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 REPLICATIONCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application 63 / 696,121 , filed September 18, 2024, the entire contents of which are incorporated by reference herein.FIELD OF THE INVENTION

[0002] The present disclosure relates to novel DNA polymerase y (POL y) 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 y (POLy) is the replicative polymerase essential for maintaining the mtDNA. POLy is a heterotrimer in human cells with one catalytic subunit (POLyA) and two accessory subunits (POLyB). POLyA belongs to the family A DNA polymerases. POLyA 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 POLyB is 485 amino acids in length and the crystal structures of both mouse and human POLyB have revealed the protein as a dimer with high similarities to aminoacyl tRNA synthetases. POLyB 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 y is required for mitochondrial replisome function.

[0004] A primary biological role of POLy is to replicate the mitochondrial genome. However, POLy 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 POLy during mtDNA replication, unwinding the dsDNA and creating a single-stranded (ss) DNA template that POLy 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 POLy can use ssDNA as a template to synthesize dsDNA. The mtSSB enhances mtDNA synthesis by increasing the processivity of POLy and also stimulates TWINKLE’S helicase activity. POLy 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. POLy 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 POLy are among the most frequent causes of mitochondrial disease. More than 300 disease-causing variants have been identified in POLy, 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 POLyA, namely POLG, are now known to cause a spectrum of overlapping phenotypes. These POLy 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 POLy 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 POLy, the need exists for potent and specific modulators of POLy.SUMMARY OF THE INVENTION

[0009] Briefly, therefore, the present disclosure is directed to compounds, pharmaceutically acceptable salts of the compounds, and methods of using the compounds, salts of the compounds to treat various neurodegenerative and metabolic disorders, cancer, and also disorders related to aging and mitochondrial diseases.

[0010] In a first aspect of the present disclosure, the present disclosure provides a compound, which, according to an embodiment of the present disclosure is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof:Formula (I); wherein:A is thiazole, 2-pyridyl, pyrazole, oxazole, azaindole, substituted thiazole, substituted 2-pyridyl, substituted pyrazole, substituted oxazole, or substituted azaindole;R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl; wherein A is connected to N via a C-N bond; and* denotes a chiral carbon.

[0011] In certain embodiments, the A (i.e. , of Formula (I)) is 2-pyridyl or substituted 2-pyridyl, and with Formula (1-1):Formula (1-1); wherein:Y1-Y3are independently carbon or nitrogen, wherein one of Yi, Y2, or Y3is nitrogen;R1is chlorine, C1-C6alkyl, or substituted C1-C6alkyl;R5is hydrogen;R6is C1-C6alkyl, substituted C1-C6alkyl, amide, substituted amide, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, cyano, C1-C6alkoxy, or substituted C1-C6alkoxy; orR5and R6connected to form a 5-membered heterocyclyl ring; and* denotes a chiral carbon.

[0012] In certain embodiments, Yi is nitrogen, Y2and Y3are carbon, and with Formula (l-1-a):Formula (l-1-a); wherein:R1is chlorine, C1-C6alkyl, or substituted C1-C6alkyl;R5is hydrogen;R6is substituted C1-C6alkyl, amide, methyl substituted amide, pyrazole, aryl, cyano, ethoxy, or substituted ethoxy; and * denotes a chiral carbon.

[0013] In certain embodiments, the pyrazole is substituted with oxetane or cyclobutane.

[0014] In certain embodiments, the aryl is phenyl and substituted with oxetane or aminesubstituted oxetane.

[0015] In certain embodiments, R5and R6connected to form a 5-membered heterocyclyl ring, and with Formula (l-1-b):Formula (l-1-b); wherein:R1is chlorine or fluorine substituted alkyl;R? is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0016] In certain embodiments, A (i.e. , of Formula (I)) is oxazole or substituted oxazole, and with Formula (I-2):Formula (I-2); wherein:R1is chlorine;R3is C1-C6alkyl, substituted C1-C6alkyl, aryl, or substituted aryl; and * denotes a chiral carbon.

[0017] In certain embodiments, Yi is nitrogen, Y2and Y3are carbon, and with Formula (l-2-a) :Formula (l-2-a); wherein:R1is chlorine;R3is C1-C6alkyl, substituted C1-C6alkyl, aryl, or substituted aryl; and * denotes a chiral carbon.

[0018] In certain embodiments, R3is substituted C1-C6alkyl or substituted aryl.

[0019] In certain embodiments, A is pyrazole or substituted pyrazole, and with Formula (I-3):Formula (I-3); wherein:Y1-Y3 are independently carbon or nitrogen, wherein one of Y1, Y2, or Y3is nitrogen;R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R4 is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl; and * denotes a chiral carbon.

[0020] In certain embodiments, wherein Y1 is nitrogen, Y2and Y3are carbon, and with Formula (l-3-a):Formula (l-3-a); wherein:R1is hydrogen, halogen, C1-C3alkyl, Cs-C6cycloalkyl, or substituted C1-C3alkyl;R4 is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV); and* denotes a chiral carbon.

[0021] In certain embodiments, R4 is aryl or substituted aryl.

[0022] In certain embodiments, the substituted aryl is aryl substituted with one or more of a halogen, cyano, hydroxy, alkoxy, amide, substituted amide, C1-C6alkyl, substituted C1-C6alkyl, or substituted heterocyclyl.

[0023] In certain embodiments, the substituted C1-C6alkyl is a C2alkyl substituted with one or more of fluorine, hydroxy, methyl, or amine.

[0024] In certain embodiments, R4is cycloalkyl or substituted cycloalkyl.

[0025] In certain embodiments, the cycloalkyl or the substituted cycloalkyl is C4or C5cycloalkyl.

[0026] In certain embodiments, the cycloalkyl is substituted with one or more hydroxy, methyl, cyano, or fluorine.

[0027] In certain embodiments, R4is heterocyclyl or substituted heterocyclyl.

[0028] In certain embodiments, the heterocyclyl is pyridine, pyridazine, pyridazinone, pyrazole, or pyridone.

[0029] In certain embodiments, the pyrazole is optionally substituted with C1-C6alkyl.

[0030] In certain embodiments, the pyridine is substituted with one or more of cyano, fluorine, methoxy, or hydroxy or fluorine substituted C2alkyl.

[0031] In certain embodiments, Y1 and Y3are carbon, Y2is nitrogen, and with Formula (l-3-b):Formula (l-3-b); wherein:R1 is chlorine;R4is substituted aryl with Formula (IV):Formula (IV); and‘denotes a chiral carbon.

[0032] In certain embodiments, Yi and Y2 are carbon, Y3 is nitrogen, and with Formula (l-3-c):Formula (l-3-c); wherein:R1is chlorine;R4is substituted aryl with Formula (IV):Formula (IV); and * denotes a chiral carbon.

[0033] In certain embodiments, wherein A is thiazole, and with Formula (I-4):Formula (1-4); wherein:Y1-Y3 are independently carbon or nitrogen, wherein one of Y1, Y2, or Y3 is nitrogen;R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R2is C1-C6alkyl, C1-C6substituted alkyl, heterocyclyl, substituted heterocyclyl, C3-C6cycloalkyl, substituted cycloalkyl, substituted aryl, C3-C6heterocycloalkyl, substituted heterocycloalkyl, or ketone; and * denotes a chiral carbon.

[0034] In certain embodiments, Yi is nitrogen, Y2and Y3are carbon, and with Formula (l-4-a):Formula (l-4-a); wherein:R1is chlorine, C1-C6alkyl, substituted C1-C6alkyl, heterocyclyl, or substituted heterocyclyl;R2is C1-C6alkyl, C1-C6substituted alkyl, heterocyclyl, substituted heterocyclyl, C3-C6cycloalkyl, substituted cycloalkyl, substituted aryl, C3-C6heterocycloalkyl, substituted heterocycloalkyl, or ketone;R10 is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0035] In certain embodiments, R2is C3-C6cycloalkyl.

[0036] In certain embodiments, the C3-C6cycloalkyl is cyclopropyl, cyclobutyl, or bridged cyclopropyl.

[0037] In certain embodiments, R2is heterocycloalkyl.

[0038] In certain embodiments, R2is tetrahydrofuran.

[0039] In certain embodiments, R2is heterocyclyl or substituted heterocyclyl.

[0040] In certain embodiments, the heterocyclyl or the substituted heterocyclyl is pyridine, pyrazine, pyridone, pyridazine, pyrazole, or pyridazinone.

[0041] In certain embodiments, the substituted heterocyclyl is pyrazole, triazole, imidazole, isoxazole, oxazole, pyridine, pyridone, or tetrazole; wherein the pyrazole is optionally substituted with C3-C6cycloalkyl substituted with a hydroxy or one or more halogen, C3-C6heterocycloalkyl, C1-C6alkyl, C1-C6alkyl substituted with or more of methyl, hydroxy, pyridine, or fluorine, deuterated C1-C6alkyl, halogen substituted heterocycloalkyl, alkyl ether, or alkyl substituted pyridone; wherein the imidazole is optionally substituted with C1-C6alkyl, C3-C6cycloalkyl, halogenated C1-C6alkyl, halogenated C3-C6cycloalkyl, cyano substituted C1-C6alkyl, or cyano substituted C3-C6cycloalkyl; wherein the oxazole, pyridone, and tetrazole are optionally substituted with C1-C6alkyl, halogenated C1-C6alkyl, or C3-C6cycloalkyl; wherein pyridine is substituted with a cyano, fluorine, or methoxy; and wherein triazole is optionally substituted with one or more of a C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or more fluorine, deuterated C1-C6alkyl, halogenated C1-C6alkyl, or cyano.

[0042] In certain embodiments, A is azaindole or substituted azaindole, with Formula (1-5):Formula (1-5); wherein:R1is chlorine or fluorine substituted alkyl;R? is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0043] In another aspect of the present disclosure, the present disclosure provides a compound, which, according to an embodiment of the present disclosure is a compound represented by formula (II), or a pharmaceutically acceptable salt thereof:Formula (II); wherein:Y1-Y3 are independently carbon or nitrogen, wherein one of Y1, Y2, or Y3is nitrogen;R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R5is hydrogen;R6is C1-C5alkyl, substituted C1-C6alkyl, amide, substituted amide, aryl, substituted aryl. Heterocyclyl, substituted heterocyclyl, cyano, C1-C6alkoxy, or substituted C1-C6alkoxy; orR5and R6connected to form a 5-membered heterocyclyl ring; and * denotes a chiral carbon.

[0044] In certain embodiments, Y1 is nitrogen, Y2and Y3are carbon, and with Formula (11-1):Formula (ll-l); wherein:R1is chlorine, C1-C3alkyl, or substituted C1-C6alkyl;R5is hydrogen;R6is substituted C1-C6alkyl, amide, methyl substituted amide, pyrazole, aryl, cyano, ethoxy, or substituted ethoxy; and * denotes a chiral carbon.

[0045] In certain embodiments, the pyrazole is substituted with oxetane or cyclobutane.

[0046] In certain embodiments, the aryl is phenyl and substituted with oxetane or aminesubstituted oxetane.

[0047] In certain embodiments, wherein R5 and R6connected to form a 5-membered heterocyclyl ring, and with FormulaFormula (II-2); wherein:R1 is chlorine or fluorine substituted alkyl;R? is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0048] In a yet another aspect of the present disclosure, the present disclosure provides a compound, which, according to an embodiment of the present disclosure is a compound represented by Formula (lll-a), Formula (lll-b), or Formula (lll-c) or a pharmaceutically acceptable salt thereof:Formula (lll-c); wherein:Y1-Y3 are independently carbon or nitrogen and one of Y1 , Y2, or Y3 is nitrogen;R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C3cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R2-R4 are hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, bridged cycloalkyl, bridged substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl; and * denotes a chiral carbon.

[0049] In certain embodiments, Y1 is nitrogen, Y2 and Y3are carbon, and with Formula (lll-a-1):Formula (lll-a-1); wherein:R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R2is C1-C6alkyl, C1-C6substituted alkyl, heterocyclyl, substituted heterocyclyl, C3-C6cycloalkyl, substituted cycloalkyl, substituted aryl, C3-C6heterocycloalkyl, substituted heterocycloalkyl, or ketone;R10 is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0050] In certain embodiments, R2is C3-C6cycloalkyl.

[0051] In certain embodiments, the C3-C6cycloalkyl is cyclopropyl, cyclobutyl, or bridged cyclopropyl.

[0052] In certain embodiments, R2is heterocycloalkyl.

[0053] In certain embodiments, R2is tetrahydrofuran.

[0054] In certain embodiments, R2 is heterocyclyl or substituted heterocyclyl.

[0055] In certain embodiments, the heterocyclyl or the substituted heterocyclyl is pyridine, pyrazine, pyridone, pyridazine, pyrazole, or pyridazinone.

[0056] In certain embodiments, the substituted heterocyclyl is pyrazole, triazole, imidazole, isoxazole, oxazole, pyridine, pyridone, or tetrazole; wherein the pyrazole is optionally substituted with C3-C6cycloalkyl substituted with a hydroxy or one or more halogen, C3-C6heterocycloalkyl, C1-C6alkyl, C1-C6alkyl substituted with or more of methyl, hydroxy, pyridine, or fluorine, deuterated C1-C6alkyl, halogen substituted heterocycloalkyl, alkyl ether, or alkyl substituted pyridone;wherein the imidazole is optionally substituted with C1-C3alkyl, C3-C6cycloalkyl, halogenated C1-C6alkyl, halogenated C3-C6cycloalkyl, cyano substituted C1-C6alkyl, or cyano substituted C3-C6cycloalkyl; wherein the oxazole, pyridone, and tetrazole are optionally substituted with C1-C6alkyl, halogenated C1-C6alkyl, or C3-C6cycloalkyl; wherein pyridine is substituted with a cyano, fluorine, or methoxy; and wherein triazole is optionally substituted with one or more of a C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or more fluorine, deuterated C1-C6alkyl, halogenated C1-C6alkyl, or cyano.

[0057] In certain embodiments, Yi is nitrogen, Y2 and Y3are carbon, and with Formula (lll-b-1):Formula (lll-b-1); wherein:R1 is hydrogen, halogen, C1-C6alkyl, C3-C6cycloalkyl, or substituted C1-C6alkyl;R3is C1-C6alkyl, substituted C1-C6alkyl, aryl, or substituted aryl; and * denotes a chiral carbon.

[0058] In certain embodiments, the substituted C1-C6alkyl is a C2-alkyl substituted with a hydroxy group.

[0059] In certain embodiments, aryl is substituted with cyano.

[0060] In certain embodiments, Y1 is nitrogen, Y2and Y3are carbon, and with Formula (lll-c-1):Formula (lll-c-1); wherein:R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R4 is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV); and* denotes a chiral carbon.

[0061] In certain embodiments, R4is aryl or substituted aryl.

[0062] In certain embodiments, the substituted aryl is aryl substituted with one or more of a halogen, cyano, hydroxy, alkoxy, amide, substituted amide, C1-C6alkyl, substituted C1-C6alkyl, or substituted heterocyclyl.

[0063] In certain embodiments, the substituted C1-C6alkyl is a C2 alkyl substituted with one or more of fluorine, hydroxy, methyl, or amine.

[0064] In certain embodiments, R4is cycloalkyl or substituted cycloalkyl.

[0065] In certain embodiments, the cycloalkyl or the substituted cycloalkyl is C4or C5 cycloalkyl.

[0066] In certain embodiments, the cycloalkyl is substituted with one or more hydroxy, methyl, cyano, or fluorine.

[0067] In certain embodiments, R4is heterocyclyl or substituted heterocyclyl.

[0068] In certain embodiments, the heterocyclyl is pyridine, pyridazine, pyridazinone, pyrazole, or pyridone; wherein the pyrazole is optionally substituted with C1-C6alkyl; and wherein the pyridine is substituted with one or more of cyano, fluorine, methoxy, or hydroxy or fluorine substituted C2alkyl.

[0069] In certain embodiments, Y1 and Y3are carbon, Y2is nitrogen, and with Formula (lll-c-2):Formula (lll-c-2); wherein:R1 is chlorine;R4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV); and * denotes a chiral carbon.

[0070] In certain embodiments, Y1 and Y2are carbon, Y3 is nitrogen, and with Formula (lll-c-3):Formula (lll-c-3); wherein:R1is chlorine;R4 is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV); and * denotes a chiral carbon.DETAILED DESCRIPTION OF THE INVENTION

[0071] Provided are compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutical composition comprising the compounds or their salts for increasing the processivity of POLy.(I) Definitions

[0072] 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.

[0073] The term “alkoxy” or “alkoxyl” as used herein refers to an -O-alkyl group. For example, the term “C1-C4 alkoxyl” means -O-C1-C4 alkyl. Examples of alkoxyl include methoxyl, ethoxyl, propoxyl (e.g., n-propoxyl and isopropoxyl), and the like.

[0074] 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-C3alkyl. Examples of alkanoyl include acetyl, propionyl, butyryl, and the like.

[0075] 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-C5cycloalkyl” encompasses each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0076] 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 (“Ce-C-w 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.

[0077] 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-membered heterobicyclic, 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.

[0078] 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 groupconsisting 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

[0079] The term “oxo” as used herein refers to a group which consists of oxygen which is double bonded to carbon or any other element.

[0080] 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).

[0081] 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.

[0082] 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”.

[0083] 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 %.

[0084] 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.

[0085] 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 ofsuch 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.(II) Compounds

[0086] In certain embodiments, the present disclosure is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by Formula (I):wherein:A is thiazole, 2-pyridyl, pyrazole, oxazole, azaindole, substituted thiazole, substituted 2-pyridyl, substituted pyrazole, substituted oxazole, or substituted azaindole;R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C3-Cecycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl; wherein A is connected to N via a C-N bond; and * denotes a chiral carbon.

[0087] In some embodiments, the halogen may be fluorine, chlorine, bromine, or iodine.

[0088] In some embodiments, A is 2-pyridyl or substituted 2-pyridyl and the compound, or pharmaceutically acceptable salt thereof is represented by Formula (1-1):Formula (1-1); wherein:Y1-Y3 are independently carbon or nitrogen, wherein one of Y1, Y2, or Y3 is nitrogen;R1 is chlorine, C1-C6alkyl, or substituted C1-C6alkyl;R5is hydrogen;R6is C1-C6alkyl, substituted C1-C6alkyl, amide, substituted amide, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, cyano, C1-C6alkoxy, or substituted C1-C6alkoxy; orR5and R6connected to form a 5-membered heterocyclyl ring; and * denotes a chiral carbon.

[0089] In some embodiments, Yi is nitrogen, Y2and Y3are carbon, and the compound, or pharmaceutically acceptable salt thereof is represented by Formula (l-1-a):Formula (l-1-a); wherein:R1is chlorine, C1-C6alkyl, or substituted C1-C6alkyl;R5is hydrogen;R6is substituted C1-C6alkyl, amide, methyl substituted amide, pyrazole, aryl, cyano, ethoxy, or substituted ethoxy; and * denotes a chiral carbon.

[0090] In some embodiments, Xi is cyano, -CF3, -C3H5, -CH2OH, -CH2OCH3, -C(O)NH2, - C(O)NHCH3, -C(O)NCH3CH3, -C(O)OH, -CD3, -CH3, -CH2CH3, -OC6H5, -OC5H9.

[0091] In some embodiments, X2-X3are each independently hydrogen.

[0092] In some embodiments, Xi is cyano, -CF3, -C3Hs, -CH2OH, -CH2OCH3, -C(O)NH2, - C(O)NHCH3, -C(O)NCH3CH3, -C(O)OH, -CD3, -CH3, -CH2CH3, -OCeH5, -OC5H9; and X2-X5are each independently hydrogen.

[0093] In some embodiments, the pyrazole is substituted with oxetane or cyclobutane.

[0094] In some embodiments, the aryl is phenyl and substituted with oxetane or amine-substituted oxetane.

[0095] In some embodiments, R5and R6connected to form a 5-membered heterocyclyl ring, and the compound, or pharmaceutically acceptable salt thereof is represented by Formula (l-1-b):Formula (l-1 -b); wherein:R1 is chlorine or fluorine substituted alkyl;R? is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0096] In some embodiments, A is oxazole or substituted oxazole, and the compound, or pharmaceutically acceptable salt thereof is represented by Formula (I-2):Formula (1-2); wherein:R1is chlorine;R3is C1-C6alkyl, substituted C1-Cs alkyl, aryl, or substituted aryl; and * denotes a chiral carbon.

[0097] In some embodiments, Y1 is nitrogen, Y2and Y3are carbon, and the compound, or pharmaceutically acceptable salt thereof is represented with Formula (l-2-a):Formula (l-2-a); wherein:R1 is chlorine;R3is C1-C6alkyl, substituted C1-C6alkyl, aryl, or substituted aryl; and * denotes a chiral carbon.

[0098] In some embodiments, R3is substituted C1-C6alkyl or substituted aryl.

[0099] In some embodiments, A is pyrazole or substituted pyrazole, and with Formula (I-3)Formula (I-3); wherein:YI-Y3are independently carbon or nitrogen, wherein one of Yi, Y2, or Y3is nitrogen;R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl heterocyclyl substituted heterocyclyl; and* denotes a chiral carbon.

[0100] In certain embodiments, wherein Yi is nitrogen, Y2 and Y3 are carbon, and with Formula(l-3-a):Formula (l-3-a); wherein:R1 is hydrogen, halogen, C1-C6alkyl, C3-C6cycloalkyl, or substituted C1-C6alkyl;R4 is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV); and* denotes a chiral carbon.

[0101] In certain embodiments, R4is aryl or substituted aryl.

[0102] In certain embodiments, the substituted aryl is aryl substituted with one or more of a halogen, cyano, hydroxy, alkoxy, amide, substituted amide, C1-C6alkyl, substituted C1-C6alkyl, or substituted heterocyclyl.

[0103] In certain embodiments, the substituted C1-C6alkyl is a C2alkyl substituted with one or more of fluorine, hydroxy, methyl, or amine.

[0104] In certain embodiments, R4is cycloalkyl or substituted cycloalkyl.

[0105] In certain embodiments, the cycloalkyl or the substituted cycloalkyl is C4or C5cycloalkyl.

[0106] In certain embodiments, the cycloalkyl is substituted with one or more hydroxy, methyl, cyano, or fluorine.

[0107] In certain embodiments, R4is heterocyclyl or substituted heterocyclyl.

[0108] In certain embodiments, the heterocyclyl is pyridine, pyridazine, pyridazinone, pyrazole, or pyridone; wherein the pyrazole is optionally substituted with C1-C6alkyl; and wherein the pyridine is substituted with one or more of cyano, fluorine, methoxy, or hydroxy or fluorine substituted C2alkyl.

[0109] In certain embodiments, Y1 and Y3 are carbon, Y2is nitrogen, and with Formula (l-3-b):Formula (l-3-b); wherein:R1is chlorine;R4is substituted aryl with Formula (IV):Formula (IV); and‘denotes a chiral carbon.

[0110] In certain embodiments, Yi and Y2are carbon, Y3is nitrogen, and with Formula (l-3-b):Formula (lll-3-b); wherein:R1is chlorine.R4is substituted aryl with Formula (IV):Formula (IV); and * denotes a chiral carbon.

[0111] In certain embodiments, wherein A is thiazole, and with Formula (I-4):Formula (1-4); wherein:Y1-Y3 are independently carbon or nitrogen, wherein one of Y1, Y2, or Y3 is nitrogen;R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R2is C1-C6alkyl, C1-C6substituted alkyl, heterocyclyl, substituted heterocyclyl, C3-C6cycloalkyl, substituted cycloalkyl, substituted aryl, C3-C6heterocycloalkyl, substituted heterocycloalkyl, or ketone; and * denotes a chiral carbon.

[0112] In certain embodiments, Y1 is nitrogen, Y2and Y3are carbon, and with Formula (l-4-a):Formula (l-4-a); wherein:R1is chlorine, C1-C6alkyl, substituted C1-C6alkyl, heterocyclyl, or substituted heterocyclyl;R2 is C1-C6alkyl, C1-C6substituted alkyl, heterocyclyl, substituted heterocyclyl, C3-C6cycloalkyl, substituted cycloalkyl, substituted aryl, C3-C6heterocycloalkyl, substituted heterocycloalkyl, or ketone;R10 is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0113] In certain embodiments, R2is C3-C6cycloalkyl.

[0114] In certain embodiments, the C3-C6cycloalkyl is cyclopropyl, cyclobutyl, or bridged cyclopropyl.

[0115] In certain embodiments, R2is heterocycloalkyl.

[0116] In certain embodiments, R2is tetrahydrofuran.

[0117] In certain embodiments, R2is heterocyclyl or substituted heterocyclyl.

[0118] In certain embodiments, the heterocyclyl or the substituted heterocyclyl is pyridine, pyrazine, pyridone, pyridazine, pyrazole, or pyridazinone.

[0119] In certain embodiments, the substituted heterocyclyl is pyrazole, triazole, imidazole, isoxazole, oxazole, pyridine, pyridone, or tetrazole; wherein the pyrazole is optionally substituted with C3-C6cycloalkyl substituted with a hydroxy or one or more halogen, C3-C6heterocycloalkyl, C1-C6alkyl, C1-C6alkyl substituted with or more of methyl, hydroxy, pyridine, or fluorine, deuterated C1-C6alkyl, halogen substituted heterocycloalkyl, alkyl ether, or alkyl substituted pyridone; wherein the imidazole is optionally substituted with C1-C6alkyl, C3-Cs cycloalkyl, halogenated C1-C6alkyl, halogenated C3-C6cycloalkyl, cyano substituted C1-C6alkyl, or cyano substituted C3-C6cycloalkyl; wherein the oxazole, pyridone, and tetrazole are optionally substituted with C1-C6alkyl, halogenated C1-C6alkyl, or C3-C6cycloalkyl; wherein pyridine is substituted with a cyano, fluorine, or methoxy; and wherein triazole is optionally substituted with one or more of a C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or more fluorine, deuterated C1-C6alkyl, halogenated C1-C6alkyl, or cyano.

[0120] In certain embodiments, A is azaindole or substituted azaindole, with Formula (I-5):Formula (1-5); wherein:R1is chlorine or fluorine substituted alkyl;R? is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0121] In a second aspect of the present disclosure, the present disclosure provides a compound, which, according to an embodiment of the present disclosure is a compound represented by formula (II), or a pharmaceutically acceptable salt thereof:Formula (II); wherein:Y1-Y3 are independently carbon or nitrogen, wherein one of Y1, Y2, or Y3is nitrogen;R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C3cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R5is hydrogen;R6is C1-C5alkyl, substituted C1-C6alkyl, amide, substituted amide, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, cyano, C1-C6alkoxy, or substituted C1-C6alkoxy; orR5and R6connected to form a 5-membered heterocyclyl ring; and * denotes a chiral carbon.

[0122] In certain embodiments, Y1 is nitrogen, Y2 and Y3 are carbon, and with Formula (11-1):Formula (11-1) wherein:R1 is chlorine, C1-C6alkyl, or substituted C1-C6alkyl;R5is hydrogen;R6is substituted C1-C6alkyl, amide, methyl substituted amide, pyrazole, aryl, cyano, ethoxy, or substituted ethoxy; and * denotes a chiral carbon.

[0123] In certain embodiments, the pyrazole is substituted with oxetane or cyclobutane.

[0124] In certain embodiments, the aryl is phenyl and substituted with oxetane or aminesubstituted oxetane.

[0125] In certain embodiments, wherein R5and R6connected to form a 5-membered heterocyclyl ring, and with Formula (II-2):Formula (I I-2) ; wherein:R1 is chlorine or fluorine substituted alkyl;R7 is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0126] In a third aspect of the present disclosure, the present disclosure provides a compound, which, according to an embodiment of the present disclosure is a compound represented by Formula (lll-a), Formula (lll-b), or Formula (lll-c) or a pharmaceutically acceptable salt thereof:Formula (lll-c); wherein:Y1-Y3 are independently carbon or nitrogen and one of Y1 , Y2, or Y3is nitrogen;R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R2-R4 are hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, bridged cycloalkyl, bridged substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl; and * denotes a chiral carbon.

[0127] In certain embodiments, Y1 is nitrogen, Y2and Y3are carbon, and with Formula (lll-a-1):Formula (lll-a-1); wherein:R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R2is C1-C6alkyl, C1-C6substituted alkyl, heterocyclyl, substituted heterocyclyl, C3-C6cycloalkyl, substituted cycloalkyl, substituted aryl, C3-C6heterocycloalkyl, substituted heterocycloalkyl, or ketone;R1o is hydrogen or C1-C6alkyl; and * denotes a chiral carbon.

[0128] In certain embodiments, R2is C3-C6cycloalkyl.

[0129] In certain embodiments, the C3-C6cycloalkyl is cyclopropyl, cyclobutyl, or bridged cyclopropyl.

[0130] In certain embodiments, R2is heterocycloalkyl.

[0131] In certain embodiments, R2is tetrahydrofuran.

[0132] In certain embodiments, R2is heterocyclyl or substituted heterocyclyl.

[0133] In certain embodiments, the heterocyclyl or the substituted heterocyclyl is pyridine, pyrazine, pyridone, pyridazine, pyrazole, or pyridazinone.

[0134] In certain embodiments, the substituted heterocyclyl is pyrazole, triazole, imidazole, isoxazole, oxazole, pyridine, pyridone, or tetrazole; wherein the pyrazole is optionally substituted with C3-C6cycloalkyl substituted with a hydroxy or one or more halogen, C3-C6heterocycloalkyl, C1-C6alkyl, C1-C6alkyl substituted with or more of methyl, hydroxy, pyridine, or fluorine, deuterated C1-C6alkyl, halogen substituted heterocycloalkyl, alkyl ether, or alkyl substituted pyridone; wherein the imidazole is optionally substituted with C1-C6alkyl, C3-C6cycloalkyl, halogenated C1-C6alkyl, halogenated C3-C6cycloalkyl, cyano substituted C1-C6alkyl, or cyano substituted C3-C6cycloalkyl; wherein the oxazole, pyridone, and tetrazole are optionally substituted with C1-C6alkyl, halogenated C1-C6alkyl, or C3-C3cycloalkyl; wherein pyridine is substituted with a cyano, fluorine, or methoxy; and wherein triazole is optionally substituted with one or more of a C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or more fluorine, deuterated C1-C6alkyl, halogenated C1-C6alkyl, or cyano.

[0135] In certain embodiments, Y1 is nitrogen, Y2and Y3are carbon, and with Formula (lll-b-1):Formula (lll-b-1); wherein:R1 is hydrogen, halogen, C1-C6alkyl, C3-C6cycloalkyl, or substituted C1-C6alkyl;R3is C1-C6alkyl, substituted C1-C6alkyl, aryl, or substituted aryl; and * denotes a chiral carbon.

[0136] In certain embodiments, the substituted C1-C6alkyl is a C2-alkyl substituted with a hydroxy group.

[0137] In certain embodiments, aryl is substituted with cyano.

[0138] In certain embodiments, Yi is nitrogen, Y2and Y3are carbon, and with Formula (lll-c-1):Formula (lll-c-1); wherein:R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C@ alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV); and* denotes a chiral carbon.

[0139] In certain embodiments, R4is aryl or substituted aryl.

[0140] In certain embodiments, the substituted aryl is aryl substituted with one or more of a halogen, cyano, hydroxy, alkoxy, amide, substituted amide, C1-C6alkyl, substituted C1-C6alkyl, or substituted heterocyclyl.

[0141] In certain embodiments, the substituted C1-C6alkyl is a C2alkyl substituted with one or more of fluorine, hydroxy, methyl, or amine.

[0142] In certain embodiments, R4is cycloalkyl or substituted cycloalkyl.

[0143] In certain embodiments, the cycloalkyl or the substituted cycloalkyl is C4or Cs cycloalkyl.

[0144] In certain embodiments, the cycloalkyl is substituted with one or more hydroxy, methyl, cyano, or fluorine.

[0145] In certain embodiments, R4is heterocyclyl or substituted heterocyclyl.

[0146] In certain embodiments, the heterocyclyl is pyridine, pyridazine, pyridazinone, pyrazole, or pyridone; wherein the pyrazole is optionally substituted with C1-C6alkyl; and wherein the pyridine is substituted with one or more of cyano, fluorine, methoxy, or hydroxy or fluorine substituted C2alkyl.

[0147] In certain embodiments, Yi and Y3are carbon, Y2is nitrogen, and with Formula (lll-c-2):Formula (lll-c-2); wherein:R1is chlorine;R4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV); and * denotes a chiral carbon.

[0148] In certain embodiments, Yi and Y2are carbon, Y3is nitrogen, and with Formula (lll-c-3):Formula (lll-c-3); wherein:R1is chlorine;R4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV); and * denotes a chiral carbon.

[0149] In certain embodiments, the compound is Compound 1 , or a pharmaceutically acceptable salt thereof:

[0150] In certain embodiments, the compound is Compound 2, or a pharmaceutically acceptable salt thereof:

[0151] In certain embodiments, the compound is Compound 3, or a pharmaceutically acceptable salt thereof:

[0152] In certain embodiments, the compound is Compound 4, or a pharmaceutically acceptable salt thereof:

[0153] In certain embodiments, the compound is Compound 5, or a pharmaceutically acceptable salt thereof:

[0154] In certain embodiments, the compound is Compound 6, or a pharmaceutically acceptable salt thereof:

[0155] In certain embodiments, the compound is Compound 7, or a pharmaceutically acceptable salt thereof:

[0156] In certain embodiments, the compound is Compound 8, or a pharmaceutically acceptable salt thereof:

[0157] In certain embodiments, the compound is Compound 9, or a pharmaceutically acceptable salt thereof:

[0158] In certain embodiments, the compound is Compound 10, or a pharmaceutically acceptable salt thereof:

[0159] In certain embodiments, the compound is Compound 11, or a pharmaceutically acceptable salt thereof:

[0160] In certain embodiments, the compound is Compound 12, or a pharmaceutically acceptable salt thereof:

[0161] In certain embodiments, the compound is Compound 13, or a pharmaceutically acceptable salt thereof:

[0162] In certain embodiments, the compound is Compound 14, orpharmaceutically acceptable salt thereof:

[0163] In certain embodiments, the compound is Compound 15, orpharmaceutically acceptable salt thereof:

[0164] In certain embodiments, the compound is Compound 16, orpharmaceutically acceptable salt thereof:

[0165] In certain embodiments, the compound is Compound 17, orpharmaceutically acceptable salt thereof:

[0166] In certain embodiments, the compound is Compound 18, orpharmaceutically acceptable salt thereof:

[0167] In certain embodiments, the compound is Compound 19, orpharmaceutically acceptable salt thereof:

[0168] In certain embodiments, the compound is Compound 20, orpharmaceutically acceptable salt thereof:

[0169] In certain embodiments, the compound is Compound 21, orpharmaceutically acceptable salt thereof:

[0170] In certain embodiments, the compound is Compound 22, orpharmaceutically acceptable salt thereof:

[0171] In certain embodiments, the compound is Compound 23 orpharmaceutically acceptable salt thereof:

[0172] In certain embodiments, the compound is Compound 24, orpharmaceutically acceptable salt thereof:

[0173] In certain embodiments, the compound is Compound 25, orpharmaceutically acceptable salt thereof:

[0174] In certain embodiments, the compound is Compound 26, orpharmaceutically acceptable salt thereof:

[0175] In certain embodiments, the compound is Compound 27, orpharmaceutically acceptable salt thereof:

[0176] In certain embodiments, the compound is Compound 28, orpharmaceutically acceptable salt thereof:

[0177] In certain embodiments, the compound is Compound 29, orpharmaceutically acceptable salt thereof:

[0178] In certain embodiments, the compound is Compound 30, orpharmaceutically acceptable salt thereof:

[0179] In certain embodiments, the compound is Compound 31, orpharmaceutically acceptable salt thereof:

[0180] In certain embodiments, the compound is Compound 32, orpharmaceutically acceptable salt thereof:

[0181] In certain embodiments, the compound is Compound 33, orpharmaceutically acceptable salt thereof:

[0182] In certain embodiments, the compound is Compound 34, orpharmaceutically acceptable salt thereof:

[0183] In certain embodiments, the compound is Compound 35, orpharmaceutically acceptable salt thereof:

[0184] In certain embodiments, the compound is Compound 36, orpharmaceutically acceptable salt thereof:

[0185] In certain embodiments, the compound is Compound 37, orpharmaceutically acceptable salt thereof:

[0186] In certain embodiments, the compound is Compound 38, orpharmaceutically acceptable salt thereof:

[0187] In certain embodiments, the compound is Compound 39, orpharmaceutically acceptable salt thereof:

[0188] In certain embodiments, the compound is Compound 40, orpharmaceutically acceptable salt thereof:

[0189] In certain embodiments, the compound is Compound 41, orpharmaceutically acceptable salt thereof:

[0190] In certain embodiments, the compound is Compound 42, orpharmaceutically acceptable salt thereof:

[0191] In certain embodiments, the compound is Compound 43, or a pharmaceutically acceptable salt thereof:

[0192] In certain embodiments, the compound is Compound 44, or a pharmaceutically acceptable salt thereof:

[0193] In certain embodiments, the compound is Compound 45, or a pharmaceutically acceptable salt thereof:

[0194] In certain embodiments, the compound is Compound 46, or a pharmaceutically acceptable salt thereof:

[0195] In certain embodiments, the compound is Compound 47, or a pharmaceutically acceptable salt thereof:

[0196] In certain embodiments, the compound is Compound 48, or a pharmaceutically acceptable salt thereof:

[0197] In certain embodiments, the compound is (S)-1-(2-(bicyclo[1.1.1]pentan-1-yl)thiazol-4-yl)- 3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 49 (Example 143), or a pharmaceutically acceptable salt thereof:

[0198] In certain embodiments, the compound is Compound 50, or a pharmaceutically acceptable salt thereof:

[0199] In certain embodiments, the compound is Compound 51, or a pharmaceutically acceptable salt thereof:

[0200] In certain embodiments, the compound is (S)-1-(8-ethyl-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(1-phenyl-1 / - / -pyrazol-3-yl)urea, Compound 52 (Example 57), or a pharmaceutically acceptable salt thereof:

[0201] In certain embodiments, the compound is (S)-1-(8-cyclopropyl-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(1-phenyl-1 / 7-pyrazol-3-yl)urea, Compound 53 (Example 56), or a pharmaceutically acceptable salt thereof:

[0202] In certain embodiments, the compound is tert-butyl (2-(3-hydroxyoxetan-3-yl)thiazol-4- yl)carbamate, Compound 54 (Example 144), or a pharmaceutically acceptable salt thereof:

[0203] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- £>]pyridin-4-yl)-3-(2-(1 -ethyl- 1 / - / -pyrazol-3-yl)thiazol-4-yl)urea, Compound 55 (Example 142), or a pharmaceutically acceptable salt thereof:

[0204] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-((R)-1-hydroxy-2-methylpropyl)thiazol-4-yl)urea, Compound 56 (Example 138), or a pharmaceutically acceptable salt thereof:

[0205] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(2-((S)-1-hydroxy-2-methylpropyl)thiazol-4-yl)urea, Compound 57 (Example 137), or a pharmaceutically acceptable salt thereof:

[0206] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1 -isopropyl- 1 H-pyrazol-3-yl)thiazol-4-yl)urea, Compound 58 (Example 141), or a pharmaceutically acceptable salt thereof:

[0207] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-neopentyl-2H-1 ,2,3-triazol-4-yl)thiazol-4-yl)urea, Compound 59 (Example 140), or a pharmaceutically acceptable salt thereof:

[0208] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-cyanopyridin-2-yl)-1H-pyrazol-3-yl)urea, Compound 60 (Example 55), or a pharmaceutically acceptable salt thereof:

[0209] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-(tert-pentyl)-2 / - / -1 ,2,3-triazol-4-yl)thiazol-4-yl)urea, Compound 61 (Example 139), or a pharmaceutically acceptable salt thereof:

[0210] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(3-fluoro-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Compound 62 (Example 49), or a pharmaceutically acceptable salt thereof:

[0211] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(3-fluoro-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Compound 63 (Example 48), or a pharmaceutically acceptable salt thereof:

[0212] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-(2,2,2-trifluoroethyl)-2H-1 ,2,3-triazol-4-yl)thiazol-4-yl)urea, Compound 64 (Example 136), or a pharmaceutically acceptable salt thereof:

[0213] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-cyclobutylthiazol-4-yl)urea, Compound 65 (Example 135), or a pharmaceutically acceptable salt thereof:

[0214] In certain embodiments, the compound is, 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(6-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea, Compound 66 (Example 12), or a pharmaceutically acceptable salt thereof:

[0215] In certain embodiments, the compound is, 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(6-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea, Compound 67 (Example 11), or a pharmaceutically acceptable salt thereof:

[0216] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(6-cyanopyridin-3-yl)-1H-pyrazol-3-yl)urea, Compound 68 (Example 47), or a pharmaceutically acceptable salt thereof:

[0217] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-isobutylthiazol-4-yl)urea, Compound 69 (Example 134), or a pharmaceutically acceptable salt thereof:

[0218] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1 -isopropyl- 1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 70 (Example 37), or a pharmaceutically acceptable salt thereof:

[0219] In certain embodiments, the compound is (S)-1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1H- pyrazol-3-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 71 (Example 43), or a pharmaceutically acceptable salt thereof:

[0220] In certain embodiments, the compound is (R)-1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1H- pyrazol-3-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 72 (Example 42), or a pharmaceutically acceptable salt thereof:

[0221] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(1-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4-yl)-1 / 7-pyrazol-3-yl)urea, Compound 73 (Example 36), or a pharmaceutically acceptable salt thereof:

[0222] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-£>]pyridin-4-yl)-3-(1-(4-fluoro-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 / - / -pyrazol-3-yl)urea,Compound 74 (Example 35), or a pharmaceutically acceptable salt thereof:

[0223] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-fluoro-3-((R)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 / - / -pyrazol-3-yl)urea, Compound 75 (Example 34), or a pharmaceutically acceptable salt thereof:

[0224] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(3-methylpyridin-2-yl)-1 H-pyrazol-3-yl)urea, Compound 76 (Example 44), or a pharmaceutically acceptable salt thereof:

[0225] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(5-cyanopyridin-2-yl)-1H-pyrazol-3-yl)urea, Compound 77 (Example 40), or a pharmaceutically acceptable salt thereof:

[0226] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-isopropylthiazol-4-yl)urea, Compound 78 (Example 133), or a pharmaceutically acceptable salt thereof:

[0227] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-((R)-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Compound 79 (Example 45), or a pharmaceutically acceptable salt thereof:

[0228] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-((S)-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Compound 80 (Example 45), or a pharmaceutically acceptable salt thereof:

[0229] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-((1r,3S)-3-hydroxycyclobutyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea,Compound 81 (Example 132), or a pharmaceutically acceptable salt thereof:

[0230] In certain embodiments, the compound is (S)-4-(4-(3-(8-chloro-3,4-dihydro-2 / - / - pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)- / V-methylbenzamide, Compound 82 (Example 127), or a pharmaceutically acceptable salt thereof:

[0231] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- £>]pyridin-4-yl)-3-(2-(4-cyanophenyl)thiazol-4-yl)urea, Compound 83 (Example 126), or a pharmaceutically acceptable salt thereof:

[0232] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-cyano-2-methylphenyl)-1 H-pyrazol-3-yl)urea, Compound 84 (Example 39), or a pharmaceutically acceptable salt thereof:

[0233] In certain embodiments, the compound is Compound 85, or a pharmaceutically acceptable salt thereof:

[0234] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(6-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea,Example 32 (Compound 86), or a pharmaceutically acceptable salt thereof:

[0235] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(6-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea, Example 33 (Compound 87), or a pharmaceutically acceptable salt thereof:

[0236] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(3-((R)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 / - / -pyrazol-3-yl)urea,Compound 88 (Example 30), or a pharmaceutically acceptable salt thereof:

[0237] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(5-methylisoxazol-4-yl)thiazol-4-yl)urea, Compound 89 (Example 99), or a pharmaceutically acceptable salt thereof

[0238] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-(methyl-d3)-2H-1 ,2,3-triazol-4-yl)thiazol-4-yl)urea, Compound 90 (Example 131), or a pharmaceutically acceptable salt thereof

[0239] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-(methoxymethyl)phenyl)-1 H-pyrazol-3-yl)urea, Compound 91 (Example 41), or a pharmaceutically acceptable salt thereof

[0240] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1 '-methyl-1 'H-[1 ,4'-bipyrazol]-3-yl)urea, Compound 92 (Example 29), or a pharmaceutically acceptable salt thereof

[0241] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(4-((R)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)thiazol-4-yl)urea, Compound 93 (Example 129), or a pharmaceutically acceptable salt thereof

[0242] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(4-((S)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)thiazol-4-yl)urea, Compound 94 (Example 128), or a pharmaceutically acceptable salt thereof:

[0243] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-(2-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Compound 95 (Example 38), or a pharmaceutically acceptable salt thereof:

[0244] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-(3,3-difluorocyclobutyl)-2H-1 ,2,3-triazol-4-yl)thiazol-4-yl)urea, Compound 96 (Example 130), or a pharmaceutically acceptable salt thereof:

[0245] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1 '-methyl-1 'H-[1 ,4'-bipyrazol]-3-yl)urea, Compound 97 (Example 26), or a pharmaceutically acceptable salt thereof:

[0246] In certain embodiments, the compound is (S)-1-(1-(3-bromophenyl)-1 H-pyrazol-3-yl)-3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 98 (Example 25), or a pharmaceutically acceptable salt thereof:

[0247] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(1-methyl-2-oxo-1 ,2-dihydropyridin-4-yl)-1 / - / -pyrazol-4-yl)thiazol-4-yl)urea, Compound 99 (Example 119), or a pharmaceutically acceptable salt thereof:

[0248] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(2-(pyridin-2-yl)thiazol-4-yl)urea, Compound 100 (Example 101), or a pharmaceutically acceptable salt thereof:

[0249] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1 -methyl- 1H-pyrazol-3-yl)thiazol-4-yl)urea, Compound 101 (Example 120), or a pharmaceutically acceptable salt thereof:

[0250] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-(2-hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea, Compound 102 (Example 24), or a pharmaceutically acceptable salt thereof:

[0251] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-((R)-1 ,1 ,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea,Compound 103 (Example 23), or a pharmaceutically acceptable salt thereof:

[0252] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-((S)-1 ,1 ,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea, Compound 104 (Example 22), or a pharmaceutically acceptable salt thereof:

[0253] In certain embodiments, the compound is (S)-4-(4-(3-(8-chloro-3,4-dihydro-2 / - / - pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)benzamide, Compound 105 (Example 125), or a pharmaceutically acceptable salt thereof:

[0254] In certain embodiments, the compound is, (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(6-(1-cyclobutyl-1 H-pyrazol-4-yl)pyridin-2-yl)urea, Compound 106 (Example 10), or a pharmaceutically acceptable salt thereof:

[0255] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-cyclopropyl-1 H-imidazol-4-yl)thiazol-4-yl)urea, Compound 107 (Example 58), or a pharmaceutically acceptable salt thereof:

[0256] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1 -(difluoromethyl)- 1 / - / -pyrazol-4-yl)thiazol-4-yl)urea, Compound 108(Example 124), or a pharmaceutically acceptable salt thereof:

[0257] In certain embodiments, the compound ((S)-1-(1-(4-cyanophenyl)-1 H-pyrazol-3-yl)-3-(8- methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 109 (Example 28), or a pharmaceutically acceptable salt thereof:

[0258] In certain embodiments, the compound is ((R)-1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3- (8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 110 (Example 27), or a pharmaceutically acceptable salt thereof:

[0259] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-(2-cyanopropan-2-yl)-2H-1 ,2,3-triazol-4-yl)thiazol-4-yl)urea, Compound 111 (Example 123), or a pharmaceutically acceptable salt thereof:

[0260] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(3-fluoro-4-(methylamino)phenyl)thiazol-4-yl)urea, Compound 112 (Example 122), or a pharmaceutically acceptable salt thereof:

[0261] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(3-fluoro-4-hydroxyphenyl)thiazol-4-yl)urea, Compound 113 (Example 121), or a pharmaceutically acceptable salt thereof:

[0262] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-((S)-tetrahydrofuran-3-yl)thiazol-4-yl)urea, Compound 114 (Example 111), or a pharmaceutically acceptable salt thereof:

[0263] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-((R)-tetrahydrofuran-3-yl)thiazol-4-yl)urea, Compound 115 (Example 110), or a pharmaceutically acceptable salt thereof:

[0264] In certain embodiments, the compound is (R)-1-(1-(4-cyanophenyl)-1 / - / -pyrazol-3-yl)-3- (3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea, Compound 116 (Example 18), or a pharmaceutically acceptable salt thereof:

[0265] In certain embodiments, the compound is (S)-1-(1-(4-cyanophenyl)-1 / - / -pyrazol-3-yl)-3- (3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea, Compound 117 (Example 17), or a pharmaceutically acceptable salt thereof:

[0266] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1 -isopropyl- 1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 118 (Example 107), or a pharmaceutically acceptable salt thereof:

[0267] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(2-cyanopropan-2-yl)-1 / - / -pyrazol-3-yl)thiazol-4-yl)urea, Compound 119 (Example 109), or a pharmaceutically acceptable salt thereof:

[0268] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(2-cyanopropan-2-yl)-1 / - / -pyrazol-4-yl)thiazol-4-yl)urea, Compound 120 (Example 108), or a pharmaceutically acceptable salt thereof:

[0269] In certain embodiments, the compound is (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 121 (Example 90), or a pharmaceutically acceptable salt thereof:

[0270] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 122 (Example 89), or a pharmaceutically acceptable salt thereof:

[0271] In certain embodiments, the compound is, (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(6-cyanopyridin-2-yl)urea, Compound 123 (Example 8), or a pharmaceutically acceptable salt thereof:

[0272] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-((1s,3R)-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)thiazol-4-yl)urea,Compound 124 (Example 115), or a pharmaceutically acceptable salt thereof:

[0273] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(4-(4-cyanophenyl)oxazol-2-yl)urea, Compound 125 (Example 13), or a pharmaceutically acceptable salt thereof:

[0274] In certain embodiments, the compound is 1-(2-((S)-1-hydroxyethyl)thiazol-4-yl)-3-((S)-8- methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 126 (Example 94), or a pharmaceutically acceptable salt thereof:

[0275] In certain embodiments, the compound is 1-(2-((S)-1-hydroxyethyl)thiazol-4-yl)-3-((R)-8- methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 127 (Example 93), or a pharmaceutically acceptable salt thereof:

[0276] In certain embodiments, the compound is (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)ureido)-1H-pyrazol-1-yl)-2-fluoro- / V-methylbenzamide, Compound 128 (Example 16), or a pharmaceutically acceptable salt thereof:

[0277] In certain embodiments, the compound is (S)-4-(4-(3-(8-chloro-3,4-dihydro-2 / - / - pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)-2-fluoro- / \ / -methylbenzamide, Compound 129 (Example 106), or a pharmaceutically acceptable salt thereof:

[0278] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(1-methoxy-2-methylpropan-2-yl)-1 / - / -pyrazol-4-yl)thiazol-4-yl)urea, Compound 130 (Example 105), or a pharmaceutically acceptable salt thereof:

[0279] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1 -methyl- 1H-pyrazol-3-yl)thiazol-4-yl)urea, Compound 131 (Example 116), or a pharmaceutically acceptable salt thereof:

[0280] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- £>]pyridin-4-yl)-3-(2-(1-(2-methylpyridin-4-yl)-1 / - / -pyrazol-4-yl)thiazol-4-yl)urea, Compound 132 (Example 100), or a pharmaceutically acceptable salt thereof:

[0281] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-methyloxazol-5-yl)thiazol-4-yl)urea, Compound 133 (Example 97), or a pharmaceutically acceptable salt thereof:

[0282] In certain embodiments, the compound is ((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(4-((S)-1-hydroxyethyl)phenyl)thiazol-4-yl)urea, Compound 134 (Example 118), or a pharmaceutically acceptable salt thereof:

[0283] In certain embodiments, the compound is ((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(4-((R)-1-hydroxyethyl)phenyl)thiazol-4-yl)urea, Compound 135 (Example 117), or a pharmaceutically acceptable salt thereof:

[0284] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(3,3-difluorocyclobutyl)-1 H-pyrazol-3-yl)thiazol-4-yl)urea, Compound 136 (Example 114), or a pharmaceutically acceptable salt thereof:

[0285] In certain embodiments, the compound is, (S)-6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)picolinamide, Compound 137 (Example 9), or a pharmaceutically acceptable salt thereof:

[0286] In certain embodiments, the compound is 4-[3-[[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl]carbamoylamino]pyrazol-1-yl]-N-(2-hydroxyethyl)benzamide, Compound 138(Example 21), or a pharmaceutically acceptable salt thereof:

[0287] In certain embodiments, the compound is, (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)pyridin-2-yl)urea, Compound 139 (Example 7), or a pharmaceutically acceptable salt thereof:

[0288] In certain embodiments, the compound is, (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)pyridin-2-yl)urea, Compound 140 (Example 6), or a pharmaceutically acceptable salt thereof:

[0289] In certain embodiments, the compound is 1-(2-((R)-1-hydroxyethyl)thiazol-4-yl)-3-((R)-8- methyl-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea, Compound 141 (Example 96), or a pharmaceutically acceptable salt thereof:

[0290] In certain embodiments, the compound is 1-(2-((R)-1-hydroxyethyl)thiazol-4-yl)-3-((S)-8- methyl-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea, Compound 142 (Example 95), or a pharmaceutically acceptable salt thereof:

[0291] In certain embodiments, the compound is Compound 143, or a pharmaceutically acceptable salt thereof:

[0292] In certain embodiments, the compound is Compound 144, or a pharmaceutically acceptable salt thereof:

[0293] In certain embodiments, the compound is (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1 -cyclobutyl- 1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 145 (Example 88), or a pharmaceutically acceptable salt thereof:

[0294] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1 -cyclobutyl- 1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 146 (Example 87), or a pharmaceutically acceptable salt thereof:

[0295] In certain embodiments, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-((1s,3S)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea,Compound 147 (Example 113), or a pharmaceutically acceptable salt thereof:

[0296] In certain embodiments, the compound is 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-((1s,3S)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea,Compound 148 (Example 112), or a pharmaceutically acceptable salt thereof:

[0297] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(2-(3,5-dimethylisoxazol-4-yl)thiazol-4-yl)urea, Compound 149 (Example 98), or a pharmaceutically acceptable salt thereof:

[0298] In certain embodiments, the compound is Compound 150 (Example 21), or a pharmaceutically acceptable salt thereof:

[0299] In certain embodiments, the compound is Compound 151 (Example 20), or a pharmaceutically acceptable salt thereof:

[0300] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 152 (Example 80), or a pharmaceutically acceptable salt thereof:

[0301] In certain embodiments, the compound is (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 153 (Example 79), or a pharmaceutically acceptable salt thereof:

[0302] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 154 (Example 86), or a pharmaceutically acceptable salt thereof:

[0303] In certain embodiments, the compound is (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 155 (Example 85), or a pharmaceutically acceptable salt thereof:

[0304] In certain embodiments, the compound is (R)-1-(2-acetylthiazol-4-yl)-3-(8-methyl-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 156 (Example 90), or a pharmaceutically acceptable salt thereof:

[0305] In certain embodiments, the compound is (R)-1-(2-acetylthiazol-4-yl)-3-(8-methyl-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 157 (Example 91), or a pharmaceutically acceptable salt thereof:

[0306] In certain embodiments, the compound is (R)-1-(8-methyl-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 / - / -pyrazol-4-yl)thiazol-4-yl)urea, Compound 158 (Example 84), or a pharmaceutically acceptable salt thereof:

[0307] In certain embodiments, the compound is (R)-1-(8-methyl-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 / - / -pyrazol-4-yl)thiazol-4-yl)urea, Compound 159 (Example 83), or a pharmaceutically acceptable salt thereof:

[0308] In certain embodiments, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-methyl-2 / - / -1,2,3-triazol-4-yl)thiazol-4-yl)urea, Compound 160 (Example 104), or a pharmaceutically acceptable salt thereof:

[0309] In certain embodiments, the compound is (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-methyl-2 / - / -1,2,3-triazol-4-yl)thiazol-4-yl)urea, Compound 161 (Example 103), or a pharmaceutically acceptable salt thereof:

[0310] In one embodiment, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2,2-difluoroethyl)-1 / - / -pyrazol-4-yl)thiazol-4-yl)urea, Compound 162 (Example 78), or a pharmaceutically acceptable salt thereof:

[0311] In one embodiment, the compound is (R)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin- 4-yl)-3-(2-(1-(2,2-difluoroethyl)-1 / - / -pyrazol-4-yl)thiazol-4-yl)urea, Compound 163 (Example 77), or a pharmaceutically acceptable salt thereof:

[0312] In one embodiment, the compound is, 1-(6-(4-(2-aminopropan-2-yl)phenyl)pyridin-2-yl)-3- (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Compound 164 (Example 5), or a pharmaceutically acceptable salt thereof:

[0313] In one embodiment, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)-3-(2-(1-(2-methoxyethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 165 (Example 76), or a pharmaceutically acceptable salt thereof:

[0314] In one embodiment, the compound is (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)-3-(2-(1-(2-methoxyethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 166 (Example 75), or a pharmaceutically acceptable salt thereof:

[0315] In one embodiment, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin- 4-yl)-3-(2-(1 -ethyl- 1 / - / -pyrazol-4-yl)thiazol-4-yl)urea Compound 167 (Example 74), or a pharmaceutically acceptable salt thereof:

[0316] In one embodiment, the compound is (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)-3-(2-(1 -ethyl- 1H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 168 (Example 73), or a pharmaceutically acceptable salt thereof:

[0317] In one embodiment, the compound is (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin- 4-yl)-3-(2-cyclopropylthiazol-4-yl)urea, Compound 169 (Example 82), or a pharmaceutically acceptable salt thereof:

[0318] In one embodiment, the compound is (R)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin- 4-yl)-3-(2-cyclopropylthiazol-4-yl)urea, Compound 170 (Example 81), or a pharmaceutically acceptable salt thereof.

[0319] In one embodiment, the compound is (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)-1H-pyrazol-1-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide, Compound171 (Example 15), or a pharmaceutically acceptable salt thereof:

[0320] In one embodiment, the compound is (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)-1H-pyrazol-1-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide, Compound 172 (Example 14), or a pharmaceutically acceptable salt thereof:

[0321] In one embodiment, the compound is 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)-3-(2-((S)-1-hydroxyethyl)thiazol-4-yl)urea Compound 173 (Example 74), or a pharmaceutically acceptable salt thereof:

[0322] In one embodiment, the compound is 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)-3-(2-((R)-1-hydroxyethyl)thiazol-4-yl)urea, Compound 174 (Example 73), or a pharmaceutically acceptable salt thereof:

[0323] In one embodiment, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)-3-(2-((S)-1-hydroxyethyl)thiazol-4-yl)urea, Compound 175 (Example 72), or a pharmaceutically acceptable salt thereof:

[0324] In one embodiment, the compound is 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-1-hydroxyethyl)thiazol-4-yl)urea, Compound 176 (Example 71), or a pharmaceutically acceptable salt thereof:

[0325] In one embodiment, the compound is (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(3,3-difluorocyclobutyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 177(Example 69), or a pharmaceutically acceptable salt thereof:

[0326] In one embodiment, the compound is ((S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2-(1-(3,3-difluorocyclobutyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 178(Example 68), or a pharmaceutically acceptable salt thereof:

[0327] In one embodiment, the compound is, (R)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)picolinamide, Compound 179 (Example 4), or a pharmaceutically acceptable salt thereof:

[0328] In one embodiment, the compound is, (S)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)picolinamide, Compound 180 (Example 3), or a pharmaceutically acceptable salt thereof:

[0329] In one embodiment, the compound is Compound 181 , or a pharmaceutically acceptable salt thereof:

[0330] In one embodiment, the compound is Compound 182, or a pharmaceutically acceptable salt thereof:

[0331] In one embodiment, the compound is (R)-1-(2-(4-(2-aminopropan-2-yl)phenyl)thiazol-4- yl)-3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea, Compound 183 (Example 67), or a pharmaceutically acceptable salt thereof:

[0332] In one embodiment, the compound is (S)-1-(2-(4-(2-aminopropan-2-yl)phenyl)thiazol-4- yl)-3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea, Compound 184 (Example 66), or a pharmaceutically acceptable salt thereof:

[0333] In one embodiment, the compound is 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)-3-(2-(2-methyl-2H-1 ,2,3-triazol-4-yl)thiazol-4-yl)urea, Compound 185 (Compound 102), or a pharmaceutically acceptable salt thereof:

[0334] In one embodiment, the compound is (S)-4-(4-(3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)ureido)thiazol-2-yl)- / V-((3-methyloxetan-3-yl)methyl)benzamide, Compound 186 (Example 65), or a pharmaceutically acceptable salt thereof:

[0335] In one embodiment, the compound is (R)-4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)thiazol-2-yl)- / V-((3-methyloxetan-3-yl)methyl)benzamide, Compound 187 (Example 64), or a pharmaceutically acceptable salt thereof:

[0336] In one embodiment, the compound is 4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)thiazol-2-yl)-2-fluoro- / V-methylbenzamide, Compound 188 (Example 63), or a pharmaceutically acceptable salt thereof:

[0337] In one embodiment, the compound is Compound 189, or a pharmaceutically acceptable salt thereof:

[0338] In one embodiment, the compound is Compound 190, or a pharmaceutically acceptable salt thereof:

[0339] In one embodiment, the compound is 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)-3-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)urea, Compound 191 (Example 62), or a pharmaceutically acceptable salt thereof:

[0340] In one embodiment, the compound is, (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, Compound 192 (Example 2), or a pharmaceutically acceptable salt thereof:

[0341] In one embodiment, the compound is, (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, Compound 193 (Example 1), or a pharmaceutically acceptable salt thereof:

[0342] In one embodiment, the compound is Compound 194, or a pharmaceutically acceptable salt thereof:

[0343] In one embodiment, the compound is Compound 195, or a pharmaceutically acceptable salt thereof:

[0344] In one embodiment, the compound is (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)-3-(2-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 196 (Example 61), or a pharmaceutically acceptable salt thereof:

[0345] In one embodiment, the compound is (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)-3-(2-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Compound 197 (Example 60), or a pharmaceutically acceptable salt thereof:

[0346] In one embodiment, the compound is 1-(2-acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea, Compound 198 (Example 59), or a pharmaceutically acceptable salt thereof:

[0347] In one embodiment, the compound is 1-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2- ((R)-3-hydroxypyrrolidin-1-yl)thiazol-4-yl)urea, Compound 199 (Example 72), or a pharmaceutically acceptable salt thereof:

[0348] In one embodiment, the compound is 1-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2- ((R)-3-hydroxypyrrolidin-1-yl)thiazol-4-yl)urea, Compound 200 (Example 71), or a pharmaceutically acceptable salt thereof:

[0349] In one embodiment, the compound is Compound 201 , or a pharmaceutically acceptable salt thereof:

[0350] In one embodiment, the compound is Compound 202, or a pharmaceutically acceptable salt thereof:

[0351] In one embodiment, the compound is Compound 203, or a pharmaceutically acceptable salt thereof:

[0352] In one embodiment, the compound is Compound 204, or a pharmaceutically acceptable salt thereof:

[0353] In one embodiment, the compound is Compound 205, or a pharmaceutically acceptable salt thereof:

[0354] In one embodiment, the compound is Compound 206, or a pharmaceutically acceptable salt thereof:

[0355] In one embodiment, the compound is Compound 207, or a pharmaceutically acceptable salt thereof:

[0356] In one embodiment, the compound is Compound 208, or a pharmaceutically acceptable salt thereof:

[0357] In one embodiment, the compound is Compound 209, or a pharmaceutically acceptable salt thereof:

[0358] In one embodiment, the compound is Compound 210, or a pharmaceutically acceptable salt thereof:

[0359] In one embodiment, the compound is Compound 211 , or a pharmaceutically acceptable salt thereof:

[0360] In one embodiment, the compound is Compound 212, or a pharmaceutically acceptable salt thereof:

[0361] In one embodiment, the compound is Compound 213, or a pharmaceutically acceptable salt thereof:

[0362] In one embodiment, the compound is Compound 214, or a pharmaceutically acceptable salt thereof:

[0363] In one embodiment, the compound is Compound 215, or a pharmaceutically acceptable salt thereof:

[0364] In one embodiment, the compound is Compound 216, or a pharmaceutically acceptable salt thereof:

[0365] In one embodiment, the compound is Compound 217, or a pharmaceutically acceptable salt thereof:

[0366] In one embodiment, the compound is Compound 218, or a pharmaceutically acceptable salt thereof:

[0367] In one embodiment, the compound is Compound 219, or a pharmaceutically acceptable salt thereof:

[0368] In one embodiment, the compound is Compound 220, or a pharmaceutically acceptable salt thereof:

[0369] In one embodiment, the compound is Compound 221 , or a pharmaceutically acceptable salt thereof:

[0370] In one embodiment, the compound is Compound 222, or a pharmaceutically acceptable salt thereof:

[0371] In one embodiment, the compound is Compound 223, or a pharmaceutically acceptable salt thereof:

[0372] In one embodiment, the compound is Compound 224, or a pharmaceutically acceptable salt thereof:

[0373] In one embodiment, the compound is Compound 225, or a pharmaceutically acceptable salt thereof:

[0374] In one embodiment, the compound is Compound 226, or a pharmaceutically acceptable salt thereof:

[0375] In one embodiment, the compound is Compound 227, or a pharmaceutically acceptable salt thereof:

[0376] In one embodiment, the compound is Compound 228, or a pharmaceutically acceptable salt thereof:

[0377] In one embodiment, the compound is Compound 229, or a pharmaceutically acceptable salt thereof:

[0378] In one embodiment, the compound is Compound 230, or a pharmaceutically acceptable salt thereof:

[0379] In one embodiment, the compound is Compound 231 , or a pharmaceutically acceptable salt thereof:

[0380] In one embodiment, the compound is Compound 232, or a pharmaceutically acceptable salt thereof:

[0381] In one embodiment, the compound is Compound 233, or a pharmaceutically acceptable salt thereof:

[0382] In one embodiment, the compound is Compound 234, or a pharmaceutically acceptable salt thereof:

[0383] In one embodiment, the compound is Compound 235, or a pharmaceutically acceptable salt thereof:

[0384] In one embodiment, the compound is Compound 236, or a pharmaceutically acceptable salt thereof:

[0385] In one embodiment, the compound is Compound 237, or a pharmaceutically acceptable salt thereof:

[0386] In one embodiment, the compound is Compound 238, or a pharmaceutically acceptable salt thereof:

[0387] In one embodiment, the compound is Compound 239, or a pharmaceutically acceptable salt thereof:

[0388] In one embodiment, the compound is Compound 240, or a pharmaceutically acceptable salt thereof:

[0389] In one embodiment, the compound is Compound 241 , or a pharmaceutically acceptable salt thereof:

[0390] In one embodiment, the compound is Compound 242, or a pharmaceutically acceptable salt thereof:

[0391] In one embodiment, the compound is Compound 243, or a pharmaceutically acceptable salt thereof:

[0392] In one embodiment, the compound is Compound 244, or a pharmaceutically acceptable salt thereof:

[0393] In one embodiment, the compound is Compound 245, or a pharmaceutically acceptable salt thereof:

[0394] In one embodiment, the compound is Compound 246, or a pharmaceutically acceptable salt thereof:

[0395] In one embodiment, the compound is Compound 247, or a pharmaceutically acceptable salt thereof:

[0396] In one embodiment, the compound is Compound 248, or a pharmaceutically acceptable salt thereof:

[0397] In one embodiment, the compound is Compound 249, or a pharmaceutically acceptable salt thereof:

[0398] In one embodiment, the compound is Compound 250, or a pharmaceutically acceptable salt thereof:

[0399] In certain embodiments, the compounds modulate POL y.

[0400] 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. Synthetic, separation, or purification methods to be used to obtain an enantiomer of a given compound are known in the art and are applicable for obtaining the compounds identified herein.

[0401] 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.

[0402] 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 bondswhich form alkenes. In the case of carbon-carbon double bonds, the geometric isomers may be E or Z isomers.

[0403] 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.

[0404] 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 (=0) form.

[0405] 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 greaterthan 95%, more preferably greater than 97%, more preferably greater than 99%. It will be understood that some variation of natural isotopic abundance may occur in any compound depending upon the source of the reagents used in the synthesis. Thus, a preparation of undeuterated compounds may inherently contain small amounts of deuterated isotopologues, such amounts being insignificant as compared to the degree of stable isotopic substitution of the deuterated compounds of the invention. See, e.g., Gannes, L Z et al., Comp Biochem Physiol Mol Integr Physiol, 119, 725 (1998). Replacement of hydrogen with deuterium may affect the activity, toxicity, and pharmacokinetics (e.g., absorption, distribution, metabolism, and excretion (“ADME”)) of some drugs. For instance, such replacement may alter the chemical stability and biochemical reactivity of a compound through kinetic isotope effects. Because of the increased mass of deuterium relative to hydrogen, epimerization at stereogenic carbons may be slowed down when hydrogen is replaced with deuterium. See Pirali et al, J. Med. Chem.62, 5276- 97 (2019). Additionally, the presence of deuterium may affect how a molecule interacts with enzymes, thereby impacting enzyme kinetics. While in certain cases the increased mass of deuterium as compared to hydrogen 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.

[0406] Deuterated POLy modulators of the present invention may be prepared using chemical reactions known to a person of ordinary skill in the art using deuterated starting materials orreagents. Deuterium-containing reagents are well known in the art and may be prepared using known procedures or purchased from commercial sources. The deuterated compounds obtained may be characterized by analytical techniques known to persons of ordinary skill in the art. For example, nuclear magnetic resonance (“NMR”) may be used to determine a compound’s structure while mass spectroscopy (“MS”) may be used to determine the amount of deuterium atom in the compound by comparison to its non-deuterated form.EXAMPLES

[0407] 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.

[0408] 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 (5H) 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 (i.e., all reported measurement values herein also include ± 5%, ± 4%, ± 3%, ± 2%, and / or ± 1%). All reported LCMS values herein also include ± 5%, ± 4%, ± 3%, ± 2%, and / or ± 1 %.

[0409] The following examples illustrate various non-limiting embodiments of the present disclosure.Examples 1 & 2: 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, Example 1 (Compound 193) 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, Example 2 (Compound 192):Boc(Compound 193) (Compound 192)Scheme 1.

[0410] Synthesis of 1-(6-bromopyridin-2-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, 1-3 [Step 1]: To a solution of 6-bromopyridin-2-amine (1-1 , 400 mg, 2.31 mmol) in dichloromethane (5 mL), was added Triethylamine (1.9 ml_, 13.9 mmol) at -5 °C and then Triphosgene (686 mg, 2.31 mmol) was added and stirred for 15 minutes at -5 °C. After that 8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine dihydrochloride (1-2, 595 mg, 2.31 mmol) dissolved in dichloromethane was added to it and stirred for 30 min at -5 °C under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. Organic extract was dried over anhydrous Na2SO4and concentrated under reduce pressure to obtain crude compound. The product was purified by combi flash column chromatography to afford 1- (6-bromo-2-pyridyl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (1-3, 500 mg). LCMS (ESI) Calcd for C14Hi2BrCIN4O2: 381.98, found [M+H]+= 383.0.

[0411] Synthesis of tert-butyl (3-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)pyridin-2-yl)phenyl)oxetan-3-yl)carbamate, 1 -5 [Step 2]: To a stirred solution of 1- (6-bromo-2-pyridyl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (1-3, 500 mg, 1.30 mmol), tert-butyl N-[3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]oxetan-3- yl]carbamate (1-4, 489 mg, 1.30 mmol) and K3PO4(553 mg, 2.61 mmol) in 1 ,4-Dioxane (2 mL) and Water (0.5 mL), was degassed with argon for 10 min and then Pd-118 (85 mg, 0.130 mmol) was added and the reaction mixture was heated at 80 °C for 16 h. Reaction mixture was filtered through celite bed, washed with ethyl acetate. Organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to get crude. The product was purified by combi flash column chromatography to afford tert-butyl (3-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)pyridin-2-yl)phenyl)oxetan-3- yl)carbamate (1-5, 400 mg).

[0412] 1H NMR (400 MHz, DMSO-cfe): 6H 9.61 (s, 1H), 9.51 (brs, 1 H), 8.13-8.06 (m, 2H), 7.78 (t, 1H), 7.65 (d, 2H), 7.50-7.47 (m, 2H), 7.37 (d, 2H), 7.15 (d, 1 H), 5.04-5.02 (m, 1 H), 4.83-4.81 (m, 2H), 4.63-4.61 (m, 2H), 4.49-4.46 (m, 1H), 4.28-4.23 (m, 1H), 2.38-2.31 (m, 1 H), 2.16-2.12 (m, 1H), 1.39 (s, 9H).

[0413] Separation of tert-butyl (S)-(3-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)pyridin-2-yl)phenyl)oxetan-3-yl)carbamate, 1-6 and tert-butyl (3-(4-(6- (3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)pyridin-2-yl)phenyl)oxetan-3- yl)carbamate, 1-7 [Step 3]: fert-butyl (3-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)pyridin-2-yl)phenyl)oxetan-3-yl)carbamate (1-5) was purified by SFC to afford peak 1 as tert-butyl (S)-(3-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)pyridin-2- yl)phenyl)oxetan-3-yl)carbamate (1-6, 250 mg) and peak 2 as tert-butyl (R)-(3-(4-(6-(3-(8-chloro- 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)pyridin-2-yl)phenyl)oxetan-3-yl)carbamate (1-7, 150 mg).

[0414] SFC method: HPLC on Waters SFC PREP 150 instruments equipped with Waters 2489 UV / Visible Detector by using Chiralpak-IG (30.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 100 ml / min, using 50% CO2in super critical state & 50% of 100% Methanol as Mobile phase. Run this isocratic mixture up to 20.0 minutes and also maintained the isobaric condition of 120 bar at 220 nm wavelength.

[0415] tert-butyl (S)-(3~(4-(6-(3-(8-chloro-3,4-clihydro-2H-pyrano[3,2~b]pyridin~4- yi)ureido)pyr!dm-2-yl)phenyl)oxetan-3-yl)carbamate, 1-6 [Peak 1]: LCMS (ESI) Calcd. for C28H30CIN5O5: 551.19, found [M+H]+= 552.2.

[0416] tert-butyl (R)-(3-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yi)ureido)pyridm-2-yl)phenyl)oxetan-3-yl)carbamate, 1-7 [Peak 2]: LCMS (ESI) Calcd. for C28H30CIN5O5: 551.19, found [M+H]+= 552.2.

[0417] 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, Example 1 (Compound 193) [Step 4]: To a solution of tert-butyl (S)-(3-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)pyridin-2-yl)phenyl)oxetan-3-yl)carbamate (1-6, 100 mg, 0.181 mmol) in dichloromethane (10 mL) at 0 °C, was added TFA (1.0 mL) and stirred at 25 °C for 16 h. The reaction mixture was evaporated to obtain crude compound. The product was purified by reverse phase preparative HPLC to afford (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 (Example 1 (Compound 193), 25 mg). LCMS (ESI) Calcd. for C23H22CIN5O3: 451.14, found [M+H]+= 452.2.1H NMR (400 MHz, DMSO-cfe): <5H 9.61 (bs, 2H), 8.12 (d, 1H), 7.77 (t, 1 H), 7.62 (d, 2H), 7.53 (d, 1 H), 7.48 - 7.44 (m,3H), 7.13 (d, 1 H), 5.02 (q, 1 H), 4.68 - 4.65 (m, 4H), 4.50 - 4.44 (m, 1 H), 4.26 - 4.21 (m, 1 H), 2.58 (bs, 2H), 2.40 - 2.34 (m, 1 H), 2.19 - 2.13 (m, 1H).

[0418] Synthesis of (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, Example 2 (Compound 192) [Step 5]: To a solution of tert-butyl (R)-(3-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)pyridin-2-yl)phenyl)oxetan-3-yl)carbamate (1-7, 100 mg, 0.181 mmol) in dichloromethane (10 mL) at 0 °C, was added TFA ( 1.0 mL) and stirred at 25 °C for 16 h. The reaction mixture was evaporated to obtain crude compound. The product was purified by reverse phase preparative HPLC to afford (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 (Example 2 (Compound 192), 27 mg). LCMS (ESI) Calcd. for C23H22CIN5O3: 451.14, found [M+H]+= 452.2.1H NMR (400 MHz, DMSO- cfe): <5H 9.61 (bs, 2H), 8.12 (d, 1 H), 7.77 (t, 1 H), 7.62 (d, 2H), 7.53 (d, 1 H), 7.48-7.44 (m, 3H), 7.13 (d, 1 H), 5.02 (q, 1 H), 4.68-4.65 (m, 4H), 4.50-4.44 (m, 1 H), 4.26-4.21 (m, 1 H), 2.55 (bs, 2H), 2.40- 2.34 (m, 1 H), 2.19-2.13 (m, 1 H).Examples 3 & 4: Synthesis of (S)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)picolinamide, Example 3 (Compound 180) and (R)-6-(3-(8-methyl-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)ureido)picolinamide, Example 4 (Compound 179):Scheme 2.

[0419] Synthesis of 2-bromo-4-methylpyridin-3-ol, 2-2 [Step 1]: To the solution of NaOH, 10% in water (70 mL) was added bromine (2.5 mL, 48.1 mmol) dropwise, followed by 4-methylpyridin-3-ol (2-1 , 3.50 g, 32.1 mmol) at OC. The reaction mixture was warmed to ambient temperature and stirred for 16 h. The reaction mixture was washed with EtOAc. The aqueous layer was neutralized 6N HCI. It was extracted with EtOAc (two times). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-bromo-4-methylpyridin-3-ol (2-2, 4.00 g). 1 HNMR (400 MHz, CDCI3): 6H 7.86 (d, 1 H), 7.06 (d, 1 H), 5.54 (br, 1 H), 2.31 (s, 3H).

[0420] Synthesis of (2-bromo-3-(but-3-en-1-yloxy)-4-methylpyridine, 4 [Step 2]: To a stirred solution of 2-bromo-4-methylpyridin-3-ol (2-2, 5.00 g, 26.6 mmol) in MeCN (200 mL) were added 4-bromobut-1-ene (2-3, 4.13 g, 30.6 mmol) and K2CO3 (11 g, 79.8 mmol) at ambient temperature and stirred at 80 °C for 16 h. The reaction mixture was filtered through celite bed, and the bed was washed with EtOAc. Combined filtrate was concentrated under reduced pressure and purified by combi flash (0-40% EtOAc in Heptane) to afford (2-bromo-3-(but-3-en-1-yloxy)-4- methylpyridine (2-4, 2.40 g). 1 H NMR (400 MHz, CDCI3): OH 8.00-7.99 (d, 1 H), 7.07-7.06 (d, 1 H), 5.99-5.89 (m, 1 H), 5.22-5.1 1 (m, 2H), 4.0-3.96 (t, 2H), 2.63-2.56 (m, 2H), 2.33 (s, 3H).

[0421] Synthesis of 8-methyl-4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine, 2-5 [Step 3]: To a stirred solution of (2-bromo-3-(but-3-en-1-yloxy)-4-methylpyridine (2-4, 2.40 g, 9.91 mmol) in DMF (25 mL) was added KOAc ( 4.86 g, 49.6 mmol), TPP (0.94 g, 3.57 mmol) and Tetra ethyl amonium chloride (3.29 g, 19.8 mmol) in a sealed tube and degassed for 10 min. Pd(OAc)2(0.22 g, 0.99 mmol) was added and stirred at 110 °C for 16 h. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate, filtered through celite bed. The filtrate was washed with cold water and brine. The organic extract was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by combi flash chromatography to afford 8-methyl-4-methylene-2,3-dihydropyrano[3,2-b]pyridine (2-5, 1.70 g). 1 H NMR (400 MHz, CDCI3): 6H8.08-8.07 (d, 1 H), 7.02-7.01 (d, 1 H), 6.29 (m, 1 H), 5.13-5.12 (m, 1 H), 4.28-4.26 (m, 2H), 4.28-4.26 (m, 2H), 2.22 (s, 3H). LCMS Calcd. for CwHuNO: 161.2; found [M+H]+: 161.9.

[0422] Synthesis of 8-methyl-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one, 2-6 [Step 4]:Ozone gas was bubbled through the stirred solution of 8-methyl-4-methylene-2,3- dihydropyrano[3,2-b]pyridine (5, 500 mg, 3.10 mmol) in DCM (25 mL) for 4 h at -78 °C. The reaction mixture was warmed to 0 °C and added dimethylsulfide (1.1 mL, 14.6 mmol) and stirred for 16 h at ambient temperature. Volatiles were evaporated under reduced pressure and resulting mass was purified by combiflash chromatography to afford 8-methyl-2,3-dihydro-4H-pyrano[3,2- b]pyridin-4-one (6, 250 mg). 1 H NMR (400 MHz, CDCI3): 0H8.31-8.30 (d, 1 H), 7.26-7.24 (d, 1 H), 4.63-4.60 (t, 2H), 2.96-2.93 (t, 2H), 2.29 (s, 3H). LCMS Calcd. for C9H9NO2: 163.17; found [M+H]+: 164.19.

[0423] Synthesis of (E)-8-methyl-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one oxime, 2-7 [Step 5]: To a stirred solution of 8-methyl-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one (2-6, 1.00g, 6.13 mmol) in Methanol (15 mL) was added NH2OH.HCI (2.13 g, 30.6 mmol) at 0 °C and the reaction mixture was stirred at ambient temperature for 2 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. Cold water was added into the reaction mixture, stirred well for 10 min and the solid was filtered and dried under reduced pressure to afford (E)-8-methyl-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one oxime (2-7, 700 mg).

[0424] 1H NMR (400 MHz, DMSO-cfe): bH12.42 (br, 1 H), 8.26-8.25 (d, 1 H), 7.68-7.67 (d, 1 H), 4.44-4.41 (t, 2H), 3.00-2.97 (t, 2H), 2.36 (s, 3H). LCMS Calcd. for C9HION202:178.19, found [M+H]+: 179.1.

[0425] Synthesis of 8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine, 2-8 [Step 6]: To a stirred solution of (E)-8-methyl-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one oxime (2-7, 700 mg, 3.93 mmol) in Ethanol (35 mL) was added Ammonium acetate (1.5 g, 19.6 mmol) followed by NH3, 25% in water (5.9 mL) and Zn dust (1 .29 g, 19.6 mmol) at 0 °C and was stirred for 30 min at same temperature. Progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through sintered funnel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 8-methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-amine (2-8, 650 mg). LCMS Calcd. for C9Hi2N20: 164.2, found [M+H]+: 165.1.

[0426] Synthesis of tert-butyl (8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yljcarbamate, 2-9 [Step 7]: To a suspension of 8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- amine (2-8, 650 mg, 3.96 mmol) in DCM (20 mL) was added Triethylamine (3.3 mL, 23.8 mmol) followed by Boc anhydride (9.1 mL, 39.6 mmol) at ice cold condition. The reaction mixture was allowed to stir at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water. Organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by combi flash chromatography to afford tert-butyl (8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)carbamate (2-9, 370 mg). LCMS Calcd. for Ci4H20N2O3: 264.3, found [M+H]+: 264.9.

[0427] Synthesis of 8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrogen chloride, 2-10 [Step 8]: To a clear solution of tert-butyl N-(8-methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)carbamate (2-9, 370 mg, 1.40 mmol) in 1 ,4-Dioxane (5 mL) was added 4M HCI in Dioxane (1.8 mL) at ice cold condition. The reaction mixture was allowed to stir at ambient temperature for 2 h. The reaction was monitored by LCMS. Upon completion, volatiles were evaporated under reduced pressure and triturated with pentane to afford 8-methyl-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-amine hydrogen chloride (2-10, 300 mg). 1 H NMR (400 MHz, DMSO- cfe): 5H 8.58 (S, 3H), 8.1 1-8.10 (d, 1 H), 7.27-7.26 (d, 1 H), 4.54 (m, 1 H), 4.44-4.42 (m, 1 H), 4.31- 4.25 (m, 1 H), 2.17 (s, 3H), 2.14-2.10 (m, 1 H). LCMS Calcd. for C9HI2N2O: 164.2, found [M+H]+: 164.8.

[0428] Synthesis of methyl (S)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)picolinate, 2-13 and methyl (R)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)picolinate, 2-14 [Step 9 & 10]: To a solution of methyl 6-aminopyridine-2- carboxylate (2-11 , 185 mg, 1.22 mmol) in dichloromethane (15 mL) at -5 °C, were added triethylamine (1.0 mL, 7.31 mmol) followed by triphosgene (361 mg, 1.22 mmol) and stirred for 15 min, after that 8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride salt (2-10, 100 mg, 1.22 mmol) dissolved in dichloromethane (4 mL) was added into it and stirred at -5 °C for 30 min. Reaction mixture was diluted with water and extracted with 5% methanol in dichloromethane. Organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduce pressure to obtain crude. The product was purified by combi flash column chromatography to afford methyl 6-[(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)carbamoylamino]pyridine-2-carboxylate (2-12, 150 mg) and then enantiomers were separated by SFC-HPLC to afford Peak 1 as methyl (S)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)ureido)picolinate (2-13, 50 mg) and peak 2 as methyl (R)-6-(3-(8-methyl-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)ureido)picolinate (2-14, 50 mg).

[0429] LCMS (ESI) Calcd. for C18H19N3O4: 342.13, found [M+H]+= 343.2 for Peak 1 and LCMS (ESI) Calcd. for CI8HI9N3O4: 342.13, found [M+H]+= 343.7 for Peak 2.

[0430] SFC method: methyl 6-[(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)carbamoylamino]pyridine-2-carboxylate (2-12) was purified by SFC HPLC on Waters SFC150 instrument equipped with Waters 2489 UV / Visible Detector by using Chiralpak IG (30.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 1 10 ml / min, using 50% CO2 in super critical state & 50%[MeOH :ACN(1 : 1)) as Mobile phase, Run this isocratic mixture up to 6.0 minutes and also maintained the isobaric condition of 80 bar at 240 nm wavelength.

[0431] Synthesis of (S)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)picolinamide, Example 3 (Compound 180) [Step 11]: To a solution of methyl (S)-6- (3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)picolinate (50 mg, 0.146 mmol) in Methanol (1 mL) was added 7 M NH3in Methanol (1.3 mL, 9.38 mmol) and heated at 70°C for 16 h. Reaction mixture was concentrated to get crude product. The product was purified by reverse phase preparative HPLC to afford (S)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)picolinamide (Example 3 (Compound 180), 17 mg).

[0432] 1H NMR (400 MHz, DMSO-d6): <5H 9.52 (s, 1 H), 8.67 (brs, 1 H), 8.04 (d, 1 H), 7.90-7.84 (m, 3H), 7.61 (d, 1 H), 7.51 (d, 1 H), 7.17 (d, 1H), 4.89-4.86 (m, 1 H), 4.35 (s, 2H), 2.66 (s, 1 H), 2.16 (s, 3H), 1.93-1.90 (m, 1 H), LCMS (ESI) Calcd. for C20H17CIF3N5O3: 327.13, found [M+H]+= 328.2, HPLC: 99.63%.

[0433] Synthesis of (R)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)picolinamide, Example 4 (Compound 179) [Step 12]: To a solution of methyl (R)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)picolinate (2-14, 50 mg, 0.146 mmol) in Methanol (1 mL) was added 7 M NH3in methanol (1.3 ml_, 9.38 mmol) and heated at 70°C for 16 h. Reaction mixture was concentrated to get crude which was purified by reverse phase preparative HPLC to afford (R)-6-(3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)picolinamide (Example 4 (Compound 179), 12 mg).

[0434] 1H NMR (400 MHz, DMSO-d6): <5H 9.52 (s, 1 H), 8.67 (brs, 1 H), 8.04 (d, 1 H), 7.90-7.84 (m, 3H), 7.61 (d, 1 H), 7.51 (d, 1 H), 7.17 (d, 1H), 4.89-4.86 (m, 1 H), 4.36-4.34 (m, 2H), 2.68-66 (m, 1 H), 2.16 (s, 3H), 1.93-1.91 (m, 1 H). LCMS (ESI) Calcd. for C20H17CIF3N5O3: 327, found [M+H]+= 328.2; HPLC purity: 99.72%.

[0435] Synthesis of (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H- pyrazol-1-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide 7 and (R)-4-(3-(3-(8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)-N-((3-methyloxetan-3- yl)methyl)benzamide, 8 [Step 4]: Racemic 4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)ureido)-1 H-pyrazol-1-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide (6, 100 mg, 0.2 mmol) was separated by SFC purification method followed by reverse phase prep HPLC purification and lyophilized to afford the first compound (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)ureido)-1 H-pyrazol-1-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide (7, 26 mg) as Peak 1 and the second compound as (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1 H-pyrazol-1-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide (8, 26 mg) as Peak 2. The stereochemistry was arbitrarily taken.

[0436] SFC method: PLC SFC Prep Purification of CR620-AM2-2023-06-17-1-P has been completed on Waters SFC Prep 80 instrument equipped with Waters 2489 UV / Visible Detector by using I Cellulose J (30.0mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 ml / min, using 50% CO2 in super critical state & 50% of (ACNJPA) as Mobile phase, Run this isocratic mixture up to 11.0 minutes and also maintained the isobaric condition of 120 bar at 301 nm wavelength.

[0437] (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)-N- ((3-methyloxetan-3-yl)methyl)benzamide (7, 26 mg) Peak 1 : LCMS (ESI) calculated for C24H25CIN6O4: 496.16, found [M+H]+: 497.2.1H NMR (400 MHz, DMSO-d6): 6H9.29 (s, 1 H), 8.62 (t, 1 H), 8.48-8.47 (m, 1 H), 8.14 (d, 1 H), 7.95 (d, 2H), 7.82 (d, 2H), 7.60 (bs, 1 H), 7.51 (d, 1 H), 6.49 (s, 1 H), 4.96-4.91 (m, 1 H), 4.49-4.37 (m, 4H), 4.21 (d, 2H), 3.47 (d, 2H), 2.51-2.50 (m, 1 H), 2.10-2.05 (m, 1 H), 1.26 (s, 3H).

[0438] (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)-N- ((3-methyloxetan-3-yl)methyl)benzamide (8, 26 mg) Peak 2: LCMS (ESI) calculated for C24H25CIN6O4: 496.16, found [M+H]+: 497.2.1H NMR (400 MHz, DMSO-d6): OH 9.28 (s, 1 H), 8.62 (t, 1 H), 8.48-8.47 (m, 1 H), 8.14 (d, 1 H), 7.95 (d, 2H), 7.82 (d, 2H), 7.60 (bs, 1 H), 7.51 (d, 1 H),6.49 (s, 1 H), 4.96-4.91 (m, 1 H), 4.49-4.39 (m, 4H), 4.21 (d, 2H), 3.47 (d, 2H), 2.51-2.50 (m, 1 H), 2.10-2.03 (m, 1 H), 1.26 (s, 3H).Example 5: Synthesis of 1-(6-(4-(2-aminopropan-2-yl)phenyl)pyridin-2-yl)-3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 5 (Compound 164)Scheme 3.

[0439] Synthesis of 1-(6-bromopyridin-2-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, 3-3 [Step 1]: To a stirred solution of 6-bromopyridin-2-amine (1-1 , 202 mg, 1 .2 mmol) in dichloromethane (25 mL) were added triethylamine (0.65 ml_, 4.7 mmol) and followed by triphosgene (346 mg, 1.2 mmol) at ice cold condition and stirred for 40 min. A solution of 8- chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-amine (3-2, 300 mg, 1.2 mmol) and triethylamine (1.3 mL, 9.3 mmol) in dichloromethane (20 mL) was added at 0°C and the reaction mixture was allowed to stir for 2 h at ambient temperature. The reaction mixture was quenched with brine solution and extracted with dichloromethane. Combined organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by combi flash chromatography to afford 1-(6-bromopyridin-2-yl)-3-(8-chloro-3,4-dihydro-2 / - / - pyrano[3,2-£>]pyridin-4-yl)urea (3-3, 310 mg). LCMS (ESI) Calcd. for C-uH^BrCIN^: 382.0, found [M+H]+: 383.07.

[0440] Synthesis of 1-(6-bromopyridin-2-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, 3-3 [Step 1]: To a stirred solution of 6-bromopyridin-2-amine (3-1 , 202 mg, 1 .2 mmol) in dichloromethane (25 mL) were added triethylamine (0.65 mL, 4.7 mmol) and followed by triphosgene (346 mg, 1.2 mmol) at ice cold condition and stirred for 40 min. A solution of 8- chloro-3,4-dihydro-2 / 7-pyrano[3,2-b]pyridin-4-amine (3-2, 300 mg, 1.2 mmol) and triethylamine (1.3 mL, 9.3 mmol) in dichloromethane (20 mL) was added at 0°C and the reaction mixture was allowed to stir for 2 h at ambient temperature. The reaction mixture was quenched with brine solution and extracted with dichloromethane. Combined organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by combi flash chromatography to afford 1-(6-bromopyridin-2-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (3-3, 310 mg). LCMS (ESI) Calcd. for C^H^BrCIN^: 382.0, found [M+H]+: 383.07.

[0441] Synthesis of tert-butyl (2-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)pyridin-2-yl)phenyl)propan-2-yl)carbamate, 3-5 [Step 2]: To a stirred solution of 1- (6-bromopyridin-2-yl)-3-(8-chloro-3,4-dihydro-2 / 7-pyrano[3,2-b]pyridin-4-yl)urea (3-3, 170 mg, 0.4 mmol) in 1 ,4-dioxane (6 mL) and water (1.5 ml_), were added (4-(2-((fert- butoxycarbonyl)amino)propan-2-yl)phenyl)boronic acid (3-4, 124 mg, 0.4 mmol) and K3PO4 (188 mg, 0.9 mmol). Reaction mixture was degassed with argon for 10 minutes. Pd-118 (29 mg, 0.04 mmol) was added into the reaction mixture and the reaction mixture was allowed to stir at 80°C for 16 h. The reaction mixture was filtered through celite pad and washed with ethyl acetate. Filtrate was concentrated under reduced pressure. The product was purified by reverse phase prep HPLC and lyophilised to afford fert-butyl (2-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- £>]pyridin-4-yl)ureido)pyridin-2-yl)phenyl)propan-2-yl)carbamate (3-5, 120 mg). LCMS (ESI) Calcd. for C28H32CIN5O4 : 537.2, found [M+H]+: 538.3.

[0442] Synthesis of 1-(6-(4-(2-aminopropan-2-yl)phenyl)pyridin-2-yl)-3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 5 (Compound 164) [Step 3]: To a stirred solution fert-butyl (2-(4-(6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)pyridin-2- yl)phenyl)propan-2-yl)carbamate (3-5, 150 mg, 0.3 mmol) in dichloromethane (3 mL) was added 4 M HCI in dioxane (0.70 mL, 3.0 mmol) at ice cold condition. The reaction mixture was allowed to stir at ambient temperature for 8 h. Volatiles were evaporated under reduced pressure. The product was purified by reverse phase prep HPLC and lyophilised to afford 1-(6-(4-(2- aminopropan-2-yl)phenyl)pyridin-2-yl)-3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea (Example 5 (Compound 164), 66 mg). LCMS (ESI) Calcd. for C23H24CIN5O2 : 437.2, found [M+H]+: 438.2.1H NMR (400 MHz, DMSO-d6) <5H: 9.71 (brs, 1 H), 9.60 (s, 1 H), 8.12 (d, 1 H), 7.75 (t, 1 H), 7.57-7.56 (m, 1 H), 7.50-7.48 (m, 2H), 7.44-7.42 (m, 1 H), 7.38-7.36 (m, 2H), 7.08-7.06 (m, 1 H), 5.03-5.00 (m, 1 H), 4.49-4.46 (m, 1 H), 4.24-4.19 (m, 1 H), 2.39-2.33 (m, 1 H), 2.18-2.15 (m, 1 H), 1.36 (s, 6H). Two amine protons are exchangeable.Examples 6 & 7: Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3- (6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)urea, Example 6 (Compound 140) and (S)-1 - (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H-pyrazol-4- yl)pyridin-2-yl)urea, Example 7 (Compound 139)(Compound 140) (Comxpoupnd 139)Absolute stereochemistry unknown Scheme 4.

[0443] Synthesis of 1-(6-bromopyridin-2-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, 1-3 [Step-1]: To a stirred solution of 6-bromopyridin-2-amine (1-1 , 500 mg) in DCM (20 mL) were added Et3N (2.0 mL, 14.5 mmol) and a solution of Triphosgene (858 mg, 2.89 mmol) in DCM at -15 °C under argon atmosphere. After 15 min stirring, a solution of 8-chloro- 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine;hydrochloride (1-2, 639 mg) in DCM was added and the reaction mixture was allowed to stir for 40 min at same condition. After the completion, the reaction mixture was quenched by the addition of water and extracted with DCM. Combined organic layer were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 1-(6-bromo-2-pyridyl)-3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (1-3, 250 mg). LCMS (ESI) Calcd. for Ci4Hi2BrCIN4O2: 383.63, found [M+H]+: 385.1.

[0444] Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-(oxetan- 3-yl)-1 H-pyrazol-4-yl)pyridin-2-yl)urea, 4-5 [Step-2]: To a stirred solution of 1-(6-bromo-2- pyridyl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (4-3, 200 mg) in 1 ,4-Dioxane (5 mL) and Water (2 mL), were added K2CO3(144 mg, 1.04 mmol) and 1 -(oxetan-3-yl)-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole (4-4, 196 mg). The reaction mixture was degassed with argon for 10 minutes and Pd(dppf)CI2(38 mg, 0.05 mmol) was added to the reaction mixture and heated at 80°C for 16h. After complete consumption of SM, the reaction mixture was filtered through celite pad, washed with ethyl acetate. The filtrate was dissolved in ethyl acetate and diluted with water. Organic extract were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure which was purified by Reverse phase Prep HPLC to afford 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H-pyrazol-4- yl)pyridin-2-yl)urea (4-5, 80 mg). LCMS (ESI) Calcd. for C2oHi9CIN603: 426.86, found [M+H]+= 427.0.1H NMR (400 MHz, DMSO-cfe): 6H 9.41 (s, 1 H), 9.19 (s, 1 H), 8.10 (d, 2H), 7.76 (s, 1 H), 7.69 (t, 1 H), 7.57 (d, 1 H), 7.23 (d, 1 H), 7.05 (d, 1H), 5.47-5.44 (m, 1 H), 5.01 (d, 1 H), 4.94-4.85 (m, 4H), 4.49-4.45 (m, 1 H), 4.36-4.34 (m, 1 H), 2.49 (s, 1 H), 2.13 (d, 1 H).

[0445] Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1- (oxetan-3-yl)-1 H-pyrazol-4-yl)pyridin-2-yl)urea, Example 6 (Compound 140) and (S)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H-pyrazol-4- yl)pyridin-2-yl)urea, Example 7 (Compound 139) [Step 3]: The racemic compound 1-(8-chloro- 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)pyridin-2-yl)urea (4-5, 80 mg) was separated by SFC prep purification method and lyophilized to afford peak 1 as (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H-pyrazol-4- yl)pyridin-2-yl)urea (Example 6 (Compound 140), 38 mg) and peak 2 as (S)-1-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)pyridin-2-yl)urea (Example 7 (Compound 139), 40 mg).

[0446] SFC method: SFC PREP PURIFICATION of CR620-SM-2023-12-23-P (85 mg) is currently running on WATERS SFC -150 instrument equipped with waters 2489 UV / VIS detector by using C-Amylose A (30 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 100 ml / min, using 55% CO2 in super critical state & 45%[100% IPA] as Mobile phase, Run this isocratic mixture up to 15.0 minutes and also maintained the isobaric condition of 100 bar at 230 nm wavelength.

[0447] (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H- pyrazol-4-yl)pyridin-2-yl)urea, Example 6 (Compound 140) (Peak 1): LCMS (ESI) Calcd. for C2oHi9CIN603: 426.86, found [M+H]+: 427.1H NMR (400 MHz, DMSO-de) 6H: 9.41 (s, 1 H), 9.20 (s, 1 H), 8.10 (s, 2H), 7.75 (s, 1 H), 7.68 (t, 1 H), 7.56 (d, 1 H), 7.22 (d, 1 H), 7.05 (d, 1 H), 5.47 (t, 1 H), 5.01 (d, 1 H), 4.94-4.85 (m, 4H), 4.49-4.44 (m, 1 H), 4.34 (m, 1 H), 2.49 (s, 1 H), 2.14 (s, 1 H).

[0448] (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-(oxetan-3-yl)-1 H- pyrazol-4-yl)pyridin-2-yl)urea, Example 7 (Compound 139) (Peak 2): LCMS (ESI) Calcd. for C2oHi9CIN603: 426.86, found [M+H]+: 427.1H NMR (400 MHz, DMSO-d6) 6H: 9.41 (s, 1 H), 9.20 (s, 1 H), 8.10 (s, 2H), 7.75 (s, 1 H), 7.68 (t, 1 H), 7.56 (d, 1 H), 7.22 (d, 1 H), 7.05 (d, 1 H), 5.47 (t, 1 H), 5.01 (d, 1 H), 4.94-4.85 (m, 4H), 4.49-4.44 (m, 1 H), 4.34 (m, 1 H), 2.49 (s, 1 H), 2.14 (s, 1 H).Examples 8 & 9: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3- (6-cyanopyridin-2-yl)urea Example 8 (Compound 123) and (S)-6-(3-(8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)ureido)picolinamide, Example 9 (Compound 137):Scheme 5.

[0449] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (5-2)[Step 1]: To a stirred solution of (S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 500 mg, 1.94 mmol) in water (12.5 mL) was added aqueous solution ofpotassium cyanate (1.57 g, 19.4 mmol) dropwise at -5°C. Then the reaction mixture was stirred at ambient temperature for 48 h. The precipitate obtained was collected and dried under reduced pressure. The solid was azeotrope with toluene to afford (S)-1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea (5-2, 340 mg). LCMS (ESI) calcd. for C9H10CIN3O2 :227.05, found [M+H]+=228.1 ,1H NMR (400 MHz, DMSO-cfe): 6H8.08 (d, 1 H), 7.44 (d, 1 H), 6.51 (d, 1 H), 5.56 (s, 2H), 7.76-4.75 (m, 1 H), 4.42-4.38 (m, 1 H), 4.29-4.25 (m, 1 H), 2.25-2.20 (m, 1 H), 2.01-1.95 (m, 1 H).

[0450] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6- cyanopyridin-2-yl)urea (Example 8, Compound 123) [Step 2]: To a stirred solution of (S)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (5-2, 250 mg, 1.10 mmol) in 1 ,4-Dioxane (5 mL) were added 6-bromopicolinonitrile (5-3, 241 mg, 1.32 mmol) followed by cesium carbonate (895 mg, 2.75 mmol) in a sealed tube and degassed by argon balloon for 15 min. Then xanthpphos (127 mg, 0.220 mmol) and palladium acetate (25 mg, 0.1 10 mmol) were added and heated at 900C for 16 h. Reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure to afford crude product. The product was purified through flash column chromatography to afford (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(6-cyanopyridin-2-yl)urea (Example 8 (Compound 123), 110 mg). LCMS (ESI) calcd. For C15H12CIN5O2: 329.07, found [M+H]+= 330.2,1H NMR (400 MHz, DMSO-cfe): 6H9.65 (s, 1 H), 8.1 1 (d, 1 H), 8.04 (bs, 1 H), 7.93 (bs, 2H), 7.58(bs, 1 H), 7.49 (d, 1 H), 4.96 (bs, 1 H), 4.45-4.39 (m, 2H), 2.50-2.33 (m, 1 H), 2.07-1.99 (m, 1 H).

[0451] Synthesis of (S)-6-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)picolinamide (Example 9, Compound 137) [Step 3]: To a stirred solution of (S)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-cyanopyridin-2-yl)urea (80 mg, 0.243 mmol) in DMSO (2mL) was added K2CO3(17 mg, 0.121 mmol) at 0 °C, followed by the addition of H2O2 (30 %) (0.05 mL, 0.364 mmol) at the same temperature. The reaction mixture was stirred at ambient temperature for 12 h under nitrogen atmosphere. It was quenched with ice cold water, solid was collected and washed with water for several times. The collected solid was dried under reduced pressure, then azeotrope with toluene to afford (S)-6-(3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)ureido)picolinamide (Example 9, (Compound 137), 25 mg). LCMS (ESI) calcd. for Ci5Hi4CIN5O3: 347.08, found [M+H]+:348.2,1H NMR (400 MHz, DMSO-d6): 6H9.46 (s, 1 H), 8.52 (brs, 1 H), 8.1 1 (d, 1 H), 7.86-7.79 (m, 3H), 7.60-7.50 (m, 3H), 4.98 (s, 1 H), 4.44 (s, 2H), 2.70-2.61 (m, 1 H), 2.04-2.01 (m, 1 H).Example 10: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1- cyclobutyl-1 H-pyrazol-4-yl)pyridin-2-yl)urea, Example 10 (Compound 106):1'1Et3N, DCM, -6'3Dioxane, water, 90°C,3h Example 105°C-RT, 2h Step 2 (Compound 106)Step 1 Scheme 6.

[0452] Synthesis of (S)-1-(6-bromopyridin-2-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, 6-3 [Step-1]: To a stirred solution of 6-bromopyridin-2-amine (1-1 , 500 mg, 2.89 mmol) in DCM (20 mL) were added EtsN (2.0 ml_, 14.5 mmol) and a solution of Triphosgene (858 mg, 2.89 mmol) in DCM at -15 °C under argon atmosphere. After 15 min, a solution of (S)- 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrogen chloride (1-2, 639 mg, 2.89 mmol) in DCM was added and the reaction mixture was allowed to stir for 40 min at same condition. After the completion, the reaction mixture was quenched by the addition of water and extracted with DCM. Combined organic layer were dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography to obtain (S)-1-(6- bromopyridin-2-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (6-3, 250 mg). LCMS (ESI) Calcd for C ,.H- BrCIN,.O : 383.63, found [M+H]+: 385.0.

[0453] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1- cyclobutyl-1H-pyrazol-4-yl)pyridin-2-yl)urea, Example 10 (Compound 106) [Step-2]: To a stirred solution of 1-(6-bromo-2-pyridyl)-3-[rac-(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl]urea (6-3, 150 mg, 0.39 mmol) in 1 ,4-Dioxane (5mL) and Water (2mL), were added K2CO3 (162 mg, 1.17 mmol) and 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazole (6-4, 197 mg, 0.39 mmol). The reaction mixture was degassed with argon for 10 min and Pd(dppf)CI2(29 mg, 0.0391 mmol) was added and heated the reaction mixture at 90 °C for 16h. After complete consumption of SM, the reaction mixture was filtered through celite pad, washed with ethyl acetate. The filtrate was dissolved in ethyl acetate and diluted with water. Organic extract were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure which was purified by Reverse phase Prep HPLC to afford (S)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(1-cyclobutyl-1 H-pyrazol-4-yl)pyridin-2- yl)urea (Example 10 (Compound 106), 90 mg). LCMS (ESI) Calcd. for C21H21CIN6O2: 424.88, found [M+H]+= 425.0.1H NMR (400 MHz, DMSO-de): 6H 9.42 (s,1 H), 9.31 (s, 1 H), 8.1 1 (d, 1 H), 7.92(s, 1 H), 7.67 (t, 2H), 7.56 (d, 1 H), 7.20 (d, 1 H), 7.00 (d, 1 H), 5.03 (d, 1 H), 4.71 (t, 1 H), 4.48 (d, 1 H), 4.35 (t, 1 H), 2.45-2.35 (m, 5H), 2.33-2.32 (m, 1 H), 1.80-1.76 (m, 2H).Examples 11 & 12: Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(6-((R)-2,2,2-trifluoro-1 -hydroxyethyl)pyridin-2-yl)urea (Example 11 (Compound 67)) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyridin-2-yl)urea (Example 12 (Compound 66)):Scheme 7.

[0454] Synthesis of 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-ol, 2 [Step 1]: To a stirred solution of 6-bromopicolinaldehyde (7-1 , 200 mg, 1.1 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (0.2 mL, 1.3 mmol) at 0 °C, followed by tetrabutylammonium fluoride (1 M in THF) (1.3 m, 1.3 mmol) and stirred the reaction mixture at ambient temperature for 4 h. The reaction mixture was diluted with water, extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford product 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-ol (7-2, 170 mg). LCMS (ESI) Calcd. for C7H5BrF3NO: 254.95, found [M+H]+= 256.0.

[0455] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-(2,2,2- trifluoro-1-hydroxyethyl)pyridin-2-yl)urea, 7-4 [Step 2]: To a stirred solution of (S)-1-(8-chloro- 3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea (7-3, 227 mg, 1 mmol), 1-(6-bromopyridin-2-yl)-2.2.2-trifluoroethan-1-ol (7-2, 170 mg, 0.7 mmol) and Cs2CO3(540 mg, 1.7 mmol) in 1 ,4-dioxane (10 mL) was degassed with Ar for 10 min. To this reaction mixture were added xantphos (1 15 mg, 0.2 mmol) and Palladium(ll) acetate (30 mg, 0.1 mmol) and stirred the reaction mixture at 90 °C 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 combi flash chromatography to afford 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (7-4, 150 mg). LCMS (ESI) Calcd. for CI6HI4CIF3N4O3: 402.07, found [M+H]+= 403.2.

[0456] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-((R)-2.2.2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea, Example 11 (Compound 67) and 1-((S)-8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyridin-2-yl)urea, Example 12 (Compound 66) [Step 3]: 1-((S)-8-chloro-3,4- dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)-3-(6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (7-4, 140 mg, 0.3 mmol) were separated by chiral HPLC-SFC to afford peak 1 assigned as 1-((S)-8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (Example 11 (Compound 67), 54 mg) and peak 2 assigned as 1-((S)-8-chloro-3,4- dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)-3-(6-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl)urea (Example 12 (Compound 66), 30 mg). Absolute stereochemistry was not determined and arbitrarily assigned.

[0457] SFC method: Separation was performed on waters SFC-150 instrument equipped with waters 2489 UV / visible Detector by using I CELLULOSE Z (30.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 mL / min, using 70% CO2 in super critical state and 30% of 100% methanol as mobile phase, run this isocratic mixture for 10 min and maintained the isobaric condition of 100 bar at 228 nm wavelength.

[0458] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-((R)-2,2,2-trifluoro-1- hydroxyethyl)pyridin-2-yl)urea (Example 12 (Compound 66)) [Peak 1]: LCMS (ESI) Calcd. for C16H14CIF3N4O3: 402.07, found [M+H]+= 403.2.1H NMR (400 MHz, DMSO-A): 6H 9.51 (s, 1 H), 9.19 (bs, 1 H), 8.08 (d, 1 H), 7.76 (t, 1 H), 7.48 (d, 1 H), 7.24 (d, 1 H), 7.13 (d, 1 H), 6.94-6.93 (m, 1 H), 4.98-4.97 (m, 1 H), 4.93-4.88 (m, 1 H), 4.45-4.42 (m, 1 H), 4.35-4.32 (m, 1 H), 2.45-2.41 (m, 1 H), 2.07-2.05 (m, 1 H).

[0459] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(6-((S)-2,2,2-trifluoro-1- hydroxyethyl)pyridin-2-yl)urea (Example 11 (Compound 67)) [Peak 2]: LCMS (ESI) Calcd. for C16H14CIF3N4O3: 402.07, found [M+H]+= 403.1.1H NMR (400 MHz, DMSO-d6): 6H9.49 (s, 1 H), 8.94 (bs, 1 H), 8.05 (d, 1 H), 7.76 (t, 1 H), 7.47 (d, 1 H), 7.29 (d, 1 H), 7.13 (d, 1 H), 6.87 (s, 1 H), 5.00- 4.99 (m, 1 H), 4.93-4.91 (m, 1 H), 4.46-4.44 (m, 1 H), 4.35-4.34 (m, 1 H), 2.46-2.41 (m, 1 H), 2.08- 2.07 (m, 1 H).Example 13: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(4-(4- cyanophenyl)oxazol-2-yl)urea, Example 13 (Compound 125):Step 3 Example 13 (Compound 125)Scheme 8.

[0460] Synthesis of 4-(2-aminooxazol-4-yl)benzonitrile, 3 [Step 1]: To a stirred solution of 4- (2-bromoacetyl)benzonitrile (8-1 , 500 mg, 2.2 mmol) in MeCN (10 mL) was added urea (8-2, 1.3 g, 22.3 mmol) and stirred at 85 °C for 16 h. The reaction mixture was cooled to ambient temperature. Volatiles were removed under reduced pressure and diluted with water andextracted with ethyl acetate. 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 4-(2-aminooxazol-4-yl)benzonitrile (8-3, 330 mg).1H NMR consistent with desired product. (400 MHz, DMSO-cfe): 5H8.11 (s, 1H), 7.83-7.78 (m, 4H), 6.88 (s, 2H).

[0461] Synthesis of phenyl (4-(4-cyanophenyl)oxazol-2-yl)carbamate, 8-5 [Step 2]: To a stirred solution of 4-(2-aminooxazol-4-yl)benzonitrile (3, 50 mg, 0.3 mmol) in DCE (5 mL) was added triethylamine (0.1 mL, 0.5 mmol) at 0 °C and stirred for 10 min. After 10 min, phenyl carbonochloridate (8-4, 0.04 mL, 0.3 mmol) was added to the reaction mixture and stirred at 50 °C for 2 h. Volatiles were removed under reduced pressure to afford product which was purified by combi flash chromatography to afford phenyl (4-(4-cyanophenyl)oxazol-2-yl)carbamate (5, 70 mg). LCMS (ESI) Calcd. for C17H11N3O3: 305.08, found [M-H] = 304.06.

[0462] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(4-(4- cyanophenyl)oxazol-2-yl)urea, Example 13 (Compound 125) [Step 3]: To a stirred solution of (S)-8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 60 mg, 0.2 mmol) in MeCN (5 mL) was added / V, / V-diisopropylethylamine (0.1 mL, 0.7 mmol) at 0 °C. After 10 min, phenyl (4-(4-cyanophenyl)oxazol-2-yl)carbamate (8-5, 71 mg, 0.2 mmol) was added to the reaction mixture and stirred at 80 °C for 2 h. Volatiles were removed under reduced pressure to afford product which was purified by preparative HPLC, lyophilized to afford (S)-1-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(4-(4-cyanophenyl)oxazol-2-yl)urea (Example 13 (Compound 125), 66 mg). LCMS (ESI) Calcd. for C19H14CIN5O3: 395.08, found [M+H]+= 396.1. 1H NMR (400 MHz, DMSO-d6): 6H10.88 (s, 1H), 9.22 (d, 1H), 8.49 (s, 1 H), 8.20 (d, 1 H), 7.91 (t, 4H), 7.52 (d, 1 H), 5.01-4.96 (m, 1 H), 4.55-4.42 (m, 2H), 2.71-2.66 (m, 1 H), 2.12-1.98 (m, 1 H).Examples 14 & 15: Synthesis of (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)ureido)-1 H-pyrazol-1-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide, Example 14 (Compound 172) and (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1 H-pyrazol-1-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide, Example 15 (Compound 171):Scheme 9.

[0463] Synthesis of methyl 4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1 H-pyrazol-1-yl) benzoate, 9-3 [Step 1]: To a stirred solution of methyl 4-(3-amino- 1 H-pyrazol-1-yl) benzoate (9-2, 169 mg, 0.78 mmol) in dichloromethane (20 mL) were added triethylamine (0.63 mL, 4.54 mmol) and followed by triphosgene (230 mg, 0.78 mmol) at ice cold condition and stirred for 40 min. Finally a solution of 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-amine hydrochloride (1-2, 200 mg, 0.78 mmol) and triethylamine (0.9 mL, 6.2 mmol) in DCM (8 mL) was added at 0° C and the reaction mixture was allowed to stir for 2 h at ambient temperature. After completion, the reaction mixture was quenched with brine solution and extracted with DCM (2 x 30 mL). Combined organic layer were separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford methyl 4-(3-(3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)benzoate (9-3, 330 mg). LCMS (ESI) Calcd. for C20H18CIN5O4: 327.1 , found [M+H]+: 327.9

[0464] Synthesis of 4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1H- pyrazol-1-yl)benzoic acid, 9-4 [Step 2]: To a stirred solution of methyl 4-(3-(3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)benzoate (9-3, 330 mg, 0.8 mmol) in tetrahydrofuran (10 mL) methanol (5 mL) and water (2.5 mL), was added LiOH.H2O (49 mg, 1.2 mmol) at ice cold condition. The reaction mixture was allowed to stir for 2h at ambient temperature. After completion, volatiles were evaporated under reduced pressure. The residue was neutralized with 1 N HCI and lyophilized to afford 4-(3-(3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)benzoic acid (9-4, 315 mg). LCMS (ESI) Calcd. for C1SH16CIN5O4: 413.09, found [M+H]+= 413.9.

[0465] Synthesis of 4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1H- pyrazol-1 -yl)-N-((3-methyloxetan-3-yl)methyl)benzamide, 9-6 [Step 3]: To a stirred solution of 4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)benzoic acid (9-4, 400 mg, 0.97 mmol) in DMF (10 mL) were added (3-methyloxetan-3-yl)methanamine (9-5, 0.1 1 mL, 1.1 mmol) and N,N-Diisopropylethylamine (0.43 mL, 2.42 mmol). Finally, HATU (441 mg, 1.16 mmol) was added to the reaction mixture and allowed to stir for 2h at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with ice cold water (3 times). The organic layer was separated, dried over anhydrous Na2SC>4 and concentrated under reduce pressure to afford the product. The product was purified by reverse phase prep HPLC and the residue was lyophilized to afford 4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide (9-6, 150 mg). LCMS (ESI) calculated for C24H25CIN6O4: 496.2, found [M+H]+:497.2.Example 16: Synthesis of (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1H-pyrazol-1-yl)-2-fluoro-N-methylbenzamide, Example 16 (Compound 128):Scheme 10.

[0466] Synthesis of 2-fluoro-N-methyl-4-(3-nitro-1H-pyrazol-1-yl)benzamide, 10-3 [Step 1]: To a stirred solution of 3-nitro-1 H-pyrazole (10-1 , 100 mg, .9 mmol) and 4-bromo-2-fluoro- / \ / - methylbenzamide (10-2, 267 mg, 1.2 mmol) in Acetonitrile (10 mL) was added oven dry K2CO3(305 mg, 2.2 mmol) at ambient temperature and the reaction mixture was degassed with argon for 10 min followed by the addition of trans / V, / V-dimethyl cyclohexanedimine (0.14 mL, 0.9 mmol) and Cui (84 mg, 0.4 mmol). The reaction mixture was heated in a sealed tube at 90° 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 combi flash chromatography to afford 2-fluoro-A / -methyl-4-(3-nitro-1 / 7-pyrazol-1-yl)benzamide (10-3, 150 mg). LCMS (ESI) Calcd. for C11H9FN4O3: 264.1 , found [M+H]+: 265.2;1H NMR (400 MHz, DMSO-d6) 6H: 8.88 (d, 1 H), 8.37 (brs, 1 H), 7.97-7.94 (m, 1 H), 7.89-7.82 (m, 2H), 7.41 (d, 1 H), 2.81-2.79 (m, 3H). NOE data confirmed the formation of desired compound 10-3.

[0467] Synthesis of 4-(3-amino-1H-pyrazol-1-yl)-2-fluoro-W-methylbenzamide, 10-4 [Step 2]: 2-fluoro- / V-methyl-4-(3-nitro-1 / - / -pyrazol-1-yl)benzamide (10-3, 135 mg, 0.5 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (2 mL). Pd / C (10% on activated Carbon, 50% wet, 50 mg) was added and the reaction mixture was hydrogenated under balloon pressure for 1 h. The reaction mixture was filtered over Celite and washed with excess ethyl acetate. Volatiles were removed under reduced pressure to afford 4-(3-amino-1H-pyrazol-1-yl)-2-fluoro- / V- methylbenzamide (10-4, 120 mg) LCMS (ESI) Calcd. forCnHnFN40: 234.1 , found [M+H]+: 235.1.

[0468] Synthesis of (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)- 1H-pyrazol-1-yl)-2-fluoro-W-methylbenzamide, Example 16 (Compound 128), [Step 3]: To a stirred solution of 4-(3-amino-1 / - / -pyrazol-1-yl)-2-fluoro- / V-methylbenzamide (10-4, 100 mg, 0.4 mmol) in dichloromethane (10 mL) was added triethyl amine (0.24 mL, 1.7 mmol) and Triphosgene (127 mg, 0.43 mmol) at -150C and stirred for 30 minutes. A solution of (S)-8-chloro- 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 94 mg, 0.43 mmol) and triethyl amine (0.36 mL, 2.6 mmol) in dichloromethane (5 mL) was added at same condition and allowed to stir for 1 h at ambient temperature. The reaction mixture was diluted with dichloromethane and washed with water followed by brine solution. Organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by prep HPLC and lyophilized to afford (S)-4-(3-(3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)ureido)-1 / - / - pyrazol-1-yl)-2-fluoro- / V-methylbenzamide (Example 16 (Compound 128), 100 mg), LCMS(ESI): calculated for C2OHI8CIFN603: 444.1 , found [M+H]+: 445.2. 1 H NMR (400 MHz, DMSO-d6) 6H: 9.32 (s, 1H), 8.50-8.49 (m, 1H), 8.19-8.14 (m, 2H), 7.74-7.65 (m, 4H), 7.52-7.51 (m, 1H), 6.48 (s, 1 H), 4.93-4.92 (m, 1 H), 4.45-4.41 (m, 2H), 2.79-2.78 (m, 3H), 2.52-2.51 (m, 1 H), 2.07-2.04 (m, 1H).Examples 17 & 18: Synthesis of (S)-1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 17 (Compound 117) and (R)-1-(1-(4- cyanophenyl)-1H-pyrazol-3-yl)-3-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 18 (Compound 116):Scheme 11.

[0469] Synthesis of 1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, 11-3 [Step 1]: To a stirred solution of 4-(3-amino-1 / - / -pyrazol-1- yl)benzonitrile (11-1 , 129 mg, 0.7 mmol) in dichloromethane (10 mL) was added triethyl amine (0.6 mL, 4.2 mmol) and Triphosgene (207 mg, 0.7 mmol) at -5 ° C and stirred for 30 minutes. A solution of 3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-amine (11-2, 105 mg, 0.7 mmol) in dichloromethane (4 mL) was added at same condition and allowed to stir for 1 h at ambient temperature. The reaction mixture was diluted with dichloromethane and washed with water followed by brine solution. Organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by prep HPLC and lyophilized to afford 1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea (11-3, 100 mg). LCMS (ESI) Calcd. for Ci9Hi6N6O2: 360.1, found [M+H]+: 361.2

[0470] Synthesis of (S)-1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea, Example 17 (Compound 117) & (R)-1-(1-(4-cyanophenyl)- 1H-pyrazol-3-yl)-3-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 18 (Compound 116) [Step 2]: 1-(1-(4-cyanophenyl)-1 / - / -pyrazol-3-yl)-3-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)urea (3, 100 mg) was separated by SFC and lyophilized to afford peak 1 arbitrarily assigned as (S)-1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (4, 40 mg) and peak 2 arbitrarily assigned as (R)-1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (5, 33 mg). Absolute stereochemistry unkbown.

[0471] SFC method: SFC PREP PURIFICATION was done on Waters SFC 80 instrument equipped with Waters 2489 UV / Visible Detector by using I CELLULOSE J (30 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 ml / min, using 50% CO2 in super critical state & 50% of [100% MeOH ] as Mobile phase, Run this isocratic mixture up to 25.0 minutes and also maintained the isobaric condition of 100 bar at 220 nm wavelength

[0472] (S)-1-(1-(4-cyanophenyl)-1 H-pyrazol-3-yl)-3-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)urea, Example 17 (Compound 117) (Peak 1): LCMS (ESI) Calcd. for C- .HAA: 360.1 , found [M+H]+: 361.2. 1 H NMR (400 MHz, DMSO-d6) 6H: 9.32 (s, 1 H), 8.55-8.54 (m, 1 H), 8.23-8.22 (m, 1 H), 7.93 (s, 4H), 7.71 (brs, 1 H), 7.32-7.25 (m, 2H), 6.53 (s, 1 H), 4.88-4.84 (m, 1 H), 4.35-4.23 (m, 2H), 2.51-2.50 (m, 1 H), 2.03-1.94 (m, 1 H).

[0473] (R)-1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)urea, Example 18 (Compound 116) (Peak 2): LCMS (ESI) Calcd. for C-isHieNaCA 360.1 , found [M+H]+: 361 .2, 1 HNMR (400 MHz, DMSO-d6) 6H: 9.31 (s, 1 H), 8.55-8.54 (m, 1 H), 8.23-8.22 (m, 1 H), 7.93 (s, 4H), 7.71 (brs, 1 H), 7.32-7.25 (m, 2H), 6.53 (s, 1 H), 4.88-4.84 (m, 1 H), 4.33-4.24 (m, 2H), 2.51-2.50 (m, 1 H), 2.00-1.98 (m, 1 H).Examples 19 & 20: Synthesis of (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)ureido)-1 H-pyrazol-1-yl)benzamide, Example 19 (Compound 151) and (S)-4-(3-(3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1H-pyrazol-1-yl)benzamide, Example 20 (Compound 150):Scheme 12.

[0474] Synthesis of methyl 4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1 H-pyrazol-1-yl) benzoate (12-3) [Step 1]: To a stirred solution of methyl 4-(3-amino- 1 H-pyrazol-1-yl) benzoate (12-2, 843 mg, 3.88 mmol) in dichloromethane (20 mL) was allowed to cool at -5°C. Triethyl amine (4.3 mL, 31.1 mmol) was added to the reaction mixture, followed by addition of triphosgene (1.15 g, 3.88 mmol). The reaction was allowed to stir for 30 mins at -5°C. Then 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 1.00 g, 3.88 mmol) was slowly added to the solution and allowed to stir for 2 h. Upon completion, the reaction was quenched by ice cold water and extracted with 10%MeOH / DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by combi-flash chromatography followed by reverse phase preparative HPLC to afford methyl 4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1 H-pyrazol-1-yl)benzoate (12-3, 130 mg). LCMS (ESI) calcd. for C20H18CIN5O4: 427.1 , found [M+H]+: 428.2,1H NMR (400 MHz, DMSO-cfe): 0H9.31 ( s, 1 H), 8.51 (s, 1 H), 8.14 (d, 1 H),8.04-8.01 (m, 2H), 7.88-7.86(m, 2H), 7.61-7.51 (m, 2H), 6.53 (s, 1 H), 4.93 (brs, 1 H), 4.45-4.40 (m, 2H), 3.86 (s, 3H), 2.25-2.08 (m, 2H).

[0475] Synthesis of methyl (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1 H-pyrazol-1-yl) benzoate (4) and methyl (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl (benzoate (12-5) [Step 2]: The racemic methyl 4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1- yl)benzoate (12-3, 105 mg, 0.245 mmol) was purified by SFC Prep HPLC (Method 1) to afford first fraction methyl (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H- pyrazol-1-yl)benzoate (12-4, 25 mg) as Peak 1 and the second fraction methyl (S)-4-(3-(3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)benzoate (12-5, 35 mg) as Peak 2.

[0476] Note: Peak 1 & Peak 2 are arbitrarily assigned.

[0477] Method 1 : SFC PREP Purification of CR620-GH-2023-02-18-P-New (105 mg) sample was done in waters SFC Prep-80 instrument equipped with waters 2489 UV / visible Detector by using CHIRALPAK IB (21 mm x 250mm), 5p operating at 35 °C temperature, maintaining flow rate of 60 ml / min, using 60 % CO2 in super critical state and 40% of 100% methanol as mobile phase, Run this isocratic mixture was run up to 9 minutes and also maintained the isobaric condition of 100 bar at 220 nm wavelength.

[0478] Methyl (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1H- pyrazol-1-yl)benzoate (12-4) [Peak 1]: LCMS (ESI) calcd. for C20HI8CIN5O4: 427.10, found [M+H]+: 428.2.

[0479] Methyl (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1H- pyrazol-1-yl)benzoate (12-5) [Peak 2]: LCMS (ESI) calcd. for C20H18CIN5O4: 427.10, found [M+H]+: 428.0.

[0480] Synthesis of (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)- 1H-pyrazol-1-yl)benzoic acid (12-6) [Step 3]: To a solution of methyl (R)-4-(3-(3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)benzoate (12-4, 25 mg, 0.0584 mmol) in Methanol (1 mL), THF (1 mL) and Water (0.5 mL), was added LiOH.H2O (7.4 mg, 0.175 mmol) and stirred at ambient temperature for 4 h. Reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ether to remove other organic impurities. Then aqueous layer was separated and acidified with 1 M HCI, solid was collected and dried under reduced pressure. The collected solid was azeotropped with toluene for several times and dried under reduced pressure to afford (F?)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1 H-pyrazol-1-yl)benzoic acid (12-6, 25 mg) which was directly used in the next step. LCMS (ESI) calcd. for C19H16CIN5O4 :413.09, found [M+H]+= 414.2.

[0481] Synthesis of (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)- 1H-pyrazol-1-yl)benzamide (Example 19) [Step 4]: To a stirred solution of (R)-4-(3-(3-(8-chloro-3.4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1 -yl)benzoic acid (12-6, 25 mg, 0.0604 mmol) in DMF (1 mL) were added DI PEA (0.032 ml_, 0.181 mmol) and Ammonium carbonate (58 mg, 0.604 mmol) followed by HATU (46 mg, 0.121 mmol) at 0°C and stirred for 16 h at ambient temperature. Reaction mixture was purified by reverse phase prep HPLC to afford (R)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1 - yl)benzamide (Example 19, 15 mg). LCMS(ESI) calcd for C19H17CIN6O3: 412.1 1 found [M+H]+: 413.2,1H NMR (400 MHz, DMSO-cfe): 6H9.28 ( s, 1 H), 8.47 (s, 1 H), 8.16 (d, 1 H), 7.98-7.94 (m, 3H), 7.82-7.80(m, 2H), 7.72 (brs, 1 H), 7.52 (d, 1 H), 7.37(s, 1 H), 6.46 (s, 1 H), 4.94-4.92 (m, 1 H), 4.48-4.40 (m, 2H), 2.54-2.50 (m, 1 H), 2.07-2.05 (m, 1 H).

[0482] Note: The absolute stereochemistry is unknown.

[0483] Synthesis of (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)- 1 H-pyrazol-1 -yl)benzoic acid (12-7) [Step 5]: To a solution of methyl (S)-4-(3-(3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)benzoate (12-5, 35 mg, 0.0818 mmol) in methanol (1 mL), THF (1 mL) and Water (0.5 mL), was added LiOH.H2O (10 mg, 0.245 mmol) and stirred at ambient temperature for 4 h. Reaction mixture was concentrated under reduce pressure, diluted with water and extracted with ether to remove organic impurities. Then aqueous layer was separated and acidified with 1 M HCI, solid was collected and dried under reduced pressure. The collected solid was azeotropped with toluene for several times and dried under reduced pressure to afford (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1 H-pyrazol-1-yl)benzoic acid (12-7, 30 mg) which was directly used in next step. LCMS (ESI) calcd. for C19H16CIN5O4 :413.09, found [M+H]+=414.2.

[0484] Synthesis of (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)- 1 H-pyrazol-1 -yl)benzamide (Example 20) [Step 6]: To a stirred solution of (S)-4-(3-(3-(8-chloro-3.4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1 H-pyrazol-1-yl)benzoic acid (12-7, 30 mg, 0.0725 mmol) in DMF (1 mL) were added DI PEA (0.04 mL, 0.217 mmol) and ammonium carbonate (70 mg, 0.725 mmol) followed by HATU (55 mg, 0.145 mmol) at 0°C and stirred for 16 h at ambient temperature. Reaction mixture was filtered through filter cartridge and purified by reverse phase prep HPLC to afford (S)-4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1 H-pyrazol-1-yl)benzamide (Example 20, 14 mg). LCMS(ESI) calcd for C19H17CIN.3O3 : 412.11 found [M+H]+: 413.2,1H NMR (400 MHz, DMSO-d6): 6H9.28 ( s, 1H), 8.47 (d, 1 H), 8.16 (d, 1 H), 7.98-7.94 (m, 3H), 7.82-7.80(m, 2H), 7.72 (brs, 1 H), 7.52 (d, 1 H), 7.37(s, 1 H), 6.46 (d, 1 H), 4.94-4.92 (m, 1 H), 4.46-4.39 (m, 2H), 2.54-2.50 (m, 1 H), 2.07-2.05 (m, 1 H).Note: - The absolute stereochemistry is unknown.Example 21 : Synthesis of 4-[3-[[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl]carbamoylamino]pyrazol-1-yl]-N-(2-hydroxyethyl)benzamide, Example 21 (Compound 138):Scheme 13.

[0485] Synthesis of methyl 4-[3-[[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl]carbamoylamino]pyrazol-1-yl]benzoate (12-3) [Step 1]: To a stirred solution of methyl 4-(3- aminopyrazol-1-yl)benzoate (12-2, 197 mg, 0.905 mmol) in DCM (10 mL) were added EtaN ( 0.50 ml_, 3.62 mmol) followed by Triphosgene (268 mg, 0.905 mmol) at -5°C, stirred for 30 min at - 5°C. (4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 200 mg, 0.905 mmol) was added to the solution and allowed to stir at the same temperature for 2 h. Reaction mixture was quenched by ice cold water and extracted with 10%MeOH / DCM. Organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The product was purified with combi-flash chromatography to afford methyl 4-[3-[[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl]carbamoylamino]pyrazol-1-yl]benzoate (12-3, 130 mg). LCMS (ESI) Calcd. for C20H18CIN5O4: 427.13, found [M+H]+= 428.20.

[0486] Synthesis of 4-[3-[[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl]carbamoylamino]pyrazol-1-yl]benzoic acid (13-4) [Step 2]: To a stirred solution of methyl 4- [3-[[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]carbamoylamino]pyrazol-1- yl]benzoate (12-3, 200 mg, 0.467 mmol) in THF (3 mL), Methanol (2 mL) and Water (1 mL) was added LiOH.H2O (49 mg, 1.17 mmol) at ambient temperature, stirred at the same temperature for 6 h. Solvent was evaporated, diluted with water, acidified with 6N aqueous HCI, filtered solid, dried to afford crude which was purified by reverse phase preparative HPLC to afford 4-[3-[[(4S)- 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]carbamoylamino]pyrazol-1-yl]benzoic acid (13- 4, 175 mg). LCMS (ESI): calcd for CI9HI6CIN5O4: 413.09, found [M+H]+: 414.18

[0487] Synthesis of 4-[3-[[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl]carbamoylamino]pyrazol-1-yl]-N-(2-hydroxyethyl)benzamide (Example 21 (Compound 138) [Step 2]: To a stirred solution of 4-[3-[[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl]carbamoylamino]pyrazol-1-yl]benzoic acid (13-4, 100 mg, 0.242 mmol) in DMF (3 mL) were added DIPEA (0.13 mL, 0.725 mmol), HATU (184 mg, 0.483 mmol), stirred at the ambient temperature for 10 minutes, Then Ethanolamine (30 mg, 0.483 mmol) was added at the ambient temperature and stirred at the ambient temperature for 16 h. Solvent was evaporated to obtain crude. The product was purified by reverse phase preparative HPLC to afford 4-[3-[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]carbamoylamino]pyrazol-1-yl]-N-(2- hydroxyethyl)benzamide (5, 40 mg). LCMS (ESI) calcd. for C21H21CIN6O4: 456.13, found [M+H]+: 457.2, HPLC :Rt(min)= 9.531 (99.64 %).1H NMR (400 MHz, DMSO-d6): 6H 9.26 (s, 1 H), 8.47- 8.43 (m, 2H), 8.15 (d, 1 H), 7.95-7.93 (m, 2H), 7.82-7.80 (m, 2H), 7.67 (bs, 1 H), 7.52 (d, 1 H), 6.47 (s, 1 H), 4.95-4.91 (m, 1 H), 4.74 (t, 1 H), 4.48-4.37 (m, 2H), 3.54-3.49 (m, 2H), 3.35-3.32 (m, 2H), 2.53-2.51 (m, 1 H), 2.09-2.03 (m, 1 H) [Single enantiomer with known absolute configuration]. Examples 22-24: Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3- (1-(4-((S)-1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-1H-pyrazol-3-yl)urea, Example 22 (Compound 104), 1 -((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((R)- 1,1 ,1 -trifl uoro-2-hydroxyp ropan -2-yl (phenyl )-1H-pyrazol-3-yl)urea, Example 23 (Compound 103), and (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-(2- hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea, Example 24 (Compound 102):Scheme 14,

[0488] Synthesis of 2-(4-bromophenyl)-1 ,1 ,1-trifluoropropan-2-ol, 14-2 [Step 1]: To a stirred solution of 1-(4-bromophenyl)-2,2,2-trifluoro-ethanone (14-1 , 500 mg, 2.0 mmol) in THF (5 ml_), methyl magnesium bromide (3 M in THF) (353 mg, 3.0 mmol) was added dropwise at 10°C, allowed to stir at an ambient temperature for 3 h. Reaction mixture was quenched by ammonium chloride solution and extracted with ethyl acetate. Organic extract was washed with brine solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude product. The product was purified by combi-flash column to afford 2-(4-bromophenyl)-1 ,1,1- trifluoro-propan-2-ol (14-2, 300 mg). 1 H NMR (400 MHz, DMSO-d6): 5H7.61-7.59(m, 2H), 7.54- 7.52 (m, 2H), 6.70 (s, 1 H), 1.67 (s, 3H).

[0489] Synthesis of 1,1 ,1-trifluoro-2-(4-(3-nitro-1 H-pyrazol-1-yl)phenyl)propan-2-ol, 14-4 [Step-2]: To a solution of 2-(4-bromophenyl)-1 ,1 ,1-trifluoro-propan-2-ol (14-2, 1.08 g, 4.0 mmol) and 3-nitro-1 H-pyrazole (10-1 , 350 mg, 3.1 mmol) in acetonitrile (20 mL) was added anhydrous K2CO3 (1068 mg, 7.7 mmol) at ambient temperature and the reaction mixture was degassed with argon for 10 min followed by the addition of trans-N, / V-dimethyl cyclohexanedimine (440 mg, 3.1 mmol) and Cul (295 mg, 1 .5 mmol). The reaction mixture was heated in a sealed tube at 90°C for 16 h. Reaction mixture was cooled to an ambient temperature, filtered through celite bed and thefiltrate was concentrated under reduced pressure to get crude product. The product was purified by combi-flash column chromatography to afford 1 , 1 , 1-trifluoro-2-[4-(3-nitropyrazol-1 - yl)phenyl]propan-2-ol (14-4, 900 mg). 1 H NMR (400 MHz, DMSO-d6): 5« 8.81 (d, 1 H), 7.96 (d, 2H), 7.79 (d, 2H), 7.36 (d, 1 H), 6.77 (d, 1 H), 1.73 (s, 3H).

[0490] Synthesis of 2-(4-(3-amino-1H-pyrazol-1-yl)phenyl)-1 ,1 ,1-trifluoropropan-2-ol, 14-5 [Step 3]: To a stirred solution of 1 ,1 ,1-trifluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]propan-2-ol (14-4, 900 mg, 3.0 mmol) in ethanol (10 mL) and water (2 mL), ammonium chloride (1279 mg, 23.9 mmol) and Fe powder (667 mg, 12.0 mmol) were added. The resulting mixture was allowed to reflux at 80°C for 1 h. Reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to remove excess ethanol. The residue was diluted with ethyl acetate and washed with brine. Organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude. The product was purified by combi-flash chromatography to afford 2-[4-(3-aminopyrazol-1-yl)phenyl]-1.1 .1-trifluoro-propan-2-ol (14-5, 150 mg). LCMS (ESI) Calcd. for C12H12F3N3O: 271.09, found [M+H]+= 271.8.1H NMR (400 MHz, DMSO-cfe): 6H8.14 (d, 1 H), 7.64 (d, 1H), 7.57 (d, 1 H), 6.57 (s, 1 H), 5.76-5.74 (m, 1 H), 5.10 (s, 2H). Note: Structure was confirmed by NOE.

[0491] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-(1,1,1- trifluoro-2-hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea, 7 [Step 4]: To a stirred solution of 2-[4-(3-aminopyrazol-1-yl)phenyl]-1 ,1 ,1-trifluoro-propan-2-ol (14-5, 100 mg, 0.4 mmol) in dichloromethane (1 mL) was allowed to cool at -5°C. A solution of triphosgene (44 mg, 0.1 mmol) in dichloromethane (0.5 mL) was added to the solution dropwise. The reaction was allowed to stir for 5 min at the same temperature. Triethylamine (0.31 mL, 2.21 mmol) and a solution of (4S)- 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 163 mg, 0.7 mmol) in dichloromethane (0.5 mL) was added to the solution. The reaction was allowed to stir at -5°C for 3 h. Reaction was diluted with dichloromethane and washed with water. Organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude. The product was purified by reverse phase preparative HPLC to afford 1-[(4S)-8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl]-3-[1-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl- ethyl)phenyl]pyrazol-3-yl]urea (14-7, 1 10 mg). LCMS (ESI) calcd. for C2iHi9CIF3N5O3: 481.1 , found [M+H]+= 482.2.

[0492] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((S)-1.1.1-trifluoro-2-hydroxypropan-2-yl)phenyl)-1H-pyrazol-3-yl)urea, 8a and 1-((S)-8-chloro- 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((R)-1 ,1,1-trifluoro-2-hydroxypropan-2- yl)phenyl)-1H-pyrazol-3-yl)urea, 8 [Step 6]: The racemic compound 1-((S)-8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)-3-(1 -(4-(1 ,1 ,1 -trifluoro-2-hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3- yl)urea (7, 99 mg, 0.2 mmol) was purified by SFC prep HPLC (Method 1) to obtain the first fraction 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((S)-1,1 ,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea (Example 22 (Compound 104), 39 mg) as Peak 1 and the second fraction 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3- (1-(4-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)-1H-pyrazol-3-yl)urea (Example 23 (Compound 103), 40 mg) as Peak 2. Note: Absolute stereochemistry of both isomers are unknown. The stereochemistry of the isomers is arbitrarily assigned.

[0493] SFC prep method (Method 1): SFC prep purification has been done in Waters PREP SFC150 instrument equipped with Waters 2489 UVA / isible Detector by using CHIRALPAK-IG (30 mm x 250mm), 5p operating at 35°C temperature, maintaining flow rate of 100 ml / min, using 55 % CO2 in super critical state & 45% of 100% methanol as mobile phase, this isocratic mixture was run up to 15.0 minutes and also maintaining the isobaric condition of 100 bar at 220 nm wavelength.

[0494] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((S)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)phenyl)-1H-pyrazol-3-yl)urea, Example 22 (Compound 104) [Peak 1]: LCMS (ESI): calcd. for C21H19CIF3N5O3: 481 .11 , found [M+H]+=482.2 .1H NMR (400 MHz, DMSO- cfe) 5H : 9.23 (s, 1H), 8.37 (d, 1 H), 8.13 (d, 1 H), 7.23 (d, 2H), 7.63 (d, 2H), 7.50 (d, 2H), 6.63 (brs, 1H), 6.44 (s, 1 H), 4.93(d, 1H), 4.47-4.43 (m, 1 H), 4.40-4.37 (m, 1H), 2.51-2.50 (m, 1 H), 2.07-2.05 (m, 1 H), 1.70 (s, 3H). The absolute stereochemistry was not determined.

[0495] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((R)-1,1 ,1-trifluoro- 2-hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea, Example 23 (Compound 103) [Peak 2]: LCMS (ESI): calcd. for C2IHI9CIF3N5O3: 481.11 , found [M+H]+=482.2.1H NMR (400 MHz, DMSO-cfe) 6H : 9.24 (s, 1 H), 8.37 (d, 1 H), 8.13 (d, 1 H), 7.23 (d, 2H), 7.63 (d, 2H), 7.50 (d, 2H), 6.64 (brs, 1H), 6.46 (s, 1H),4.93 (d, 1 H), 4.48-4.43 (m, 1H), 4.38-4.39 (m, 1H), 2.51-2.50 (m, 1 H), 2.08-2.05 (m, 1H), 1 .70 (s, 3H). The absolute stereochemistry was not determined.

[0496] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-(2- hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea, Example 24 (Compound 102):Scheme 15.

[0497] Synthesis of 2-(4-bromophenyl)propan-2-ol, 15-2 [Step 1]: To a stirred solution of 1-(4- bromophenyl)ethanone (15-1, 1.5 g, 7.5 mmol) in THF (15 mL), methyl magnesium bromide (3M in THF) (1.35 g, 11.1 mmol) was added dropwise at 10°C. After completion of addition, thereaction mixture was allowed to stir at an ambient temperature for 3 h. Reaction mixture was quenched by ammonium chloride solution and extracted with ethyl acetate. Organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude. The product was purified by combi-flash column to afford 2-(4-bromophenyl)propan-2-ol (15-2, 510 mg).1H NMR (400 MHz, DMSO-d6): 5H7.48-7.40 (m, 4H), 5.09 (s, 1 H),1 .40 (s, 6H).

[0498] Synthesis of 2-(4-(3-nitro-1 H-pyrazol-1-yl)phenyl)propan-2-ol, 4 [Step 2]: To a stirred solution of 2-(4-bromophenyl)propan-2-ol (15-2, 502 mg, 2.3 mmol) and 3-nitro-1 H-pyrazole (10- 1 , 203 mg, 1.8 mmol) in acetonitrile (6 ml_), K2CO3 (619 mg, 4.5 mmol) was added at ambient temperature and the reaction mixture was degassed with argon for 10 min followed by the addition of trans N,N-dimethyl cyclohexanedimine (255 mg, 1.80 mmol) and Cui (171 mg, 0.9 mmol). The reaction mixture was heated in a sealed tube at 90°C for 16 h. Reaction mixture was cooled to an ambient temperature, filtered through celite bed and the filtrate was concentrated under reduced pressure to get crude. The product was purified by combi-flash chromatography to afford 2-[4-(3- nitropyrazol-1-yl)phenyl]propan-2-ol (15-4, 330 mg).1H NMR (400 MHz, DMSO-cfe): <5H8.76 (d, 1 H),7.84 (d, 2H), 7.66 (d, 2H), 7.34 (d, 1 H), 5.18 (s, 1 H), 1.46 (s, 6H). Note: Structure was confirmed by NOE.

[0499] Synthesis of 2-(4-(3-amino-1 H-pyrazol-1-yl)phenyl)propan-2-ol, 5 [Step 3]: To a stirred solution of 2-[4-(3-nitropyrazol-1-yl)phenyl]propan-2-ol (15-4, 330 mg, 1.33 mmol) in ethanol (6 ml_) and water (1.2 mL), ammonium chloride (571 mg, 10.7 mmol) and Fe powder (298 mg, 5.3 mmol) were added. The resulting mixture was allowed to reflux at 80°C for 1 h. Reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was evaporated under reduced pressure to remove excess ethanol. The residue was diluted with water and extracted with ethyl acetate. Organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified by combi-flash chromatography to afford 2-[4-(3-aminopyrazol-1-yl)phenyl]-1 , 1 ,1-trifluoro-propan-2-ol (15-5, 150 mg). LCMS (ESI) calcd. for C12H15N3O: 217.12, found [M+H]+= 218.06.1H NMR (400 MHz, DMSO-d6): 6H8.07(d, 1 H), 7.55 (d, 1 H), 7.45 (d, 1 H), 6.53 (d, 1 H), 5.70 (d, 1 H), 4.99 (s, 2H), 1.42 (s, 6H).

[0500] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-(2- hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea, Example 24 (Compound 102) [Step 4]: To a stirred solution of 2-(4-(3-amino-1 H-pyrazol-1-yl)phenyl)propan-2-ol (5, 50 mg, 0.2 mmol) in dichloromethane (1 mL) was allowed to cool at -5°C. A solution of triphosgene (27 mg, 0.1 mmol) in dichloromethane (0.5 mL) was added to the solution dropwise, allowed to stir for 15 min at the same temperature. Triethylamine (0.19 mL, 1.4 mmol) and a solution of (S)-8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2,102 mg, 0.5 mmol) in dichloromethane (0.5 mL) was added to the solution. The reaction was allowed to stir at -5°C for 3 h. Reaction was diluted with water and extracted with dichloromethane. Organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The product was purified byreverse phase preparative HPLC to afford (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)-3-(1-(4-(2-hydroxypropan-2-yl)phenyl)-1 H-pyrazol-3-yl)urea (Example 24 (Compound 102), 34 mg). LCMS (ESI) calcd. for C21H22CIN5O3: 427.14, found [M+H]+= 428.20.1H NMR (400 MHz, DMSO-dg): 5H9.19 (s, 1 H), 8.31 (d, 1 H), 8.13 (d, 1 H), 7.63 (d, 2H), 7.52-7.40 (m, 3H), 6.40 (s, 1 H), 5.05 (s, 1 H), 4.95-4.91 (m, 1 H), 4.61-4.42 (m, 2H), 4.40-4.34 (m, 1 H), 2.60-2.55 (m, 1 H), 2.27-2.22 (m, 1 H), 1.55 (s, 6H)Example 25: Synthesis of (S)-1-(1-(3-bromophenyl)-1 H-pyrazol-3-yl)-3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 25 (Compound 98):Scheme 16.

[0501] Synthesis of 1-(3-bromophenyl)-3-nitro-1 H-pyrazole, 16-3 [Step 1]: To a stirred solution of 3-nitro-1 H-pyrazole (10-1 , 250 mg, 2.21 mmol) in MeOH (10 ml_), (3-bromophenyl) boronic acid (16-2, 533 mg, 2.65 mmol) was added and degassed for 10 min with argon balloon. Then Cu(OAc)2 (40 mg, 0.221 mmol) was added to the reaction mixture and the reaction mixture was heated at 80 °C for 16 h. Reaction mixture was diluted with ice cold water, extracted with ethyl acetate. Organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. Then crude was purified by combi flash column chromatography to afford 1-(3-bromophenyl)-3-nitro-1 H-pyrazole (16-3, 100 mg).1H NMR (400 MHz, DMSO-d6): 6H8.87 (d, 1 H), 8.18 (t, 1 H), 7.98-7.95 (m, 1 H), 7.70-7.67 (m, 1 H), 7.55 (t, 1 H), 7.39 (d, 1 H).

[0502] Synthesis of 1-(3-bromophenyl)-1 H-pyrazol-3-amine, 16-4 [Step-2]: To a stirred solution of 1 -(3-bromophenyl)-3-nitro-pyrazole (16-3, 75 mg, 0.280 mmol) in ethanol (5 mL) and water (1 mL), ammonium chloride (120 mg, 2.24 mmol) and Fe powder (62 mg, 1.12 mmol) were added. The resulting mixture was allowed to reflux at 80 °C for 2 h. Reaction mixture was diluted with ice cold water, extracted with ethyl acetate. Organic extract was concentrated under reduced pressure to afford 1-(3-bromophenyl)-1 H-pyrazol-3-amine (16-4, 60 mg). LCMS (ESI) calcd. for C9H8BrN3: 236.9, found [M+H]+= 238.2.

[0503] Synthesis of (S)-1-(1-(3-bromophenyl)-1 H-pyrazol-3-yl)-3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea, Example 25 (Compound 98) [Step 3]: To a stirred solution of 1 -(3-bromophenyl)- 1 H-pyrazol-3-amine (16-4, 75 mg, 0.31 mmol) in DCM (5 mL) at - 5 °C, triphosgene (93 mg, 0.31 mmol) and triethylamine (0.26 mL, 1.89 mmol) were added and stirred the reaction mixture for 30 min at the same temperature. Then (S)-8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (70 mg, 0.31 mmol) was added to the reactionmixture and stirred for 1 h at the same temperature. Reaction mixture was concentrated under reduced pressure to get crude. The crude product was purified by reverse phase Preparative HPLC and lyophilized to afford (S)-1-(1-(3-bromophenyl)-1 H-pyrazol-3-yl)-3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (Example 25 (Compound 98), 30 mg). LCMS (ESI) calcd for Ci8Hi5BrCIN502: 447.0, [M+H]+= 448.1 , HPLC: Rt(min)= 8.89 (99.02%).1H NMR (400 MHz, DMSO-d6): bH9.25 (s, 1 H), 8.44 (s, 1 H), 8.15 (d, 1 H), 7.90 (s, 1 H), 7.75 (s, 1 H), 7.59 (s, 1 H), 7.50 (d, 1 H), 7.40 (d, 2H), 6.44 (s, 1 H), 4.93-4.89 (m, 1 H), 4.43-4.35 (m, 2H), 2.49 (bs, 1 H), 2.04 (bs, 1 H).Example 26: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(T- methyl-1'H-[1 ,4'-bipyrazol]-3-yl)urea, Example 26 (Compound 97):Scheme 17.

[0504] Synthesis of r-methyl-3-nitro-rH-1 ,4'-bipyrazole, 17-3 [Step 1]: To a stirred solution of 4-bromo-1-methyl-pyrazole (1 , 513 mg, 3.18 mmol) and 3-nitro-1 H-pyrazole (10-1 , 300 mg, 2.65 mmol) in MeCN (5 mL) was added anhydrous K2CO3 (915 mg, 6.63 mmol) at ambient temperature and the reaction mixture was degassed with argon for 10 min followed by the addition of trans N,N-dimethyl cyclohexanedimine (0.41 mL, 2.65 mmol) and Cui (253 mg, 1.33 mmol). The reaction mixture was heated in a sealed tube at 90 °C for 16 h. Reaction mixture was diluted with water, extracted with ethyl acetate. Organic extract was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure to get crude product. The crude product was purified through combi flash chromatography to afford 1-(1-methylpyrazol-4-yl)-3- nitro-pyrazole (17-3, 150 mg). LCMS (ESI) calcd. for C7H7N502: 193.1 , found [M+H]+= 193.9.

[0505] Synthesis of T-methyl-TH-[1 ,4'-bipyrazol]-3-amine, 17-4 [Step 2]: To a stirred solution of 1-(1-methylpyrazol-4-yl)-3-nitro-pyrazole (17-3, 178 mg, 0.922 mmol) in ethanol (5 mL) and water (1 mL), ammonium chloride (394 mg, 7.37 mmol) and Fe powder (206 mg, 3.69 mmol) were added. The resulting mixture was allowed to reflux at 80 °C for 2 h. Reaction mixture was diluted with ice cold water, extracted with ethyl acetate. Combined organic extract was concentrated under reduced pressure to afford 1 '-methyl-TH-[1 ,4'-bipyrazol]-3-amine (17-4, 120 mg). LCMS (ESI) calcd. for C7H9N5: 163.1 , found [M+H]+= 164.1.

[0506] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(T-methyl- rH-[1,4'-bipyrazol]-3-yl)urea, Example 26 (Compound 97) [Step 3]: To a stirred solution of T- methyl-1 'H-[1 ,4'-bipyrazol]-3-amine (17-4, 130 mg, 0.79 mmol) in dichloromethane (5 mL) at - 5 °C, triethylamine (0.67 mL, 4.78 mmol) and then triphosgene (236 mg, 0.79 mmol) were added and stirred the reaction mixture for 30 min at the same temperature. Then (S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine (176 mg, 0.79 mmol) was added to the reaction mixture and stirred at -5 °C for 1 h. Reaction mixture was diluted with water and extracted with dichloromethane. Organic extract was concentrated under reduced pressure to get crude product. The product was purified by reverse phase preparative HPLC to afford (S)-1-(8-chloro- 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(T-methyl-1'H-[1 ,4'-bipyrazol]-3-yl)urea (Example 26 (Compound 97), 50 mg). LCMS (ESI) calcd. for CI6HI5CIN7O2: 373.1 ,[M+H]+=374.2, HPLC:Rt(min)=6.17 (99.65%).1H NMR (400 MHz, DMSO-cfe): 6H9.03 (s, 1 H), 8.11 (d, 1 H), 7.96 (s, 1 H), 7.94 (d, 1 H), 7.68 (s, 1 H), 7.48 (d, 1 H), 7.30 (brs, 1 H), 6.35-6.34 (m, 1 H), 4.93-4.89 (m, 1 H), 4.43-4.32 (m, 2H), 3.83 (s, 3H), 2.1 1-2.02 (m, 2H).Examples 27 & 28: Synthesis of ((R)-1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(8-methyl-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 27 (Compound 110) & ( (S)-1 -( 1 -(4- cyanophenyl)-1 H-pyrazol-3-yl)-3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 28 (Compound 109):Scheme 18.

[0507] Synthesis of 1-(1-(4-cyanophenyl)-1 H-pyrazol-3-yl)-3-(8-methyl-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea, 18-3 [Step 1]: To a stirred solution of 4-(3-amino-1 / - / -pyrazol-1- yl)benzonitrile (11-1 , 150 mg, 0.8 mmol) in dichloromethane (20 mL) was added triethyl amine (0.45 mL, 3.3 mmol) and Triphosgene (242 mg, 0.8 mmol) at -50C and stirred for 30 min. A solution of 8-methyl-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-amine hydrochloride (2-10, 163 mg, 0.8 mmol) and triethyl amine (0.68 mL, 4.9 mmol) in dichloromethane (10 mL) was added at same condition and allowed to stir for 1 h at ambient temperature. The reaction mixture was diluted with dichloromethane and washed with water followed by brine solution. The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by prep HPLC and lyophilized to afford 1-(1-(4-cyanophenyl)-1 / - / -pyrazol-3- yl)-3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (18-3, 100 mg). LCMS (ESI) Calcd. for C20H18N6O2: 374.15, found [M+H]+: 375.2

[0508] Synthesis of ((R)-1-(1-(4-cyanophenyl)-1 H-pyrazol-3-yl)-3-(8-methyl-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea, Example 27 (Compound 110) & ((S)-1-(1-(4-cyanophenyl)- 1H-pyrazol-3-yl)-3-(8-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 28 (Compound 109) [Step 2]: The racemic compound 1-(1-(4-cyanophenyl)-1 / - / -pyrazol-3-yl)-3-(8- methyl-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea (18-3, 100 mg) was submitted for HPLC SFC prep purification. The fractions obtained were evaporated under reduced pressure and finallylyophilized to afford peak 1 arbitrarily assigned as ((R)-1-(1-(4-cyanophenyl)-1 / - / -pyrazol-3-yl)-3- (8-methyl-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea (Example 27 (Compound 110), 40 mg) and peak 2 arbitrarily assigned as ((S)-1-(1-(4-cyanophenyl)-1 / - / -pyrazol-3-yl)-3-(8-methyl-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (Example 28 (Compound 109), 33 mg). Absolute stereochemistry was confirmed later.

[0509] SFC method: HPLC SFC Prep Purification of 1-(1-(4-cyanophenyl)-1 / - / -pyrazol-3-yl)-3- (8-methyl-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea (18-3, 100 mg) was done on Waters PREP SFC ISO instrument equipped with Waters 2489 UV / Visibie Detector by using I- Cellulose-Z (30.0 mm x 250 mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 100 ml / min, using 55% CO? in super critical state & 45% of 100% MeOH as Mobile phase. Run this isocratic mixture up to 10.0 minutes and maintained the isobaric condition of 100 bar at 220 nm wavelength.

[0510] ((R)-1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(8-methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, Example 27 (Compound 110) (Peak 1): 1 H NMR (400 MHz, DMSO-d6) 0 : 9.31 (s, 1 H), 8.54 (d, 1 H), 8.08 (d, 1 H), 7.93 (s, 4H), 7.74 (brs, 1 H), 7.19 (d, 1 H), 6.52 (s, 1 H), 4.84-4.82 (m, 1 H), 4.35-4.29 (m, 2H), 2.51-2.50 (m, 1 H), 2.17 (s, 3H), 2.00-1.96 (m, 1 H); LCMS (ESI): Calcd. for C2oHi8N602: 374.15, found [M+H]+: 375.2.

[0511] ((S)-1-(1-(4-cyanophenyl)-1H-pyrazol-3-yl)-3-(8-methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, Example 28 (Compound 109) (Peak 2): 1 HNMR (400 MHz, DMSO-d6) 6H: 9.31 (s, 1 H), 8.54 (s, 1 H), 8.08 (s, 1 H), 7.93 (s, 4H), 7.71 (brs, 1 H), 7.19 (s, 1 H), 6.52 (s, 1 H), 4.83 (s, 1 H), 4.35-4.32 (m, 2H), 2.51-2.50 (m, 1 H), 2.17 (s, 3H), 2.00-1.97 (m, 1 H); LCMS (ESI): Calcd. for C2oHi8N602: 374.15, found [M+H]+: 375.2. Stereochemistry of both the compounds are known.Example 29: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(T- methyl-1'H-[1 ,4'-bipyrazol]-3-yl)urea, Example 29 (Compound 92):Scheme 19.

[0512] Synthesis of 4-(3-nitro-1 H-pyrazol-1-yl)phenol, 19-3 [Step 1]: To a stirred solution of 3- nitro-1 H-pyrazole (10-1 , 500 mg, 4.42 mmol) in DCM (20 mL) was added pyridine (1.8 mL, 22.1 mmol) and (4-hydroxyphenyl)boronic acid (19-2, 1.2 gm, 8.84 mmol) followed by addition of Copper(ll) acetate (402 mg, 2.21 mmol) at ambient temperature under argon atmosphere. The reaction mixture was stirred for 16 h under oxygen atmosphere. The reaction mass was filtered through celite bed by DCM and evaporated. The product was purified by column chromatography to give 4-(3-nitro-1 H-pyrazol-1-yl)phenol (19-3, 400 mg). LCMS (ESI) Calcd. for C9H7N3O3: 205.05, found [M+H]+= 206.1.

[0513] Synthesis of 4-(3-amino-1H-pyrazol-1-yl)phenol, 19-4 [Step 2]: In a 50 mL round bottom flask containing a solution of 4-(3-nitro-1 H-pyrazol-1-yl)phenol (19-3, 250 mg, 1.22 mmol) in Methanol (3mL) and Ethyl acetate (5mL) was added 10% Palladium on carbon (156 mg, 1.46 mmol) under nitrogen atmosphere. The flask was evacuated then filled with hydrogen gas balloon and stirred at ambient temperature for 2 h. The reaction mixture was then diluted with ethyl acetate and filtered through a bed of celite. The filtrate was dried under vaccum to give 4-(3-amino-1 H- pyrazol-1-yl)phenol (19-4, 170 mg). LCMS (ESI) Calcd. forC9H9N30: 175.07, found [M+H]+= 176.03.

[0514] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- hydroxyphenyl)-1 H-pyrazol-3-yl)urea, Example 29 (Compound 92) [Step 3]: To a stirred solution of 4-(3-amino-1H-pyrazol-1-yl)phenol (70 mg, 0.4 mmol) in MeCN (8 mL) were added Pyridine (0.03 mL, 0.4 mmol) and N,N'-Disuccinimidyl carbonate ( 102 mg, 0.4 mmol) at 0 °C and the reaction mixture was stirred for 10 min. To this was added DIPEA (0.21 mL, 1.20 mmol) followed by (S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (88 mg, 0.4 mmol) in MeCN (2 mL) at 0 °C and reaction was stirred at ambient temperature for 2 h. After completion, reaction mixture was concentrated under reduced pressure and crude obtained was dissolved in EtOAc. Organic layer was washed with 2N HCI solution, water, brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure to give the crude compound. The crude was purified by Prep HPLC to give (S)-1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-hydroxyphenyl)-1 H-pyrazol-3-yl)urea (Example 29 (Compound 92), 75 mg). LCMS (ESI) Calcd. for CI8HI6CIN5O3: 385.09, found [M+H]+= 386.2.1H NMR (400 MHz, d6-DMSO) 6H: 9.50 (s, 1 H), 9.09 (s, 1 H), 8.15-8.11 (m, 2H), 7.60-7.47 (m, 4H), 6.80 (d, 2H), 6.33 (s, 1 H), 4.92-4.90 (m, 1 H), 4.45-4.36 (m, 2H), 2.56 (s, 1 H), 2.08 (s, 1 H).Examples 30 & 31 : Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(1-(3-((R)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 30 (Compound 88) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-((S)- 2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 31 (Compound 87):Scheme 20.

[0515] Synthesis of tert-butyl (S)-3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)-1H-pyrazole-1-carboxylate, 3 [Step 1]: To a stirred solution of tert- butyl 3-amino-1 / - / - pyrazole-1 -carboxylate (20-1 , 414 mg, 2.3 mmol) in DCM (10 mL) was added triethylamine (1.9 ml_, 13.6 mmol) followed by triphosgene (671 mg, 2.3 mmol) and stirred at -5 °C, after 30 min (S)- 8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 500 mg, 2.3 mmol) was added and stirred at same temperature for 2 h. Volatiles were removed under reduced pressure and diluted with water and extracted with ethyl acetate. Organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduce pressure to afford product, which was purified by combi flash chromatography to afford tert-butyl (S)-3-(3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)ureido)-1 / - / -pyrazole-1-carboxylate (20-3, 730 mg). LCMS (ESI) Calcd. for C17H20CIN5O4: 393.12, found [M+H]+= 394.2.

[0516] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1H- pyrazol-3-yl)urea hydrochloride, 20-4 [Step 2]: To a stirred solution of tert-butyl (S)-3-(3-(8- chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)ureido)-1 / - / -pyrazole-1 -carboxylate (20-3, 730 mg, 1.8 mmol) in 1 ,4-dioxane (10 mL) was added HCI (4M Dioxane) (7.0 mL, 27.8 mmol) at 0 °C and stirred at ambient temperature for 16 h. Volatiles were removed under reduced pressure to afford (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)-3-(1 H-pyrazol-3-yl)urea hydrochloride (20-4, 500 mg). The product was used for the next step without further purification. LCMS (ESI) Calcd. for C12H12CIN5O2: 293.07, found [M+H]+= 394.1 1.

[0517] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-(2,2,2- trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, 20-6 [Step 3]: In a sealed tube a stirred solution of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1 / - / -pyrazol-3-yl)urea hydrochloride (20-4, 200 mg, 0.6 mmol) in MeCN (10 mL) was added 1-(3-bromophenyl)-2,2,2- trifluoroethan-1-ol (20-5, 201 mg, 0.8 mmol) followed by K2CO3(209 mg, 1.5 mmol), the reactionmixture was degassed with Ar for 10 min. To this reaction mixture was added trans-N,N'- Dimethylcyclohexane-1 ,2-diamine (0.1 mL, 0.6 mmol) and copper iodide (58 mg, 0.3 mmol) and stirred the reaction mixture at 90 °C for 16 h. The reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was concentrated under reduced pressure to afford product which was purified by preparative HPLC, lyophilized to afford 1-((S)-8-chloro-3,4-dihydro- 2 / 7-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 / - / -pyrazol-3-yl)urea (20-6, 92). LCMS (ESI) Calcd. for C20H17CIF3N5O3: 467.10, found [M+H]+= 468.2.

[0518] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-((R)- 2, 2,2-trif I uoro-1 -hydroxyethyl (phenyl )-1 / 7-pyrazol-3-yl)urea, Example 30 (Compound 88) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-((S)-2,2,2-trifluoro-1- hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 31 (Compound 87) [Step 4]: Diastereomers of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-(2,2,2- trifluoro-1-hydroxyethyl)phenyl)-1 / - / -pyrazol-3-yl)urea (20-6, 90 mg, 0.2 mmol) were separated by chiral HPLC-SFC to afford peak 1 assigned as 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- £>]pyridin-4-yl)-3-(1-(3-((R)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 / - / -pyrazol-3-yl)urea (Example30 (Compound 88), 44 mg) and peak 2 assigned as 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(3-((S)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea (Example31 (Compound 87), 27 mg).

[0519] SFC method: Separation was performed on Pic solutions-175 instrument equipped with Knauer 40D Detector by using I Cellulose J (30.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 90 mL / min, using 60% CO2in super critical state and 40% of 100% methanol as mobile phase, run this isocratic mixture for 14 min and maintained the isobaric condition of 100 bar at 280 nm wavelength.

[0520] Absolute stereochemistry was not determined and arbitrarily assigned.

[0521] Note: NOE analysis confirmed that desired product formed.

[0522] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-((R)-2,2,2-trifluoro- 1-hydroxyethyl)phenyl)-1H-pyrazol -3-yl) urea, Example 30 (Compound 88) (Peak 1): LCMS (ESI) Calcd. for C20H17CIF3N5O3: 467.10, found [M+H]+= 468.2,1H NMR (400 MHz, DMSO-cfe): 0H9.24 (s, 1 H), 8.36 (d, 1 H), 8.12 (d, 1 H), 7.83 (bs, 1 H), 7.75-7.72 (m, 1 H), 7.49-7.45 (m, 2H), 7.33 (d, 2H), 6.94 (bs, 1 H), 6.51 (d, 1 H), 5.19 (q, 1 H), 4.93 (q, 1 H), 4.48-4.42 (m, 1 H), 4.38-4.33 (m, 1 H), 2.44-2.41 (m, 1 H), 2.09-2.05 (m, 1 H).

[0523] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-((S)-2,2,2-trifluoro- 1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 31 (Compound 87) (Peak 2): LCMS (ESI) Calcd. For C2oHi7CIF3N503:467.10, found [M+H]+= 468.2,1H NMR (400 MHz, DMSO-cfe): 0H9.26 (s, 1 H), 8.36 (d, 1 H), 8.12 (d, 1 H), 7.82 (bs, 1 H), 7.75-7.72 (m, 1 H), 7.49-7.45 (m, 2H), 7.33 (d, 2H), 6.94 (bs, 1 H), 6.51 (d, 1 H), 5.19 (q, 1 H), 4.94-4.92 (m, 1 H), 4.45-4.35 (m, 2H), 2.44- 2.41 (m, 1 H), 2.09-2.05 (m, 1 H).Examples 32 & 33: Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(1-(6-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)-1H-pyrazol-3-yl)urea, Example 32 (Compound 86) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6-((R)- 2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea, Example 33 (Compound 85):Scheme 21.

[0524] Synthesis of 1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-ol, 21-2 [Step 1]: To an ice-cold solution of 5-bromopyridine-2-carbaldehyde (21-1 , 1 .50 g, 8.06 mmol) in THF (5 mL) was added trimethyl(trifluoromethyl)silane (1.72 g, 12.1 mmol) followed by TBAF (1 M in THF) (20 mL, 20.2 mmol). The mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Organic extract was washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure to obtain crude product. The product was purified over combi flash column chromatography to afford 1-(5-bromo- 2-pyridyl)-2,2,2-trifluoro-ethanol (21-2, 1.8 g, 86.14%).1H NMR (400 MHz, DMSO-d6): <5H 8.73 (m, 1 H), 8.17 (d, 1 H), 7.60 (d, 1 H), 7.16 (d, 1 H) and 5.15 (m, 1 H).

[0525] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6-(2,2,2- trifluoro-1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea, 21-4 [Step 2]: To a stirred solution of 1-(5-bromo-2-pyridyl)-2,2,2-trifluoro-ethanol (21-2, 214 mg, 0.83 mmol) and 1-(1 H-pyrazol-3- yl)-3-(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]urea;hydrochloride (21-3, 212 mg, 0.64 mmol) in MeCN (5 mL) was added anhydrous K2CO3 ( 266 mg, 1.93 mmol) at ambient temperature and the reaction mixture was degassed with argon for 10 min followed by the addition of trans N,N-dimethyl cyclohexanedimine (0.10 mL, 0.642 mmol) and Cui (61 mg, 0.321 mmol). The reaction mixture was heated in a sealed tube at 90 °C for 16 h. Reaction mixture was cooled to ambient temperature, filtered through celite and the filtrate was concentrated under reduced pressure to obtain crude compound. The product was purified by combi flash column chromatography to afford 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea (21-4, 47 mg). LCMS (ESI) cacld. for Ci9Hi6CIF3N603: 468.09, found [M+H]+: 469.20.

[0526] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6-((S)-2.2.2-trifluoro-1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea, Example 32 (Compound86) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6-((R)-2,2,2- trifluoro-1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea, Example 33 (Compound 88) [Step 3]: 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6-(2,2,2-trifluoro-1- hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea was purified on Waters PREP SFC 150 instrument equipped with Waters 2489 UV / Visible Detector by using Chiralpak-IG (30.0 mm x 250 mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 120 ml / min, using 50% CO2 in super critical state & 50% of ACN / MeOH (1 :1) as Mobile phase. Run this isocratic mixture up to 10.0 minutes and also maintained the isobaric condition of 100 bar at 287 nm wavelength to afford the first fraction 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6-((S)-2.2.2-trifluoro-1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea (Example 32 (Compound 86), 9 mg) as Peak 1 and the second fraction 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(1-(6-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea (Example 33 (Compound 85), 8 mg) as Peak 2. 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(1-(6-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-yl)-1H-pyrazol-3-yl)urea, Example 32 (Compound 86): LCMS (ESI) Cacld. for Ci9Hi6CIF3N6O3: 468.09, found [M+H]+: 469.19, HPLC: Rt(min) = 8.06 (99.00 %).1H NMR (400 MHz, DMSO-cfe): 6H 9.33 (s, 1 H), 9.02 (d, 1 H), 8.49 (d, 1 H), 8.22-8.19 (m, 1 H), 8.13 (d, 1 H), 7.69 (d, 1 H), 7.50 (d, 2H), 7.08 (s, 1 H), 6.55 (d, 1 H), 5.17- 5.15 (m, 1 H), 4.96-4.91 (m, 1 H), 4.45-4.38 (m, 2H), 2.49-2.48 (m, 1 H), 2.08-2.05 (m, 1 H).

[0527] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6-((R)-2,2,2-trifluoro- 1-hydroxyethyl)pyridin-3-yl)-1 H-pyrazol-3-yl)urea, Example 33 (Compound 85): LCMS (ESI) Cacld. for CI9HI6CIF3N6O3: 468.09, found [M+H]+: 469.20, HPLC: Rt(min) = 8.05 (99.44 %).1H NMR (400 MHz, DMSO-d6): 6H 9.33 (s, 1 H), 9.02 (d, 1 H), 8.49 (d, 1 H), 8.22-8.19 (m, 1 H), 8.13 (d, 1 H), 7.69 (d, 1 H), 7.50 (d, 2H), 7.08 (s, 1 H), 6.55 (d, 1H), 5.17-5.15 (m, 1 H), 4.95-4.91 (m, 1 H), 4.45-4.38 (m, 2H), 2.49-2.48 (m, 1 H), 2.08-2.05 (m, 1 H).Examples 34 8( 35: Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(1-(4-fluoro-3-((R)-2,2,2-trifluoro-1 -hydro xyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 34 (Compound 75) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- fluoro-3-((S)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 35 (Compound 74):Scheme 22.

[0528] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- fluoro-3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, 22-3 [Step 1]: In a sealed tube a stirred solution of (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)-3-(1H- pyrazol-3-yl)urea hydrochloride (20-4, 200 mg, 0.6 mmol) in MeCN (10 mL) was added 1-(5- bromo-2-fluorophenyl)-2,2,2-trifluoroethan-1-ol (22-2, 215 mg, 0.8 mmol) followed by K2CO3(293 mg, 2.1 mmol) the reaction mixture was degassed with Ar for 10 min. To this reaction mixture was added frans-A / ,A / '-dimethylcyclohexane-1 ,2-diamine (0.1 mL, 0.6 mmol) and Cuprous iodide (58 mg, 0.3 mmol) and stirred the reaction mixture at 90 C for 16 h. The reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was concentrated under reduced pressure to afford product which was purified by preparative HPLC, lyophilized to afford 1-((S)-8- chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-fluoro-3-(2,2,2-trifluoro-1- hydroxyethyl)phenyl)-1 / - / -pyrazol-3-yl)urea (22-3, 55 mg). LCMS (ESI) Calcd. for C2oHi6CIF4N503: 485.09, found [M+H]+= 486.2. NOE analysis confirmed the formation of desired product.

[0529] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- fluoro-3-((R)-2,2,2-trifluoro-1 -hydro xyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 34 (Compound 75) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- fluoro-3-((S)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 35 (Compound 74) [Step 2]: 1-((S)-8-chloro-3,4-dihydro-2 / 7-pyrano[3,2-5]pyridin-4-yl)-3-(1-(4- fluoro-3-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 / - / -pyrazol-3-yl)urea (22-3, 50 mg, 0.1 mmol) were separated by chiral HPLC-SFC to afford peak 1 assigned as 1-((S)-8-chloro-3,4-dihydro- 2 / 7-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-fluoro-3-(( / ?)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 / 7- pyrazol-3-yl)urea (Example 34 (Compound 75), 28 mg) and peak 2 assigned as 1-((S)-8-chloro- 3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-fluoro-3-((S)-2,2,2-trifluoro-1- hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea (Example 35 (Compound 74), 20 mg). Absolute stereochemistry was not determined and arbitrarily assigned.

[0530] SFC method: Separation was performed on Pic solutions-175 instrument equipped with Knauer 40D Detector by using CHIRALPAK IC (30.0 mm x 250mm), 5p Column operating at 35 °C 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 for 10 min and maintained the isobaric condition of 100 bar at 280 nm wavelength.

[0531] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-fluoro-3-((R)-2,2,2- trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 34 (Compound 75) (Peak1): LCMS (ESI) Calcd. for C20Hi6CIF4N5O3: 485.09, found [M+H]+= 486.2,1H NMR (400 MHz, DMSO-de): 6H9.23 (s, 1 H), 8.36-8.35 (m, 1 H), 8.12 (d, 1 H), 7.93-7.92 (m, 1 H), 7.81-7.79 (m, 1 H), 7.46 (d, 1 H), 7.37 (t, 1 H), 7.20-7.12 (m, 2H), 6.53-6.52 (m, 1 H), 5.40-5.37 (m, 1 H), 4.95-4.91 (m, 1 H), 4.46-4.42 (m, 1 H), 4.37-4.35 (m, 1 H), 2.49-2.48 (m, 1 H), 2.10-2.03 (m, 1 H).

[0532] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-fluoro-3-((S)-2,2,2- trifluoro-1-hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 35 (Compound 74) (Peak2): LCMS (ESI) Calcd. for C2oHi6CIF4N503:485.09, found [M+H]+= 486.2,1H NMR (400 MHz, DMSO-dg): 6H9.31 (s, 1 H), 8.36 (d, 1H), 8.11 (d, 1 H), 7.93-7.92 (m, 1 H), 7.82-7.79 (m, 1 H), 7.47 (d, 1 H), 7.38 (t, 1 H), 7.26-7.24 (m, 2H), 6.53-6.52 (m, 1 H), 5.41-5.39 (m, 1 H), 4.94-4.92 (m, 1 H), 4.44-4.42 (m, 1 H), 4.37-4.35 (m, 1 H), 2.43-2.40 (m, 1 H), 2.08-2.07 (m, 1 H).Example 36: Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(2- (2,2,2-trifluoro-1-hydroxyethyl)pyridin-4-yl)-1 / 7-pyrazol-3-yl)urea, Example 36 (Compound 73):rans , - me y cyclohexanedimine Compound 73Step 1Scheme 23.

[0533] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(2-(2,2,2- trifluoro-1 -hydroxyethyl )pyridin-4-yl)-1 H-pyrazol-3-yl)urea, Example 36 (Compound 73) [Step 1]: In a sealed tube a stirred solution of (S)-1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin- 4-yl)-3-(1 / - / -pyrazol-3-yl)urea hydrochloride (20-4, 200 mg, 0.6 mmol) in MeCN (5 mL) was added 1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-ol (23-2, 202 mg, 0.8 mmol) followed by K2CO3(209 mg, 1.5 mmol), the reaction mixture was degassed with Ar for 10 min. To this reaction mixture was added trans-N, / V'-Dimethylcyclohexane-1 ,2-diamine (0.1 mL, 0.6 mmol) and Cui (58 mg, 0.3 mmol) stirred the reaction mixture at 90 C for 16 h. The reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was concentrated under reduced pressure to afford product which was purified by preparative HPLC, lyophilized to afford 1-((S)-8-chloro-3,4- dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)-3-(1-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4-yl)-1 / - / - pyrazol-3-yl)urea (Example 36 (Compound 73), 50 mg). LCMS (ESI) Calcd. for C19H16CIF3N6O3: 468.09, found [M+H]+= 468.09,1H NMR (400 MHz, DMSO-d6): 6H9.04 (s, 1 H), 8.61 (d, 1 H), 8.56 (d, 1 H), 8.13-8.1 1 (m, 1 H), 7.91 (s, 1 H), 7.77-7.75 (m, 1 H), 7.48 (d, 1 H), 7.26 (bs, 1 H), 7.11 (d,1 H), 6.65 (d, 1 H), 5.15-5.12 (m, 1 H), 4.95-4.93 (m, 1 H), 4.45-4.42 (m, 1 H), 4.39-4.36 (m, 1 H), 2.45-2.42 (m,1 H), 2.09-2.06 (m, 1 H). NOE analysis confirmed the formation of desired product.Example 37: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- isopropyl-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 37 (Compound 70):dimethylcyclohexane Example 37 diamine, CH3CN, 90C, 16h (Compound 70)Step 1Scheme 24.

[0534] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- isopropyl-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 37 (Compound 70) [Step 1]: To a solution of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1 H-pyrazol-3-yl)urea hydrochloride (20-4, 300 mg, 0.91 mmol) and 2-iodopyridine (24-2, 242 mg, 1.18 mmol) in MeCN (5 mL) was added K2CO3(502 mg, 3.63 mmol) at ambient temperature and the reaction mixture was degassed with argon for 10 min followed by the addition of trans N,N-dimethyl cyclohexanedimine (0.14 mL, 0.91 mmol) and Cui (87 mg, 0.45 mmol). The reaction mixture was heated in a sealed tube at 90°C for 16 h. The reaction mixture was filtered through celite pad and washed with EtOAc.The filtrate was evaporated under reduced pressure which was purified by Reverse Phase PREP HPLC to afford (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(1-(pyridin-2-yl)-1 H-pyrazol-3-yl)urea (Example 37 (Compound 70), 50 mg). LCMS (ESI) Calcd. for C17H15CIN6O2: 370.79, found [M+H]+= 371 .2.1H NMR (400 MHz, DMSO-d6): 6H9.30 (s, 1 H), 8.46-8.45 (m, 1 H), 8.42-8.40 (m, 1 H), 8.15-8.13 (m, 1 H), 7.95-7.92 (m, 1 H), 7.71 (d, 1 H), 7.61 (bs, 1 H), 7.50-7.49 (m, 1 H), 7.28-7.25 (m, 1 H), 6.51-6.50 (m, 1 H), 4.95-4.93 (m, 1 H), 4.45- 4.39 (m, 2H), 2.08-2.06 (m, 2H).Example 38: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- (2-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 38 (Compound 95):Scheme 25.

[0535] Synthesis of 2-(4-(3-nitro-1 H-pyrazol-1-yl)phenyl)ethan-1-ol, 3 [Step 1]: To a solution of 3-nitro-1 H-pyrazole (10-1 , 150 mg, 1.33 mmol) and 2-(4-bromophenyl)ethan-1-ol (25-2, 347 mg, 1.72 mmol) in MeCN (10 mL) was added oven dried K2CO3 (458 mg, 3.32 mmol) at ambient temperature and the reaction mixture was degassed with argon for 10 min. trans N,N-dimethyl cyclohexanedimine (0.21 mL, 1.33 mmol) and Cui (126 mg, 0.663 mmol) were added to it and heated in a sealed tube at 90 °C for 16 h. the reaction mixture was cooled to ambient temperature, filtered through celite bed and the filtrate was concentrated under reduced pressure. The crude product was purified by combi flash chromatography to afford 2-(4-(3-nitro-1 H-pyrazol-1- yl)phenyl)ethan-1-ol (25-3, 240 mg). LCMS (ESI) Calcd. for C11 H11 N3O3: 233.22, found [M+H]+: 234.2. 1 H NMR (400 MHz, DMSO-d6) bH: 8.73 (d, 1 H), 7.81 (d, 2H), 7.42 (d, 2H), 7.33 (d, 1 H), 4.68 (t, 1 H), 3.66-3.62 (m, 2H), 2.79 (t, 2H). NOE analysis confirmed the formation of desired product.

[0536] Synthesis of 2-(4-(3-amino-1 H-pyrazol-1-yl)phenyl)ethan-1-ol, 25-4 [Step 2]: To a stirred solution of 2-(4-(3-nitro-1 H-pyrazol-1-yl)phenyl)ethan-1-ol (25-3, 200 mg, 0.9 mmol) in methanol (20 mL) was added 10% Pd / C (110 mg, 1.03 mmol) under inert atmosphere and hydrogenated under hydrogen balloon pressure for 16h at ambient temperature. The reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 2-(4-(3-amino-1 H-pyrazol-1-yl)phenyl)ethan-1-ol (25-4, 160 mg). LCMS (ESI) Calcd. for C11 H13N3O: 203.24, found [M+H]+: 204.3. 1 H NMR (400 MHz, DMSO-d6) 6H: 8.06 (d, 1 H), 7.52 (d, 2H), 7.21 (d, 2H), 5.70 (d, 1 H), 4.98 (d, 2H), 4.63 (s, 1 H), 3.58 (t, 2H), 2.69 (t, 2H).

[0537] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-(2- hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, 6 [Step 3]: To a stirred solution of 2-(4-(3-amino- 1 H-pyrazol-1-yl)phenyl)ethan-1-ol (25-4, 50 mg, 0.25 mmol) in dichloromethane (6 mL) were added triethylamine (0.17 mL, 1.23 mmol) and triphosgene (73 mg, 0.25 mmol) in dichloromethane (1.5 mL) at -15 °C and stirred for 30 min. A solution of (S)-8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 55 mg, 0.25 mmol) in dichloromethane (1.5 mL) was added to the reaction mixture and stirred for 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 preparative HPLC, lyophilized to afford to afford (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-(2-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea (Example 38 (Compound 95), 22 mg). LCMS (ESI) Calcd. for C20H2OCIN5O3: 413.86, found [M+H]+: 414.24.1H NMR (400 MHz, DMSO-d6) 6H: 9.17 (s, 1 H), 8.29 (d, 1 H), 8.13 (d, 1 H), 7.61 (d, 3H), 7.50 (d, 1 H), 7.27 (d, 2H), 6.38 (s, 1 H), 4.94-4.89 (m, 1 H), 4.63 (t, 1 H), 4.48-4.34 (m, 2H), 3.62-3.58 (m, 2H), 2.72 (t, 2H), 2.08-2.03 (m, 1 H).Example 39: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- cyano-2-methylphenyl)-1H-pyrazol-3-yl)urea, Example 39 (Compound 84):Int. of Compound 73 K2CO3, Cui, (Compound 84) ACN, 90 °C, 16 hStep 1Scheme 26.

[0538] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- cyano-2-methylphenyl)-1H-pyrazol-3-yl)urea, 3 [Step 1]: To a stirred solution of (S)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1 H-pyrazol-3-yl)urea hydrochloride (20-4, 100 mg, 0.30 mmol) and K2CO3 (104 mg, 0.75 mmol) in acetonitrile (6 mL) was added 4-bromo- 3-methylbenzonitrile (26-2, 77 mg, 0.39 mmol) at ambient temperature. The reaction mixture was degassed with argon for 10 min followed by addition of trans-N,N -Dimethylcyclohexane-1 ,2- diamine (0.04 mL, 0.30 mmol) and Cui (29 mg, 0.15 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was dissolved in ethyl acetate and filtered through celite bed. The filtrate was diluted with ethyl acetate and washed with water (twice). The organic part was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by prep HPLC and lyophilized to give (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-cyano-2-methylphenyl)-1 H-pyrazol-3-yl)urea (Example 39 (Compound 84), 18 mg). Formation of desired product was confirmed by NOE and COSY NMR. LCMS (ESI) Calcd. for C20HI7CIN6O2: 408.11 , found [M+H]+= 409.2.1H NMR (400 MHz, d6-DMSO) 6H: 9.18 (s, 1H), 8.09-8.08 (m, 1 H), 8.06-8.05 (m, 1 H), 7.87 (s, 1 H), 7.79-7.77 (m, 1 H), 7.57 (d, 1 H), 7.47 (d, 1H), 7.37 (s, 1 H), 6.48 (s, 1H), 4.93-4.92 (m, 1 H), 4.43-4.14 (m, 2H), 2.35 (s, 4H), 2.08-2.07 (m, 1H).Example 40: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(5- cyanopyridin-2-yl)-1H-pyrazol-3-yl)urea, Example 40 (Compound 77):Compound 77Scheme 27.

[0539] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(5- cyanopyridin-2-yl)-1H-pyrazol-3-yl)urea, Example 40 (Compound 77) [Step 1]: To a stirred solution of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1 H-pyrazol-3-yl)urea hydrochloride (20-4, 150 mg, 0.45 mmol) in DMSO (2 mL) were added K2CO3(188 mg, 1.36 mmol) followed by 6-fluoropyridine-3-carbonitrile (27-2, 61 mg, 0.50 mmol) slowly under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 24h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4and concentrated under reduced pressure. The crude product was purified by reverse phase and lyophilized to afford (S)-1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(1-(5-cyanopyridin-2-yl)-1 H-pyrazol-3-yl)urea (Example 40 (Compound 77), 40 mg). LCMS Calcd. For CI8HI4CIN7O2:395.8; found [M+H]+: 396.2. 1 H NMR (400 MHz, DMSO-cfe): OH 9.45 (s, 1 H), 8.89 (s, 1 H), 8.53 (d, 1H), 8.43-8.41 (d, 1 H), 8.15-8.14 (d, 1H), 7.84-7.81 (d, 1H), 7.63 (bs, 1 H), 7.49-7.48 (d, 1H), 6.62 (s, 1 H), 4.96-4.91 (m, 1 H), 4.47-4.38 (m, 2H), 2.55 (m, 1H), 2.09-2.02 (m, 1 H).Example 41 : Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- (methoxymethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 41 (Compound 91):Scheme 28.

[0540] Synthesis of 1-(4-(methoxymethyl)phenyl)-3-nitro-1H-pyrazole, 28-3 [Step 1]: To a stirred solution of 3-nitro-1H-pyrazole (10-1, 100 mg, 0.89 mmol) in DCM (10 mL) was added pyridine ( 0.36 mL, 4.42 mmol) and (4-(methoxymethyl)phenyl)boronic acid (28-2, 294 mg, 1.77 mmol) followed by addition of Copper(ll) acetate (80 mg, 0.442 mmol) at ambient temperature under oxygen atmosphere and stirred for 16 h. The reaction mass was filtered through celite bed, and the bed was washed with DCM. The crude product was purified by flash chromatography to afford 1-(4-(methoxymethyl)phenyl)-3-nitro-1 H-pyrazole 10-1 (28-3, 100 mg). LCMS (ESI) Calcd. for C11H11N3O3: 233.22, found [M+H]+: 234.0. 1 H NMR (400 MHz, DMSO-d6) bH: 8.78 (d, 1 H), 7.91 (d, 2H), 7.52 (d, 2H), 7.35 (d, 1 H), 4.48 (s, 2H), 3.32 (s, 3H). NOE analysis confirmed the formation of desired product.

[0541] Synthesis of 1-(4-(methoxymethyl)phenyl)-1H-pyrazol-3-amine, 4 [Step 2]: To a stirred solution of 1-(4-(methoxymethyl)phenyl)-3-nitro-1H-pyrazole 10-1 (28-3, 60 mg, 0.25 mmol) in methanol (10 mL) was added 10% Pd / C (32 mg) and hydrogenated under hydrogen balloon pressure for 16h. The reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 1-(4-(methoxymethyl)phenyl)-1 H-pyrazol-3-amine (28-4, 50 mg). LCMS (ESI) Calcd. for C11H13N3O: 203.24, found [M+H]+: 204.0.

[0542] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- (methoxymethyl)phenyl)-1H-pyrazol-3-yl)urea, 6 [Step 3]: To a stirred solution of 1-(4- (methoxymethyl)phenyl)-1 H-pyrazol-3-amine (28-4, 50 mg, 0.39 mmol) in dichloromethane (6 mL) were added triethylamine (0.17 ml_, 1.23 mmol) and triphosgene (73 mg, 0.25 mmol) in dichloromethane (1.5 mL) at -15 °C and stirred for 30 min. A solution of (S)-8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 55 mg, 0.25 mmol) in dichloromethane (1.5 mL) was added to the reaction mixture and stirred for further 30 min at ambient temperature. The reaction mixture was diluted with dichloromethane and washed with water and brine, dried over anhydrous is^SCU, and concentrated under reduced pressure. The crude product was purified by preparative HPLC, lyophilized to afford to afford (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(4-(methoxymethyl)phenyl)-1 H-pyrazol-3-yl)urea (Example 41 (Compound 91), 18 mg). LCMS (ESI) Calcd. for C20H2OCIN5O3: 413.86, found [M+H]+: 414.24.1H NMR (400 MHz, DMSO-de) 0H: 9.19 (s, 1H), 8.34 (d, 1H), 8.13 (d, 1H), 7.70 (d, 3H), 7.50 (d, 1 H), 7.38 (d, 2H), 6.40 (s, 1 H), 4.92 (m, 1 H), 4.45- 4.38 (m, 4H), 2.07 (s, 1 H).Examples 42 & 43: Synthesis of (R)-1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1H-pyrazol-3-yl)-3- (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 42 (Compound 72) and (S)-1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1H-pyrazol-3-yl)-3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea, Example 43 (Compound 71):Scheme 29.

[0543] Synthesis of tert-butyl (S)-(3-(4-(3-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)ureido)-1 H-pyrazol-1-yl) phenyl )oxetan-3-y I (carbamate, 29-3 [Step 1]: To a stirred solution of tert-butyl (3-(4-(3-amino-1H-pyrazol-1-yl)phenyl)oxetan-3-yl)carbamate (1, 194 mg, 0.6 mmol) in dichloromethane (15 mL) was added triethyl amine (0.33 mL, 2.3 mmol) and Triphosgene (174 mg, 0.6 mmol) at -15 °C and stirred for 30 min at same temperature. A solution of (S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 200 mg, 0.908 mmol) and triethyl amine (0.25 mL, 4.5 mmol) in dichloromethane (5 mL) was added to the reaction mixture and the reaction mixture was allowed to stir for 60 min at same condition. The reaction mixture was diluted with dichloromethane, washed with water and brine. The organiclayer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by combi flash chromatography to afford tert-butyl (S)-(3-(4-(3-(3- (8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)ureido)-1 / - / -pyrazol-1-yl)phenyl)oxetan-3- yl)carbamate (29-3, 140 mg). LCMS (ESI) Calcd. for C26H29CIN6O5: 540.2, found [M+H]+: 541.0.

[0544] Synthesis of 1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1H-pyrazol-3-yl)-3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, 29-4 [Step 2]: tert-butyl (S)-(3-(4-(3-(3-(8-chloro-3.4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)-1H-pyrazol-1-yl)phenyl)oxetan-3-yl)carbamate (3, 100 mg, 0.18 mmol) was charged in a sealed tube and added Hexafluoro-2-propanol (4.0 ml_, 38.1 mmol). This was stirred at 100 °C for 24 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by prep HPLC and lyophilized to afford 1-(1- (4-(3-aminooxetan-3-yl)phenyl)-1 H-pyrazol-3-yl)-3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)urea (29-4, 39 mg); LCMS (ESI) Calcd. for C2iH2iCIN6O3:440.1 , found [M+H]+= 441.2.

[0545] Note: HPLC SFC development data showed 3:7 ratio of two peaks. Both the peaks were separated by SFC.

[0546] Synthesis of (R)-1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1H-pyrazol-3-yl)-3-(8-chloro-3.4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 42 (Compound 72) & (S)-1-(1-(4-(3- aminooxetan-3-yl)phenyl)-1 H-pyrazol-3-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, Example 43 (Compound 71) [Step 3]: 1-(1-(4-(3-aminooxetan-3-yl)phenyl)- 1H-pyrazol-3-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (29-4, 39 mg) was submitted for SFC prep purification. The fractions obtained were evaporated under reduced pressure and finally lyophilized to afford peak 1 as (R)-1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1 / - / - pyrazol-3-yl)-3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea (Example 42 (Compound 72), 6 mg) and peak 2 as (S)-1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1 / - / -pyrazol-3-yl)- 3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea (Example 43 (Compound 71), 15 mg). SFC method: SFC PREP PURIFICATION of 1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1H-pyrazol-3- yl)-3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)urea (4, 39 mg) was done on PIC SOLUTIONS-175 instrument equipped with Knauer 40D Detector by using Chiralpak IB (21.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 60 ml / min, using 50% CO2 in super critical state & 50%[ MeOH:ACN ] as Mobile phase, Run this isocratic mixture up to 15.0 minutes and also maintained the isobaric condition of 120 bar at 281 nm wavelength.

[0547] (R)-1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1H-pyrazol-3-yl)-3-(8-chloro-3,4-dihydro- 2 / 7-pyrano[3,2-b]pyridin-4-yl)urea, Example 42 (Compound 72) (Peak 1): LCMS (ESI): Calcd. for C2IH2ICIN6O3: 440.1 , found [M+H]+: 441.2. 1 H NMR (400 MHz, DMSO-d6) 6H: 9.21 (s, 1 H), 8.37-8.36 (m, 1H), 8.14 (d, 1 H), 7.74-7.71 (m, 2H), 7.65-7.60 (m, 2H), 7.57-7.55 (m, 1 H), 7.51- 7.50 (m,1H), 6.42 (s, 1H), 4.96-4.92 (m, 1 H) 4.71-4.70 (m, 2H), 4.66-4.65 (m, 2H), 4.48-4.36 (m, 2H), 2.57-2.56 (m, 1 H), 2.08-2.04 (m, 1 H).

[0548] (S)-1-(1-(4-(3-aminooxetan-3-yl)phenyl)-1H-pyrazol-3-yl)-3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea, Example 43 (Compound 71) (Peak 2): LCMS (ESI): Calcd. for C21H21CIN6O3: 440.1 , found [M+H]+: 441.2. 1 H NMR (400 MHz, DMSO-d6) 6H: 9.21 (s, 1 H), 8.37- 8.36 (m, 1 H), 8.14 (d, 1 H), 7.74-7.71 (m, 2H), 7.65-7.60 (m, 2H), 7.57-7.55 (m, 1 H), 7.51-7.50 (m,1 H), 6.42 (s, 1 H), 4.96-4.92 (m, 1 H) 4.71-4.70 (m, 2H), 4.66-4.65 (m, 2H), 4.48-4.36 (m, 2H), 2.57-2.56 (m, 1 H), 2.08-2.04 (m, 1 H)Example 44: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3- methylpyridin-2-yl)-1 H-pyrazol-3-yl)urea, Example 44 (Compound 76):Scheme 30.

[0549] Synthesis of 3-methyl-2-(3-nitro-1 H-pyrazol-1-yl)pyridine, 3 [Step 1]: To a solution of 3-nitro-1 H-pyrazole (10-1 , 50 mg, 0.44 mmol) and 2-iodo-3-methylpyridine (30-2, 145 mg, 0.66 mmol) in MeCN (10 mL) was added oven dry K2CO3(183 mg, 1.32 mmol) at ambient temperature and degassed with argon for 10 min followed by the addition of trans N,N-dimethyl cyclohexanedimine (0.07 mL, 0.44 mmol) and Cui (42 mg, 0.22 mmol). The reaction mixture was heated in a sealed tube at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by combi flash chromatography to afford 3-methyl-2-(3-nitro-1 H- pyrazol-1 -yl)pyridine (30-3, 90 mg). LCMS (ESI) Calcd. for C9H8N4O2: 204.19, found [M+H]+: 205.2. 1 H NMR (400 MHz, DMSO-d6) 6H: 8.58 (d, 1 H), 8.44 (d, 1 H), 7.99 (d, 1 H), 7.55-7.52 (m, 1 H), 7.31 (d, 1 H), 2.44 (s, 3H).

[0550] Synthesis of 1-(3-methylpyridin-2-yl)-1 H-pyrazol-3-amine, 30-4 [Step 2]: To a stirred solution of 3-methyl-2-(3-nitro-1 H-pyrazol-1-yl)pyridine (30-3, 90 mg, 0.44 mmol) in Methanol (10 mL) was added 10% Pd / C (56 mg) and hydrogenated under hydrogen balloon pressure for 16h. The reaction mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 1-(3-methylpyridin-2-yl)-1 H-pyrazol-3-amine (30-4, 80 mg). LCMS (ESI) Calcd. for C9H10N4: 174.2, found [M+H]+: 175.1. 1 H NMR (400 MHz, DMSO-d6) bH: 8.22 (d, 1 H), 8.07 (s, 1 H), 7.71 (d, 1 H),7.18-7.15 (m, 1 H) 5.73 (s, 1 H), 4.99 (d, 2H), 2.53 (s, 3H), 1.35 (s, 2H).

[0551] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3- methylpyridin-2-yl)-1 H-pyrazol-3-yl)urea, 6 [Step 3]: To a stirred solution of 1-(3-methylpyridin- 2-yl)-1 H-pyrazol-3-amine (30-4, 90 mg, 0.51 mmol) in dichloromethane (6 mL) were added triethylamine (0.43 mL, 3.09 mmol) and triphosgene (153 mg, 0.51 mmol) in dichloromethane (1 .5 mL) at 15 °C and stirred for 30 min A solution of (S) 8 chloro 3 4 dihydro 2H pyrano[3 2b]pyridin-4-amine hydrochloride (1-2, 114 mg, 0.51 mmol) in dichloromethane (1.5 mL) was added to the reaction mixture and stirred for 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 preparative HPLC, lyophilized to afford to afford (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(3-methylpyridin-2-yl)-1 H-pyrazol-3-yl)urea (Example 44 (Compound 76), 72 mg). LCMS (ESI) Calcd. for Ci8Hi7CIN6O2: 384.82, found [M+H]+: 385.18.1H NMR (400 MHz, DMSO-d6) bH: 9.20 (s, 1H), 8.29 -8.25 (m, 2H), 8.06 (d, 1H), 7.75 (d, 1 H), 7.46 (d, 2H), 7.26-7.24 (m, 1 H), 6.40 (s, 1 H), 4.97-4.93 (m, 1 H), 4.47-4.30 (m, 2H), 2.40-2.37 (m, 1H), 2.32 (s, 3H), 2.11- 2.05 (m, 1 H).Examples 45 & 46: Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(1-(4-((S)-1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 45 (Compound 80) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-(( / ?)-1- hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 46 (Compound 79):Scheme 31.

[0552] Synthesis of 1-(4-bromophenyl)ethan-1-ol, 31-2 [Step 1]: To a stirred solution of 1-(4- bromophenyl)ethan-1-one (31-1 , 2.00 g, 10.0 mmol) in methanol (20 mL) was added sodium borohydride (456 mg, 12.1 mmol) at 0°C and 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 afford 1-(4-bromophenyl)ethan-1-ol (31-2, 1.60 g). GCMS Calcd. for CsHsBrO: 199.98, found [M] = 199.9.1H NMR (400 MHz, DMSO-cfe): OH 7.51-7.47 (m, 2H), 7.31- 7.29 (m, 2H), 5.25 (d, 1 H), 4.71-4.67 (m, 1H), 1.29 (d, 3H).

[0553] Synthesis of 1-(4-(3-nitro-1H-pyrazol-1-yl)phenyl)ethan-1-ol, 31-4 [Step 2]: To a stirred solution of 1-(4-bromophenyl)ethan-1-ol (31-2, 1.0 g, 5.00 mmol) and 3-nitro-1 H-pyrazole 10-1 (3, 435 mg, 3.85 mmol) in acetonitrile (15 mL) was added anhydrous K2CO2(1.33 g, 9.62 mmol) at ambient temperature in a sealed tube and the reaction mixture was degassed with argon for 10 min followed by the addition of trans-N, / V-dimethyl cyclohexanedimine (0.60 mL, 3.85 mmol) andCui (366 mg, 1.92 mmol) and heated at 90 ° C for 16 h. Reaction mixture was cooled to ambient temperature, filtered through celite bed and the filtrate was concentrated under reduced pressure to get crude product. The crude product was purified by combi flash column chromatography to afford 1-(4-(3-nitro-1 H-pyrazol-1-yl)phenyl)ethan-1-ol (31-4, 790 mg). LCMS (ESI) Calcd. for C11H11N3O3: 233.08, found [M+H]+= 234.20.1H NMR (400 MHz, DMSO-cfe): 6H 8.76 (d, 1H), 7.86 (d, 2H), 7.54 (d, 2H), 7.35-7.32 (m, 1 H), 5.32 (d, 1H), 4.83-4.77 (m, 1H), 1.36-1.30(m, 3H).

[0554] Synthesis of 1-(4-(3-amino-1H-pyrazol-1-yl)phenyl)ethan-1-ol, 31-5 [Step 3]: To a stirred solution of 1-(4-(3-nitro-1 H-pyrazol-1-yl)phenyl)ethan-1-ol (31-4, 650 mg, 2.79 mmol) in ethanol (10 mL) and water (2.5 mL), ammonium chloride (1193 mg, 22.3 mmol) and Fe-powder (623 mg, 11.1 mmol) were added. The resulting mixture was allowed to reflux at 800C for 2 h. Reaction mixture was filtered through celite bed and extracted with ethyl acetate. Organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 1- (4-(3-amino-1H-pyrazol-1-yl)phenyl)ethan-1-ol (31-5, 550 mg). LCMS (ESI) Calcd. for C11H13N3O: 203.11 , found [M+H]+= 204.13.1H NMR (400 MHz, DMSO-cf6): OH 8.08 (s, 1 H), 7.57 (d, 2H), 7.34 (d, 2H), 5.76-5.71 (m, 1H), 5.12 (d, 1 H), 5.01 (s, 2H), 4.72-4.69 (m, 1 H), 1.32(d, 3H).

[0555] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-(1- hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, 31-7 [Step 4]: To a stirred solution of 1-(4-(3- amino-1 H-pyrazol-1-yl)phenyl)ethan-1-ol (31-5, 200 mg, 0.984 mmol) in dichloromethane (4 mL) was allowed to cool at -50C. Then triethylamine (0.82 mL, 5.90 mmol) followed by a solution of triphosgene (175 mg, 0.590 mmol) in dichloromethane (0.5 mL) were added to the solution dropwise at -5 ° C and allowed to stir for 15 min. Then a solution of (S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-amine hydrochloride (1-2, 435 mg, 1.97 mmol) in a mixture dichloromethane (2 mL) and triethylamine (0.4 mL) was added to the solution and allowed to stir at -5 ° C for 1 h. Reaction was diluted with water and extracted with dichloromethane. The combined organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude product. The product was purified by reverse phase preparative HPLC to afford 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-(1- hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea (31-7, 55 mg). LCMS (ESI) Calcd. for C20H20CIN5O3 :413.13, found [M+H]+= 414.21.1H NMR (400 MHz, DMSO-cfe): 0H9.18 (s, 1 H), 8.32 (s, 1 H), 8.14 (d, 1H), 7.66-7.64 (m, 3H), 7.51 (d, 1 H), 7.39 (d, 2H), 6.40 (s, 1 H), 5.18 (d, 1 H), 4.93-4.92 (m, 1 H), 4.73-4.72 (m, 1H), 4.48-4.45 (m, 1 H), 4.43-4.39 (m, 1 H), 2.07-2.03(m, 1 H), 1.33 (d, 3H). Note: 1 proton is missing which visible in MeOD.

[0556] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((S)-1- hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 45 (Compound 80) and 1-((S)-8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((R)-1 -hydroxyethyl)phenyl)-1H- pyrazol-3-yl)urea, Example 46 (Compound 79) [Step 5]: The racemic compound 1-((S)-8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-(1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea (31-7, 45 mg) was purified by SFC preparative HPLC (Method 1) to afford the first fraction 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((S)-1-hydroxyethyl)phenyl)- 1 H-pyrazol-3-yl)urea (b, 17 mg) as Peak 1 and the second fraction 1-((S)-8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((R)-1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea (c, 17 mg) as Peak 2 . Note: Peak 1 & Peak 2 are arbitrarily assigned.

[0557] Method 1 : HPLC SFC prep purification was done on PIC SOLUTIONS-175 instrument equipped with Knauer 40D Detector by using CHIRALPAK-IB (21.0 mm x 250 mm), 5p column operating at 35 °C temperature, maintaining flow rate of 70 ml / min, using 55 % CO2 in super critical state and 40% of 100% methanol as mobile phase. Run this isocratic mixture up to 25.0 minutes and also maintained the isobaric condition of 100 bar at 280 nm wavelength.

[0558] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((S)-1- hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 45 (Compound 80) [Peak 1]: LCMS (ESI) Calcd. for C20H20CIN5O3:413.13, found [M+H]+= 414.2.1H NMR (400 MHz, DMSO-cfe): OH9.22 (s, 1 H), 8.32 (d, 1 H), 8.14 (d, 1 H), 7.66-7.64 (m, 3H), 7.51 (d, 1 H), 7.39 (d, 2H), 6.40 (s, 1 H),5.23 (brs, 1 H), 4.95-4.92 (m, 1 H), 4.74-4.73 (m, 1 H), 4.45-4.43 (m, 1 H), 4.39-4.38 (m, 1 H), 2.07- 2.05(m, 1 H), 1.33 (d, 3H). Note: absolute stereochemistry was not determined.1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4-((R)-1- hydroxyethyl)phenyl)-1H-pyrazol-3-yl)urea, Example 46 (Compound 79) [Peak 2]: LCMS (ESI) Calcd. for C2oH2oCIN503:413.13, found [M+H]+= 414.2.1H NMR (400 MHz, DMSO-cfe): 0H9.22 (s, 1 H), 8.32 (d, 1 H), 8.14 (d, 1 H), 7.66-7.64 (m, 3H), 7.51 (d, 1 H), 7.39 (d, 2H), 6.40 (s, 1 H),5.23 (brs, 1 H), 4.94-4.92 (m, 1 H), 4.74-4.73 (m, 1 H), 4.45-4.43 (m, 1 H), 4.40-4.38 (m, 1 H), 2.07- 2.05(m, 1 H), 1.33 (d, 3H). Note: absolute stereochemistry was arbitrarily assigned.Example 47: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6- cyanopyridin-3-yl)-1 H-pyrazol-3-yl)urea, Example 47 (Compound 68):Int. of Compound 84 K2CO3, Cui, Example 47ACN, 90 °C, 16 h Compound 68Step 1Scheme 32.

[0559] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(6- cyanopyridin-3-yl)-1 H-pyrazol-3-yl)urea, Example 47 (Compound 68) [Step 1]: To a stirred solution of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1 H-pyrazol-3-yl)urea hydrochloride (20-4, 250 mg, 0.57 mmol) and K2CO3 (261 mg, 1.90 mmol) in Acetonitrile (8 mL)was added 5-bromopicolinonitrile (32-2, 228 mg, 1.14 mmol) at ambient temperature. The reaction mixture was degassed with argon for 10 min followed by addition of trans-N,N - Dimethylcyclohexane-1 ,2-diamine (0.12 mL, 0.75 mmol) and Cui (72 mg, 0.38 mmol). The reaction mixture was stirred at 800C for 16 h. The reaction mixture was dissolved in ethyl acetate and filtered through celite bed. The filtrate was washed by water (twice). The organic part was dried over anhydrous Na2SO4and evaporated to give the crude compound. The crude product was purified by Prep HPLC and lyophilized to give (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(1-(6-cyanopyridin-3-yl)-1 H-pyrazol-3-yl)urea (Example 47 (Compound 68), 30 mg). Formation of desired product was confirmed by NOE and COSY analysis. LCMS (ESI) Calcd. for CI8HI4CIN7O2: 395.09, found [M+H]+= 396.17.1H NMR (400 MHz, d6-DMSO) 0H: 9.43 (s, 1 H), 9.22 (d, 1 H), 8.63 (d, 1 H), 8.32-8.30 (m, 1 H), 8.16-8.14 (m, 1 H), 8.16-8.14 (m, 2H), 7.66 (brs, 1 H), 7.51 (d, 1 H), 6.61 (d, 1 H), 4.94-4.92 (m, 1 H), 4.45-4.40 (m, 2H), 2.53 (s, 1 H), 2.07-2.04 (m, 2H).Examples 48 & 49: Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(1-(3-fluoro-4-((R)-2,2,2-trifluoro-1 -hydro xyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 48 (Compound 63) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3- fluoro-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 49 (Compound 62):cyclohexanedimineStep 1Example 48 Example 49 Compound 63 Compound 62Absolute stereochemistry unknownScheme 33.

[0560] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3- fluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea, 3 [Step 1]: To a stirred solution of (S)-1 -(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1 H-pyrazol-3-yl)urea hydrochloride (20-4, 200 mg, 0.60 mmol) and K2CO3(209 mg, 1.51 mmol) in acetonitrile (6 mL) was added 1-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethan-1-ol (33-2, 215 mg, 0.78 mmol) at ambient temperature. The reaction mixture was degassed with argon for 10 min followed by addition of trans N,N-dimethyl cyclohexanedimine (0.1 mL, 0.60 mmol) and Cui (58 mg, 0.30mmol) and heated at 80 °C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through celite bed and the filtrate was concentrated under reduced pressure. The crude product was purified by prep HPLC and lyophilized to afford 1-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-fluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 H-pyrazol-3- yl)urea (33-3, 35 mg). LCMS (ESI) Calcd. for C2oHi6CIF4N503: 485.09, found [M+H]+= 486.2.

[0561] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3- fluoro-4-((R)-2,2,2-trifluoro-1 -hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 48 (Compound 63) and 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3- fluoro-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 49 (Compound 62) [Step 2]: 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3- fluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea (33-3, 25 mg, 0.05 mmol) were separated by chiral SFC to afford peak 1 assigned as 1-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-fluoro-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)-1 H-pyrazol- 3-yl)urea (Example 48 (Compound 63), 10 mg) and peak 2 assigned as 1-((S)-8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-fluoro-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)phenyl)- 1 H-pyrazol-3-yl)urea (Example 49 (Compound 62), 10 mg).

[0562] SFC method : Separation was performed on Waters SFC 150 instrument equipped with Waters 2489 UV / Visible Detector by using I Cellulose-Z (30 mm x 250 mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 1 10 mL / min, using 75% CO2in super critical state and 25% of 100% Methanol as mobile phase, run this isocratic mixture for 10 min and maintained the isobaric condition of 100 bar at 288 nm wavelength.

[0563] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-fluoro-4-((R)-2,2,2- trifluoro-1 -hydroxyethyl )phenyl)-1 H-pyrazol-3-yl)urea, Example 48 (Compound 63) (peak1): LCMS (ESI) Calcd. for C20H16CIF4N5O3: 485.09, found [M+H]+= 486.1 ;1H NMR (400 MHz, DMSO-d6J: 6H9.31 (s, 1 H), 8.45 (d, 1 H), 8.13 (d, 1 H), 7.69-7.63 (m, 4H), 7.51 (d, 1 H), 7.04 (brs, 1 H), 6.48 (s, 1 H), 5.36-5.34 (m, 1 H), 4.93-4.91 (m, 1 H), 4.45-4.38 (m, 2H), 2.08 (s, 2H).

[0564] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(3-fluoro-4-((S)-2,2,2- trifluoro-1-hydroxyethyl)phenyl)-1 H-pyrazol-3-yl)urea, Example 49 (Compound 62) (peak2): LCMS (ESI) Calcd. for C20HI6CIF4N5O3: 485.09, found [M+H]+= 486.1 ;1H NMR (400 MHz, DMSO-dg): 6H9.30 (s, 1 H), 8.45 (d, 1 H), 8.13 (d, 1 H), 7.69-7.63 (m, 4H), 7.51 (d, 1 H), 7.10 (brs, 1 H), 6.48 (s, 1 H), 5.36-5.34 (m, 1 H), 4.93-4.91 (m, 1 H), 4.45-4.38 (m, 2H), 2.10 (s, 2H).Example 55: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- cyanopyridin-2-yl)-1 H-pyrazol-3-yl)urea, Example 55 (Compound 60):Step 1Scheme 35.

[0565] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- cyanopyridin-2-yl)-1 H-pyrazol-3-yl)urea, Example 55 (Compound 60) [Step 1]: To a stirred solution of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1 H-pyrazol-3-yl)urea hydrochloride (20-4, 250 mg, 0.75 mmol) and K2CO3 (261 mg, 1.90 mmol) in acetonitrile (8 ml_) was added 2-bromoisonicotinonitrile (35-2, 208 mg, 1.14 mmol) at ambient temperature. The reaction mixture was degassed with argon for 10 min followed by addition of trans-N,N - dimethylcyclohexane-1 ,2-diamine (0.12 mL, 0.75 mmol) and Cui (72 mg, 0.38 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was dissolved in ethyl acetate and filtered through celite bed. The filtrate was washed by water (twice). The organic part was dried over anhydrous Na2SO4 and evaporated. The crude product was purified by Prep HPLC and lyophilized to give (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-(4- cyanopyridin-2-yl)-1 H-pyrazol-3-yl)urea (Example 55 (Compound 60), 18 mg). LCMS (ESI) Calcd. for C18H14CIN7O2: 395.09, found [M+H]+= 396.2.1H NMR (400 MHz, d6-DMSO) 6H: 10.60 (s, 1 H), 8.59 (d, 1 H), 8.25 (s, 1 H), 8.18-8.16 (m, 1 H), 8.12 (d, 1H), 7.76-7.74 (m, 1 H), 7.68 (d, 1 H), 7.48 (d, 1 H), 6.67 (s, 1 H), 4.99-4.94 (m, 1 H), 4.49-4.44 (s, 1 H), 4.32-4.27 (m, 1 H), 2.32-2.23 (m, 2H).Example 56: Synthesis of (S)-1-(8-cyclopropyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3- (1-phenyl-1 H-pyrazol-3-yl)urea, Example 56 (Compound 53):Scheme 36.

[0566] Synthesis of (S)-1-(8-cyclopropyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1- phenyl-1 H-pyrazol-3-yl)urea, Example 56 (Compound 53) [Step 1]: To a stirred solution of 1- phenyl-1 / 7-pyrazol-3-amine (36-1 , 50 mg, 0.3 mmol) in dichloromethane (9 mL) was added N,N- Diisopropylethylamine (0.33 mL, 1.9 mmol) at ambient temperature and stirred for 2 min. A solution of triphosgene (34 mg, 0.1 mmol) in dichloromethane (0.5 mL) was added drop wise into the reaction mixture at -15°C and stirred for 1 min at the same temperature. A solution of (S)-8- cyclopropyl-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-amine dihydrochloride (36-2, 83 mg, 0.3 mmol) in dichloromethane (0.5 mL) was added into the reaction mixture at -15°C and stir for 1 h at ambient temperature under nitrogen. The reaction mixture was diluted with dichloromethane and washed with water and followed by brine solution. The organic extract was dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The product was purified by reverse phase prep HPLC to afford (S)-1-(8-cyclopropyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)-3-(1-phenyl-1 H-pyrazol-3-yl)urea (Example 56 (Compound 53), 58 mg). LCMS (ESI) Calcd. for C21H21N5O2 : 375.2, found [M+H]+: 376.2.1H NMR (400 MHz, DMSO-d6) 0H: 9.16 (s, 1 H), 8.36-8.35 (m, 1 H), 8.04 (d, 1 H), 7.73-7.66 (m, 3H), 7.43 (t, 2H), 7.21 (t, 1 H), 6.78 (d, 1 H), 6.40 (brs, 1 H), 4.85-4.81 (m, 1 H), 4.40-4.35 (m, 1 H), 4.31-4.28 (m, 1 H), 2.16-2.10 (m, 1 H), 2.04-1.97 (m, 1 H), 1 .03-1.01 (m, 2H), 0.76-0.75 (m, 2H). One proton is merged with solvent peak at dH: 2.50.Example 57: Synthesis of (S)-1-(8-ethyl-3,4-dihydro-2H-pyrano[3,2-h]pyridin-4-yl)-3-(1- phenyl-1H-pyrazol-3-yl)urea, Example 57 (Compound 52):Step 1Scheme 37.

[0567] Synthesis of (S)-1-(8-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(1-phenyl- 1H-pyrazol-3-yl)urea, Example 57 (Compound 52) [Step 1]: To a stirred solution of 1-phenyl- 1 / - / -pyrazol-3-amine (36-1 , 50 mg, 0.3 mmol) in dichloromethane (9 mL) was added N,N- Diisopropylethylamine (0.33 mL, 1.9 mmol) at ambient temperature and stirred for 2 min. A solution of triphosgene (34 mg, 0.1 mmol) in dichloromethane (0.5 mL) was added drop wise into the reaction mixture at -15°C and stirred for 1 min at the same temperature. A solution of (S)-8- ethyl-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-amine dihydrochloride (37-2, 79 mg, 0.3 mmol) in dichloromethane (0.5 mL) was added into the reaction mixture at -15°C and stir for 1 h at ambient temperature under nitrogen The reaction mixture was diluted with dichloromethane and washedwith water and followed by brine solution. The organic extract was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by reverse phase prep HPLC to afford (S)-1-(8-ethyl-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)-3-(1-phenyl-1 / - / -pyrazol-3- yl)urea (Example 57 (Compound 52), 65 mg). LCMS (ESI) Calcd. for C20H21N5O2 : 363.2, found [M+H]+: 364.3.1H NMR (400 MHz, DMSO-d6) 6H : 9.16 (s, 1 H), 8.36-8.35 (m, 1 H), 8.1 1 (d, 1 H), 7.73-7.71 (m, 3H), 7.43 (t, 2H), 7.23-7.18 (m, 2H), 6.41 (brs, 1 H), 4.86-4.83 (m, 1 H), 4.38-4.33 (m, 1 H), 4.29-4.25 (m, 1 H), 2.60-2.55 (m, 2H), 2.03-1.96 (m, 1 H), 1.17-1.14 (m, 3H). One proton is merged with solvent peak at 6H : 2.50.Example 58: Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- cyclopropyl-1 H-imidazol-4-yl)thiazol-4-yl)urea, Example 58 (Compound 107):Scheme 38.

[0568] Synthesis of (1-cyclopropyl-4-iodo-1H-imidazole, 3 [Step 1]: To the solution 4-iodo-1 H- imidazole (38-1 , 5 g, 25.8 mmol) in DCE (150 mL) were added 2-(2-pyridyl)pyridine (4.0 g, 25.8 mmol), CU(OAC)2(4.7 g, 25.8 mmol), cyclopropylboronic acid (38-2, 3.8 g, 43.8 mmol) and K2CO3(7.1 g, 51.6 mmol) and stirred at ambient temperature for 24 h. The reaction mixture was filtered. Filtrate was concentrated and partitioned between water and EtOAc. The organic layer was collected and washed with a solution of 20% CuSO4in water, 10% aqueous NaOH and finally with brine. The organic layer was separated and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash to afford (1- cyclopropyl-4-iodo-1 H-imidazole (38-3, 2.4 g). LCMS Calcd. for C6H7IN2: 234.04, found [M+H]+: 234.92. 1H NMR (400 MHz, CDCI3): 6H7.56 (s, 1 H), 7.05 (s, 1 H), 3.37-3.32 (m, 1 H), 1.01-0.91 (m, 4H). Formation of desired product was confirmed by NOE analysis.

[0569] Synthesis of 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- imidazole, 38-4 [Step 2]: To a stirred solution of 1-cyclopropyl-4-iodo-1 H-imidazole (38-3, 500 mg, 2.14 mmol) in 1 ,4-dioxane (15 mL) was added dry KOAc (629 mg, 6.41 mmol), bis (pinacolato)diboron (2.2 g, 8.55 mmol) and the reaction mixture was degassed with argon for 10 min. Pd(dppf)CI2(313 mg, 0.43 mmol) was added to the reaction mixture and stirred at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through celite bed and washed with EtOAc. The filtrate was evaporated under reduced pressure to afford 1-cyclopropyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-imidazole (38-4, 1 g). Used this crude compound for forwarding step without purification. LCMS Calcd. for Ci2HigBN2O2: 234.1 , found [M+H]+: 234.95.

[0570] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- cyclopropyl-1 H-imidazol-4-yl)thiazol-4-yl)urea, Example 58 (Compound 107) [Step 3]: A suspension of (S)-1-(2-bromothiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)urea (38-5, 2.5 g, 6.42 mmol) and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)imidazole (38-4, 7.5 g, 16.0 mmol) in 1 ,4-dioxane (100 mL) and water (10 mL) was degassed with nitrogen and added K3PO4(3.75 g, 7.7 mmol) and Pd(dppf)CI2CH2CI2 (524 mg, 0.64 mmol) at ambient temperature. The reaction mixture was heated at 100 °C for 7 h. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography followed by prep HPLC and lyophilized to afford (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- cyclopropyl-1 H-imidazol-4-yl)thiazol-4-yl)urea (Example 58 (Compound 107), 418.55 mg). LCMS: Calcd. for Ci7Hi7CIN4O3: 416.88, found [M+H]+: 417.2. 1 H NMR (400 MHz, DMSO-cfe): OH 9.22 (s, 1 H), 8.1 1-8.10 (d, 1 H), 7.80 (d, 1 H), 7.58 (d, 1 H), 7.48-7.47 (d, 1H), 7.06-7.05 (d, 1 H), 7 (s, 1 H), 4.92-4.90 (m, 1 H), 4.44-4.42 (m, 1 H), 4.35-4.30 (m, 1 H), 3.58-3.54 (m, 1 H), 2.39-2.35 (m, 1 H), 2.09-2.06 (m, 1 H), 1.02-0.95 (m, 4H).Examples 59, 62 & 71-74 : Synthesis of 1-(2-acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea, Example 59 (Compound 198), 1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)urea, Example 62 (Compound 191), 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-1- hydroxyethyl)thiazol-4-yl)urea, Example 71 (Compound 176), 1-((S)-8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-1-hydroxyethyl)thiazol-4-yl)urea, Example 72 (Compound 175), 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-1- hydroxyethyl)thiazol-4-yl)urea, Example 73 (Compound 174), and 1-((R)-8-ch loro-3, 4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-1-hydroxyethyl)thiazol-4-yl)urea Example 74 (Compound 173):Scheme 39.

[0571] Synthesis of 2-bromo-4-chloropyridin-3-ol, 39-2 [Step 1]: Bromine (12.0 mL, 232 mmol) was added drop wise to 10% aqueous NaOH solution (400 mL) at -10 °C. and the reaction mixture was stirred at -10 °C for 5 min. 4-chloropyridin-3-ol (39-1 , 20 g, 154 mmol) was added portion wise at -10 °C. The reaction mixture was stirred at ambient temperature for 10 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with cold water and acidified up to pH~ 7 with concentrated HCI followed by pH~2 using portion wise addition of solid NaHSCU. The precipitate solid was filtered and dried under reduced pressure to afford 2-bromo-4-chloro-pyridin-3-ol (39-2, 18 g).1H NMR (400 MHz, DMSO-d6) 6H: 10.82 (brs, 1 H), 7.86 (d, 1 H), 7.51 (d, 1 H).

[0572] Synthesis of 2-bromo-3-(but-3-en-1-yloxy)-4-chloropyridine, 39-4 [Step 2]: To a stirred solution of 2-bromo-4-chloro-pyridin-3-ol (39-2, 5.0 g, 24 mmol) in acetonitrile (50 mL) were added potassium carbonate (9.9 g, 72 mmol) followed by 4-bromobut-1-ene (39-3, 2.9 g, 28.8 mmol) at ambient temperature. The reaction mixture was heated in a sealed tube at 80 °C for 16 h. Upon completion, the reaction mixture was diluted with ethyl acetate and washed with cold water followed by brine solution. The organic extract was dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by column chromatography to afford 2-bromo-3-(but-3-en-1-yloxy)-4-chloropyridine (39-4, 4.6 g). LCMS (ESI) Calculd. for CgHgBrCINO: 260.96, found [M+H]+= 262.1.

[0573] Synthesis of 8-chloro-4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine, 39-5 [Step 3]: To a stirred solution of 2-bromo-3-(but-3-en-1-yloxy)-4-chloropyridine (39-4, 5 g, 19 mmol) in DMF (50 mL) were added potassium acetate (9.4 g, 95.2 mmol), triphenyl phosphine (1.5 g, 5.71 mmol) and tetraethylammonium chloride (5.1 g, 30.5 mmol) at ambient temperature and degassed with argon for 10 mins. Palladium acetate (428 mg, 1.9 mmol) was added, and the resulting mixture was heated at 110 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate (twice). The combined organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by combi flash chromatography to afford 8-chloro-4-methylene-3,4-dihydro-2H-pyrano[3,2- b]pyridine (39-5, 2.8 g). LCMS (ESI) Calcd. for CgHsCINO: 181.03, found [M+H]+= 182.1

[0574] Synthesis of 8-chloro-4-(hydroxymethyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ol, 39-6 [Step 4]: To a stirred solution of 8-chloro-4-methylene-3,4-dihydro-2H-pyrano[3,2-b]pyridine (39-5, 4 g, 22 mmol) in DCM (60 mL) was added N-methyl morpholine N-oxide (7.7 g, 66.1 mmol) followed by OsO4 (4% in water) (12 mL, 5.51 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was forwarded to the next step immediately. LCMS (ESI) Calcd. for C9HI0CINO3: 215.03, found [M+H]+= 216.2

[0575] Synthesis of 8-chloro-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one, 39-7 [Step 5]: To a stirred solution of 8-chloro-4-(hydroxymethyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ol (39-6, 4.7 g, 21 .8 mmol) in THF (21 mL) and water (21 mL) was added NalO4(1.4 g, 65.4 mmol) 0 °C. The reaction mixture was stirred at 25 °C for 2 h. Progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with cold H2O, extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by combiflsh column chromatography to afford 8-chloro-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one (39-7, 2.7 g); LCMS (ESI) Calcd. for C8H6CINO2: 183.01 , found [M+H]+= 183.8

[0576] Synthesis of (E)-8-chloro-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one oxime, 39-8 [Step 6]: To a stirred solution of 8-chloro-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one (39-7, 2.5 g, 13.6 mmol) in methanol (37.5 mL) was added hydroxylammonium chloride (4.7 g, 68.1 mmol) at0 °C and reaction mixture was stirred at ambient temperature for 2 h. Progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. Water was added into it and the solid was filtered and concentrated under reduced pressure to afford (E)-8-chloro-2,3-dihydro-4H-pyrano[3,2-b]pyridin-4-one oxime (39-8, 2.7 g) which was used as such for the next reaction. LCMS (ESI) Calcd. for C8H7CIN2O2: 198.02, found [M+H]+= 198.9.

[0577] Synthesis of 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine, 39-9 [Step 7]: To a stirred solution of (E)-8-chloro-2,3-dihydropyrano[3,2-b]pyridin-4-one oxime (39-8, 2.7 g, 13.6 mmol) in ethanol (135 mL) was added ammonium acetate (5.24 g, 68 mmol) followed by aqueous ammonia (22 mL) and zinc dust (4.4 g, 68 mmol) at 0 °C. Reaction mixture was stirred for 20 min. Progress of reaction was monitored by TLC and LCMS. After completion, reaction mixture was filtered through sintered funnel and washed with ethyl acetate (twice). Filtrate was concentrated under reduced pressure to afford 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine (9, 2.5 g). CMS (ESI) Calcd. for C8H9CIN2O: 184.04, found [M+H]+= 185.2.

[0578] Synthesis of tert-butyl (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)carbamate, 39-10 [Step 8]: To a suspension of 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-amine (39-9, 2.5 g, 13.5 mmol) in dichloromethane (75 mL) was added Triethylamine (5.7 mL, 40.6 mmol) followed by Boc anhydride (16 mL, 67.7 mmol) at ice cold condition. The reaction mixture was allowed to stir at ambient temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over anhydrous Na2SO4and concentrated under reduced pressure. The product was purified by combi flash chromatography to afford tert-butyl (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)carbamate (39-10, 2.2 g). LCMS (ESI) Calcd. for C13H17CIN2O3: 284.09, found [M+H]+= 284.9.

[0579] Synthesis of 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride, 1-2 [Step 9]: To a clear solution of tert-butyl (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)carbamate (39-10, 750 mg, 2.6 mmol) in 1 ,4-Dioxane (5 mL) was added 4M HCI in Dioxane (4.0 mL, 13.2 mmol) at ice cold condition. The reaction mixture was allowed to stir at ambient temperature for 2 h. The reaction was monitored by LCMS. Upon completion, volatiles were evaporated under reduced pressure to afford 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- amine hydrochloride (1-2, 582 mg). LCMS (ESI) Calcd. for C8Hi0Cl2N2O: 184.04, found [M+H]+= 185.0.

[0580] Synthesis of 1-(2-bromothiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, 38-5 [Step 10]: To a stirred solution of tert-butyl N-(2-bromothiazol-4- yl)carbamate (39-12, 126 mg, 0.45 mmol) in DCM (5 mL) were added 2-chloropyridine (0.13 mL, 1.4 mmol), trifluoromethanesulfonic anhydride (0.11 mL, 0.68 mmol) at ice cold condition and stirred at ambient temperature for 50 min. A solution of triethylamine (0.32 mL, 2.3 mmol), and 8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine;hydrochloride (1-2, 50 mg, 0.23 mmol) indichloromethane (4 mL) were added at ice cold condition and the reaction mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with DCM and washed with water. Organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by flash chromatography to afford 1-(2-bromothiazol-4-yl)-3- (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 60 mg). LCMS (ESI) Calcd. for Ci2HioBrCIN402S: 387.94, found [M+H]+= 391.1.

[0581] Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- ethoxyvinyl)thiazol-4-yl)urea, 39-15 [Step 11]: To a stirred solution of 1-(2-bromothiazol-4-yl)- 3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 60 mg, 0.15 mmol) in 1 ,4- Dioxane (4 mL) at ambient temperature was added tributyl(1-ethoxyvinyl)stannane (39-14, 0.1 mL, 0.31 mmol). The reaction mixture was degassed with N2for 10 min. Bis(triphenylphosphine)palladium(ll) dichloride (1 1 mg, 0.015 mmol) was added into the reaction mixture and heated to 100 ° C for 2 h. The reaction mixture was filtered through celite bed and washed with Ethyl acetate (twice). Filtrate was washed with water followed by brine solution. The combined organic extract was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- ethoxyvinyl)thiazol-4-yl)urea (39-15, 58 mg). LCMS (ESI) Calcd. for C16H17CIN4O3S: 380.07, found [M+H]+= 381.0.

[0582] Synthesis of 1-(2-acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, Example 59 (Compound 198) [Step 12]: To a stirred solution of 1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-ethoxyvinyl)thiazol-4-yl)urea (15, 58 mg, 0.15 mmol) in 1 ,4-Dioxane (1.2 mL) was added 2 N aqueous HCI (1.2 mL) at ice cold condition and stirred at ambient temperature for 2h. Volatiles were evaporated under reduced pressure. The product was purified by reverse phase prep HPLC to afford 1-(2-acetylthiazol-4-yl)-3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (Example 59 (Compound 198) , 24 mg). LCMS (ESI) Calcd. for Ci4Hi3CIN4O3S: 352.04, found [M+H]+: 353.1.1H NMR (400 MHz, DMSO- d6) 6H: 9.71 (s, 1 H), 8.10 (d, 1 H), 7.69 (s, 1 H), 7.47 (d, 1 H), 6.97-6.95 (m, 1 H), 4.96-4.91 (m, 1 H), 4.47-4.42 (m, 1 H), 4.37-4.32 (m, 1 H), 2.58 (s, 3H), 2.42-2.37 (m, 1 H), 2.12-2.04 (m, 1 H).

[0583] Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(2- hydroxypropan-2-yl)thiazol-4-yl)urea, Example 62 (Compound 191 ) [Step 13]: To a stirred solution of 1-(2-acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (Example 59 (Compound 198) , 30 mg, 0.08 mmol) in THF (2 mL) was added methyllithium, 1 .6 M in diethyl ether (0.13 mL, 0.21 mmol) at -78 °C and stirred at same temperature for 1 h. The reaction mixture was warmed to ambient temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous NH4CI at 0 °C and extracted with ethyl acetate (twice). The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by RP preparative HPLC and lyophilized to afford 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)urea (Example 62 (Compound 191), 8 mg). LCMS (ESI) Calcd. for C15H17CIN4O3S: 368.07, found [M+H]+: 369.1. 1 HNMR (400 MHz, DMSO-d6) 6H: 9.27 (s, 1 H), 8.09-8.08 (m, 1 H), 7.47-7.46 (m, 1 H), 6.96-6.93 (m, 2H), 5.89 (s, 1 H), 4.93-4.88 (m, 1 H), 4.47-4.41 (m, 1 H), 4.35-4.29 (m, 1 H), 2.37-2.32 (m, 1 H), 2.08-2.04 (m, 1 H), 1.42-1.35 (m, 6H).

[0584] Synthesis of (S)-1-(2-acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea, 39-18 and (R)-1-(2-acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea, 39-19 [Step 14]: Enantiomers of 1-(2-acetylthiazol-4-yl)-3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (Example 59 (Compound 198), 202 mg, 0.6 mmol) were separated by chiral HPLC-SFC to afford peak 1 assigned as (S)-1-(2- acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (39-18, 65 mg) and peak 2 assigned as (R)-1-(2-acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)urea (39-19, 65 mg). Absolute stereochemistry was arbitrarily assigned.

[0585] SFC method: Separation was performed on Waters SFC150 instrument equipped with Waters 2489 UV / Visible Detector by using (R,R)Whelk-O1 (21 .1 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 ml / min, using 80% CO2 in super critical state & 20%[ 0.1 %IPAmine in IPA) as Mobile phase, Run this isocratic mixture up to 19.0 minutes and also maintained the isobaric condition of 110 bar at 220 nm wavelength. Absolute stereochemistry was arbitrarily assumed.

[0586] (S)-1-(2-acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)urea, 39-18 (Peak 1): LCMS (ESI) Calcd. for C14H13CIN4O3S: 352.04, found [M+H]+= 353.

[0587] (R)-1-(2-acetylthiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yljurea, 39-19 (Peak 2): LCMS (ESI) Calcd. for C14H13CIN4O3S: 352.04, found [M+H]+= 353.2

[0588] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- hydroxyethyl)thiazol-4-yl)urea, 39-20 [Step 15]: To a stirred solution of (S)-1-(2-acetylthiazol- 4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (39-19, 65 mg, 0.2 mmol) in methanol (6 mL) was added sodium borohydride (14 mg, 0.4 mmol) at 0 °C and stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with 10% methanol in dichloromethane. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product which was purified by preparative HPLC, and the residue was lyophilized to afford 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3- (2-(1-hydroxyethyl)thiazol-4-yl)urea (39-20, 38 mg). LCMS (ESI) Calcd. for C^HisCI^ChS: 354.06, found [M+H]+= 354.8.

[0589] Synthesis of 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-1- hydroxyethyl)thiazol-4-yl)urea, Example 71 (Compound 176) and 1-((S)-8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-1-hydroxyethyl)thiazol-4-yl)urea, Example 72 (Compound 175) [Step 16]: 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-hydroxyethyl)thiazol-4-yl)urea (39-20, 67 mg, 0.2 mmol) were separated by chiral HPLC-SFC to afford peak 1 as 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-1- hydroxyethyl)thiazol-4-yl)urea (Example 71 (Compound 176), 31 mg) and peak 2 assigned as 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-1-hydroxyethyl)thiazol-4- yl)urea (Example 72 (Compound 175), 28 mg). Absolute stereochemistry unknown.

[0590] SFC method: Separation was performed on Waters SFC150 instrument equipped with Waters 2489 UV / Visible Detector by using C Amylose A(30.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 100 ml / min, using 55% CO2 in super critical state & 45%[MeOH : ACN(1 :1) ] as Mobile phase, Run this isocratic mixture up to 7.0 minutes and also maintained the isobaric condition of 100 bar at 281 nm wavelength. Absolute stereochemistry was not determined and arbitrarily assigned.

[0591] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-1- hydroxyethyl)thiazol-4-yl)urea, Example 71 (Compound 176) (Peak 1): LCMS (ESI) Calcd. for C14H15CIN4O3S: 354.06, found [M+H]+: 355.1 ,1H NMR (400 MHz, DMSO-cfe): 0H9.23 (s, 1 H), 8.09 (d, 1 H), 7.47 (d, 1 H), 7.02 (s, 1 H), 6.94 (d, 1 H), 6.04 (d, 1 H), 4.91-4.83 (m, 2H), 4.44-4.41 (m, 1 H), 4.35-4.33 (m, 1 H), 2.35-2.33 (m, 1 H), 2.15-1.95 (m, 1 H), 1.40 (d, 3H).

[0592] 1-((S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-1- hydroxyethyl)thiazol-4-yl)urea, Example 72 (Compound 175) (Peak 2): LCMS (ESI) Calcd. for C14H15CIN4O3S: 354.06, found [M+H]+: 355.1.1H NMR (400 MHz, DMSO-cfe): 6H 9.20 (s, 1 H), 8.09 (d, 1 H), 7.47 (d, 1 H), 7.03 (s, 1 H), 6.91 (d, 1 H), 6.04 (d, 1 H), 4.91-4.83 (m, 2H), 4.44-4.42 (m, 1 H), 4.34-4.32 (m, 1 H), 2.34-2.33 (m, 1 H), 2.15-1.95 (m, 1 H), 1.40 (d, 3H).

[0593] Synthesis of 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- hydroxyethyl)thiazol-4-yl)urea, 39-21 [Step 17]: To a stirred solution of (R)-1-(2-acetylthiazol- 4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (39-19, 65 mg, 0.2 mmol) in methanol (6 mL) was added sodium borohydride (14 mg, 0.4 mmol) at 0 °C and stirred at ambient temperature for 1 h. The reaction mixture was diluted with water and extracted with 10% methanol in dichloromethane. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by preparative HPLC, and the residue was lyophilized to afford 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2- (1-hydroxyethyl)thiazol-4-yl)urea (39-21 , 42 mg).

[0594] Synthesis of 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-1- hydroxyethyl)thiazol-4-yl)urea, Example 73 (Compound 174) and 1-((R)-8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-1-hydroxyethyl)thiazol-4-yl)urea, Example 74 (Compound 173) [Step 18]: 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2- (1-hydroxyethyl)thiazol-4-yl)urea (3, 64 mg, 0.2 mmol) were separated by chiral HPLC-SFC to afford peak 1 as 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-1- hydroxyethyl)thiazol-4-yl)urea (Example 73 (Compound 174), 24 mg) and peak 2 assigned as1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-1-hydroxyethyl)thiazol-4- yl)urea (Example 74 (Compound 173), 23 mg). Absolute stereochemistry unknown.

[0595] SFC method : Separation was performed in Waters SFC150 instrument equipped with Waters 2489 UV / Visible Detector by using C Amylose A(30.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 100 ml / min, using 60% CO2 in super critical state & 40%[MeOH : ACN(1 :1) ] as Mobile phase, Run this isocratic mixture up to 15.0 minutes and also maintained the isobaric condition of 100 bar at 281 nm wavelength. Absolute stereochemistry was not determined and arbitrarily assigned.

[0596] 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-1- hydroxyethyl)thiazol-4-yl)urea, Example 73 (Compound 174) (Peak 1): LCMS (ESI) Calcd. for C14H15CIN4O3S: 354.06, found [M+H]+: 355.1.1H NMR (400 MHz, DMSO-cfe): 0H9.21 (s, 1 H), 8.09 (d, 1 H), 7.47 (d, 1 H), 7.03 (s, 1 H), 6.93 (d, 1 H), 6.04 (bs, 1 H), 4.91-4.84 (m, 2H), 4.46- 4.41 (m, 1 H), 4.34-4.30 (m, 1 H), 2.37-2.33 (m, 1 H), 2.07-2.04 (m, 1 H), 1.40 (d, 3H).

[0597] 1-((R)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-1- hydroxyethyl)thiazol-4-yl)urea, Example 74 (Compound 173) (Peak 2): LCMS (ESI) Calcd. For C14H15CIN4O3S: 354.06, found [M+H]+: 355.1.1H NMR (400 MHz, DMSO-d6): OH 1 H NMR (400 MHz, DMSO-cfe): 0H9.25 (s, 1 H), 8.09 (d, 1 H), 7.46 (d, 1 H), 7.02 (s, 1 H), 6.97 (d, 1 H), 6.05 (bs, 1 H), 4.91-4.83 (m, 2H), 4.44-4.42 (m, 1 H), 4.35-4.33 (m, 1 H), 2.35-2.33 (m, 1 H), 2.07-2.04 (m, 1 H), 1.40 (d, 3H).Examples 60 & 61 : Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)thiazol-4-yl)urea, Example 60 (Compound 197) & (R)- 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 H-pyrazol-4- yl)thiazol-4-yl)urea, Example 61 (Compound 196):Example 60 Example 61(Compound 197) (Compound 196)Scheme 40.

[0598] Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, 40-3 [Step 1]: To a suspension of 1-(2-bromothiazol-4- yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 100 mg, 0.26 mmol) and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (40-2, 96 mg, 0.4 mmol) in 1 ,4-Dioxane (4.5 mL) and water (1.5 mL) was added K2CO3(71 mg, 0.5 mmol) and degassed with argon for 10 min. Pd(dppf)CI2 (19 mg, 0.026 mmol) was added to it and heated at 90 °C for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water followed by brine solution. The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure and purified by column chromatography to afford 1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea (40-3, 85 mg). LCMS (ESI) Calcd. for C- H- CiN.-O -S: 432.08, found [M+H]+: 433.2.

[0599] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- (oxetan-3-yl)-1H-pyrazol-4-yl)thiazol-4-yl)urea, Example 60 (Compound 197) & (R)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 H-pyrazol-4- yl)thiazol-4-yl)urea, Example 61 (Compound 196) [Step 2]: The racemic compound 1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)thiazol-4- yl)urea (40-3, 85 mg, 0.2 mmol) was separated by SFC and lyophilized to afford Peak 1 as (S)-1- (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)thiazol- 4-yl)urea (Example 60 (Compound 197), 29 mg) and Peak 2 as (R)-1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea (Example 61 (Compound 196), 30 mg). The stereochemistry was arbitrarily assigned.

[0600] SFC method: HPLC SFC Prep Purification of CR620-SJ2-2023-1 1-34-P sample is currently running on Waters SFC150 instrument equipped with Waters 2489 UV / Visible Detector by using (R,R)Whelk-O1 (21.1 mm x 250mm), 5p Column operating at 350C temperature, maintaining flow rate of 70 ml / min, using 65% CO2 in super critical state & 35% [100% MeOH] as Mobile phase, Run this isocratic mixture up to 15.0 minutes and also maintained the isobaric condition of 100 bar at 225 nm wavelength.

[0601] (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 H- pyrazol-4-yl)thiazol-4-yl)urea, Example 60 (Compound 197) (Peak 1): LCMS (ESI): Calcd. for CisHvCINsOsS: 432.08, found [M+H]+: 433.1 .1H NMR (400 MHz, DMSO-d6at 20°C) 6H: 9.39 (bs, 1 H), 8.42 (s, 1 H), 8.11-8.10 (m, 1 H), 7.99 (s, 1 H), 7.48-7.47 (m, 1 H), 7.06 (s, 1 H), 7.02-7.00 (m, 1 H), 5.66-5.59 (m, 1 H), 4.95-4.89 (m, 5H), 4.48-4.42 (m, 1 H), 4.36-4.31 (m, 1 H), 2.39-2.32 (m, 1 H), 2.10-2.05 (m, 1 H).

[0602] (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(oxetan-3-yl)-1 H- pyrazol-4-yl)thiazol-4-yl)urea, Example 61 (Compound 196) (Peak 2): LCMS (ESI): Calcd. for CI8HI7CIN6O3S: 432.08, found [M+H]+: 433.1.1H NMR (400 MHz, DMSO-d6 at 20°C) 6H: 9.38 (bs, 1 H), 8.42 (s, 1 H), 8.11-8.10 (m, 1 H), 7.99 (s, 1 H), 7.48-7.47 (m, 1 H), 7.06 (s, 1 H), 7.01-7.00 (m, 1 H), 5.66-5.59 (m, 1 H), 4.95-4.91 (m, 5H), 4.48-4.42 (m, 1 H), 4.36-4.31 (m, 1 H), 2.40-2.32 (m, 1 H), 2.1 1-1.99 (m, 1 H).Example 63: Synthesis of 4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)-2-fluoro-A / -methylbenzamide, Example 63 (Compound 188):Step 1 (Compound 188) Scheme 41.

[0603] Synthesis4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)-2-fluoro-A / -methylbenzamide, Example 63 (Compound 188) [Step 1]: To a stirred solution of 1-(2-bromothiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea (38-5, 200 mg, 0.5 mmol) in 1 ,4-dioxane (8 mL) and water (2 mL) were added 2-fluoro- / V-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzamide (41-2, 143 mg, 0.5 mmol) and K3PO4 (218 mg, 1.0 mmol). The reaction mixture was degassed with argon for 10 min. Pd-1 18 (33 mg, 0.05 mmol) was added into the reaction mixture and the reaction mixture was allowed to stir at 80 °C for 2h. The reaction mixture was filtered through celite pad and washed with 10% methanol in dichloromethane. Filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase prep HPLC and lyophilised to afford 4-(4-(3-(8- chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)-2-fluoro-A / -methylbenzamide (Example 63 (Compound 188), 55 mg). LCMS (ESI) Calcd. for C20H17CIFN5O3S: 461.1 , found [M+H]+: 462.1.1H NMR (400 MHz, DMSO-cfe) <5«: 9.52 (s, 1 H), 8.33 (brs, 1 H), 8.12-8.11 (m, 1 H), 7.77-7.71 (m, 3H), 7.49-7.48 (m, 1 H), 7.33 (s, 1 H)7. 14-7.13 (m, 1 H), 4.95-4.93 (m, 1 H), 4.47-4.43 (m, 1 H), 4.37-4.35 (m, 1 H), 2.79-2.78 (m, 3H), 2.43-2.40 (m, 1 H), 2.09-2.07 (m, 1 H).Example 64 & 65: Synthesis of (R)-4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide, Example 64 (Compound 187) and (S)-4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)- N-((3-methyloxetan-3-yl)methyl)benzamide, Example 65 (Compound 186):Peak 2Absolute stereochemistry unknownScheme 42.

[0604] Synthesis of methyl 4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)benzoate, 42-3 [Step 1]: To a solution of 1-(2-bromothiazol-4-yl)-3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 150 mg, 0.38 mmol) and methyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (42-2, 151 mg, 0.58 mmol) in 1 ,4- Dioxane (6 mL) and water (1 .5 mL) was added K3PO4(163 mg, 0.770 mmol). The reaction mixture was purged with argon for 10 min. Pd-1 18 (25 mg, 0.04 mmol) was added to it and heated at 80 ° C for 1.5 h. The reaction mixture was filtered through celite bed, and the bed was washed with 10% MeOH in DCM. Combined filtrate was concentrated under reduced pressure and purified under flash column chromatography to afford methyl 4-(4-(3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)benzoate (42-3, 100 mg). LCMS (ESI) Calcd. for C20H17CIN4O4S: 444.1 , found [M+H]+: 445.2.

[0605] Synthesis of 4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)benzoic acid, 42-4 [Step 2]: To a stirred solution of methyl 4-(4-(3-(8- chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)benzoate (42-3, 100 mg, 0.22 mmol) in tetrahydrofuran (6 mL) and water (1.25 mL) was added LiOH.H2O (28 mg, 0.67 mmol) and stirred for overnight at ambient temperature. The reaction mixture was neutralized with 1 N HCI and lyophilized to afford 4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)benzoic acid (42-4, 96 mg). LCMS (ESI) Calcd. for C19H15CIN4O4S: 430.1 , found [M+H]+: 431.

[0606] Synthesis of 4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)-N-((3-methyloxetan-3-yl)methyl)benzamide, 42-6 [Step 3]: To a stirred solution of (3-methyloxetan-3-yl)methanamine (9-5, 0.03 mL, 0.26 mmol) in DMF (4 mL) were added 4-(4-(3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)benzoic acid (42-4, 104 mg, 0.24 mmol) and N,N-Diisopropylethylamine (0.11 mL, 0.60 mmol) followed by HATU (1 10 mg, 0.29 mmol) and stirred for 90 min at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with ice cooled water (thrice). The organic layer was dried over anhydrous Na2SC>4 and evaporated under reduce pressure. The crude product was purified by reverse phase prep HPLC and lyophilized to afford 4-(4-(3-(8-chloro-3,4-dihydro-2 / - / - pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)- / V-((3-methyloxetan-3-yl)methyl)benzamide (42-6, 72 mg). LCMS (ESI) Calcd. for C24H24CIN5O4S: 513.1 , found [M+H]+= 514.2.

[0607] Synthesis of (R)-4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)- / V-((3-methyloxetan-3-yl)methyl)benzamide, Example 64 (Compound 187) and (S)-4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)- N-((3-methyloxetan-3-yl)methyl)benzamide, Example 65 (Compound 186) [Step 4]: 4-(4-(3- (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)-A / -((3-methyloxetan-3- yl)methyl)benzamide (6, 72 mg, 0.14 mmol) was separated by SFC and lyophilized to afford the Peak 1 as (R)-4-(4-(3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)- / \ / -((3-methyloxetan-3-yl)methyl)benzamide (Example 64 (Compound 187), 27 mg) and Peak 2 as (S)-4-(4-(3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)-A / -((3- methyloxetan-3-yl) methyl) benzamide (Example 65 (Compound 186), 29 mg).The stereochemistry was arbitrarily taken.

[0608] SFC method: PLC SFC Prep Purification of CR620-AM2-2023-06-17-1-P sample is running in Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using Chiralpak IB (21.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 ml / min, using 50% CO2 in super critical state & 50% of 100% Methanol as Mobile phase, Run this isocratic mixture up to 15.0 minutes and also maintained the isobaric condition of 100 bar at 220 nm wavelength.

[0609] (R)-4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)- A / -((3-methyloxetan-3-yl)methyl)benzamide, Example 64 (Compound 187) (Peak 1): LCMS (ESI) Calcd. for C24H24CIN5O4S: 513.1 , found [M+H]+: 514.2.1H NMR (400 MHz, DMSO-d6): OH 9.56 (s, 1 H), 8.73 (t, 1 H), 8.12 (d, 1 H), 7.96 (s, 4H), 7.48 (d, 1 H), 7.30 (s, 1 H), 7.08 (m, 1 H), 4.97 (m, 1 H), 4.42 (m, 3H), 4.33 (m, 1 H), 4.21 (d, 2H), 3.48 (d, 2H), 2.41 (m, 1 H), 2.08 (m, 1 H), 1.25 (s, 3H).

[0610] (S)-4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)- N-((3-methyloxetan-3-yl)methyl)benzamide, Example 65 (Compound 186) (Peak 2): LCMS (ESI) Calcd. for C24H24CIN5O4S: 513.1 , found [M+H]+: 514.2.1H NMR (400 MHz, DMSO-de): 0H9.56 (s, 1 H), 8.73 (t, 1 H), 8.12 (d, 1 H), 7.96 (s, 4H), 7.48 (d, 1 H), 7.30 (s, 1 H), 7.08 (m, 1 H), 4.97 (m, 1 H), 4.42 (m, 3H), 4.33 (m, 1 H), 4.21 (d, 2H), 3.48 (d, 2H), 2.41 (m, 1 H), 2.08 (m, 1 H), 1.25 (s, 3H).Examples 66 & 67: Synthesis of (S)-1-(2-(4-(2-aminopropan-2-yl)phenyl)thiazol-4-yl)-3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 66 (Compound 184) & (R)- 1-(2-(4-(2-aminopropan-2-yl)phenyl)thiazol-4-yl)-3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)urea, Example 67 (Compound 183):Scheme 43.

[0611] Synthesis of tert-butyl (2-(4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)phenyl)propan-2-yl)carbamate, 43-3 [Step 1]: ferf-butyl (2- (4- (4- (3- (8- chloro-3,4-dihydro-2 / 7-pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)phenyl)propan-2- yl)carbamate was synthesized following step 1 , Scheme 42 using (4-(2-((ferf- butoxycarbonyl)amino)propan-2-yl)phenyl)boronic acid (3-4). LCMS (ESI) Calcd. for C26H30CIN5O4S: 543.2, found [M+H]+= 544.3.

[0612] Synthesis of tert-butyl (S)-(2-(4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)ureido)thiazol-2-yl)phenyl)propan-2-yl)carbamate, 4 & tert-butyl (R)-(2-(4-(4-(3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)phenyl)propan-2- yl)carbamate, 43-5 [Step 2]: ferf-butyl (2-(4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin- 4-yl)ureido)thiazol-2-yl)phenyl)propan-2-yl)carbamate (43-3, 100 mg, 0.2 mmol) was separated by SFC and lyophilized to afford Peak 1 as ferf-butyl (S)-(2-(4-(4-(3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2-yl)phenyl)propan-2-yl)carbamate (43-4, 39 mg) and Peak 2 as ferf-butyl (R)-(2-(4-(4-(3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)phenyl)propan-2-yl)carbamate (43-5, 35 mg). Absolute stereochemistry unknown.

[0613] SFC method: HPLC SFC Prep Purification of has been done on Waters SFC PREP 150 instrument equipped with Waters 2489 UV / Visible Detector by using Chiralpak-IC (30 mm x 250 mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 100 ml / min, using 50% CO2in super critical state & 50% of 100% Methanol as Mobile phase. Run this isocratic mixture up to 10.0 minutes and maintained the isobaric condition of 110 bar at 230 nm wavelength.

[0614] ferf-butyl (S)-(2-(4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)phenyl)propan-2-yl)carbamate, 43-4 (Peak 1): LCMS (ESI) Calcd. for C26H30CIN5O4S: 543.2, found [M+H]+: 544.4.

[0615] ferf-butyl (R)-(2-(4-(4-(3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)phenyl)propan-2-yl)carbamate, 43-5 (Peak 2): LCMS (ESI) Calcd. for C26H30CIN5O4S: 543.2, found [M+H]+: 544.3.

[0616] Synthesis of (S)-1-(2-(4-(2-aminopropan-2-yl)phenyl)thiazol-4-yl)-3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 66 (Compound 184) [Step 3]: To a stirred solution of ferf-butyl (S)-(2-(4-(4-(3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)phenyl)propan-2-yl)carbamate (43-4, 30 mg, 0.05 mmol) in dichloromethane (1 mL) was added 4M HCI in dioxane (0.14 mL, 0.5 mmol) at ice cold condition. The reaction mixture was allowed to stir at ambient temperature for 8 h. Volatiles were evaporated under reduced pressure. The product was purified by reverse phase prep HPLC and lyophilized to afford (S)-1-(2-(4-(2-aminopropan-2-yl)phenyl)thiazol-4-yl)-3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)urea (Example 66 (Compound 184), 12 mg). LCMS (ESI) Calcd. for C21H22CIN5O2S: 443.1 , found [M+H]+: 444.2.1H NMR (400 MHz, DMSO-cfs) 6H: 9.48 (s, 1 H), 8.12-8.1 1 (m, 1 H), 7.80-7.78 (m, 2H), 7.64-7.63 (m, 2H), 7.49-7.48 (m, 1 H), 7.17 (s, 1 H), 7.07-7.05 (m, 1 H), 4.96-4.91 (m, 1 H), 4.48-4.43 (m, 1 H), 4.37-4.32 (m, 1 H), 2.45-2.37 (m, 1 H), 2.12-2.05 (m, 1 H), 1.40 (s, 6H). Two amine protons are exchangeable. Absolute stereochemistry unknown.

[0617] Synthesis of (R)-1-(2-(4-(2-aminopropan-2-yl)phenyl)thiazol-4-yl)-3-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea, Example 67 (Compound 183) [Step 4]: To a stirred solution of tert-butyl (R)-(2-(4-(4-(3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4- yl)ureido)thiazol-2-yl)phenyl)propan-2-yl)carbamate (43-5, 35 mg, 0.06 mmol) in dichloromethane (1 mL) was added 4M HCI in dioxane (0.16 ml_, 0.6 mmol) at ice cold condition. The reaction mixture was allowed to stir at ambient temperature for 8 h. Volatiles were evaporated under reduced pressure. The product was purified by reverse phase prep HPLC and lyophilized to afford (R)-1-(2-(4-(2-aminopropan-2-yl)phenyl)thiazol-4-yl)-3-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2- b]pyridin-4-yl)urea (Example 67 (Compound 183), 15 mg). LCMS (ESI) Calcd. for C21H22CIN5O2S: 443.1 , found [M+H]+= 444.2.1H NMR (400 MHz, DMSO-cfe) 6H: 9.47 (s, 1 H), 8.12-8.1 1 (m, 1 H), 7.79-7.77 (m, 2H), 7.64-7.63 (m, 2H), 7.49-7.48 (m, 1 H), 7.17 (s, 1 H), 7.07- 7.05 (m, 1 H), 4.96-4.91 (m, 1 H), 4.48-4.43 (m, 1 H), 4.37-4.32 (m, 1 H), 2.43-2.37 (m, 1 H), 2.1 1- 2.06 (m, 1 H), 1.38 (s, 6H). Two amine protons are exchangeable. Absolute stereochemistry unknown.Examples 68 & 69: Synthesis of ((S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(2-(1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea, Example 68 (Compound 178) & ((R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(3,3- difluorocyclobutyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 69 (Compound 177):Scheme 44.

[0618] Synthesis of 3-(4-bromo-1 H-pyrazol-1-yl)cyclobutan-1-one, 2 [Step 1]: To the stirred solution of 4-bromo-1 H-pyrazole (44-1 , 500 mg, 3.40 mmol) in acetonitrile (20 mL), K2CO3(939 mg, 6.80 mmol) was added at 0 °C. After 1 h of stirring 3-bromocyclobutanone (760 mg, 5.10 mmol) was added and the reaction was continued at 60 °C for 16 h. The reaction mixture was diluted with ice cold water, extracted with ethyl acetate. Organic extract was dried over sodium sulfate, filtered, concentrated under reduced pressure to get crude. The product was purified by combi-flash column chromatography to afford 3-(4-bromopyrazol-1-yl)cyclobutanone (44-2, 600mg).1H NMR (400 MHz, CDCI3): <5H7.53 (s, 2H), 5.01-4.94 (m, 1 H), 3.79-3.70 (m, 2H), 3.59-3.49 (m, 2H).

[0619] Synthesis of 4-bromo-1-(3,3-difluorocyclobutyl)-1 H-pyrazole, 3 [Step 2]: To a solution of 3-(4-bromopyrazol-1-yl)cyclobutanone (44-2, 600 mg, 2.79 mmol) in dichloromethane (10 mL) at 0 °C, was added DAST (899 mg, 5.58 mmol) and stirred for 16 h at 25 °C. The reaction mixture was quenched with saturated NaHCO3solution and extracted, dried over Na2SC>4, and concentrated under reduce pressure to obtain crude. The product was purified by combi flash column chromatography to afford 4-bromo-1-(3,3-difluorocyclobutyl)pyrazole (44-3, 500 mg).1H NMR (400 MHz, CDCI3): <5H 7.51 (s, 1 H), 7.47(s, 1 H), 4.67-4.62 (m, 1 H), 3.25-3.04 (m, 4H).

[0620] Synthesis of 1-(3,3-difluorocyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1 H-pyrazole, 44-4 [Step 3]: To a solution of 4-bromo-1-(3,3-difluorocyclobutyl)pyrazole (3, 490 mg, 2.07 mmol), Bis(pinacolato)diboron (630 mg, 2.48 mmol) and potassium acetate (406 mg, 4.13 mmol) in 1 ,4-Dioxane (20 mL) into a sealed tube, was purged by argon for 15 min, then Xanthphos (197 mg, 0.413 mmol) and tris(dibenzylideneacetone)dipalladium (0) (189 mg, 0.207 mmol) was added and stirred at 85 °C for 16 h. The reaction mixture was then diluted with water, extracted with ethyl acetate. Organic extract was washed with brine, dried over Na2SO4, and concentrated to obtain crude compound. The product was purified by combi flash column chromatography to afford 1-(3,3-difluorocyclobutyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazole (44-4, 300 mg).1H NMR (400 MHz, CDCI3): <5H 7.83 (s, 1 H), 7.75(s, 1 H), 4.74-4.72 (m, 1 H), 3.18-3.12 (m, 4H), 1.30 (s, 12H).

[0621] Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(3,3- difluorocyclobutyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, 44-6 [Step 4]: To the stirred solution of 1-(2-bromothiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 200 mg, 0.513 mmol) and 1-(3,3-difluorocyclobutyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrazole (44-4, 219 mg, 0.770 mmol) in 1 ,4-Dioxane (10 mL) and Water (1 mL), Pd 118 (33 mg, 0.0513 mmol) was added and degassed under argon balloon for 20 min. Tripotassium phosphate (327 mg, 1.54 mmol) was added and the reaction was stirred for 16 h at 80°C. The reaction mixture was diluted with water, extracted with ethyl acetate. Organic extract was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain crude. The product was purified by reverse phase preparative HPLC to afford 1-(8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)-3-[2-[1-(3,3-difluorocyclobutyl)pyrazol-4-yl]thiazol-4-yl]urea (44-6, 100 mg). LCMS (ESI) Calcd. for Ci9Hi7CIF2N6O2S: 466.1 , found [M+H]+= 467.1

[0622] Synthesis of (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(3,3- difluorocyclobutyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 68 (Compound 178) and ( / ?)- 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(3,3-difluorocyclobutyl)-1H- pyrazol-4-yl)thiazol-4-yl)urea, Example 69 (Compound 177) [Step 5]: 1-(8-chloro-3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)-3-[2-[1-(3,3-difluorocyclobutyl)pyrazol-4-yl]thiazol-4-yl]urea waspurified by SFC HPLC (6, 82 mg) was separated by SFC to afford peak 1 as (S)-1-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(3,3-difluorocyclobutyl)-1 H-pyrazol-4-yl)thiazol-4- yl)urea (Example 68 (Compound 178), 36 mg) and peak 2 as (R)-1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(3,3-difluorocyclobutyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea as peak 2 (Example 69 (Compound 177), 36 mg).

[0623] SFC method: Waters SFC150 instrument equipped with Waters 2489 UV / Visible Detector by using Chiralpak IB(21 .0 mm x250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 ml / min, using 50% CO2 in super critical state & 50%[100% MeOH ] as Mobile phase, Run this isocratic mixture up to 10.0 minutes and also maintained the isobaric condition of 100 bar at 230nm wavelength.

[0624] (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(3,3- difluorocyclobutyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 68 (Compound 178) [Peak1]: LCMS (ESI) Calcd. for C19H17CIF2N6O2S: 466.08, found [M+H]+= 467.1 , HPLC: Rt(min)= 8.69 (99.70%).1H NMR (400 MHz, DMSO-cfe): 5H 9.38 (s, 1 H), 8.41 (s, 1 H), 8.10 (d, 1 H), 7.96 (s, 1 H), 7.47 (d, 1 H), 7.06 (s, 1 H), 7.00 (d, 1 H), 5.00-4.91 (m, 2H), 4.47-4.42 (m, 1 H), 4.35-4.33 (m, 1 H), 3.21 -3.13 (m, 4H), 2.37-2.35 (m, 1 H), 2.09-2.07 (m, 1 H).

[0625] (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(3,3- difluorocyclobutyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 69 (Compound 177) [Peak2]: LCMS (ESI) Calcd. for C19H17CIF2N6O2S: 466.08, found [M+H]+= 467.1 , HPLC: Rt(min)= 8.69 (99.96%).1H NMR (400 MHz, DMSO-cfe): 6H 9.39 (s, 1 H), 8.41 (s, 1 H), 8.10 (d, 1 H), 7.96 (s, 1 H), 7.47 (d, 1 H), 7.06 (s, 1 H), 7.01 (d, 1 H), 5.00-4.91 (m, 2H), 4.46-4.42 (m, 1 H), 4.35-4.33 (m, 1 H), 3.21 -3.13 (m, 4H), 2.37-2.32 (m, 1 H), 2.09-2.07 (m, 1 H).Example 70: Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(2- methyl-2 / 7-1 ,2,3-triazol-4-yl)thiazol-4-yl)urea, Example 70 (Compound 185): 1-(8-chloro-3,4- dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)-3-(2-(2-methyl-2 / - / -1 ,2,3-triazol-4-yl)thiazol-4-yl)urea was synthesized using (2-methyl-2 / - / -1 ,2,3-triazol-4-yl)boronic acid following step 1 Scheme 43. LCMS (ESI) Calcd. for Ci5Hi4CIN702S: 391.06, found [M+H]+= 392.1.1H NMR (400 MHz, DMSO- cfe): <5H9.50 (s, 1 H), 8.13 (s, 1 H), 8.10 (d, 1 H), 7.47 (s, 1 H), 7.27 (s, 1 H), 6.96-6.95 (d, 1 H), 4.94- 4.92 (m, 1 H), 4.47-4.43 (m, 1 H), 4.36- 4.34 (m, 1 H), 4.22 (s, 3H), 2.39-2.33 (m, 1 H), 2.10-2.08 (m, 1 H).Examples 71 & 72: Synthesis of 1-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-3- hydroxypyrrolidin-1-yl)thiazol-4-yl)urea, Example 71 (Compound 200) and 1-(3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)thiazol-4-yl)urea, Example 71 (Compound 199):, 45-1 TEA.DCM, 16h Step 2 xamp e (Compound 200)Step 1Scheme 45.

[0626] Synthesis of 1-(2-bromothiazol-4-yl)-3-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)urea, 45-3 [Step 1]: To a stirred solution of tert-butyl (2-bromothiazol-4-yl)carbamate (45-2, 1.5 g, 5.3 mmol) in dichloromethane (15 mL) were added 2-chloropyridine (1.5 mL, 16.0 mmol), trifluoromethanesulfonic anhydride (1 .3 mL, 8 mmol) at ice cold condition and it was stirred at ambient temperature for 50 min. Triethylamine (2.2 mL, 16.0 mmol) followed by 3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-amine (45-1 , 400 mg, 2.7 mmol) were added at ice cold condition and the reaction mixture was stirred at ambient temperature for 2 h. Volatiles were evaporated under reduced pressure. The crude product was purified by flash chromatography to afford 1-(2- bromothiazol-4-yl)-3-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (3, 400 mg). LCMS (ESI) Calcd. for Ci2HnBrN4O2S: 353.98, found [M+H]+: 355.0.

[0627] Synthesis of 1-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-3- hydroxypyrrolidin-1-yl)thiazol-4-yl)urea, Example 71 (Compound 200) [Step 2]: To a stirred solution of 1-(2-bromothiazol-4-yl)-3-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (45-3, 70 mg, 0.2 mmol) in MeCN (4 mL) were added (R)-pyrrolidin-3-ol (45-4, 34 mg, 0.4 mmol) and K3PO4 (84 mg, 0.4 mmol) and the reaction mixture was irradiate in MW at 90 °C for 30 min. 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 prep-HPLC and lyophilized to afford 1-(3,4-dihydro- 2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((R)-3-hydroxypyrrolidin-1-yl)thiazol-4-yl)urea (Example 71 (Compound 200), 7 mg). LCMS (ESI) Calcd. for C16H19N5O3S: 361 .42, found [M+H]+= 362.2.1H NMR (400 MHz, DMSO-d6) 6H: 8.94 (s, 1 H), 8.14 -8.13 (m, 1 H), 7.26 -7.21 (m, 2H), 7.08 (bs, 1 H), 6.12 (s, 1 H), 5.05 -5.04 (m, 1 H), 4.83 -4.78 (m, 1 H), 4.36 -4.33 (m, 1 H), 4.32 -4.27 (m, 1 H), 4.19 - 4.14 (m, 1 H), 3.44 -3.30 (m, 3H), 3.18 -3.14 (m, 1 H), 2.35 -2.32 (m, 1 H), 2.08- 1.85 (m, 3H).

[0628] Synthesis of 1-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-3- hydroxypyrrolidin-1-yl)thiazol-4-yl)urea, Example 72 (Compound 199): 1-(3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(2-((S)-3-hydroxypyrrolidin-1-yl)thiazol-4-yl)urea was synthesized following Scheme 7 step 2 using (S)-pyrrolidin-3-ol. LCMS (ESI) Calcd. for Ci6Hi9N503S: 361.42, found [M+H]+: 362.2.1H NMR (400 MHz, DMSO-d6) dH: 8.94 (s, 1 H), 8.14-8.13 (m, 1 H), 7.26-7.21 (m, 2H), 7.08 (bs, 1 H), 6.12 (s, 1 H), 5.05-5.04 (m, 1 H), 4.81 -4.80 (m, 1 H), 4.37-4.30 (m, 1 H),4.29-4.27 (m, 1 H), 4.19-4.15 (m, 1 H), 3.44-3.30 (m, 3H), 3.18-3.14 (m, 1 H), 2.35-2.32 (m, 2H), 2.05-1.89 (m, 1 H).Examples 73 & 74: Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(2-(1 -ethyl-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 73 (Compound 168) and (S)-1-(8- chloro-3, 4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1 -ethyl-1 H-pyrazol-4-yl)thiazol-4- yl)urea, Example 74 (Compound 167):Example 73 Example 74Compound 168 Compound 167Scheme 46.

[0629] Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1 -ethyl-1H- pyrazol-4-yl)thiazol-4-yl)urea, 3 [Step 1]: To a stirred solution of 1-(2-bromothiazol-4-yl)-3-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 100 mg, 0.25 mmol) in 1 ,4-Dioxane (4mL) and Water (1 ml_), were added K3PO4 (109 mg, 0.51 mmol) and 1 -ethyl-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (46-2, 85 mg, 0.38 mmol). Reaction mixture was degassed with argon for 10 minutes and Pd-1 18 (17 mg, 0.02 mmol) was added and 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 crude product was mixed with the batch having id- CR620-MM-2023- 11-76-1 and purified together by Prep HPLC to give 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-ethyl-1 H-pyrazol-4- yl)thiazol-4-yl)urea (46-3, 70 mg). LCMS (ESI) Calcd. for CvHvCINeChS: 404.08, found [M+H]+= 405.2.

[0630] Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-ethyl- 1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 73 (Compound 168) and (S)-1-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1 -ethyl-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 74 (Compound 167) [Step 2]:. Diastereomers of 1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(2-(1 -ethyl- 1 H-pyrazol-4-yl)thiazol-4-yl)urea (46-3, 70 mg, 0.17 mmol) were separated by chiral HPLC-SFC to afford peak 1 assigned as (R)-1-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1 -ethyl- 1 H-pyrazol-4-yl)thiazol-4-yl)urea (46-4, 25 mg) and peak 2 assigned as (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1- ethyl-1 H-pyrazol-4-yl)thiazol-4-yl)urea (46-5, 25 mg)

[0631] SFC method: Separation was performed Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using Chiralpak !C (30 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 100 mL / min, using 55% CO2 in super critical state and 45% of 100% Methanol as mobile phase, run this isocratic mixture for 10 min and maintained the isobaric condition of 100 bar at 226 nm wavelength. Absolute stereochemistry was not determined and arbitrarily assigned.

[0632] (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-ethyl-1 H-pyrazol-4- yl)thiazol-4-yl)urea, Example 73 (Compound 168) (Peak 1): LCMS (ESI) Calcd. for C17H17CIN6O2S: 404.08, found [M+H]+= 405.2;1H NMR (400 MHz, DMSO-d6 / 6H 9.34 (s, 1 H), 8.27 (s, 1 H), 8.1 1 (d, 1 H), 7.83 (s, 1 H), 7.47 (d, 1 H), 7.02-6.98 (m, 2H), 4.92-4.91 (m, 1 H), 4.44- 4.33 (m, 2H), 4.19-4.14 (m, 2H), 2.40-2.30 (m, 1 H), 2.20-2.00 (m, 1 H), 1.39 (t, 3H).

[0633] (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-ethyl-1 H-pyrazol-4- yl)thiazol-4-yl)urea, Example 74 (Compound 167) (Peak 2): LCMS (ESI) Calcd. for C17H17CIN6O2S: 404.08, found [M+H]+= 405.2,1H NMR (400 MHz, DMSO-cfe): 0H9.34 (s, 1 H), 8.27 (s, 1 H), 8.1 1 (d, 1 H), 7.83 (s, 1 H), 7.47 (d, 1 H), 7.02-6.99 (m, 2H), 4.92-4.91 (m, 1 H), 4.44- 4.33 (m, 2H), 4.19-4.14 (m, 2H), 2.40-2.30 (m, 1 H), 2.20-2.00 (m, 1 H), 1.39 (t, 3H).Examples 75 & 76: Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(2-(1-(2-methoxyethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 75 (Compound 166) and (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-methoxyethyl)-1H- pyrazol-4-yl)thiazol-4-yl)urea, Example 76 (Compound 165):Scheme 47.

[0634] Synthesis of 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H- pyrazole, 47-3 [Step 1]: To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (47-1 , 500 mg, 2.58 mmol) in MeCN (10 mL) were added Cesium carbonate (1.68 g, 5.15 mmol) and 1-bromo-2-methoxy-ethane (47-2, 537 mg, 3.87 mmol) and the mixture was stirred at 80°C for 6 hours. The reaction solution was diluted with ethyl acetate, and the obtained organic layer was washed with water and brine sequentially and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure which waspurified by combi flash column chromatography to afford 1-(2-methoxyethyl)-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (3, 450 mg). LCMS (ESI) Calcd. for C12H21BN2O3: 252.12, [M+H]+= 253.14.1H NMR (400 MHz, DMSO-cfe;: 6H 7.89 (s, 1 H), 7.57 (s, 1H), 4.26 (t, 2H), 3.66 (t, 2H), 3.21 (s, 3H), 1.24 (s, 12H).

[0635] Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2- methoxyethyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea, 47-5 [Step 2]: To a stirred solution of 1-(2- bromothiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 120 mg, 0.31 mmol) in 1 ,4-Dioxane (4 mL) and Water (1 ml_), were added 1-(2-methoxyethyl)-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (47-3, 116 mg, 0.46 mmol) and K3PO4 (131 mg, 0.62 mmol). The reaction mixture was degassed with argon for 10 minutes and Pd-118 (21 mg, 0.03 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 EtOAc. The filtrate was dissolved in ethyl acetate and washed with water. The Organic extract were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure which was purified by Reverse Phase PREP HPLC to afford 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3- (2-(1-(2-methoxyethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea (47-5, 62 mg). LCMS (ESI) Calcd. for C18H19CIN6O3S: 434.9, [M+H]+=435.0.1H NMR (400 MHz, DMSO-d6): 0H9.35 (s, 1H), 8.22 (s, 1H), 8.11 (d, 1H), 7.84-7.81 (m, 1H), 7.69-7.63 (m, 1H), 7.47 (d, 1H), 7.03-6.97 (m, 2H), 4.93- 4.91 (m, 1H), 4.45-4.43 (m, 1H), 4.35-4.29 (m, 3H), 3.72-3.69 (m, 2H), 3.23 (s, 3H), 2.39-2.32 (m, 1H), 2.09-2.08 (m, 1H).

[0636] Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2- methoxyethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 75 (Compound 166) and (S)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4- yl)thiazol-4-yl)urea, Example 76 (Compound 165) [Step 3]: 1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-methoxyethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea (47-5, 62 mg, 0.14 mmol) were separated by preparative HPLC chiral (SFC) to afford peak 1 assigned as (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-methoxyethyl)-1 H-pyrazol-4- yl)thiazol-4-yl)urea (Example 75 (Compound 166), 26 mg). LCMS (ESI) Calcd. for CisHigClNsOsS: 434.9, [M+H]+= 435.1.1H NMR (400 MHz, DMSO-d6): 6H9.36 (s, 1H), 8.22 (s, 1H), 8.11 (d, 1H), 7.85 (s, 1H), 7.09 (d, 1H), 7.47 (d, 1H), 7.03-6.98 (m, 2H), 4.94-4.89 (m, 1H), 4.47-4.43 (m, 1H), 4.35-4.29 (m, 3H), 3.72-3.69 (m, 2H), 3.23 (s, 3H), 2.39-2.32 (m, 1H), 2.10-2.04 (m, 1H).

[0637] 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-methoxyethyl)-1 H- pyrazol-4-yl)thiazol-4-yl)urea (47-5, 62 mg, 0.14 mmol) were separated by preparative HPLC chiral (SFC) to afford peak 2 assigned as (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)-3-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea (Example 76 (Compound 165), 30 mg). LCMS (ESI) Calcd. for Ci8Hi9CIN6O3S: 434.9, [M+H]+= 435.2.1H NMR (400 MHz, DMSO-d6): 6H 9.36 (s, 1H), 8.22 (s, 1 H), 8.11 (d, 1 H), 7.85 (s, 1 H), 7.09 (d, 1 H), 7.47 (d, 1 H), 7.03-6.98 (m, 2H), 4.94-4.89 (m, 1 H), 4.47-4.43 (m, 1 H), 4.36-4.29 (m, 3H), 3.71 (t, 2H), 3.23 (s, 3H), 2.39- 2.32 (m, 1 H), 2.10-2.03 (m, 1 H).

[0638] SFC method: SFC Prep Purification of sample was completed in Waters SFC 80 instrument equipped with waters 2489 UV / Visible detector by using Chiralpak IB (21.1 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 ml / min, using 50% CO2 in super critical state & 50% of 100% Methanol as Mobile phase, Run this isocratic mixture up to 10.0 minutes and also maintained the isobaric condition of 120 bar at 220 nm wavelength.Examples 77 & 78: Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(2-(1 -(2,2-difluoroethyl)-1 / 7-pyrazol-4-yl)thiazol-4-yl)urea, Example 77 (Compound 163) and (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-methoxyethyl)-1H- pyrazol-4-yl)thiazol-4-yl)urea, Example 76 (Compound 162):Scheme 48.

[0639] Synthesis of 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H- pyrazole, 3 [Step 1]:. To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (47-1 , 2 g, 10.3 mmol) in DMF (20 mL) was added Cs2CO3(6.7 g, 20.6 mmol) followed by 2,2-difluoroethyl trifluoromethanesulfonate (48-2, 2.2 g, 10.3 mmol) at 0 °C and stirred the reaction mixture at 50 °C for 16 h. The reaction mixture was cooled to ambient temperature and diluted with ice cold water and extracted with ethyl acetate. 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-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole (48-3, 1.2 g).1H NMR (400 MHz, DMSO-d6): 6H7.99 (s, 1 H), 7.65 (s, 1 H), 6.49-6.21 (m, 1 H), 4.68-4.60 (m, 2H), 1.25 (s, 12H).

[0640] Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2,2- difluoroethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, 48-5 [Step 2]: To a stirred solution of 1-(2- bromothiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 100 mg, 0.3 mmol) and 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 / - / - pyrazole(48-3, 100 mg, 0.4 mmol) in 1 ,4-dioxane (5 mL) and water (1 mL) was added K3PO4(109 mg, 0.5 mmol). Reaction mixture was degassed with argon for 10 minutes and Pd-1 18 (17 mg, 0 03mmol) was added and the reaction mixture was stirred at 80 °C for 3 h The reaction mixturewas filtered through celite bed and washed with ethyl acetate. Filtrate was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to afford product which was purified by combi flash column chromatography to afford 1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4- yl)-3-(2-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea (48-5, 70 mg). LCMS (ESI) Calcd. for Ci7Hi5CIF2N6O2S: 440.06, found [M+H]+= 441.0.

[0641] Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2,2- difluoroethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 77 (Compound 163) and (S)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2,2-difluoroethyl)-1 H-pyrazol-4- yl)thiazol-4-yl)urea, Example 78 (Compound 162) [Step 3]: Enantiomers of 1-(8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2,2-difluoroethyl)-1 / - / -pyrazol-4-yl)thiazol-4-yl)urea (48-5, 70 mg, 0.2 mmol) were separated by chiral HPLC-SFC to afford peak 1 assigned as (R)- 1-(8-chloro-3,4-dihydro-2 / - / -pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2,2-difluoroethyl)-1H-pyrazol-4- yl)thiazol-4-yl)urea (Example 77 (Compound 163) , 20 mg) and peak 2 assigned as (S)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2,2-difluoroethyl)-1 H-pyrazol-4- yl)thiazol-4-yl)urea (Example 78 (Compound 162) , 20 mg)

[0642] SFC method : Separation was performed on waters SFC 80 instrument equipped with waters 2489 UV / visible detector by using Chiralpak-IB (21.1 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 mL / min, using 50% CO2in super critical state and 50% of 100% methanol as mobile phase, run this isocratic mixture for 15 min and maintained the isobaric condition of 120 bar at 220 nm wavelength.

[0643] (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2,2-difluoroethyl)- 1H-pyrazol-4-yl)thiazol-4-yl)urea, Example 77 (Compound 163) (Peak 1): LCMS (ESI) Calcd. For Ci7Hi5CIF2N6O2S: 440.06, found [M+H]+= 441.1 ,1H NMR (400 MHz, DMSO-d6): 6H 9.37 (s, 1 H), 8.35 (s, 1 H), 8.11 (d, 1 H), 7.94 (s, 1 H), 7.47 (d, 1 H), 7.07 (s, 1 H), 6.97 (d, 1 H), 6.55-6.26 (m, 1 H), 4.93-4.91 (m, 1 H), 4.72-4.64 (m, 2H), 4.45-4.44 (m, 1 H), 4.35-4.33 (m, 1 H), 2.36-2.32(m, 1 H), 2.09-1.07 (m, 1 H).

[0644] (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2,2-difluoroethyl)- 1H-pyrazol-4-yl)thiazol-4-yl)urea, Example 78 (Compound 162) (Peak 2): LCMS (ESI) Calcd. For Ci7Hi5CIF2N6O2S: 440.06, found [M+H]+= 441.1 ,1H NMR (400 MHz, DMSO-cfe): 6H 9.37 (s, 1 H), 8.32 (s, 1 H), 8.11 (d, 1H), 7.94 (s, 1 H), 7.47 (d, 1 H), 7.07 (s, 1 H), 6.97 (d, 1 H), 6.54-6.27 (m, 1 H), 4.93-4.91 (m, 1 H), 4.72-4.64 (m, 2H), 4.45-4.42 (m, 1 H), 4.36-4.33 (m, 1 H), 2.39-2.36(m, 1 H), 2.09-2.07 (m, 1 H).Examples 79 & 80: Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(2-(1-(2-hydroxyethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, Example 79 (Compound 153) and (S)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-hydroxyethyl)-1H- pyrazol-4-yl)thiazol-4-yl)urea, Example 80 (Compound 152):Scheme 49.

[0645] Synthesis of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1- yl)ethan-1-ol, 3 [Step 1]: To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (47-1 , 750 mg, 3.87 mmol) in DMA (8 mL) were added sodium hydroxide (232 mg, 5.80 mmol) and 1 ,3-dioxolan-2-one (49-2, 681 mg, 7.73 mmol) and the reaction mixture was heated at 140 °C for 16 h. The reaction solution was diluted with ethyl acetate, and the obtained organic layer was washed with water and brine sequentially and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure which was purified by combi flash column chromatography to afford 2-(4-(4, 4,5, 5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazol-1-yl)ethan-1-ol (49-3, 190 mg). LCMS (ESI) Calcd. for C11H19BN2O3: 238.09, [M+H]+= 239.1.

[0646] Synthesis of 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2- hydroxyethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea, 49-5 [Step 2]: To a stirred solution of 1-(2- bromothiazol-4-yl)-3-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 125 mg, 0.32 mmol) in 1 ,4-Dioxane (6 mL) and Water (1 .5 mL), were added 2-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1-yl)ethan-1-ol (49-3, 191 mg, 0.80 mmol) and K3PO4 (136 mg, 0.64 mmol). The reaction mixture was degassed with argon for 10 minutes and Pd-118 (21 mg, 0.03 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 EtOAc. The filtrate was dissolved in ethyl acetate and washed with water. The Organic extract were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure which was purified by Reverse Phase PREP HPLC to afford 1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2- hydroxyethyl)-1 H-pyrazol-4-yl)thiazol-4-yl)urea (49-5, 85 mg). LCMS (ESI) Calcd. for Ci7Hi7CIN6O3S: 420.8, [M+H]+=420.9.1H NMR (400 MHz, DMSO-d6): 6H9.35 (s, 1 H), 8.22 (s,1 H), 8.11 (d, 1 H), 7.84 (s, 1 H), 7.47 (d, 1 H), 7.01-6.99 (m, 2H), 4.95-4.91 (m, 2H), 4.45-4.33 (m, 2H), 4.12-4.17 (m, 2H), 3.77-3.73 (m, 2H), 2.38-2.33 (m, 1 H), 2.09-1.99 (m, 1H).

[0647] Synthesis of (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2- hydroxyethyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea, Example 79 (Compound 153) and (S)-1-(8- chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-hydroxyethyl)-1H-pyrazol-4- yl)thiazol-4-yl)urea, Example 80 (Compound 152) [Step 3]: 1-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazol-4-yl)urea (49-5, 90 mg, 0.21 mmol) were separated by preparative HPLC chiral (SFC) to afford peak 1 assigned as (R)-1-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(1-(2-hydroxyethyl)-1 H-pyrazol-4- yl)thiazol-4-yl)urea (Example 79 (Compound 153), 41 mg)...

Claims

CLAIMSWhat is claimed is:1 . A compound, or a pharmaceutically acceptable salt thereof, according to Formula (I):Formula (I); wherein:A is thiazole, 2-pyridyl, pyrazole, oxazole, azaindole, substituted thiazole, substituted 2-pyridyl, substituted pyrazole, substituted oxazole, or substituted azaindole;R1 is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C3-Cecycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl; wherein A is connected to N via a C-N bond.

2. The compound of claim 1, wherein A is 2-pyridyl or substituted 2-pyridyl, and with Formula (1-1):Formula (1-1); wherein:Y1-Y3 are independently carbon or nitrogen, wherein one of Y1, Y2, or Y3 is nitrogen;R1 is chlorine, C1-C6alkyl, or substituted C1-C6alkyl;R5is hydrogen; andR6is C1-C6alkyl, substituted C1-C6alkyl, amide, substituted amide, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, cyano, C1-C6alkoxy, or substituted C1-C6alkoxy; orR5and R6connected to form a 5-membered heterocyclyl ring.

3. The compound of claim 2, wherein Y1 is nitrogen, Y2and Y3are carbon, and with Formula (l-1-a):Formula (l-1-a) ; wherein:R1is chlorine, C1-Ca alkyl, or substituted C1-C6alkyl;R5is hydrogen; andR6is substituted C1-C6alkyl, amide, methyl substituted amide, pyrazole, aryl, cyano, ethoxy, or substituted ethoxy.

4. The compound of claim 3, wherein the pyrazole is substituted with oxetane or cyclobutane.

5. The compound of claim 3, wherein the aryl is phenyl and substituted with oxetane or amine-substituted oxetane.

6. The compound of claim 2, wherein R5and R6connected to form a 5-membered heterocyclyl ring, and with Formula (1-1 -b):Formula (l-1-b); wherein:R1is chlorine or fluorine substituted alkyl; and R? is hydrogen or C1-C6alkyl.

7. The compound of claim 1 , wherein A is oxazole or substituted oxazole, and with Formula (I-2):Formula (1-2); wherein:R1 is chlorine; andR3is C1-C6alkyl, substituted C1-C6alkyl, aryl, or substituted aryl.

8. The compound of claim 7, wherein Yi is nitrogen, Y2 and Y3 are carbon, and with Formula (l-2-a):Formula (l-2-a); wherein:R1 is chlorine; andR3is C1-C6alkyl, substituted C1-C6alkyl, aryl, or substituted aryl.

9. The compound of claim 8, wherein R3is substituted C1-C6alkyl or substituted aryl.

10. The compound of claim 1 , wherein A is pyrazole or substituted pyrazole, and with Formula (I-3):wherein:Y1-Y3 are independently carbon or nitrogen, wherein one of Yi, Y2, or Y3is nitrogen;R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl; andR4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl.

11. The compound of claim 10, wherein Yi is nitrogen, Y2and Y3are carbon, and with Formula (l-3-a):Formula (l-3-a); wherein:R1is hydrogen, halogen, C1-C6alkyl, C3-C6 cycloalkyl, or substituted C1-C6alkyl; andR4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV).

12. The compound of claim 11 , wherein R4is aryl or substituted aryl.

13. The compound of claim 12, wherein the substituted aryl is aryl substituted with one or more of a halogen, cyano, hydroxy, alkoxy, amide, substituted amide, C1-C6alkyl, substituted C1-C6alkyl, or substituted heterocyclyl.

14. The compound of claim 13, wherein the substituted C1-C6alkyl is a C2alkyl substituted with one or more of fluorine, hydroxy, methyl, or amine.

15. The compound of claim 11 , wherein R4is cycloalkyl or substituted cycloalkyl.

16. The compound of claim 15, wherein the cycloalkyl or the substituted cycloalkyl is C4or C5 cycloalkyl.

17. The compound of claim 16, wherein the cycloalkyl is substituted with one or more hydroxy, methyl, cyano, or fluorine.

18. The compound of claim 11 , wherein R4is heterocyclyl or substituted heterocyclyl.

19. The compound of claim 18, wherein the heterocyclyl is pyridine, pyridazine, pyridazinone, pyrazole, or pyridone; wherein the pyrazole is optionally substituted with C1-C6alkyl; and wherein the pyridine is substituted with one or more of cyano, fluorine, methoxy, or hydroxy or fluorine substituted C2alkyl.

20. The compound of claim 10, wherein Y1 and Y3are carbon, Y2is nitrogen, and withFormulaFormula (l-3-b); wherein:R1 is chlorine; andR4is substituted aryl with Formula (IV):Formula (IV).

21. The compound of claim 10, wherein Y1 and Y2are carbon, Y3is nitrogen, and with Formula (l-3-c):Formula (l-3-c); wherein:R1 is chlorine; andR4is substituted aryl with Formula (IV):Formula (IV).

22. The compound of claim 1 , wherein A is thiazole, and with Formula (I-4):Formula (I-4); wherein:Y1-Y3 are independently carbon or nitrogen, wherein one of Y1, Y2, or Y3is nitrogen;R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C3alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl; andR2is CrC6alkyl, C1-C6substituted alkyl, heterocyclyl, substituted heterocyclyl, C3-C6cycloalkyl, substituted cycloalkyl, substituted aryl, C3-C6heterocycloalkyl, substituted heterocycloalkyl, or ketone.

23. The compound of claim 22, wherein Y1is nitrogen, Y2and Y3are carbon, and with Formula (l-4-a):Formula (l-4-a); wherein:R1is chlorine, C1-C6alkyl, substituted C1-C6alkyl, heterocyclyl, or substituted heterocyclyl;R2is C1-C6alkyl, C1-C6substituted alkyl, heterocyclyl, substituted heterocyclyl, C3-C6cycloalkyl, substituted cycloalkyl, substituted aryl, C3-Cs heterocycloalkyl, substituted heterocycloalkyl, or ketone; andR10 is hydrogen or C1-C6alkyl.

24. The compound of claim 23, wherein R2is C3-C6cycloalkyl.

25. The compound of claim 24, wherein the C3-C6cycloalkyl is cyclopropyl, cyclobutyl, or bridged cyclopropyl.

26. The compound of claim 23, wherein R2is heterocycloalkyl.

27. The compound of claim 26, wherein R2is tetra hydrofuran.

28. The compound of claim 23, wherein R2is heterocyclyl or substituted heterocyclyl.

29. The compound of claim 28, wherein the heterocyclyl or the substituted heterocyclyl is pyridine, pyrazine, pyridone, pyridazine, pyrazole, or pyridazinone.

30. The compound of claim 28, wherein the substituted heterocyclyl is pyrazole, triazole, imidazole, isoxazole, oxazole, pyridine, pyridone, or tetrazole; wherein the pyrazole is optionally substituted with C3-C6cycloalkyl substituted with a hydroxy or one or more halogen, C3-C6heterocycloalkyl, C1-C6alkyl, C1-C6alkyl substituted with or more of methyl, hydroxy, pyridine, or fluorine, deuterated C1-C6alkyl, halogen substituted heterocycloalkyl, alkyl ether, or alkyl substituted pyridone; wherein the imidazole is optionally substituted with C1-C6alkyl, C3-C6cycloalkyl, halogenated C1-C6alkyl, halogenated C3-C6cycloalkyl, cyano substituted C1-C6alkyl, or cyano substituted C3-C6cycloalkyl;wherein the oxazole, pyridone, and tetrazole are optionally substituted with C1-C6alkyl, halogenated C1-C6alkyl, or C3-C6cycloalkyl; wherein pyridine is substituted with a cyano, fluorine, or methoxy; and wherein triazole is optionally substituted with one or more of a C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or more fluorine, deuterated C1-C6alkyl, halogenated C1-C6alkyl, or cyano.

31. The compound of claim 1 , wherein A is azaindole or substituted azaindole, withFormula (I-5):Formula (I-5); wherein:R1 is chlorine or fluorine substituted alkyl; and R- is hydrogen or C1-C6alkyl.

32. A compound, or a pharmaceutically acceptable salt thereof, according to Formula (II):Formula (II); wherein:YI-Y3are independently carbon or nitrogen, wherein one of Y-i, Y2, or Y3is nitrogen;R1 is hydrogen, halogen, C1-C@ alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R5is hydrogen; andR6is C1-C6alkyl, substituted C1-C6alkyl, amide, substituted amide, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, cyano, C1-C6alkoxy, or substituted C1-C6alkoxy; orR5and R6connected to form a 5-membered heterocyclyl ring.

33. The compound of claim 32, wherein Yi is nitrogen, Y2and Y3are carbon, and with Formula (11-1):Formula (ll-l); wherein:R1is chlorine, C1-C6alkyl, or substituted C1-C6alkyl;R5is hydrogen; andR6is substituted C1-C3alkyl, amide, methyl substituted amide, pyrazole, aryl, cyano, ethoxy, or substituted ethoxy.

34. The compound of claim 33, wherein the pyrazole is substituted with oxetane or cyclobutane.

35. The compound of claim 33, wherein the aryl is phenyl and substituted with oxetane or amine-substituted oxetane.

36. The compound of claim 33, wherein R5and R6connected to form a 5-membered heterocyclyl ring, and with Formula (I I-2):Formula (II-2); wherein:R1is chlorine or fluorine substituted alkyl; andR7is hydrogen or C1-C6alkyl.

37. A compound, or a pharmaceutically acceptable salt thereof, according to any of Formula (lll-a), Formula (lll-b), or Formula (lll-c):Formula (lll-b); orFormula (lll-c); wherein:Y1-Y3 are independently carbon or nitrogen and one of Y1, Y2, or Y3is nitrogen;R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C3-C6cycloalkyl, substituted C3-C6cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R2-R4are hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, bridged cycloalkyl, bridged substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl; and* denotes a chiral carbon.

38. The compound of claim 37, wherein Yi is nitrogen, Y2and Y3are carbon, and with Formula (lll-a-1):Formula (lll-a-1); wherein:R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R2is C1-C6alkyl, C1-C6substituted alkyl, heterocyclyl, substituted heterocyclyl, C3-C6cycloalkyl, substituted cycloalkyl, substituted aryl, C3-C6heterocycloalkyl, substituted heterocycloalkyl, or ketone; andR10 is hydrogen or C1-C6alkyl.

39. The compound of claim 38, wherein R2is C3-C6cycloalkyl.

40. The compound of claim 39, wherein the C3-C6cycloalkyl is cyclopropyl, cyclobutyl, or bridged cyclopropyl.

41. The compound of claim 38, wherein R2is heterocycloalkyl.

42. The compound of claim 41 , wherein R2is tetra hydrofuran.

43. The compound of claim 38, wherein R2is heterocyclyl or substituted heterocyclyl.

44. The compound of claim 43, wherein the heterocyclyl or the substituted heterocyclyl is pyridine, pyrazine, pyridone, pyridazine, pyrazole, triazole, or pyridazinone.

45. The compound of claim 43, wherein the substituted heterocyclyl is pyrazole, triazole, imidazole, isoxazole, oxazole, pyridine, pyridone, or tetrazole; wherein the pyrazole is optionally substituted with C3-C6cycloalkyl substituted with a hydroxy or one or more halogen, C3-C6heterocycloalkyl, C1-C6alkyl, C1-C6alkyl substituted with or more of methyl, hydroxy, pyridine, or fluorine, deuterated C1-C6alkyl, halogen substituted heterocycloalkyl, alkyl ether, or alkyl substituted pyridone; wherein the imidazole is optionally substituted with C1-C6alkyl, C3-C6cycloalkyl, halogenated C1-C6alkyl, halogenated C3-C6cycloalkyl, cyano substituted C1-C6alkyl, or cyano substituted C3-C6cycloalkyl;wherein the oxazole, pyridone, and tetrazole are optionally substituted with C1-C6alkyl, halogenated C1-C6alkyl, or C3-C6cycloalkyl; wherein pyridine is substituted with a cyano, fluorine, or methoxy; and wherein triazole is optionally substituted with one or more of a C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or more fluorine, deuterated C1-C6alkyl, halogenated C1-C6alkyl, or cyano.

46. The compound of claim 37, Yi is nitrogen, Y2and Y3are carbon, and with Formula (lll-b-1):Formula (lll-b-1); wherein:R1is hydrogen, halogen, C1-C6alkyl, C3-C6 cycloalkyl, or substituted C1-C6alkyl; and R3is C1-C6alkyl, substituted C1-C6alkyl, aryl, or substituted aryl.

47. The compound of claim 46, wherein the substituted C1-C6alkyl is a C2-alkyl substituted with a hydroxy group.

48. The compound of claim 46, wherein aryl is substituted with cyano.

49. The compound of claim 37, wherein Yi is nitrogen, Y2and Y3are carbon, and with Formula (lll-c-1):Formula (lll-c-1); wherein:R1is hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;R4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV); and* denotes a chiral carbon.

50. The compound of claim 49, wherein R4is aryl or substituted aryl.51 . The compound of claim 50, wherein the substituted aryl is aryl substituted with one or more of a halogen, cyano, hydroxy, alkoxy, amide, substituted amide, C1-C6alkyl, substituted C1-C6alkyl, or substituted heterocyclyl.

52. The compound of claim 51 , wherein the substituted C1-C6alkyl is a C2 alkyl substituted with one or more of fluorine, hydroxy, methyl, or amine.

53. The compound of claim 49, wherein R4is cycloalkyl or substituted cycloalkyl.

54. The compound of claim 53, wherein the cycloalkyl or the substituted cycloalkyl is C4or C5cycloalkyl.

55. The compound of claim 54, wherein the cycloalkyl is substituted with one or more hydroxy, methyl, cyano, or fluorine.

56. The compound of claim 49, wherein R4is heterocyclyl or substituted heterocyclyl.

57. The compound of claim 56, wherein the heterocyclyl is pyridine, pyridazine, pyridazinone, pyrazole, or pyridone; wherein the pyrazole is optionally substituted with C1-C6alkyl; and wherein the pyridine is substituted with one or more of cyano, fluorine, methoxy, or hydroxy or fluorine substituted C2 alkyl.

58. The compound of claim 37, wherein Y1 and Y3are carbon, Y2is nitrogen, and with Formula (lll-c-2):Formula (lll-c-2); wherein:R1 is chlorine; andR4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV).

59. The compound of claim 37, wherein Yi and Y2 are carbon, Y3 is nitrogen, and with Formula (lll-c-3):Formula (lll-c-3); wherein:R1 is chlorine; andR4is aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, or Formula (IV):Formula (IV).

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

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