridine (250 mg, 1.06 mmol) in toluene (5 mL) was added n-BuLi (1.6 M in hexanes, 0.53 mL, 0.844 mmol) at -78 °C and stirred at -78 °C for 0.5 h. Oxetan-3-one (76 mg, 1.06 mmol) was added dissolving in toluene (1 mL) dropwise at -78 °C and stirred for 4 h. Reaction mixture was quenched with saturated NH4Cl solution and diluted with ethyl acetate. Organic extracts were washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to get crude. The crude product was purified by column chromatography to afford 3-(6- bromopyridin-2-yl)oxetan-3-ol (150 mg). LCMS (ESI) Calcd. for C8H8BrNO2: 229, found [M+H]+= 230.1.

[0276] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(3-hydroxyoxetan-3-yl)pyridin-2- yl)urea (Example 61) [Step 2]: (S)-1-(8-Chlorochroman-4-yl)-3-(6-(3-hydroxyoxetan-3- yl)pyridin-2-yl)urea was synthesized following Scheme 6, step 1. LCMS (ESI) Calcd. for C18H18ClN3O4: 375.1, found [M+H]+= 376.2.1H NMR (400 MHz, DMSO-d6): δH 9.51 (s, 1H), 9.31 (s, 1H), 7.68 (t, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 7.14 (d, 1H), 7.06 (d, 1H), 6.85 (t, 1H), 5.07-5.05 (m, 1H), 4.62-4.57 (m, 2H), 4.43-4.41 (m, 1H), 4.35-4.34 (m, 2H), 4.33-4.27 (m, 1H), 2.34- 2.21(m, 1H), 2.07-2.05 (m, 1H). Example 62: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(1- hydroxycyclopropyl)pyridin-2-yl)urea:Scheme 22.

[0277] Synthesis of 1-(6-bromo-2-pyridyl)vinyloxy-tert-butyl-dimethyl-silane (22-2) [Step 1]: To a solution of 1-(6-bromo-2-pyridyl)ethanone (2.0 g, 10.0 mmol) in dichloromethane (50 mL) was added Et3N (4.2 mL, 30.0 mmol) followed by TBSOTF ( 2.8 mL, 15.0 mmol) at 0°C and stirred at ambient temperature for 16 h. The reaction mixture was diluted with crushed ice and extracted with ethyl acetate. Organic extract was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to get crude. The crude product was purified by combi-flash column chromatography to afford 1-(6-bromo-2- pyridyl)vinyloxy-tert-butyl-dimethyl-silane (22-2, 1.5 g). LCMS (ESI) Calcd. for C13H20BrNOSi: 313.05, found [M+H]+: 314.31.

[0278] Synthesis of [1-(6-bromo-2-pyridyl)cyclopropoxy]-tert-butyl-dimethyl-silane (22-3)[Step 2]: To a solution of diethylzinc (1.2 mL, 5.57 mmol) in dichloromethane (5 mL) at 0 °C wasadded chloroiodomethane (1.8 g, 10.3 mmol) dissolved in dichloromethane (2 mL) dropwise. The reaction mixture was stirred at 0 °C for 15 minutes. A solution 1-(6-bromo-2- pyridyl)vinyloxy-tert-butyl-dimethyl-silane (500 mg, 1.59 mmol) in dichloromethane (3.0 mL) was added. The reaction mixture was stirred at 0°C for 2 h and allowed to stir at ambient temperature for 16 h. Reaction was quenched with cold saturated aqueous solution of ammonium chloride and extracted with dichloromethane. Organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude. The crude product was purified by combi-flash column chromatography to afford [1-(6-bromo-2-pyridyl)cyclopropoxy]-tert-butyl-dimethyl-silane (22-3, 140 mg). LCMS (ESI) Calcd. for C14H22BrNOSi: 328.0, found [M+H]+= 328.8.

[0279] Synthesis of 1-[6-[1-[tert-butyl(dimethyl)silyl]oxycyclopropyl]-2-pyridyl]-3-[(4S)-8- chlorochroman-4-yl]urea (22-4) [Step 3]: 1-[6-[1-[tert-butyl(dimethyl)silyl]oxycyclopropyl]-2- pyridyl]-3-[(4S)-8-chlorochroman-4-yl]urea was synthesized following Scheme 6, step 1 using [1-(6-bromo-2-pyridyl)cyclopropoxy]-tert-butyl-dimethyl-silane. LCMS (ESI) Calculated for C24H32ClN3O3Si: 473.2, found [M+H]+= 474.2.

[0280] Synthesis of 1-[6-(1-hydroxycyclopropyl)-2-pyridyl]-3-[(4S)-8-chlorochroman-4- yl]urea (Example 62) [Step 4]: To a stirred solution of 1-[6-[1-[tert- butyl(dimethyl)silyl]oxycyclopropyl]-2-pyridyl]-3-[(4S)-8-chlorochroman-4-yl]urea (50 mg, 0.105 mmol) in 1,4-dioxane (1 mL) was added HCl in dioxane (177 mg, 0.791 mmol), 0 °C, stirred at ambient temperature for 2 h. Solvent was concentrated to get crude which was purified by reverse phase preparative HPLC to afford 1-[6-(1-hydroxycyclopropyl)-2-pyridyl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 62, 17 mg). LCMS (ESI) Calcd. for C18H18ClN3O3: 359.2, found [M+H]+= 360.2.1H NMR (400 MHz, DMSO-d6): δH9.31 (s, 1H), 8.93 (brs, 1H), 7.64 (t, 1H), 7.35 (d, 1H), 7.22-7.17 (m, 2H), 6.95-6.87 (m, 2H), 6.03 (s, 1H), 4.97-4.95 (m, 1H), 4.42- 4.39 (m, 1H), 4.21 (t, 1H), 2.13-2.11 (m, 1H), 2.01-1.97 (m, 1H), 0.98 (s, 1H), 0.81-0.79 (m, 1H), 0.75-0.74 (m, 1H), 0.49 (s, 1H). Examples 63 & 64: Synthesis of (S)-1-(6-(4-(3-aminooxetan-3-yl)phenyl)pyridin-2-yl)-3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (isomer 1) and (R)-1-(6-(4-(3- aminooxetan-3-yl)phenyl)pyridin-2-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)urea (isomer 2):Scheme 23.

[0281] Synthesis of (S)-1-(6-acetyl-5-fluoropyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (23- 3) [Step 1]: (S)-1-(6-acetyl-5-fluoropyridin-2-yl)-3-(8-chlorochroman-4-yl)urea was synthesized following Scheme 6, step 1 using 1-(6-bromo-3-fluoropyridin-2-yl)ethan-1-one. LCMS (ESI) Calcd. for C17H15ClFN3O3: 363.08, found [M+H+2]+= 366.1,1H NMR (400 MHz, DMSO-d6): δH 9.47 ( s, 1H), 8.19-8.17 (m, 1H), 7.85-7.75 (m, 2H), 7.34 (d, 1H), 7.27 (d, 1H), 6.90 (t, 1H), 5.02- 5.00 (m, 1H), 4.43-4.40 (m, 1H), 4.30-4.26 (m, 1H), 2.31 (s, 3H), 2.19-2.15 (m, 1H), 2.06-2.03 (m, 1H).

[0282] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(5-fluoro-6-(1-hydroxyethyl)pyridin-2- yl)urea (23-4) [Step 2]: To a stirred solution of (S)-1-(6-acetyl-5-fluoropyridin-2-yl)-3-(8- chlorochroman-4-yl)urea (23-3, 150 mg, 0.412 mmol) in methanol (3 mL) was added sodium borohydride (19 mg, 0.495 mmol) at 0°C and was allowed to stir at ambient temperature for 2 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. Organic extract was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford crude product. The product was purified by reverse phase preparative HPLC to afford 1-((S)-8-chlorochroman-4-yl)-3-(5-fluoro-6-(1- hydroxyethyl)pyridin-2-yl)urea (23-4, 95 mg). LCMS (ESI) Calcd. for C17H17ClFN3O3: 365.09, found [M+H+2]+= 368.3.

[0283] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(5-fluoro-6-((S)-1- hydroxyethyl)pyridin-2-yl)urea (Example 63) and 1-((S)-8-chlorochroman-4-yl)-3-(5-fluoro- 6-((R)-1-hydroxyethyl)pyridin-2-yl)urea (Example 64) [Step 3]: The racemic compound was purified by SFC-HPLC to afford the first product 1-((S)-8-chlorochroman-4-yl)-3-(5-fluoro-6-((S)- 1-hydroxyethyl)pyridin-2-yl)urea as peak 1 (Example 63, 32 mg) and the second product 1-((S)- 8-chlorochroman-4-yl)-3-(5-fluoro-6-((R)-1-hydroxyethyl)pyridin-2-yl)urea as peak 2 (Example 64, 43 mg). The absolute stereochemistry of both the diastereomers were assigned arbitrarily.

[0284] 1-((S)-8-chlorochroman-4-yl)-3-(5-fluoro-6-((S)-1-hydroxyethyl)pyridin-2-yl)urea (Example 63) [Peak 1]: LCMS (ESI) Calcd. for C17H17ClFN3O3: 365.09, found [M+H]+= 366.1.1H NMR (400 MHz, DMSO-d6): δH9.37 ( s, 1H), 8.79 (brs, 1H), 7.60 (t, 1H), 7.33-7.31 (m, 1H), 7.28-7.24 (m, 2H), 6.88 (t, 1H), 5.19 (brs, 1H), 5.04-4.99(m, 1H), 4.88-4.84 (m, 1H), 4.43-4.38 (m, 1H), 4.33-4.27 (m, 1H), 2.20-2.13 (m, 1H), 2.05-1.99 (m, 1H), 1.10 (d, 3H).

[0285] 1-((S)-8-chlorochroman-4-yl)-3-(5-fluoro-6-((R)-1-hydroxyethyl)pyridin-2-yl)urea (Example 64) [Peak 2]: LCMS (ESI) Calcd. for C17H17ClFN3O3: 365.09, found [M+H]+= 366.1.1H NMR (400 MHz, DMSO-d6): δH 9.35 ( s, 1H), 8.66 (brs, 1H), 7.60 (t, 1H), 7.33-7.27 (m, 3H),6.89 (t, 1H), 5.21 (brs, 1H), 5.04-5.00(m, 1H), 4.89-4.85 (m, 1H), 4.43-4.37 (m, 1H), 4.33-4.28 (m, 1H), 2.19-2.15 (m, 1H), 2.05-2.00 (m, 1H), 1.21 (d, 3H).

[0286] SFC Method: SFC PREP Purification was performed on waters SFC Prep-80 instrument equipped with waters 2489 UV / visible Detector by using I-Cellulose-J (30.0 mm x 250mm ), 5µ operating at 35 ºC temperature, maintaining flow rate of 70 ml / min ,using 60 % CO2 in super critical state and 40% of 100% methanol as mobile phase, this isocratic mixture was run up to 10.0 minutes and also maintained the isobaric condition of 120 bar at 220 nm wavelength. Examples 65 & 66: Synthesis of (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)- N,N-dimethylacetamide and (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)-N- methylacetamide:Scheme 24.

[0287] Synthesis of (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)acetic acid (24- 2) [Step 1]: To a solution of methyl (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)acetate (24-1, 170 mg, 0.45 mmol) in THF (4 mL) was added LiOH,H2O (1M) (0.70 mL, 0.679 mmol) at 0 °C and stirred at ambient temperature for 3 h. Reaction mixture was concentrated under reduced pressure, acidified with saturated KHSO4solution and extracted with 5 % THF-ethyl acetate. Organic extract was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)acetic acid (24-2, 140 mg). LCMS (ESI) Calcd. for C17H16ClN3O4: 361.08, found [M+H]+= 362.1

[0288] Synthesis of (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)-N,N- dimethylacetamide (Example 65) [Step 2]: To a solution of (S)-2-(6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)acetic acid (24-2, 100 mg, 0.28 mmol) in DMF (3 mL) were added T3P (50 % in ethyl acetate) (0.060 mL, 0.36 mmol) and TEA (0.14 mL, 1.11 mmol) at 10 °C followed by the addition of dimethyl amine (1M in THF) (0.35 mL, 1.38 mmol) at the same temperature. The reaction mixture was stirred at ambient temperature for 16 h. Ice water was added to the reaction mixture and extracted with ethyl acetate. Organic extract was dried over anhydrousNa2SO4and concentrated to get crude which was purified by reverse phase preparative HPLC to afford (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)-N,N-dimethylacetamide (Example 65, 16 mg). LCMS (ESI) Calcd. for C19H21ClN4O3: 388.13, found [M+H]+= 389.2.1H NMR (400 MHz, DMSO-d6): δH 9.30 (s, 1H), 8.89 (s, 1H), 7.62 (t, 1H), 7.32 (d, 1H), 7.23 (d, 1H), 7.13 (d, 1H), 6.90-6.81 (m, 2H), 5.04-5.03 (m, 1H), 4.38-4.36 (m, 1H), 4.30-4.28 (m, 1H), 3.63 (s, 2H), 2.83 (s, 3H), 2.66 (s, 3H), 2.11-2.09 (m, 2H).

[0289] Synthesis of (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)-N- methylacetamide (Example 66) [Step 3]: To a solution of (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)acetic acid (24-2, 100 mg, 0.276 mmol) in DMF (3 mL) were added EDCI(69 mg, 0.359 mmol), HOAt (45 mg, 0.332 mmol) and TEA (0.16 mL, 1.11 mmol) at 0 °C and stirred at ambient temperature for 15 min. Methyl amine hydrochloride (24 mg, 0.359 mmol) was added at 0 °C, stirred at ambient temperature for 16 h. Ice water was added to the reaction mixture and extracted with ethyl acetate. Organic extract was washed with brine, dried over anhydrous Na2SO4,and concentrated to get crude. The crude was purified by reverse phase preparative HPLC to afford (S)-2-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)-N- methylacetamide (Example 66, 20 mg). LCMS (ESI) Calcd. for C18H19ClN4O3: 374.11, found [M+H]+= 375.2.1H NMR (400 MHz, DMSO-d6): δH9.27 (s, 1H), 8.74 (s, 1H), 7.84 (d, 1H), 7.61 (t, 1H), 7.31-7.29 (m, 1H), 7.24-7.22 (m, 1H), 7.19-7.17 (m, 1H), 6.88 (t, 1H), 6.83 (d, 1H), 5.08- 5.03 (m, 1H), 4.39-4.32 (m, 2H), 3.44 (s, 2H), 2.44 (d, 3H), 2.16-2.07 (m, 2H). Example 67: Synthesis of (S)-6-(3-(8-chloro-6-methoxychroman-4-yl)ureido)-N- methylpicolinamide:Scheme 25.

[0290] Synthesis of 3-(2-chloro-4-methoxy-phenoxy)propanenitrile (25-3) [Step-1]: To the mixture of 2-chloro-4-methoxy-phenol (25-1, 5.00 g, 31.5 mmol) and prop-2-enenitrile (25-2, 3.35 g, 63.1 mmol), triethylamine (0.88 mL, 6.31 mmol) was added at an ambient temperature and heated at 80oC for 18 h. Reaction mixture was quenched with water and extracted with ethyl acetate. Organic extract was successively washed with 10% aqueous NaOH (20 mL), 2(N) HCl (20 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get crude. The crude was purified by combi flash column chromatography to obtain 3-(2-chloro-4-methoxy-phenoxy)propanenitrile (25-3, 3 g).1H NMR (400 MHz, DMSO-d6): δH 7.12 (d, 1H), 7.05 (d, 1H), 6.88 (dd, 1H), 4.18 (t, 2H), 3.72 (s, 3H), 2.99 (t, 2H).

[0291] Synthesis of 3-(2-chloro-4-methoxy-phenoxy)propanoic acid (25-4) [Step-2]: Amixture of 3-(2-chloro-4-methoxy-phenoxy)propanenitrile (25-3, 7.30 g, 34.5 mmol) and conc Hydrochloric acid (12N, 60 mL) was heated at 100 °C for 4 h. Reaction mixture was quenched with crushed ice, white precipitation occurred, filtered the solid, dried under vacuum followed by pentane and ether wash to afford 3-(2-chloro-4-methoxy-phenoxy)propanoic acid (25-4, 5.30 g) as white solid. LCMS (ESI) Calcd. for C10H11ClO4: 230.03, found [M+H]+= 231.2.1H NMR (400 MHz, DMSO-d6): δH7.09 (d, 1H), 7.02 (d, 1H), 6.86 (dd, 1H), 4.18-4.10 (m, 2H), 3.71 (s, 3H), 2.69-2.64 (m, 2H).

[0292] Synthesis of 8-chloro-6-methoxy-chroman-4-one (25-5) [Step-3]: Phosphorouspentachloride (3.07 g, 14.7 mmol) was added to a suspension of 3-(2-chloro-4-methoxy- phenoxy)propanoic acid (25-4, 2.00 g, 8.67 mmol) in Benzene (10 mL). The resultant clear solution was heated quickly to boiling for 30 min. Aluminium chloride (3.24 g, 24.3 mmol) was added at 00C in portions and the reaction was continued for stir for another 1 h at 0 °C. Reaction mixture was quenched with crushed ice and extracted with ethyl acetate. Organic extract was washed with aqueous NaHCO3solution, dried over anhydrous Na2SO4, concentrated under reduced pressure. The product was purified by combi-flash column chromatography to afford 8- chloro-6-methoxy-chroman-4-one (25-5, 1.30 g). LCMS (ESI) Calcd. for C10H9ClO3: 212.02, found [M+H]+= 213.1.1H NMR (400 MHz, DMSO-d6): δH7.40 (d, 1H), 7.18 (d, 1H), 4.59 (t, 2H), 3.76 (s, 3H), 2.83 (t, 2H).

[0293] Synthesis of (R, E)-N-(8-chloro-6-methoxychroman-4-ylidene)-2-methylpropane-2-sulfinamide (25-7) [Step 4]: To a stirred solution of 8-chloro-6-methoxy-chroman-4-one (25-5,2.0 g, 9.41 mmol) in THF (30 mL) was added (R)-2-methylpropane-2-sulfinamide (25-6, 1.71 g, 14.1 mmol) followed by titanium (IV) ethoxide (5.0 mL, 23.5 mmol) under argon atmosphere atambient temperature. Then the reaction mixture was heated at 70°C for 16 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate twice. Organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude. The crude was purified by combi-flash column chromatography to afford (R,E)-N-(8-chloro-6-methoxychroman-4-ylidene)-2-methylpropane-2- sulfinamide (25-7, 2.1 g). LCMS (ESI) Calcd. for C14H18ClNO3S: 315.07, found [M+H]+= 316.30.1H NMR (400 MHz, CDCl3): δH 7.37 (d, 1H), 7.09 (d, 1H), 4.44-4.32 (m, 2H), 3.76 (s, 3H),3.53- 3.45 (m, 1H), 3.31-3.23 (m, 1H), 1.30 (s, 9H).

[0294] Synthesis of (R)-N-((S)-8-chloro-6-methoxychroman-4-yl)-2-methylpropane-2-sulfinamide (25-8) [Step 5]: To a stirred solution of (R,E)-N-(8-chloro-6-methoxychroman-4-ylidene)-2-methylpropane-2-sulfinamide (25-7, 2.10 g, 6.65 mmol) in methanol (25 mL) was added sodium borohydride (252 mg, 6.65 mmol) at 0°C. The reaction mixture was allowed to stir at ambient temperature for 2 h. Reaction mixture was quenched with ice cold water and extracted with ethyl acetate. Organic extract was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain crude. The crude was purified by combi flash chromatography to isolate both isomers. We isolated (R)-N-((R)-8- chloro-6-methoxychroman-4-yl)-2-methylpropane-2-sulfinamide (25-8a, 210 mg) as minor isomer and (R)-N-((S)-8-chloro-6-methoxychroman-4-yl)-2-methylpropane-2-sulfinamide (25-8, 1.1 g) as major isomer. LCMS (ESI) Calcd. for C14H20ClNO3S: 317.09, found [M+H]+= 318.1,1H NMR (400 MHz, DMSO-d6): δH6.93 (d, 1H), 6.85 (d, 1H), 5.76 (d, 1H), 4.46-4.41 (m, 1H), 4.33- 4.29 (m, 1H), 4.25-4.21 (m, 1H), 3.67 (s, 3H), 2.18-2.15 (m, 1H), 2.12-2.07 (m, 1H), 1.16 (s, 9H).

[0295] Synthesis of (S)-8-chloro-6-methoxychroman-4-amine hydrochloride (9) [Step 6]: To a stirred solution of (R)-N-((S)-8-chloro-6-methoxychroman-4-yl)-2-methylpropane-2- sulfinamide (25-8, 1.4 g, 4.4 mmol) in methanol (15 mL) was added 4(M) HCl in 1, 4-dioxane (5.5 mL, 22.0 mmol) at 0 °C and stirred at ambient temperature for 4 h. The excess HCl was removed under reduced pressure. The product was triturated with n-Pentane and diethyl ether and dried again under reduced pressure to afford (S)-8-chloro-6-methoxychroman-4-amine hydrochloride (25-9, 1.1 g). The product was carried to the next step without further purification. LCMS (ESI) Calcd. for C10H12ClNO2: 213.06, found [M+H]+= 213.8.1H NMR (400 MHz, DMSO- d6): δH 8.67 (s, 2H), 7.21 (s, 1H), 7.08 (s, 1H), 4.52 (s, 1H) ,4.29 (s, 2H), 3.73 (s, 3H), 2.32-2.24 (m, 1H), 2.13-2.09 (m, 1H).

[0296] Synthesis of (S)-6-(3-(8-chloro-6-methoxychroman-4-yl)ureido)-N- methylpicolinamide (Example 67) [Step 7]: (S)-6-(3-(8-Chloro-6-methoxychroman-4- yl)ureido)-N-methylpicolinamide was synthesized following Scheme 1, step 1 using 6-amino-N- methylpicolinamide. LCMS (ESI) Calcd. for C18H19ClN4O4: 390.11, found [M+H]+= 391.2,1H NMR (400 MHz, DMSO-d6): δH 9.06 (s, 1H), 8.14 (brs, 1H), 7.93 (d, 1H), 7.88-7.80 (m, 2H), 7.52 (d, 1H), 6.99 (d, 1H), 6.86 (d, 1H), 4.95-4.94 (m, 1H), 4.32-4.20 (m, 2H), 3.68 (s, 3H), 2.74 (d, 3H), 2.33-2.26 (m, 1H),2.14-2.04 (m, 1H).

[0297] Synthesis of N-methyl-6-nitropicolinamide (25-2a) [Step 1a]: To a stirred solution of 6-nitropyridine-2-carboxylic acid (25-1a, 500 mg, 2.97 mmol) in DMF (5 mL) were added HATU (1.36 g, 3.57 mmol) and DIPEA (1.3 mL, 7.44 mmol) at 0 °C. After 10 min, methylamine solution (2 M in THF) (3.0 mL, 5.95 mmol) was added to this reaction mixture and stirred at ambient temperature for 2 h. Reaction mixture was diluted with ice cold water and extracted with ethyl acetate. Organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product. The crude was purified by combiflash chromatography to afford N-methyl-6-nitropicolinamide (25-2a, 360 mg). LCMS (ESI) Calcd. for C7H7N3O3: 181.15, found [M+H]+= 182.2.1H NMR (400 MHz, DMSO-d6): δH8.71 (brs, 1H), 8.49-8.46 (m, 1H), 8.43-8.41 (m, 2H), 2.86 (d, 3H).

[0298] Synthesis of 6-amino-N-methylpicolinamide (25-10) [Step 2a]: To a stirred solution of N-methyl-6-nitropicolinamide (25-2a, 350 mg, 1.93 mmol) in Methanol (5 mL) was added 10% Pd / C (103 mg, 0.966 mmol). The reaction vessel was evacuated and filled with hydrogen and stirred under hydrogen balloon pressure for 16 h. After completion of reaction the reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 6-amino-N-methylpicolinamide (25-10, 280 mg). The product was carried to the next step without further purification. LCMS (ESI) Calcd. for C7H9N3O: 151.07, found [M+H]+= 152.1.1H NMR (400 MHz, DMSO-d6): δH8.19-8.18 (m, 1H), 7.51 (t, 1H), 7.14 (d, 1H), 6.61 (d, 1H), 6.04 (s, 2H), 2.79 (d, 3H). Examples 68 & 69: Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-1- methoxyethyl)pyridin-2-yl)urea (isomer 1) and 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-1- methoxyethyl)pyridin-2-yl)urea (isomer 2):Scheme 26.

[0299] Synthesis of 1-(6-bromopyridin-2-yl)ethan-1-ol (26-2) [Step 1]: To a stirred solution of 1-(6-bromopyridin-2-yl)ethan-1-one ( 26-1, 5 g, 25 mmol ) in methanol ( 15 mL ), NaBH4 ( 2.8 g, 75 mmol ) was added at 0 °C and continued stirring at ambient temperature for 1 h. The reaction was quenched with aqueous NH4Cl, volatiles are removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water and brine. Combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product was purified through flash column chromatography to afford 1-(6-bromopyridin-2- yl)ethan-1-ol (26-2, 4 g). LCMS (ESI) Calcd. for C7H8BrNO: 200.98, found [M+H]+= 202.0.

[0300] Synthesis of 2-bromo-6-(1-methoxyethyl)pyridine, 26-3 [Step 2]: To a stirred solution of 1-(6-bromopyridin-2-yl)ethan-1-ol (26-2, 1 g, 5 mmol ) in THF (10 mL), NaH (400 mg, 10 mmol) was added at 0 °C and stirred for 15 min. After 15 min, methyl iodide (1.5 mL, 25 mmol) was added and continued stirring at ambient temperature for 2 h. The reaction was quenched with water, diluted with ethyl acetate, washed with water and brine. The combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product was purified by flash column chromatography to afford 2-bromo-6-(1- methoxyethyl)pyridine (26-3, 800 mg). LCMS (ESI) Calcd. for C8H10BrNO: 215.0, found [M+H]+= 216.0

[0301] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-1-methoxyethyl)pyridin-2- yl)urea (Example 68) and 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-1-methoxyethyl)pyridin-2- yl)urea (Example 69) [Step 3]: A stirred suspension of 2-bromo-6-(1-methoxyethyl)pyridine (26- 3, 230 mg, 1.1 mmol), (S)-1-(8-chlorochroman-4-yl)urea (26-4, 200 mg, 0.9 mmol) and Cs2CO3(580 mg, 1.8 mmol) in 1,4-dioxane (4 mL) was purged with argon. After 20 min, XPhos Pd G3(150 mg, 0.18 mmol) was added and continued stirred at 80 °C for 8 h. The reaction mixture was filtered through a celite bed and washed with ethyl acetate. The combined filtrate was washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC and the diastereomers were separated by chiral preparative HPLC (SFC) to afford the first product 1- ((S)-8-chlorochroman-4-yl)-3-(6-((R)-1-methoxyethyl)pyridin-2-yl)urea (Example 68, 90 mg) as peak 1 and the second product 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-1-methoxyethyl)pyridin-2- yl)urea (Example 69, 40 mg) as peak 2. The absolute stereochemistry was not determined and arbitrarily assigned.

[0302] 1-((S)-8-chlorochroman-4-yl)-3-(6-((R)-1-methoxyethyl)pyridin-2-yl)urea (Example 68) [Peak 1]: LCMS (ESI) Calcd. for C18H20ClN3O3: 361.1, found [M+H]+= 362.2.1H NMR (400 MHz, DMSO-d6): δH 9.37 (s, 1H), 9.08 (s, 1H), 7.68 (t, 1H), 7.33( d, 1H), 7.26 (d, 1H), 7.19 (d, 1H), 6.91-6.87 (m, 2H), 5.01-5.00 (m, 1H), 4.44-4.40 (m, 1H), 4.26 (t, 1H), 4.12-4.07 (m, 1H), 3.10 (s, 3H), 2.20-2.16 (m, 1H), 2.03-2.00 (m, 1H), 1.12 (d, 3H).

[0303] 1-((S)-8-chlorochroman-4-yl)-3-(6-((S)-1-methoxyethyl)pyridin-2-yl)urea (Example 69) [Peak 2]: LCMS (ESI) Calcd. for C18H20ClN3O3: 361.1, found [M+H]+= 362.2.1H NMR (400 MHz, DMSO-d6): δH9.38 (s, 1H), 9.06 (s, 1H), 7.69 (t, 1H), 7.33( d, 1H), 7.26 (d, 1H), 7.18 (d, 1H), 6.91-6.86 (m, 2H), 5.04-4.99 (m, 1H), 4.44-4.41 (m, 1H), 4.27 (t, 1H), 4.15-4.10 (m, 1H), 3.05 (s, 3H), 2.22-2.16 (m, 1H), 2.03-2.00 (m, 1H), 1.16 (d, 3H).

[0304] SFC HPLC method: SFC PREP purification was perforemed Waters SFC Prep 80 instrument equipped with Waters 2489 UV / Visible Detector by using I-CELLULOSE J (30.0mm x 250mm ), 5µ Column operating at 35oC temperature, maintaining flow rate of 70 mL / min ,using 60 % CO2in super critical state and 40% of (100% methanol ) as mobile phase, run this isocratic mixture up to 13.0 minutes and maintained the isobaric condition of 100 bar at 220 nm.Example 70: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-fluoro-N- methylpicolinamide:Scheme 27.

[0305] Synthesis of methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-fluoropicolinate (27- 3) [Step 1]: Methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-fluoropicolinate was synthesized Scheme 4, step 3. LCMS (ESI) Calcd. for C17H15ClFN3O4: 379.0, found [M+H]+= 380.1.1H NMR (400 MHz, DMSO-d6): δH9.70 (s, 1H), 8.60 (d, 1H), 7.85 (t, 1H), 7.66-7.63 (m, 1H), 7.35-7.33 (m, 1H), 7.26-7.25 (m, 1H), 6.90 (t, 1H), 5.05-5.01 (m, 1H), 4.46-4.41 (m, 1H), 4.29-4.24 (m, 1H), 3.70 (s, 3H), 2.22-2.14 (m, 1H), 2.03-1.96 (m, 1H).

[0306] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-fluoropicolinic acid (27-4) [Step 2]: To a stirred solution of methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-fluoropicolinate (100 mg, 0.3 mmol) in THF (3 mL) and H2O (2 mL) was added LiOH.H2O (50 mg, 1 mmol) at 0oC and continued stirring for 4 h. The reaction mixture was neutralized with 1N aqueous HCl and extracted with ethyl acetate. Combined organic extracts were washed with brine, water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford (S)- 6-(3-(8-chlorochroman-4-yl)ureido)-3-fluoropicolinic acid (27-4, 80 mg). The product was used in the next step without further purification. LCMS (ESI) Calcd. forC16H13ClFN3O4: 365.0, found [M+H]+= 366.0.

[0307] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3-fluoro-N-methylpicolinamide (Example 70) [Step 3]: To a stirred solution of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3- fluoropicolinic acid (27-4, 80 mg, 0.2 mmol) and methanamine hydrochloride salt (25 mg, 0.4 mmol) in DMF (3 mL) were added DIPEA (0.1 mL, 0.6 mmol), HATU (140 mg, 0.3 mmol) at 0 °C. and continued stirring for 16 h at ambient temperature. The reaction was diluted with dichloromethane and washed with water and brine. Combined organic extracts were dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product waspurified by reverse phase preparative HPLC to afford (S)-6-(3-(8-chlorochroman-4-yl)ureido)-3- fluoro-N-methylpicolinamide (Example 70, 25 mg). LCMS (ESI) Calcd. for^C17H16ClFN4O3: 378.1, found [M+H]+= 379.1.1H NMR (400 MHz, DMSO-d6): δH 9.21 (s, 1H), 8.31 (d, 1H), 7.84- 7.82 (m, 1H), 7.78-7.76 (m, 2H), 7.34 (d, 1H), 7.27 (d, 1H), 6.89 (t, 1H), 4.98 (d, 1H), 4.42-4.38 (m, 1H), 4.28-4.24 (m, 1H), 2.71 (d, 3H), 2.16-2.15 (m, 1H), 2.02-1.99 (m, 1H).

[0308] Examples 71 & 72: Synthesis of N-((S)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2- yl)ethyl)methanesulfonamide (isomer 1) & N-((R)-1-(6-(3-((S)-8-chlorochroman-4- yl)ureido)pyridin-2-yl)ethyl)methanesulfonamide (isomer 2):Scheme 28.

[0309] Synthesis of N-(1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2- yl)ethyl)methanesulfonamide (28-3) [Step 1]: To a stirred solution of 1-(6-(1- aminoethyl)pyridin-2-yl)-3-((S)-8-chlorochroman-4-yl)urea (18-4, 120 mg, 0.14 mmol) in Dichloromethane (10mL), triethylamine (0.15 mL, 1.04 mmol) and methanesulfonyl chloride (28- 2, 0.04 mL, 0.52 mmol) were added at 0°C The reaction mixture was then stirred at 25°C for 16h. The reaction mixture was dissolved in dichloromethane and washed by water (twice). The organic part was dried over anhydrous Na2SO4and evaporated to afford the crude product. The crude product was purified by prep HPLC to afford N-(1-(6-(3-((S)-8-chlorochroman-4- yl)ureido)pyridin-2-yl)ethyl)methanesulfonamide (28-3, 60 mg). LCMS(ESI) Calcd. for C18H21ClN4O4S: 424.9, found [M+H]+: 425.23.

[0310] Synthesis of N-((S)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2- yl)ethyl)methanesulfonamide (Example 71) & N-((R)-1-(6-(3-((S)-8-chlorochroman-4- yl)ureido)pyridin-2-yl)ethyl)methanesulfonamide (Example 72) [Step 2]: N-(1-(6-(3-((S)-8- chlorochroman-4-yl)ureido)pyridin-2-yl)ethyl)methanesulfonamide (3, 60 mg, 0.14 mmol) wasseparated by SFC chiral and lyophilized to afford peak 1 as N-((S)-1-(6-(3-((S)-8- chlorochroman-4-yl)ureido)pyridin-2-yl)ethyl)methanesulfonamide (Example 71, 24 mg) and peak 2 as N-((R)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2- yl)ethyl)methanesulfonamide (Example 72) , 29 mg). The absolute stereochemistry of both the diastereomers is arbitrarily assigned.

[0311] SFC method: SFC prep purification has been done in Waters an SFC 80 instrument equipped with Waters 2489 UV / Visible Detector by using Chiralcel-OX-H (21.0 mm x 250mm), 5µ Column operating at 35 ºC temperature, maintaining flow rate of 70 ml / min, using 65% CO2 in super critical state & 35% of [100% IPA] as Mobile phase. Run this isocratic mixture up to 10.0 minutes and maintained the isobaric condition of 110 bar at 240 nm wavelength.

[0312] N-((S)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2- yl)ethyl)methanesulfonamide (Example 71) [Peak 1]: LCMS (ESI) Calcd. for C18H21ClN4O4S: 424.9, found [M+H]+: 425.19.1H NMR (400 MHz, DMSO-d6) δH: 9.26 (s, 1H), 8.63 (s, 1H), 7.69 (t, 1H), 7.55 (d, 1H), 7.32 (d, 1H), 7.27-7.24 (m, 2H),7.01 (d, 1H), 6.89 (t, 1H), 5.03-4.99 (m, 1H), 4.42 -4.27 (m, 3H), 2.75 (s, 3H), 2.17- 2.08 (m, 2H), 1.20 (d, 3H).The absolute stereochemistry was unknown.

[0313] N-((R)-1-(6-(3-((S)-8-chlorochroman-4-yl)ureido)pyridin-2- yl)ethyl)methanesulfonamide (Example 72) [Peak 2]: LCMS (ESI) Calcd. for C18H21ClN4O4S: 424.9, found [M+H]+: 425.20.1H NMR (400 MHz, DMSO-d6) δH: 9.25 (s, 1H), 8.63 (s, 1H), 7.69 (t, 1H), 7.55 (d, 1H), 7.32 (d, 1H), 7.29-7.25 (m, 2H),7.02 (d, 1H), 6.89 (t, 1H), 5.02-5.01 (m, 1H), 4.40 -4.28 (m, 3H), 2.75 (s, 3H), 2.16- 2.07 (m, 2H), 1.24-1.19 (m, 3H).The absolute stereochemistry was unknown. Example 73: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N-dimethylpyrazine-2- carboxamide:Scheme 29.

[0314] Synthesis of methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)pyrazine-2-carboxylate (29-3) [Step 1]: To a stirred solution of (S)-1-(8-chlorochroman-4-yl)urea (29-2, 250 mg, 1.10 mmol) in 1,4-Dioxane (5 mL) were added methyl 6-bromopyrazine-2-carboxylate (29-1, 287 mg, 1.32 mmol) followed by cesium carbonate (898 mg, 2.76 mmol) in a sealed tube. The reaction mixture was degassed by argon for 10 min. Then added palladium acetate (25 mg, 0.110 mmol) and xanthpphos (128 mg, 0.221 mmol) and heated at 90oC for 16 h. The reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure to afford crude product. The crude was purified through combiflash chromatography to afford (S)- 6-(3-(8-chlorochroman-4-yl)ureido)pyrazine-2-carboxylate (29-3, 160 mg). LCMS (ESI) calcd. for C16H15ClN4O34: 362.08, found [M+H]+= 363.3,1H NMR (400 MHz, DMSO-d6): δH 9.96 (s, 1H), 9.03 (s, 1H), 8.72 (s, 1H) , 8.19 (d, 1H) ,7.35 (d, 1H), 7.27 (d, 1H), 6.91 (t, 1H), 5.08-5.03 (m, 1H), 4.44-4.35 (m, 1H), 4.30-4.26 (m, 1H), 3.80(s, 3H), 2.21-2.16 (m, 1H), 2.04-2.01 (m, 1H).

[0315] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)pyrazine-2-carboxylic acid (29- 4) [Step 2]: To a solution of (S)-6-(3-(8-chlorochroman-4-yl)ureido)pyrazine-2-carboxylate (29-3, 160 mg, 0.441 mmol) in methanol (1 mL), THF (1 mL) and water (0.5 mL), was added LiOH.H2O (56 mg, 1.32 mmol) and stirred at ambient temperature for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ether to remove other organic impurities. The aqueous layer was separated and acidified with 1M HCl, extracted with 20% IPA in dichloromethane. Organic extracts were dried over anhydrous Na2SO4and concentrated under reduced pressure to afford (S)-6-(3-(8-chlorochroman-4-yl)ureido)pyrazine- 2-carboxylic acid (29-4, 100 mg). The product was carried to the next step without further purification. LCMS (ESI) Calcd. for C15H13ClN4O4: 348.06, found [M-H]- = 347.13,1H NMR (400 MHz, DMSO-d6): δH9.84 (s, 1H), 9.00 (s, 1H), 8.70 (s, 1H), 8.26 (brs, 1H),7.34-7.27 (m, 2H), 6.90 (t, 1H), 5.05 (brs, 1H), 4.41-4.30 (m, 2H), 2.32-2.03(m, 2H).

[0316] Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N,N-dimethylpyrazine-2- carboxamide (Example 73) [Step 3]: In a screwcap vial, to a solution of (S)-6-(3-(8- chlorochroman-4-yl)ureido)pyrazine-2-carboxylic acid (29-4, 100 mg, 0.287 mmol) in dry DMF (1 mL) were added HATU (131 mg, 0.344 mmol) and DIPEA (0.21 mL, 1.15 mmol) at 0 °C, followed by the addition of Dimethylamine in THF (2M) (1.5 mL, 2.87 mmol) at the same temperature. The reaction mixture was stirred at ambient temperature for 16 h. Reaction mixture was quenched with water and extracted with ethyl acetate. Organic extract was washed with cold brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude. The product was purified by reverse phase preparative HPLC to afford (S)-6-(3-(8- chlorochroman-4-yl)ureido)-N,N-dimethylpyrazine-2-carboxamide (Example 73, 43 mg). LCMS (ESI) Calcd. for C17H18ClN5O3: 375.11, found [M+H]+:376.2, 1H NMR (400 MHz, DMSO-d6): δH 9.49 (s, 1H), 9.03 (s, 1H), 8.31 (s, 1H),7.70 (d, 1H), 7.36-7.34 (m, 1H), 7.26 (d,1H), 6.91 (t, 1H), 5.00 - 4.98 (m, 1H), 4.41-4.39 (m, 1H), 4.25-4.22 (m, 1H), 2.93 (s, 3H), 2.84 (s, 3H), 2.17- 2.15 (m, 1H), 2.06-2.05 (m, 1H).

[0317] Example 74: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(2-methyl-1H-pyrrolo[2,3-b] pyridin-6-yl) urea:Scheme 30.

[0318] Synthesis of 2-methyl-1H-pyrrolo[2,3-b] pyridine 7-oxide (30-2) [Step 1]: To a stirred solution of 2-methyl-1H-pyrrolo[2,3-b] pyridine (30-1, 3.0 g, 22.7 mmol) in 1,2-Dimethoxy ethane (30 mL) was added meta-chloroperoxibenzoic acid (77%, 7.6 g, 34.0 mmol) portion wise at 0 °C under argon atmosphere. The reaction was allowed to stir at ambient temperature for 3 h. The reaction was quenched with ice, aqueous K2CO3 solution was added to raise the pH to 9 and extracted with 20% IPA in dichloromethane. The extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product waspurified through combi flash chromatography to afford 2-methyl-1H-pyrrolo[2,3-b] pyridine 7- oxide (30-2, 1.50 g). LCMS (ESI) Calcd. for C8H8N2O: 148, found [M+H]+= 148.9.1H NMR (400 MHz, DMSO-d6) δH: 12.29 (brs, 1H), 8.00 (d, 1H), 7.48 (d, 1H), 7.01-6.98(m, 1H),6.26 (s,1H), 2.38 (s, 3H).

[0319] Synthesis of methyl 6-chloro-2-methyl-1H-pyrrolo[2,3-b] pyridine-1-carboxylate (30-3) [Step 2]: To a stirred solution of 2-methyl-1H-pyrrolo[2,3-b] pyridine 7-oxide (30-2, 1.5 g, 10.1 mmol) in THF (15 mL) was added HMDS (2.1 mL, 10.1 mmol) under an inert atmosphere of argon at ambient temperature. The reaction mixture was cooled at 0 °C and treated with methyl carbonochloridate (2.0 mL, 25.3 mmol). After addition the reaction mixture was heated at 25oC for 16 h. The reaction mixture was concentrated under reduced pressure to remove the excess solvent. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. Combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure. The crude compound was purified through combi flash column chromatography to afford methyl 6-chloro-2-methyl-1H- pyrrolo[2,3-b] pyridine-1-carboxylate, (30-3 ,270 mg). LCMS (ESI) Calcd. for C10H9ClN2O2: 224, found [M+H]+= 225.1H NMR (400 MHz, DMSO-d6): δH7.97 (d, 1H), 7.32 (d, 1H), 6.53(s, 1H), 3.99(s,3H), 2.56 (s, 3H).

[0320] Synthesis of methyl (S)-6-(3-(8-chlorochroman-4-yl)ureido)-2-methyl-1H- pyrrolo[2,3-b]pyridine-1-carboxylate (30-6) [Step 3]: The stirred solution of (S)-1-(8- chlorochroman-4-yl)urea (30-5, 125 mg, 0.551 mmol) in 1,4-dioxane (2 mL) was added methyl 6-chloro-2-methyl-1H-pyrrolo[2,3-b] pyridine-1-carboxylate ( 140 mg, 0.607 mmol) and cesium carbonate (450 mg, 1.38 mmol) in a sealed tube was degassed with argon balloon for 10 min. Then xanthphos (65 mg, 0.110 mmol) and palladium acetate (12 mg, 0.0551 mmol) was added and heated at 80oC for 16 h. The reaction mixture was filtered through celite bed and concentrated under reduced pressure. The crude product was purified through combi flash column chromatography to afford methyl (S)-6-(3-(8-chlorochroman-4-yl) ureido)-2-methyl-1H- pyrrolo[2,3-b] pyridine-1-carboxylate (30-6, 130 mg). LCMS (ESI) Calcd. for C20H19ClN4O4: 414, found [M+H]+= 415.1H NMR (400 MHz, DMSO-d6): δH9.79 ( d, 1H), 9.61 (s, 1H), 7.80 (d, 1H), 7.31 (d, 1H), 7.22 (d, 1H), 6.91 (d, 1H), 6.86 (t, 1H), 6.34(s,1H) 5.18-5.13 (m, 1H), 4.40 (t, 2H), 3.59 (s, 3H), 2.45 (s, 3H), 2.22-2.17 (m, 1H),2.11-2.06 (m, 1H).

[0321] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(2-methyl-1H-pyrrolo[2,3-b] pyridin-6- yl) urea (Example 74) [Step-4]: To a stirred solution of (S)-6-(3-(8-chlorochroman-4-yl) ureido)-2-methyl-1H-pyrrolo[2,3-b] pyridine-1-carboxylate (30-6, 125 mg, 0.301 mmol) in methanol (5mL) was added 1M NaOH (6.0 mL, 6.03 mmol) at 0 °C and the reaction mixture was stirred at ambient temperature for another 16 h. The excess solvent was removed under reduced pressure and resulting suspension was extracted with dichloromethane. Organic extract was washed with brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to provide the crude product. The crude was purified through reverse phase preparative HPLC to afford (S)-1-(8-chlorochroman-4-yl)-3-(2-methyl-1H-pyrrolo[2,3-b] pyridin-6- yl) urea (Example 74, 59 mg, 0.165 mmol). LCMS (ESI) Calcd. for C18H17ClN4O2: 356, found [M+H]+= 357, 1H NMR (400 MHz, DMSO-d6) δH 11.13 (s, 1H), 9.13 (s, 1H), 8.99 (brs, 1H), 7.67(d, 1H), 7.33-7.26(m,2H), 6.94-6.87 (m, 2H), 5.99 (s, 1H), 5.16-5.11 (m, 1H), 4.45-4.33 (m, 2H), 2.30(s, 3H),2.23-2.20 (m, 1H), 2.07-2.04 (m, 1H). Example 75: Synthesis of (S)-1-(6-(4-(3-aminooxetan-3-yl)phenyl)pyridin-2-yl)-3-(8- chlorochroman-4-yl)urea:Scheme 31.

[0322] Synthesis of (S)-1-(6-bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (31-3) [Step 1]: To a stirred solution of 6-bromopyridin-2-amine (31-1, 300 mg, 1.73 mmol) in dichloromethane (6 mL), were added triethylamine (1.2 mL, 8.67 mmol). A solution of triphosgene (309 mg, 1.04 mmol) in dichloromethane (1 mL) was added dropwise at -5 °C and stirred for 15 min. A solution of (S)-8-chlorochroman-4-amine hydrochloride (31-2, 420 mg, 1.91 mmol) in dichloromethane (3 mL) was added and the reaction mixture was allowed to stir for 40 min at same condition. The reaction mixture was quenched by the addition of brine solution and extracted with dichloromethane. Organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude product. This crude product was purified by column chromatography to afford (S)-1-(6-bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (31-3, 180 mg). LCMS(ESI) Calcd. for C15H13BrClN3O2: 380.99, found[M+H+2]+= 384.1,1H NMR (400 MHz, DMSO-d6): δH 9.31 (s, 1H), 7.73-7.71 (m, 1H), 7.66- 7.62 (m, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 7.30-7.24 (m, 1H), 7.17 (d, 1H), 6.91 (t, 1H), 4.98-4.95 (m, 1H), 4.43-4.39 (m, 1H), 4.27-4.22 (m, 1H), 2.19-2.16 (m, 1H), 2.02-1.99 (m, 1H).

[0323] Synthesis of tert-butyl (S)-(3-(4-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2- yl)phenyl)oxetan-3-yl)carbamate (31-5) [Step 2]: To a stirred solution of (S)-1-(6- bromopyridin-2-yl)-3-(8-chlorochroman-4-yl)urea (31-3, 180 mg, 0.470 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL), were added tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)oxetan-3-yl)carbamate (31-4, 177 mg, 0.470 mmol) followed by K3PO4 (200 mg, 0.941 mmol). Reaction mixture was degassed with argon for 10 min and Pd-118 (31 mg, 0.0470 mmol) was added and the reaction mixture was heated at 80 °C for 16 h. Reaction mixture was filtered through celite bed and washed with ethyl acetate and washed with water and brine. Organic extract was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to afford crude product. The product was purified by combiflash column chromatography to afford tert-butyl (S)-(3-(4-(6-(3-(8-chlorochroman-4-yl)ureido)pyridin-2- yl)phenyl)oxetan-3-yl)carbamate (31-5, 120 mg). LCMS (ESI) Calcd. for C29H31ClN4O5: 550.2, found[M+H]+= 551.4.

[0324] Synthesis of (S)-1-(6-(4-(3-aminooxetan-3-yl)phenyl)pyridin-2-yl)-3-(8- chlorochroman-4-yl)urea (Example 75) [Step 3]: To a stirred solution of tert-butyl (S)-(3-(4-(6- (3-(8-chlorochroman-4-yl)ureido)pyridin-2-yl)phenyl)oxetan-3-yl)carbamate (31-5, 120 mg, 0.218 mmol) in dichloromethane (2 mL) was added TFA (0.17 mL, 2.18 mmol) at 0 °C. Then the reaction mixture was stirred at an ambient temperature for 10 h. Excess TFA was removed under reduced pressure. The product was purified through reverse phase preparative HPLC to afford (S)-1-(6-(4-(3-aminooxetan-3-yl)phenyl)pyridin-2-yl)-3-(8-chlorochroman-4- yl)urea (Example 75, 41 mg) as white solid. LCMS (ESI) Calcd. For C24H23ClN4O3: 450.15, found [M+H]+= 451.1,1H NMR (400 MHz, DMSO-d6): δH9.56 ( s, 1H), 9.50 (brs, 1H), 7.77 (t, 1H), 7.60 (d, 2H), 7.47 (t, 3H), 7.41-7.39 (m, 1H), 7.33 (d, 1H), 7.14(d, 1H), 6.94 (t, 1H), 5.03- 5.01 (m, 1H), 4.70-4.65 (m, 4H), 4.44-4.41 (m, 1H), 4.18-4.15 (m, 1H), 2.17-2.10 (m, 2H). (Note: Two protons are not visible in this1H NMR). Examples 76-79: Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(2-((S)-1- hydroxyethyl)pyrimidin-4-yl)urea, 1-((S)-8-chlorochroman-4-yl)-3-(2-((S)-1- hydroxyethyl)pyrimidin-4-yl)urea, & 1-((S)-8-chlorochroman-4-yl)-3-(2-((R)-1- hydroxyethyl)pyrimidin-4-yl)urea:

[0325] Synthesis of (S)-1-(2-bromopyrimidin-4-yl)-3-(8-chlorochroman-4-yl)urea, 32-3 [Step 1]: To a stirred solution of 2-bromopyrimidin-4-amine (32-1, 200 mg, 1.13 mmol) in dichloromethane (10 mL) were added triethylamine (0.63 mL, 4.54 mmol) and triphosgene (337 mg, 1.13 mmol) in dichloromethane (1.5 mL) at -150C and stirred for 30 min. A solution of (S)- 8-chlorochroman-4-amine hydrochloride (32-2, 250 mg, 1.53 mmol) in dichloromethane (1.5 mL) was added to the reaction mixture and stirred further 30 min at ambient temperature. The reaction mixture was diluted with dichloromethane and washed with water and brine, dried over anhydrous Na2SO4,and concentrated under reduced pressure. The crude product was purified by column chromatography to afford (S)-1-(2-bromopyrimidin-4-yl)-3-(8-chlorochroman-4-yl)urea (32-3, 100 mg). LCMS (ESI) Calcd. for C14H12BrClN4O2: 383.63, found [M+2H]+: 385.2.

[0326] Synthesis of (S)-1-(2-acetylpyrimidin-4-yl)-3-(8-chlorochroman-4-yl)urea, Example 76 [Step 2]: To a stirred solution of (S)-1-(2-bromopyrimidin-4-yl)-3-(8-chlorochroman-4-yl)urea (32-3, 100 mg, 0.26 mmol) in 1,4-dioxane (5 mL), tributyl(1-ethoxyvinyl)stannane (188 mg, 0.5 mmol) was added. The reaction mixture was degassed with nitrogen for 15 min. After that, Bis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.03 mmol) was added and heated to 90 oC for 16 h.6N HCl was added to the reaction and stirred at ambient temperature for 16 h The reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. Crude mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to afford crude compound. The crude material was purified by prep-HPLC to afford (S)-1-(2-acetylpyrimidin-4-yl)-3-(8-chlorochroman-4-yl)urea (Example 76, 12 mg). LCMS(ESI) Calcd. for C16H15ClN4O3: 346.77, found [M+H]+: 347.3.1H NMR (400 MHz, DMSO-d6) δH: 9.97 (s, 1H), 8.67 (d, 1H), 8.41 (bs, 1H), 7.62 (d, 1H), 7.33 (d, 1H), 7.27 (d, 1H), 6.90 (t, 1H), 6.80 (d, 1H), 5.04-5.02 (m, 1H), 4.43-4.32 (m, 2H), 2.49 (s, 3H), 2.20-2.18 (m, 1H), 2.05-2.04 (m, 1H).

[0327] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(2-(1-hydroxyethyl)pyrimidin-4-yl)urea, Example 77 [Step 3]: To a stirred solution of (S)-1-(2-acetylpyrimidin-4-yl)-3-(8-chlorochroman- 4-yl)urea (Example 76, 180 mg, 0.52 mmol) in methanol (10 mL), sodium borohydride (118 mg, 3.11 mmol) was added at 0 °C and the reaction mixture was stirred at 25 °C for 16 h. The crude reaction mixture was quenched with water and evaporated under reduced pressure. The crude compound was purified by prep-HPLC and lyophilized to afford 1-((S)-8-chlorochroman-4-yl)-3- (2-(1-hydroxyethyl)pyrimidin-4-yl)urea (Example 77, 30 mg). LCMS (ESI) Calcd. for C16H17ClN4O3: 348.78, found [M+H]+: 349.1.1H NMR (400 MHz, DMSO-d6) δH: 9.71 (s, 1H), 8.64 (bs, 1H), 8.45 (d, 1H), 7.33 (d, 1H), 7.28-7.26 (m, 2H), 6.89 (d, 1H), 5.12 (t, 1H), 5.03-5.01 (m, 1H), 4.57-4.54 (m, 3H), 2.32-2.05 (m, 2H), 1.27-1.21 (d, 3H).

[0328] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(2-((S)-1-hydroxyethyl)pyrimidin-4- yl)urea, Example 78 & 1-((S)-8-chlorochroman-4-yl)-3-(2-((R)-1-hydroxyethyl)pyrimidin-4- yl)urea, Example 79 [Step 4]: 1-((S)-8-chlorochroman-4-yl)-3-(2-(1-hydroxyethyl)pyrimidin-4- yl)urea (Example 77, 50 mg, 0.14 mmol) was separated by SFC chiral and lyophilized to afford peak 1 as 1-((S)-8-chlorochroman-4-yl)-3-(2-((S)-1-hydroxyethyl)pyrimidin-4-yl)urea (Example 78, 10 mg) and peak 2 as 1-((S)-8-chlorochroman-4-yl)-3-(2-((R)-1-hydroxyethyl)pyrimidin-4- yl)urea (Example 79, 10 mg). The absolute stereochemistry of both the diastereomers is arbitrarily assigned.

[0329] SFC prep method: SFC prep purification has been done in Waters SFC 80 instruments equipped with Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using Chiral cel OX-H (21.0 mm x 250mm), 5µ Column operating at 35 ºC temperature, maintaining flow rate of 50 ml / min, using 60% CO2 in super critical state & 40% of {0.1%IPAmine in ACN: MeOH} as Mobile phase. Run this isocratic mixture up to 9.0 minutes and also maintained the isobaric condition of 120 bar at 268 nm wavelength.

[0330] 1-((S)-8-chlorochroman-4-yl)-3-(2-((S)-1-hydroxyethyl)pyrimidin-4-yl)urea Example 78 (Peak 1): LCMS (ESI) Calcd. for C16H17ClN4O3: 348.78, found [M+H]+: 349.2.1H NMR (400 MHz, DMSO-d6) δH: 9.72 (s, 1H), 8.66 (bs, 1H), 8.45 (d, 1H), 7.33 (d, 1H), 7.27-7.25 (m, 2H), 6.89 (t, 1H), 5.12 (s, 1H), 5.02 (s, 1H), 4.56-4.27 (m, 3H), 2.32-2.03 (m, 2H), 1.27-1.21 (d, 3H). The absolute stereochemistry was unknown.

[0331] 1-((S)-8-chlorochroman-4-yl)-3-(2-((R)-1-hydroxyethyl)pyrimidin-4-yl)urea Example 79 (Peak 2): LCMS (ESI) Calcd. for C16H17ClN4O3: 348.78, found [M+H]+: 349.2.1H NMR (400 MHz, DMSO-d6) δH: 9.72 (s, 1H), 8.66 (bs, 1H), 8.45 (d, 1H), 7.33-7.26 (m, 2H), 6.89 (t, 1H),5.11 (s, 1H), 5.02 (s, 1H), 4.56-4.31 (m, 3H), 3.69 (s, 1H), 2.17 -2.03 (m, 2H), 1.27-1.21 (d, 3H). The absolute stereochemistry was unknown. Example 80: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(2-methyl-1H-pyrrolo[3,2- b]pyridin-5-yl)urea:Scheme 33.

[0332] Synthesis of tert-butyl (5-amino-6-bromopyridin-2-yl)carbamate, 33-2 [Step 1]: To a stirred solution of tert-butyl N-(5-amino-2-pyridyl)carbamate (33-1, 1000 mg, 4.78 mmol) in DMF (10 mL) was added NBS ( 213 mg, 1.19 mmol) slowly at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by combi Flash chromatography to afford tert-butyl N-(5-amino-6-bromo-2-pyridyl)carbamate (33-2, 400 mg).1H NMR (400 MHz, DMSO-d6): δH: 9.46 (s, 1H), 7.47 (d, 1H), 7.13 (d, 1H), 5.13 (d, 2H), 1.42 (s, 9H).

[0333] Synthesis of tert-butyl (5-amino-6-(prop-1-yn-1-yl)pyridin-2-yl)carbamate, 33-3 [Step 2]: In a 50 mL sealable reaction tube, tert-butyl N-(5-amino-6-bromo-2-pyridyl)carbamate (33-2, 800 mg, 2.78 mmol) was dissolved in acetonitrile (10 mL). Triethylamine (0.77 mL, 5.55 mmol) was added to it. The solution was degassed with argon for 10 min. PdCl2(PPh3)2 (97 mg, 0.139 mmol) and CuI (11 mg, 0.0555 mmol) were added and stirred at same temperature for 5 min. It was cooled to -10oC. Propyne gas was pursed through the solution for 5 min. The reaction tube was sealed and heated at 80 °C for 4 h. The reaction mixture was cooled to ambient temperature and filtered through celite pad. The filtrate was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography to afford tert-butyl N-(5-amino-6-prop-1-ynyl-2-pyridyl)carbamate (33-3, 400 mg).1H NMR (400 MHz, CDCl3): δH 7.70 (s, 1H), 7.27 (s, 1H), 7.06 (t, 1H), 7.05 (d, 1H), 5.11 (d, 1H), 2.16 (s, 3H), 1.45 (s, 9H).

[0334] Synthesis of tert-butyl (2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate, 34-4 [Step 3]: A mixture of tert-butyl N-(5-amino-6-prop-1-ynyl-2-pyridyl)carbamate (33-3, 400 mg, 1.62 mmol), CuI (154 mg, 0.809 mmol) in DMF (6 mL) was stirred at 80 °C for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by combi flash column chromatography to afford tert- butyl N-(2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (33-4, 150 mg). LCMS (ESI) Calcd. for C13H17N3O2: 247.29: found [M+H]+: 248.2.1H NMR (400 MHz, DMSO)-d6): δH 10.99 (s, 1H), 9.22 (s, 1H), 7.56 (d, 1H), 7.45 (d, 1H), 6.07 (s, 1H), 4.05-3.99 (m, 1H), 2.41 (s, 3H), 1.45 (s, 9H).

[0335] Synthesis of 2-methyl-1H-pyrrolo[3,2-b]pyridin-5-amine, hydrochloride, 33-5 [Step 4]: To a stirred solution of tert-butyl N-(2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)carbamate (33-4, 150 mg, 0.607 mmol) in DCM (5 mL) was added 4M HCl in dioxane (2.0 mL, 3.03 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 4 h. Volatiles were removed under reduced pressure to afford 2-methyl-1H-pyrrolo[3,2-b]pyridin-5- amine hydrochloride (33-5, 70 mg). LCMS (ESI) Calcd. for C8H9N3: 147.18, found [M+H]+: 148.0.

[0336] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(2-methyl-1H-pyrrolo[3,2-b]pyridin-5- yl)urea, Example 80 [Step 5]: To a stirred solution of rac-(4S)-8-chlorochroman-4- amine;hydrochloride (33-6, 60 mg, 0.273 mmol) and 2-methyl-1H-pyrrolo[3,2-b]pyridin-5-amine (33-5, 44 mg, 0.300 mmol) in DCM (4 mL) was added Et3N (0.20 mL, 1.36 mmol) at ice cold condition and stirred for 15 min at ambient temperature. A solution of triphosgene (30 mg, 0.101 mmol) in DCM (1 mL) was added drop wise at -10 °C and the reaction mixture was allowed to stir for 20 min at same condition. The reaction mixture was diluted with DCM and washed with water. Organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified through prep HPLC and lyophilized to afford 1-[(4S)-8-chlorochroman-4-yl]-3-(2-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)urea (Example 80, 10 mg). LCMS (ESI) Calcd. for C18H17ClN4O2: 356.81, found [M+H]+= 357.2.1H NMR (400 MHz, DMSO): δH 11.01 (s, 1H), 9.50 (bs, 1H), 9.08 (s, 1H), 7.56 (d, 1H), 7.33-7.28 (m, 2H), 6.92-6.87 (m, 2H), 5.94 (s, 1H), 5.08-5.03 (m, 1H), 4.45 (t, 1H), 4.32 (t,1H), 2.34 (s,1H), 2.08-2.02 (m, 2H).

[0337] Synthesis of 1-(4-chloropyrimidin-2-yl)-2,2,2-trifluoroethan-1-ol, 34-2 [Step 1]: To a stirred solution of 4-chloropyrimidine-2-carbaldehyde (34-1, 500 mg, 3.5 mmol) in THF (20 mL) was added trimethyl(trifluoromethyl)silane (0.6 mL, 4.2 mmol) at 0oC followed by tetrabutylammonium fluoride (1 M in THF) (4.2 mL, 4.2 mmol) and stirred the reaction mixture at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford product which was purified by combi flash chromatography to afford 1-(4-chloropyrimidin-2-yl)-2,2,2-trifluoroethan-1-ol (34-2, 250 mg).1H NMR (400 MHz, DMSO-d6): δH 8.89 (d, 1H), 7.81 (d, 1H), 7.14 (d, 1H), 5.28-5.21 (m, 1H)

[0338] Synthesis of 1-((S)-8-chlorochroman-4-yl)-3-(2-(2,2,2-trifluoro-1- hydroxyethyl)pyrimidin-4-yl)urea, Example 81 [Step 2]: To a stirred solution of (S)-1-(8- chlorochroman-4-yl)urea (34-3, 161 mg, 0.7 mmol), 1-(4-chloropyrimidin-2-yl)-2,2,2- trifluoroethan-1-ol (34-2, 100 mg, 0.5 mmol) and Cs2CO3(384 mg, 1.2 mmol) in 1,4-dioxane (5 mL) was degassed with Ar for 10 min. To this reaction mixture were added xantphos (82 mg, 0.1 mmol) and palladium(II) acetate (21 mg, 0.1 mmol) and stirred the reaction mixture at 80oC for 16 h. The reaction mixture was cooled to ambient temperature and filtered through celite bed using ethyl acetate. The filtrate was concentrated under reduced pressure to afford product which was purified by preparative HPLC, lyophilized to afford 1-((S)-8-chlorochroman-4-yl)-3-(2- (2,2,2-trifluoro-1-hydroxyethyl)pyrimidin-4-yl)urea (Example 81, 22 mg). LCMS (ESI) Calcd. for C17H15ClF3N3O3: 402.07, found [M+H]+= 403.1,1H NMR (400 MHz, DMSO-d6): δH9.86 (bs, 1H), 8.55 (d, 1H), 8.26 (bs, 1H), 7.53-7.50 (m, 1H), 7.34-7.31 (m, 1H), 7.26-7.23 (m, 1H), 6.88 (t, 1H),6.81 (d, 1H), 5.03-4.99 (m, 2H), 4.40-4.38 (m, 1H), 4.29-4.27 (m, 1H), 2.33-2.32 (m, 1H), 2.04-2.03 (m,1H).Example 82: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(2-(2-methyl-2H-1,2,3-triazol-4- yl)pyrimidin-4-yl)urea:Scheme 35.

[0339] Synthesis of (S)-1-(2-bromopyrimidin-4-yl)-3-(8-chlorochroman-4-yl)urea, 35-3 [Step 1]: To a stirred solution of 2-bromopyrimidin-4-amine (35-1, 158 mg, 0.90 mmol) in DCM (10 mL) were added Et3N (0.51 mL, 3.63 mmol) and a solution of Triphosgene (270 mg, 0.90 mmol) in DCM at -5 °C and stirred for 15 min. Finally, a solution of (4S)-8-chlorochroman-4- amine; hydrochloride (35-2,200 mg, 0.90 mmol) in DCM was added and the reaction mixture was allowed to stir for 40 min at same condition. After the completion of reaction, reaction mixture was quenched by the addition of brine solution and extracted with DCM. Combined organic layer were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by combi Flash column chromatography to afford (S)-1-(2- bromopyrimidin-4-yl)-3-(8-chlorochroman-4-yl)urea (35-3, 200 mg). LCMS (ESI) Calcd. for C14H12BrClN4O2: 383.63, found [M-H]+: 383.05.1HNMR (400 MHz, DMSO-d6) δH: 9.80 (s, 1H), 8.37 (d, 1H), 7.86-7.80 (m, 1H), 7.44 (d, 1H), 7.35 (d,1H), 7.25 (d, 1H), 6.93 - 6.89 (m, 1H), 4.97 (d, 1H), 4.41-4.38 (m, 1H), 4.03 (s, 1H), 2.18-2.14 (m, 1H), 2.03-1.98 (m, 1H).

[0340] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(2-(2-methyl-2H-1,2,3-triazol-4- yl)pyrimidin-4-yl)urea, Example 82 [Step 2]: To a stirred solution of (S)-1-(2-bromopyrimidin-4- yl)-3-(8-chlorochroman-4-yl)urea (35-3, 200 mg, 0.52 mmol) in 1,4-Dioxane (3mL) and Water (1mL), were added K3PO4 (221 mg, 1.04 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)triazole (35-4, 131 mg, 0.62 mmol). Reaction mixture was degassed with argon for 10 minutes and Pd-118 (34 mg, 0.05 mmol) was added and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was filtered through celite pad and washed with Ethyl acetate. The filtrate was dissolved in ethyl acetate and washed water. Organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure which was purified by Prep HPLC to afford (S)-1-(8-chlorochroman-4-yl)-3-(2-(2- methyl-2H-1,2,3-triazol-4-yl)pyrimidin-4-yl)urea (Example 82, 37 mg). LCMS (ESI) Calcd. forC17H16ClN7O2: 385.81, found [M+H]+: 386.2.1HNMR (400 MHz, DMSO-d6) δH: 9.96 (s, 1H), 8.96 (s,1H), 8.55 (d, 2H), 8.0 (s, 1H), 7.36 (d, 1H), 7.29 (t, 2H), 6.92 (t, 1H), 5.0 (t, 1H), 4.48-4.46 (m, 1H), 4.40-4.35 (m, 1H), 4.15 (s, 3H), 2.23 - 2.17 (m, 1H), 2.07-2.04 (m, 1H). Example 83: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(2-methyl-2H-1,2,3-triazol-4- yl)pyrazin-2-yl)urea:Scheme 36.

[0341] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-chloropyrazin-2-yl)urea, 36-3 [Step 1]: To a stirred solution of (S)-1-(8-chlorochroman-4-yl)urea (36-2, 1000 mg, 4.41 mmol) in 1,4- Dioxane (20 mL) was added 2-bromo-6-chloro-pyrazine (36-1, 939 mg, 4.85 mmol) and Cesium carbonate (3594 mg, 11.0 mmol).The reaction mixture was degassed under argon atmosphere for 10 minutes followed by addition of Palladium acetate (99 mg, 0.44 mmol) and Xanthphos (511 mg, 0.88 mmol). The reaction mixture was stirred at 90 C for 16 h. After completion, reaction mixture was filtered through celite bed, diluted with water and extracted with ethyl acetate, washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified through combi flash chromatography to afford (S)-1-(8-chlorochroman-4-yl)-3-(6-chloropyrazin-2-yl)urea (36-3, 600 mg). LCMS (ESI) Calcd. for C14H12Cl2N4O2: 339.18, found [M+H]+: 341.21HNMR (400 MHz, DMSO-d6) δH: 9.49 (s, 1H), 9.11 (s,1H), 8.31 (s, 1H), 7.35-7.30 (m, 2H), 7.26 (d, 1H), 6.93 (m, 1H), 4.98 (d, 1H), 4.42-4.38 (m, 1H), 4.26-4.22 (m, 1H), 2.16-1.98 (m, 3H).

[0342] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(6-(2-methyl-2H-1,2,3-triazol-4- yl)pyrazin-2-yl)urea, Example 83 [Step 2]: In a sealed vial (S)-1-(8-chlorochroman-4-yl)-3-(6- chloropyrazin-2-yl)urea (36-3, 180 mg, 0.53 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)triazole (36-4, 133 mg, 0.63 mmol) and Cesium carbonate (519 mg, 1.59 mmol) were taken in 1,4-Dioxane (4.5mL) and Water (1.5mL) was purged with argon for 10 min. Then Xphos Pd G3 (45 mg, 0.05 mmol) was added into the mixture and continued to stir at 80 C for 16 h. After completion, reaction mixture was filtered through celite bed, diluted with water and extracted with ethyl acetate, washed with brine. The organic layer was dried overanhydrous Na2SO4, concentrated under reduced pressure. The product was purified by reverse phase Prep HPLC to afford (S)-1-(8-chlorochroman-4-yl)-3-(6-(2-methyl-2H-1,2,3-triazol-4- yl)pyrazin-2-yl)urea (5, 32 mg). LCMS (ESI) Calcd. for C17H16ClN7O2: 385.81, found [M+H]+: 386.2.1HNMR (400 MHz, DMSO-d6) δH: 9.68 (s, 1H), 8.80 (s ,1H), 8.66 (s, 1H), 8.28 (d, 1H), 7.95 (s, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 6.93 (t, 1H), 5.05-5.00 (m, 1H), 4.45-4.42 (m, 1H), 4.32- 4.27 (m, 1H), 4.20 (s, 3H), 2.21-2.16 (m, 1H), 2.08-2.06 (m, 1H). Example 84: Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(4-(2-methyl-2H-1,2,3-triazol-4- yl)pyrimidin-2-yl)urea:Scheme 37.

[0343] Synthesis of (S)-1-(4-bromopyrimidin-2-yl)-3-(8-chlorochroman-4-yl)urea, 37-3 [Step 1]: To a stirred solution of 4-bromopyrimidin-2-amine (37-1, 100 mg, 0.57 mmol) in DCM (10 mL) was added triethylamine ( 0.32 mL, 2.30 mmol) followed by addition of triphosgene (171 mg, 0.57 mmol) in DCM (2 mL) at -150C. After 5 mins was added (S)-8-chlorochroman-4-amine hydrochloride (37-2, 139 mg, 0.63 mmol) in DCM (3 mL) at same temperature. The reaction mixture was stirred at ambient temperature for 2 h. All the volatiles were evaporated. The reaction mixture was dissolved in ethyl acetate and washed by water (thrice). The organic part was dried over anhydrous Na2SO4and evaporated. The crude product was purified by column chromatography to give (S)-1-(4-bromopyrimidin-2-yl)-3-(8-chlorochroman-4-yl)urea (3, 70 mg).1H NMR (400 MHz, d6-DMSO) δH: 10.3 (s, 1H), 9.15-9.12 (m, 1H), 8.48 (d, 1H), 7.34-718 (m, 3H), 6.92-6.87 (m, 1H), 5.11-5.06 (m, 1H), 4.43-4.24 (m, 2H), 2.23-1.98 (m, 2H).

[0344] Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(4-(2-methyl-2H-1,2,3-triazol-4- yl)pyrimidin-2-yl)urea, Example 84 [Step 2]: To a stirred solution of (S)-1-(4-bromopyrimidin-2- yl)-3-(8-chlorochroman-4-yl)urea (37-3, 62 mg, 0.16 mmol) in 1,4-Dioxane (4 mL) and Water (1 mL), were added K3PO4 (69 mg, 0.32 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2H-1,2,3-triazole (37-4, 41 mg, 0.32 mmol). Reaction mixture was degassed with argon for 10 minutes and Pd-118 (11 mg, 0.01 mmol) was added and the reaction mixture was heated at 80°C for 16h. Reaction mixture was cooled to ambient temperature, filteredthrough celite and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep HPLC to give (S)-1-(8-chlorochroman-4-yl)-3-(4-(2-methyl-2H-1,2,3-triazol-4- yl)pyrimidin-2-yl)urea (Example 84, 45 mg). LCMS (ESI) Calcd. for^C17H16ClN7O2: 385.11, found [M+H]+= 386.2.1H NMR (400 MHz, d6-DMSO) δH: 10.09 (s, 1H), 9.73-9.70 (m, 1H), 8.64 (d, 1H), 7.81 (s, 1H), 7.45-7.30 (m, 3H), 6.90 (t, 1H), 5.09-5.07 (m, 1H), 4.46-4.33 (m, 2H), 4.19 (s, 3H), 2.21-2.07 (m, 2H). Example 85: Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[6-(4-methylsulfonylphenyl)-2- pyridyl]urea:^ Scheme 38.

[0345] Synthesis of 6-(4-methylsulfonylphenyl)pyridin-2-amine, 38-3 [Step 1]:^^ To a degassed solution of^6-bromopyridin-2-amine (38-2, 0.50 g, 2.89 mmol)^in^1,4-dioxane (5 mL)^and^water (5 mL)^was added^K2CO3 (0.79 g, 5.78 mmol)^and the reaction mixture was stirred at RT for^15 min followed by^the addition of Pd(dppf)Cl2 (0.02 g, 0.02 mmol) and the reaction mixture was stirred at 90^°C^for 16 h. Progress of the reaction was monitored by TLC and LCMS. After completion, reaction mixture was filtered to remove unwanted solid material,^reaction was quenched with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4^and concentrated under reduced pressure. Crude compound was purified by combi flash (30% EtOAc / hexane) to afford (6-(4-methylsulfonylphenyl)pyridin-2-amine, 38-3 (0.50 g, 69.68 %) as white solid.1H NMR (400 MHz, DMSO-d6) δ = 8.27 - 8.17 (m, 2H), 8.01 - 7.93 (m, 2H), 7.57 - 7.48 (m, 1H), 7.18 (d, J = 7.3 Hz, 1H), 6.51 (d, J = 8.3 Hz, 1H), 6.11 (brs, 2H), 3.24 (d, J = 1.5 Hz, 3H); LCMS: [M+H]+^=249.10, 70.62 %, RT-1.12.^ ^

[0346] Syntesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[6-(4-methylsulfonylphenyl)-2- pyridyl]urea (Example 85) [Step 2]: ^^ To a stirred solution of 6-(4- methylsulfonylphenyl)pyridin-2-amine, 38-3 (0.05 g, 0.20 mmol) in DCM (2 mL) was added triphosgene (0.03 g, 0.10 mmol) and DIPEA (0.07 g, 0.60 mmol)^at 0^°C^and the^reaction mixture was stirred at RT for 20 min. To this was added (4S)-8-chlorochroman-4-amine (0.03 g, 0.20mmol) and the reaction was stirred at RT for 14 h.^Progress of reaction was monitored by TLC and LCMS.^After completion, reaction was quenched with H2O and extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4^and concentrated under reduced pressure. Crude compound was purified by prep-HPLC to afford Example 85 (0.01 g, 16.85 %)^as a white solid.1H NMR (400 MHz, DMSO-d6) δ^= 9.52 (s, 1H), 8.89 (d, J = 4.9 Hz, 1H), 7.95 - 7.91 (m, 2H), 7.88 - 7.82 (m, 3H), 7.61 (d, J = 7.5 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.32 (d, J = 6.9 Hz, 1H), 6.93 (t, J = 7.8 Hz, 1H), 5.04 - 4.99 (m, 1H), 4.45 - 4.39 (m, 1H), 4.23 - 4.16(m, 1H), 3.23 (s, 3H), 2.21 - 2.15 (m, 1H), 2.12 - 2.06 (m, 1H); LCMS: [M+H]+^= 457.8, 98.99%,RT-2.07; HPLC: 98.71%, RT- 7.36.^ Biological / Biochemical Evaluation DNA polymerization assay to monitor effects on human wildtype POLγ and five disease- causing mutant variants of human POLγ.

[0347] The ability of small molecules to stimulate the polymerase activity of POLγ was analyzed in a quantitative fluorescence SYBR Green I assay with fluorescence intensity (FI) readout.

[0348] In the presence of dNTPs, wild type human POLγ and mutant derivatives thereof were incubated with single-stranded, circular M13mp18 ssDNA hybridized to a short DNAoligonucleotide that functions as a primer for initiation of DNA synthesis. POLγ and mutantderivatives thereof will extend the primer and use the M13mp18 molecule as a template tosynthesize long stretches of double-stranded DNA. SYBR Green I, which is a double-stranded DNA-binding dye, was used to quantify formation of double-stranded DNA in the reaction.When bound to double-stranded DNA, SYBR Green I fluorescence increases by up to 100-fold.

[0349] The assay was performed in the 384-well plate format. Upon addition of compounds, changes in double-stranded DNA synthesis activity can be monitored by following effects on fluorescent intensity.

[0350] Proteins used in the polymerization assays were wild type POLγA (POLγA:WT) and mutant derivatives thereof in which an Alanine in position 467 of the amino acids sequence had been changed to Threonine (POLγA:A467T), a Glycine in position 848 of the amino acids sequence had been changed to Serine (POLγA:G848S), an Arginine in position 309 of the amino acids sequence had been changed to Cysteine (POLγA:R309C), or a Tyrosine in position 955 of the amino acid sequence had been changed to Cysteine (POLγA:Y955C). W748S substitution arises because of a G to C mutation at position 2243 in exon 13. The W748S mutation is generally found in cis with the E1143G polymorphism, which is caused by an A to Gtransition at nucleotide 3428 in exon 21 of POLγ. The reactions also contained the accessory POLγB subunit, and the human mitochondrial single stranded DNA binding protein (mtSSB).

[0351] The protein mixture used in the assays contained POLγA or a mutant derivative (1 nM), POLγB (1.3 nM, concentration calculated as a dimer), 25 mM Tris-HCl (pH 8.0), 0.1 mg / mL bovine serum albumin, 1 mM Bond-Breaker TCEP solution (pH 7) [Thermo Fisher], 25 mM NaCl, and 0.02% Triton X-100.

[0352] The primed circular ssDNA template used in the polymerization assay was generated by hybridizing circular, single-stranded DNA from M13mp18 with a 20 nucleotides longoligonucleotide (5'-GTA AAA CGA CGG CCA GTG CC-3') using a Bio-Rad T100 Thermal Cycler.

[0353] The DNA template mixture used in the assay contained 0.5 nM primed M13 mp18ssDNA, 400 nM mtSSB, 0.1 mM Tris-HCl (pH 8.0), 0.1 mM dNTP, 10 mM MgCl2, 0.1 mg / mL BSA, 1 mM Bond-Breaker TCEP solution [Thermo Fisher], and 0.02% Triton X-100. The DNA template mixture for the wild-type protein contained either 100 µM dNTP or 0.1 µM dNTP.

[0354] Microplates with compounds (0.1µL in each well) to be tested in the assay were prepared from 10 mM compound stocks in 100% DMSO, and equal amounts of DMSO without anycompound were added to positive and negative control wells.

[0355] The protein mixture was dispensed (5 µL into each well) into compound plates and incubated at 37 °C for 15 minutes. After incubation, 5 µL of the DNA template mixture was dispensed into each well. The plates were then incubated at 37 °C for 2 hours.

[0356] During incubation, a combined stop buffer and detection reagent solution was prepared. The buffer contained 25 mM EDTA (pH 8.0), 0.02% Triton X-100, and SYBR Green I diluted10,000 X (for fluorescent readout). EDTA will stop the enzymatic reaction by chelating magnesium ions.

[0357] After the incubation period, SYBR Green I solution was added (10 µL) to the screening plates and the plates were incubated at room temperature in the dark for 20 minutes before the fluorescent signal was read between 485-520 nM on a microtiter plate reader. The compound concentrations for half maximum activity (AC50) are provided in Table 1.

[0358] Table 1: AC50 Values on Human POLγ and Human Mutant POLγ.Numbered exemplary embodiments

[0359] The invention is further described with reference to the following numbered exemplary embodiments.

[0360] Embodiment 1: A compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein X1 – X3 are independently carbon or nitrogen; R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O- CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6; wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of SO2R6, CCH3CH3NH2, NH2, and C3H6O; wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH; wherein heterocyclodiene is optionally substituted with C1-C6alkyl; R3is absent, hydrogen, C1-C4alkyl, or halogen; wherein C1-C4alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)R6, halogen, or R2and R3are interconnected to form a five-member heteroatom ring; R4 and R5 are each independently absent or hydrogen; R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3; R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2OR6; n is 1-4; and *denotes a chiral carbon.

[0361] Embodiment 2: The compound of embodiment 1, wherein R1is independently selected from the group consisting of hydrogen, halogen, and cyano.

[0362] Embodiment 3: The compound of embodiment 1, wherein R1is independently selected from the group consisting of hydrogen, chlorine, and cyano.

[0363] Embodiment 4: The compound of embodiment 1, wherein R1is independently selected from the group consisting of hydrogen, halogen, and O-CH3.

[0364] Embodiment 5: The compound of embodiment 1, wherein R1is independently selected from the group consisting of hydrogen, chlorine, and O-CH3.

[0365] Embodiment 6: The compound of embodiment 1, wherein R1is independently selected from the group consisting of hydrogen and halogen.

[0366] Embodiment 7: The compound of embodiment 1, wherein R1is independently selected from the group consisting of hydrogen and chlorine.

[0367] Embodiment 8: The compound of embodiment 1, wherein R1is independently selected from the group consisting of hydrogen and cyano.

[0368] Embodiment 9: The compound of embodiment 1, wherein R1is independently selected from the group consisting of hydrogen and O-CH3.

[0369] Embodiment 10: The compound of any one of embodiments 1-9, wherein X1– X3comprise one nitrogen and two carbons.

[0370] Embodiment 11: The compound of any one of embodiments 1-9, wherein X1– X3comprise two nitrogens and one carbon.

[0371] Embodiment 12: The compound of any one of embodiments 1-9, wherein X1– X3are carbon.

[0372] Embodiment 13: The compound of any one of embodiments 1-12, wherein R2is selected from the group consisting of hydrogen, halogen, cyano, and methyl.

[0373] Embodiment 14: The compound of any one of embodiments 1-12, wherein R2is selected from C1-C6alkyl, cycloalkyl, heterocyclyl, and aryl; wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl; C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: SO2R6, CCH3CH3NH2, NH2, and C3H6O; and wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH.

[0374] Embodiment 15: The compound of any one of embodiments 1-12, wherein R2is heterocyclodiene optionally substituted with C1-C6alkyl.

[0375] Embodiment 16: The compound of any one of embodiments 1-12, wherein R2is selectedfrom C(O)OR6, C(O)NR6R7, cycloalkyl and C(O)R6, OR6, whereinR6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, CH2C(O)OCH2CH3; and R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, CH2CH2OR6.

[0376] Embodiment 17: The compound of any one of embodiments 1-16, wherein R3is hydrogen, chlorine, or fluorine.

[0377] Embodiment 18: A compound of formula (II), or a pharmaceutically acceptable salt thereof:wherein R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O- CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C(O)OR6,C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3; and R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2OR6;*denotes a chiral carbon.

[0378] Embodiment 19: The compound of embodiment 18, wherein the halogen of R1is chlorine.

[0379] Embodiment 20: A compound of formula (III) or a pharmaceutically acceptable salt thereof:wherein R2is 2-R6-1,2,3, triazole or C(O)NR6R6; and R6is methyl; *denotes a chiral carbon.

[0380] Embodiment 21: A compound of formula (IV), or a pharmaceutically acceptable salt thereof: wR2is 2-R6-1,2,3, triazole; (R1)1 is chlorine; and R6is methyl, *denotes a chiral carbon.

[0381] Embodiment 22: A compound of Formula (V) or a pharmaceutically acceptable salt thereof:wherein X1– X3are independently carbon or nitrogen; R2is selected from the group consisting of H, CN, SO2R6, pyrolidine, pyrrolidin-3-ol, 2-methyl- 1,2,3, triazole, imidazole, C1-3 alkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, OR6, C(O)NR6R6, andC(O)R6; wherein C1-3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, F, NHSO2R6, and methyl; wherein C3-6cycloalkyl and C3-6heterocyclyl are independently optionally substituted OH, or C(O)R6; R3is hydrogen or fluorine; or R2and R3are interconnected to form a 5-membered 2,3-dihydro-1H-pyrrole or 5-methyl-2,3- dihydro-1H-pyrrole; R4and R5are H; (R1)1is chlorine; and R6is methyl.

[0382] Embodiment 23: A compound of formula (Ia), or a pharmaceutically acceptable salt thereof:wherein X1 – X3 are independently carbon or nitrogen; R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O- CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, methyl, C1-C6alkyl,C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6; wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: SO2R6, CCH3CH3NH2, NH2, and C3H6O; wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH; wherein heterocyclodiene is optionally substituted with C1-C6alkyl; R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, CH2C(O)OCH2CH3; R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, CH2CH2OR6; R3is absent, hydrogen, C1-C4alkyl, or halogen; wherein C1-C4alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)R6, halogen; or R2and R3are interconnected to form a five-member heteroatom ring; R4 and R5 are each independently absent or hydrogen; and n is 1-4.

[0383] Embodiment 24: The compound of embodiment 23, or a pharmaceutically acceptable salt thereof wherein the compound is*denotes a chiral carbon.

[0384] Embodiment 25: The compound of embodiment 23 or embodiment 24, or a pharmaceutically acceptable salt thereof wherein the compound is.

[0385] Embodiment 26: The compound of embodiment 23, or a pharmaceutically acceptable salt thereof wherein the compound is*denotes a chiral carbon.

[0386] Embodiment 27: The compound of embodiment 23 or embodiment 26, or a pharmaceutically acceptable salt thereof wherein the compound is.

Claims

CLAIMS What is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:wherein X1– X3are independently carbon or nitrogen; R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O- CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6; wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of SO2R6, CCH3CH3NH2, NH2, and C3H6O; wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH; wherein heterocyclodiene is optionally substituted with C1-C6alkyl; R3is absent, hydrogen, C1-C4alkyl, or halogen; wherein C1-C4alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)R6, halogen, or R2and R3are interconnected to form a five-member heteroatom ring; R4 and R5 are each independently absent or hydrogen; R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3; R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3CH2CHCH3OH, or CH2CH2OR6;n is 1-4; and *denotes a chiral carbon.

2. The compound of claim 1, wherein R1is independently selected from the group consisting of hydrogen, halogen, and cyano.

3. The compound of claim 1, wherein R1is independently selected from the group consisting of hydrogen, chlorine, and cyano.

4. The compound of claim 1, wherein R1is independently selected from the group consisting of hydrogen, halogen, and O-CH3.

5. The compound of claim 1, wherein R1is independently selected from the group consisting of hydrogen, chlorine, and O-CH3.

6. The compound of claim 1, wherein R1is independently selected from the group consisting of hydrogen and halogen.

7. The compound of claim 1, wherein R1is independently selected from the group consisting of hydrogen and chlorine.

8. The compound of claim 1, wherein R1is independently selected from the group consisting of hydrogen and cyano.

9. The compound of claim 1, wherein R1is independently selected from the group consisting of hydrogen and O-CH3.

10. The compound of claim 1, wherein X1– X3comprise one nitrogen and two carbons.

11. The compound of claim 1, wherein X1– X3comprise two nitrogens and one carbon.

12. The compound of claim 1, wherein X1 – X3 are carbon.

13. The compound of claim 1, wherein R2is selected from the group consisting of hydrogen, halogen, cyano, and methyl.

14. The compound of claim 1, wherein R2is selected from C1-C6alkyl, cycloalkyl, heterocyclyl, and aryl; wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl; C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6, wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: SO2R6, CCH3CH3NH2, NH2, and C3H6O; and wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH.

15. The compound of claim 1, wherein R2is heterocyclodiene optionally substituted with C1- C6alkyl.

16. The compound of claim 1, wherein R2 is selected from C(O)OR6, C(O)NR6R7, cycloalkyland C(O)R6, OR6, wherein R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, CH2C(O)OCH2CH3; and R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, CH2CH2OR6.

17. The compound of claim 1, wherein R3is hydrogen, chlorine, or fluorine.

18. A compound of formula (II), or a pharmaceutically acceptable salt thereof:whereinR1is independently selected from the group consisting of hydrogen, halogen, cyano, and O- CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, C1-C6alkyl, C(O)OR6,C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3; and R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2OR6; *denotes a chiral carbon.

19. The compound of claim 18, wherein the halogen of R1is chlorine.

20. A compound of formula (III) or a pharmaceutically acceptable salt thereof:wherein R2is 2-R6-1,2,3, triazole or C(O)NR6R6; and R6is methyl; *denotes a chiral carbon.

21. A compound of formula (IV), or a pharmaceutically acceptable salt thereof:wherein R2is 2-R6-1,2,3, triazole;(R1)1 is chlorine; and R6is methyl, *denotes a chiral carbon.

22. A compound of Formula (V) or a pharmaceutically acceptable salt thereof:X1– X3are independently carbon or nitrogen; R2is selected from the group consisting of H, CN, SO2R6, pyrolidine, pyrrolidin-3-ol, 2-methyl-1,2,3, triazole, imidazole, C1-3 alkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, OR6, C(O)NR6R6, andC(O)R6; wherein C1-3alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, F, NHSO2R6, and methyl; wherein C3-6cycloalkyl and C3-6heterocyclyl are independently optionally substituted OH, or C(O)R6; R3is hydrogen or fluorine; or R2and R3are interconnected to form a 5-membered 2,3-dihydro-1H-pyrrole or 5-methyl-2,3- dihydro-1H-pyrrole; R4 and R5 are H; (R1)1 is chlorine; and R6is methyl.

23. A compound of formula (Ia), or a pharmaceutically acceptable salt thereof:wherein X1– X3are independently carbon or nitrogen; R1is independently selected from the group consisting of hydrogen, halogen, cyano, and O- CH3; R2is selected from the group consisting of hydrogen, halogen, cyano, methyl, C1-C6alkyl,C(O)OR6, C(O)NR6R7, cycloalkyl, heterocyclyl, aryl, C(O)R6, OR6, and heterocyclodiene;wherein C1-C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(O)NR6R7, SO2R6, OR6, heterocyclyl, cycloalkyl, NHC(O)R6, CF3, and NHS(O)(O)R6; wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of: SO2R6, CCH3CH3NH2, NH2, and C3H6O; wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)R6and OH; wherein heterocyclodiene is optionally substituted with C1-C6alkyl; R6is H, methyl, ethyl, C3-6cycloalkyl, CH2C(O)NH2, CH2C(O)OCH2CH3; R7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, CH2CH2OR6; R3is absent, hydrogen, C1-C4alkyl, or halogen; wherein C1-C4alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)R6, halogen; or R2and R3are interconnected to form a five-member heteroatom ring; R4 and R5 are each independently absent or hydrogen; and n is 1-4.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof wherein the compound is*denotes a chiral carbon.

25. The compound of claim 23, or a pharmaceutically acceptable salt thereof wherein the compound is.

26. The compound of claim 23, or a pharmaceutically acceptable salt thereof wherein the compound is*denotes a chiral carbon.

27. The compound of claim 23, or a pharmaceutically acceptable salt thereof wherein the compound is

Images