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WO2025015178A1 - Modulateurs de la réplication d'adn mitochondrial - Google Patents

Modulateurs de la réplication d'adn mitochondrial Download PDF

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Publication number
WO2025015178A1
WO2025015178A1 PCT/US2024/037620 US2024037620W WO2025015178A1 WO 2025015178 A1 WO2025015178 A1 WO 2025015178A1 US 2024037620 W US2024037620 W US 2024037620W WO 2025015178 A1 WO2025015178 A1 WO 2025015178A1
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alkyl
optionally substituted
mmol
independently
group
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Simon Giroux
Andrew Griffin
Gabriel Martinez Botella
Jeremy Green
Paul S. Charifson
Andrew Mckenzie
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Pretzel Therapeutics Inc
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Pretzel Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • Embodiments of the invention relate to novel DNA polymerase ⁇ (POL ⁇ ) modulators, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. Embodiments of the invention also relate to methods of using such compounds and compositions, including to modulate POL ⁇ .
  • POL ⁇ DNA polymerase ⁇
  • POL ⁇ is the replicative polymerase essential for maintaining the mtDNA.
  • POL ⁇ is a heterotrimer in human cells with one catalytic subunit (POL ⁇ A) and two accessory subunits (POL ⁇ B).
  • POL ⁇ A belongs to the family A DNA polymerases.
  • POL ⁇ A 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 POL ⁇ B is 485 amino acids in length and the crystal structures of both mouse and human POL ⁇ B have revealed the protein as a dimer with high similarities to aminoacyl tRNA synthetases.
  • POL ⁇ B acts as a processivity factor, which increases the affinity of the polymerase for DNA and promotes tighter nucleotide binding, thereby increasing the polymerase rate. See, e.g., Gustafsson, C.M., et al., “Maintenance and expression of mammalian mitochondrial DNA,” Annu. Rev.
  • TWINKLE travels in front of POL ⁇ during mtDNA replication, unwinding the dsDNA and creating a single- stranded (ss) DNA template that POL ⁇ 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 POL ⁇ can use ssDNA as a template to synthesize dsDNA.
  • the mtSSB enhances mtDNA synthesis by increasing the processivity of POL ⁇ and also stimulates TWINKLE’s helicase activity. POL ⁇ cannot initiate DNA synthesis de novo, as it needs a short RNA primer to initiate DNA synthesis.
  • the mitochondrial RNA polymerase In mitochondria, the mitochondrial RNA polymerase (POLRMT) has a dual function; it acts as an RNA polymerase involved in mtDNA transcription but it also synthesizes the primers needed to initiate mtDNA replication from mitochondrial origins of replication. See, e.g., Gustafsson 2016. [0005]
  • the mitochondrial genome encodes subunits of the oxidative phosphorylation (OXPHOS) system.
  • the OXPHOS system is composed of four respiratory chain complexes, which are responsible for electron transport and generation of the proton gradient across the mitochondrial inner membrane. ATP synthase uses this proton gradient to produce ATP. See, e.g., id.
  • the biogenesis of the OXPHOS system is under dual genetic control and requires the concerted expression of nuclear DNA and mtDNA encoded genes. Mitochondria contain multiple copies of ds mtDNA, which encodes 2 ribosomal RNAs (mt-rRNAs), 22 transfer RNAs (mt-tRNAs), and 11 messenger RNAs (mt-mRNAs) producing 13 protein subunits of OXPHOS complexes I, III, IV, and ATP synthase (sometime referred to as complex V).
  • mt-rRNAs 2 ribosomal RNAs
  • mt-tRNAs 22 transfer RNAs
  • mt-mRNAs 11 messenger RNAs producing 13 protein subunits of OXPHOS complexes I, III, IV, and ATP synthase
  • mtDNA Similar to the nuclear genome, expression of mammalian mtDNA requires several essential steps, including genome maintenance, replication, transcription, RNA maturation, and translation. All proteins involved in these processes are encoded in the nuclear genome, translated in the cytosol, and imported into the mitochondrial network. It is estimated that approximately one quarter of the ⁇ 1200 nucleus-encoded mitochondrial proteins are devoted to the control of mtDNA gene expression in mammals. See, e.g., Shokolenko, I.N., et al., “Mitochondrial transcription in mammalian cells,” Front. Biosci. (Landmark Ed.), 22:835-853 (2017).
  • POL ⁇ 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.
  • ATP production is in turn vital for energy homeostasis in the cell.
  • POL ⁇ mutations correlated to a broad clinical spectrum of neurodegenerative and mitochondrial diseases. See, e.g., Rahman, S., et al., “POLG-related disorders and their neurological manifestations,” Nat. Rev. Neurol., 15:40-52 (2019) (Rahman 2019). Many disease-causing variants of POL ⁇ are associated with decreased replication processivity of the mtDNA replication machinery, leading to replication stalling.
  • the present invention is directed to a compound, or a pharmaceutically acceptable salt thereof, represented by formula (I): (I) wherein: 1 R is selected from the group consisting of H, C1-C3 alkyl, Cl, F, and CN; R 2 is H or C 1 -C 3 alkyl substituted with OH or OCH 3 ; R 3 is each independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH; R 4 is each independently H or C1-C4 alkyl; Z is selected from the group consisting of C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-heterocyclyl, and aryl-heteroaryl, wherein C1-C6 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR 6 R 7 , NR
  • compositions comprising a compound of the invention, a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • alkyl refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms in a specified range.
  • C1-C7 alkyl means linear or branched chain alkyl groups, including all possible isomers, having 1, 2, 3, 4, 5, 6, or 7 carbon atoms.
  • alkyl groups allow for substituents to be located on any of the carbon atoms.
  • a substituted C 3 alkyl group allows for the substituent to be located on any one, or more, of the three carbon atoms.
  • alkoxy or “alkoxyl” as used herein refers to an -O-alkyl group.
  • C1-C4 alkoxyl means -O-C1-C4 alkyl.
  • alkoxy may be represented by “OR” wherein R is an optionally substituted alkyl group.
  • alkoxyl include methoxyl, ethoxyl, propoxyl (e.g., n-propoxyl and isopropoxyl), and the like.
  • azole refers to a class of five-membered heterocyclic compounds containing a nitrogen atom and at least one other non-carbon atom (i.e., nitrogen, sulfur, or oxygen) as part of the ring.
  • azole rings include, but not limited to, pyrrole, furazan, pyrazole, thiazole, oxazole, triazole, thiadiazole, oxadiazole, imidazole, 1,2 pyrazole, 2,3 thiazole, 2,4 thiazole, 2,3 oxazole, 1,2,4 triazole, 1,2,4 thiadiazole, and 1,2,4 oxadiazole.
  • halogen or “halo” as used herein refers any of the six nonmetallic elements that constitute Group 17 (Group VIIa) of the periodic table.
  • halogen elements include, but are not limited to, fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), and iodine or iodo (I).
  • cycloalkyl refers to a completely saturated or partially unsaturated cyclic group that includes monocyclic or multicyclic ring system.
  • cycloalkyl groups contain 3 to 14 carbon atoms in the ring system (“C4-C14 cycloalkyl”).
  • each of the cycloalkyl rings may contain one or more double or triple bonds.
  • cycloalkyl examples include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.0]hexane, octahydro-1H-indene, decahydronaphthalene, and tetradecahydroanthracene.
  • heterocyclyl refers to a cycloalkyl group, as described above, in which at least one or more heteroatoms are present in a ring that includes, but is not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms, wherein the heteroatom may be oxidized, e.g., NO, SO, SO2, SO4, and the N may be quaternized.
  • heterocyclyl groups contain 3 to 14 atoms in the ring system (“3- to 14-membered heterocyclyl”). Heterocyclyl can be attached to the core structure via a ring carbon atom or a ring heteroatom.
  • Typical monocyclic heterocyclyl rings include, but are not limited to, azetidinyl, pyrrolidyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidyl, piperazinyl, hexahydroazepinyl, 4- piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,3-dioxanyl, and tetrahydro- 1,1-dioxythienyl.
  • aryl refers to a monocyclic or multicyclic ring system having the characteristics of a conjugated pi-electron system.
  • aryl groups contain 4 to 14 carbon atoms in the ring system (“C4-C14 aryl”).
  • Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring. Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthalenyl, anthracenyl, and phenantherenyl.
  • heteroaryl or “heteroaromatic” as used herein refers to an aryl group, as described above, containing one or more heteroatoms that includes, but is not limited to, N, O, and S atoms, wherein the heteroatom may be oxidized, e.g., NO, SO, SO2, SO4, and the N may be quaternized.
  • heteroaryl or heteroaromatic groups contain 4 to 14 atoms in the ring system (“4- to 14-membered heteroaryl”).
  • aryl-cycloalkyl refers to an aryl group, as defined above, that is fused to a cycloalkyl group, as defined above, by any two or more atoms in the ring.
  • aryl-cycloalkyl groups contain 6 to 14 atoms in the ring system (“6- to 14-membered aryl-cycloalkyl”).
  • Aryl-cycloalkyl can be attached to the core structure via a ring carbon atom on the aryl ring or on the cycloalkyl ring.
  • aryl-cycloalkyl examples include, but are not limited to, indane, indene, tetrahydronaphthalene, 1,4- dihydronaphthalene, and bicyclo[4.2.0]octa-1,3,5-triene.
  • aryl-heteroaryl refers to an aryl group, as defined above, that is fused to a heteroaryl group, as defined above. Examples of aryl-heteroaryl include quinoline, quinazoline, quinoxaline, and benzofuran.
  • heteroaryl-cycloalkyl refers to a heteroaryl group, as defined above, which is fused to a cycloalkyl group, as defined above, by any two or more atoms in the ring.
  • heteroaryl-cycloalkyl groups contain 6 to 14 atoms in the ring system (“6- to 14-membered heteroaryl-cycloalkyl”).
  • Heteroaryl-cycloalkyl can be attached to the core structure via a ring carbon atom or heteroatom on the aryl ring or via a carbon atom on the cycloalkyl ring.
  • heteroaryl-cycloalkyl examples include, but are not limited to, 1,4,5,6-tetrahydrocyclopenta[b]pyrrole, 4,5,6,7-tetrahydro-1H-indole, 2,3- cyclopentenopyridine, and 5,6,7,8-tetrahydroquinoline.
  • aryl-heterocyclyl refers to an aryl group, as defined above, which is fused to a heterocyclyl group, as defined above, by any two or more atoms in the ring.
  • aryl-heterocyclyl groups contain 6 to 14 atoms in the ring system (“6- to 14-membered aryl-heterocyclyl”).
  • Aryl-heterocyclyl can be attached to the core structure via a ring carbon atom on the aryl ring or a ring carbon atom or heteroatom on the heterocyclyl ring.
  • aryl-heterocyclyl examples include, but are not limited to, benzopyran, chromane, 4H-chromene, isochromane, thiochromane, isothiochromane, 1,2,3,4- tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydrobenzofuran, 1,3- dihydroisobenzofuran, 2,3-dihydrobenzo[b]thiophene, 1,3-dihydrobenzo[c]thiophene, indoline, isoindoline, and benzdioxane.
  • heteroaryl-heterocyclyl refers to a heteroaryl group, as defined above, which is fused to a heterocyclyl group, as defined above, by any two or more atoms in the ring.
  • heteroaryl-heterocyclyl groups contain 6 to 14 atoms in the ring system (“6- to 14-membered heteroaryl-heterocyclyl”).
  • Heteroaryl- heterocyclyl can be attached to the core structure via a ring carbon atom or heteroatom on the aryl ring or a ring carbon atom or heteroatom on the heterocyclyl ring.
  • aryl- heterocyclyl examples include, but are not limited to 2,3-dihydro-1 ⁇ 2 ,6 ⁇ 2 -pyrrolo[2,3-b]pyrrole, 4,7- dihydro-5H-1 ⁇ 2 ,6 ⁇ 2 -pyrrolo[2,3-c]pyridine, 5,7-dihydro-6 ⁇ 2 -pyrrolo[3,4-b]pyridine, and 3,4- dihydro-2H-1 ⁇ 2 -1,8-naphthyridine.
  • the term “optionally substituted” or “optional substituents” as used herein means that the groups are either unsubstituted or substituted with one or more the substituents specified.
  • the substituents may be the same or different.
  • independently when using the terms “independently,” “independently are,” and “independently selected from” means that the groups may be the same or different.
  • dependently when using the terms “independently,” “independently are,” and “independently selected from” means that the groups may be the same or different.
  • 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”.
  • 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.
  • the term “deuterated compound” refers to a compound which contains one or more carbon-bound deuterium(s).
  • 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%.
  • 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.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • pharmaceutically acceptable salt 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.
  • the invention when the compounds of the invention contain at least one basic group (i.e., groups that can be protonated), the invention includes the compounds in the form of their acid addition salts with organic or inorganic acids such as, for example, but not limited to, salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, acetic acid, citric acid, glutamic acid, lactic acid, and methanesulfonic acid.
  • the invention 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.
  • salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine, or amino acids. Additional examples of such salts can be found in Stahl, P. H. et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2 nd Revised Edition, Wiley, 2011.
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I): I) where in: R 1 is selected from the group consisting of H, C1-C3 alkyl, Cl, F, and CN; R 2 is H or C 1 -C 3 alkyl substituted with OH or OCH 3 ; R 3 is each independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH; R 4 is each independently H or C1-C4 alkyl; Z is selected from the group consisting of C 1 -C 6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-heterocyclyl, and aryl-heteroaryl, wherein C 1 -C 6 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR 6 R 7
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, and CN; R 2 is H or C1 alkyl substituted with OH or OCH3; R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is selected from the group consisting of C 1 -C 5 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aryl-heterocyclyl, wherein C 1 -C 5 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR 6 R 7 , NR 5 R 5 , NR 5 -C(O)CH 3 , and SO 2 R 5 , wherein cycloalkyl is optionally substituted with one or
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, and CN; R 2 is H or C1 alkyl substituted with OH or OCH3; R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is C 1 -C 5 alkyl optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)NR 6 R 7 , NR 5 R 5 , NR 5 - C(O)CH 3 , and SO 2 R 5 ; R 5 is each independently H or C1-C2 alkyl; n is 1-2; p is 1; with the proviso that a compound selected from the group consisting of: 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-y
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R 2 is H or C 1 alkyl substituted with OH or OCH 3 ; R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is cycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of F, C(O)NR 5 R 5 , NR 5 R 5 , and NR 5 -C(O)CH 3 ; R 5 is each independently H or C1-C2 alkyl; n is 1-2; and p is 1.
  • R 1 is selected from the group consisting of H, C1 alkyl, Cl, F, and CN
  • R 2 is H or C 1 alkyl substituted with OH or OCH 3
  • R 3 is each independently H or C1 alkyl
  • R 4 is each
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, and CN; R 2 is H or C1 alkyl substituted with OH or OCH3; R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is heterocyclyl optionally substituted with one or more groups each independently selected from the group consisting of keto, C3 cycloalkyl, C(O)CH3, C(O)NR 5 R 5 , and C 1 -C 2 alkyl that is optionally substituted with OH; R 5 is each independently H or C1-C2 alkyl; n is 1-2; p is 1; with the proviso that a compound selected from the group consisting of: 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(8-methylchroman-4-yl)ure
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R 2 is H or C 1 alkyl substituted with OH or OCH 3 ; R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is aryl optionally substituted with one or more groups each independently selected from the group consisting of: C1-C3 alkyl that is optionally substituted with one or more F, OH, or NR 5 R 5 , C 3 cycloalkyl that is substituted with NR 5 R 5 , halogen, CN, OR 5 , SO2R 5 , SO 2 NR 5 R 5 , and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C 1 alkyl, and NR 5 R 5
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, and CN; R 2 is H or C1 alkyl substituted with OH or OCH3; R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR 6 R 7 or NR 6 R 7 ; R 5 is each independently H or C 1 -C 2 alkyl; R 6 is H or C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR 5 R 5 ; R 7 is H, C3-C5 cycloalkyl, or C1-C3 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR 5 R 5
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R 2 is H or C 1 alkyl substituted with OH or OCH 3 ; R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR 6 R 7 or NR 6 R 7 ; R 5 is each independently H or C 1 -C 2 alkyl; R 6 is H or C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR 5 R 5 ; R 7 is C1-C3 alkyl substituted with C3 cycloalkyl optionally substituted with a group selected from the group consisting of O-C 1 alkyl, CN, NR 5 R
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, and CN; R 2 is H or C1 alkyl substituted with OH or OCH3; R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR 6 R 7 or NR 6 R 7 ; R 6 and R 7 together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C 1 alkyl; n is 1-2; and p is 1.
  • R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, and CN;
  • R 2 is H or C1 alkyl substituted with OH or OCH3;
  • R 3 is each independently H or C 1 alkyl
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, CN; R 2 is H or C1 alkyl substituted with OH or OCH3; R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is heteroaryl optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR 5 R 5 , OR 5 , NR 5 R 5 , oxo, SO2R 5 , and C1- C 3 alkyl optionally substituted with NR 5 R 5 ; R 5 is each independently H or C1-C2 alkyl; n is 1-2; and p is 1.
  • R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, CN
  • R 2 is H or C1 alkyl substituted with OH or OCH3
  • R 3 is each
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, and CN; R 2 is H or C1 alkyl substituted with OH or OCH3; R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is aryl-heterocyclyl optionally substituted with one or more groups each independently fluoro or C1 alkyl that is optionally substituted with OH; n is 1-2; and p is 1.
  • R 1 is selected from the group consisting of H, C 1 alkyl, Cl, F, and CN
  • R 2 is H or C1 alkyl substituted with OH or OCH3
  • R 3 is each independently H or C 1 alkyl
  • R 4 is each independently H or C1 alkyl
  • Z is aryl-heterocyclyl optionally substituted with one or more groups each independently flu
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (I) wherein: R 1 is selected from the group consisting of H, C1 alkyl, Cl, F, and CN; R 2 is H or C 1 alkyl substituted with OH or OCH 3 ; R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is aryl-heteroaryl optionally substituted with C1-C3 alkyl that is optionally substituted with OH; n is 1-2; and p is 1.
  • R 1 is selected from the group consisting of H, C1 alkyl, Cl, F, and CN
  • R 2 is H or C 1 alkyl substituted with OH or OCH 3
  • R 3 is each independently H or C1 alkyl
  • R 4 is each independently H or C 1 alkyl
  • Z is aryl-heteroaryl optionally substituted with C1-C3 alkyl that is optionally substituted with
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II): I) wherein R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is selected from the group consisting of C1-C2 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aryl-heterocyclyl, wherein C 1 -C 2 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR 6 R 7 , NR 5 R 5 , NR 5 -C(O)CH 3 , and SO 2 R 5 , wherein cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, C(O)NR 5 R 5 , NR 5 R 5 , and NR 5 -C(O)CH
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is C 1 -C 5 alkyl optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)NR 6 R 7 , NR 5 R 5 , NR 5 - C(O)CH 3 , and SO 2 R 5 ; and R 5 is each independently H or C1-C2 alkyl.
  • formula (II) wherein: R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is C 1 -C 5 alkyl optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)NR 6 R 7 , NR 5 R 5 , NR 5 - C(O)CH 3 , and SO 2 R 5
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is cycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of F, C(O)NR 5 R 5 , NR 5 R 5 , and NR 5 -C(O)CH 3 ; and R 5 is each independently H or C1-C2 alkyl.
  • R 3 is each independently H or C1 alkyl
  • R 4 is each independently H or C 1 alkyl
  • Z is cycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of F, C(O)NR 5 R 5 , NR 5 R 5 , and NR 5 -C(O)CH 3
  • R 5 is each independently H or C1-C2 alkyl.
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H or C1 alkyl; Z is heterocyclyl optionally substituted with one or more groups each independently selected from the group consisting of keto, C3 cycloalkyl, C(O)CH3, C(O)NR 5 R 5 , and C 1 -C 2 alkyl that is optionally substituted with OH; and R 5 is each independently H or C1-C2 alkyl.
  • R 3 is each independently H or C1 alkyl
  • R 4 is each independently H or C1 alkyl
  • Z is heterocyclyl optionally substituted with one or more groups each independently selected from the group consisting of keto, C3 cycloalkyl, C(O)CH3, C(O)NR 5 R 5 , and C 1 -C 2 alkyl that is optionally substituted with OH
  • R 5 is each independently H or C1-
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is aryl optionally substituted with one or more groups each independently selected from the group consisting of: C1-C3 alkyl that is optionally substituted with one or more F, OH, or NR 5 R 5 , C 3 cycloalkyl that is substituted with NR 5 R 5 , halogen, CN, OR 5 , SO 2 R 5 , SO2NR 5 R 5 , and 4- or 5-membered heterocyclic ring that is optionally substituted with one or more groups each independently selected from the group consisting of F, C1 alkyl, and NR 5 R 5 ; and R 5 is each independently H or C1-C2 alkyl.
  • R 3 is each independently H or C1 alkyl
  • R 4 is each independently H or C 1 alkyl
  • Z is aryl
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR 6 R 7 or NR 6 R 7 ; R 5 is H or C1-C2 alkyl; R 6 is H or C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR 5 R 5 ; and R 7 is H, C3-C5 cycloalkyl, or C1-C3 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR 5 R 5 , heteroaryl, and heterocyclyl optionally substituted with C1 alkyl or CN.
  • formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR 6 R 7 or NR 6 R 7 ; R 5 is each independently H or C1-C2 alkyl; R 6 is H or C 1 -C 4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR 5 R 5 ; and R 7 is C 1 -C 3 alkyl substituted with C 3 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1 alkyl, CN, NR 5 R 5 , and one or more fluoro.
  • formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is ary
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR 6 R 7 or NR 6 R 7 ; and R 6 and R 7 together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C 1 alkyl.
  • formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H or C1 alkyl; Z is aryl optionally substituted with one or more groups each independently C(O)NR 6 R 7 or NR 6 R 7 ; and R 6 and R 7 together with their connecting nitrogen form a 4- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C 1 alkyl.
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is heteroaryl optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR 5 R 5 , OR 5 , NR 5 R 5 , oxo, SO2R 5 , and C1- C 3 alkyl optionally substituted with NR 5 R 5 ; and R 5 is each independently H or C1-C2 alkyl.
  • formula (II) wherein: R 3 is each independently H or C 1 alkyl; R 4 is each independently H or C1 alkyl; Z is heteroaryl optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR 5 R 5 , OR 5 , NR 5 R 5 , oxo, SO2R 5 , and C1- C 3 alkyl optionally substituted with NR
  • the present invention is directed to a compound or a pharmaceutically acceptable salt thereof, represented by formula (II) wherein: R 3 is each independently H or C1 alkyl; R 4 is each independently H or C 1 alkyl; Z is aryl-heterocyclyl optionally substituted with one or more groups each independently fluoro or C 1 alkyl that is optionally substituted with OH; and R 5 is each independently H or C1-C2 alkyl.
  • R 1 is H, C 1 -C 3 alkyl, Cl, F, or CN.
  • R 1 is H.
  • R 1 is C1-C3 alkyl.
  • R 1 is C1 alkyl.
  • R 1 is C2 alkyl. In embodiments, R 1 is C 3 alkyl. In embodiments, R 1 is Cl. In embodiments, R 1 is Cl. In embodiments, R 1 is CN. [0053] In embodiments, R 2 is H or C 1 -C 3 alkyl substituted with OH or OCH 3 . In embodiments, R 2 is H. In embodiments, R 2 is C1 alkyl substituted with OH. In embodiments, R 2 is C 2 alkyl substituted with OH. R 2 is C 3 alkyl substituted with OH. In embodiments, R 2 is C1 alkyl substituted with OCH3. In embodiments, R 2 is C2 alkyl substituted with OCH3.
  • R 2 is C 3 alkyl substituted with OCH 3 .
  • R 3 is independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH.
  • R 3 is H.
  • R 3 is C 1 alkyl optionally substituted with one or more halogen.
  • R 3 is C1 alkyl optionally substituted with one or more OH.
  • R 3 is C 2 alkyl optionally substituted with one or more halogen.
  • R 3 is C2 alkyl optionally substituted with one or more OH.
  • R 3 is C 3 alkyl optionally substituted with one or more halogen.
  • R 3 is C3 alkyl optionally substituted with one or more OH. In embodiments, R 3 is C 4 alkyl optionally substituted with one or more halogen. In embodiments, R 3 is C 4 alkyl optionally substituted with one or more OH. [0055] In embodiments, R 4 is independently H or C1-C4 alkyl. In embodiments, R 4 is H. In embodiments, R 4 is C1 alkyl. In embodiments, R 4 is H or C2 alkyl. In embodiments, R 4 is C3 alkyl. In embodiments, R 4 is C 4 alkyl.
  • Z is C 1 -C 5 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl- heterocyclyl, or aryl-heteroaryl.
  • Z is C1-C5 alkyl optionally substituted with phenyl.
  • Z is C 1 -C 5 alkyl optionally substituted with OH.
  • Z is C1-C5 alkyl optionally substituted with NR 5 R 5 .
  • Z is C1-C5 alkyl optionally substituted with C(O)NR 5 R 5 .
  • Z is C 1 -C 5 alkyl optionally substituted with NR 5 -C(O)CH3.
  • Z is cycloalkyl optionally substituted with one or more groups each independently selected from the group consisting of F, C(O)NR 5 R 5 , NR 5 R 5 , and NR 5 - C(O)CH 3 .
  • Z is cycloalkyl optionally substituted with one or more F.
  • Z is cycloalkyl optionally substituted with one or more C(O)NR 5 R 5 .
  • Z is cycloalkyl optionally substituted with one or more NR 5 R 5 .
  • Z is cycloalkyl optionally substituted with one or more NR 5 -C(O)CH3.
  • Z is heterocyclyl optionally substituted with one or more groups each independently selected from the group consisting of keto, C3 cycloalkyl, C(O)CH3, C(O)NR 5 R 5 , and C 1 -C 2 alkyl that is optionally substituted with OH.
  • Z is heterocyclyl substituted with one or more keto.
  • Z is heterocyclyl substituted with one or more C 3 cycloalkyl.
  • Z is heterocyclyl substituted with one or more C(O)CH3.
  • Z is heterocyclyl substituted with one or more C(O)NR 5 R 5 . In embodiments, Z is heterocyclyl substituted with one or more C 1 -C 2 alkyl that is optionally substituted with OH. [0059] In embodiments, Z is aryl that is optionally substituted with one or more C 1 -C 3 alkyl that is optionally substituted with one or more F, OH, or NR 5 R 5 . In embodiments, Z is aryl that is substituted with one or more C 1 -C 3 alkyl that is substituted with one or more F.
  • Z is aryl that is substituted with one or more C1-C3 alkyl that is substituted with one or more OH, In embodiments, Z is aryl that is substituted with one or more C 1 -C 3 alkyl that is substituted with one or more NR 5 R 5 . [0060] In embodiments, Z is aryl that is optionally substituted with one or more C3 cycloalkyl that is substituted with NR 5 R 5 . [0061] In embodiments, Z is aryl that is substituted with one or more halogen. In embodiments, Z is aryl that is substituted with one or more CN. In embodiments, Z is aryl that is substituted with one or more OR 5 .
  • Z is aryl that is substituted with one or more C(O)NR 6 R 7 . In embodiments, Z is aryl that is optionally substituted with one or more NR 6 R 7 . In embodiments, Z is aryl that is substituted with one or more SO2R 5 . In embodiments, Z is aryl that is substituted with one or more SO 2 NR 5 R 5 . In embodiments, Z is aryl that is substituted with a 4- or 5-membered heterocyclic ring that is substituted with one or more F. In embodiments, Z is aryl that is substituted with a 4- or 5-membered heterocyclic ring that is substituted with one or more C1 alkyl.
  • Z is aryl that is substituted with a 4- or 5-membered heterocyclic ring that is substituted with NR 5 R 5 .
  • Z is heteroaryl that is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR 5 R 5 , OR 5 , NR 5 R 5 , oxo, SO2R 5 , and C1-C3 alkyl optionally substituted with NR 5 R 5 .
  • Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of C(O)NR 5 R 5 .
  • Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of OR 5 . In embodiments, Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of NR 5 R 5 . In embodiments, Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of oxo. In embodiments, Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of SO2R 5 . In embodiments, Z is heteroaryl that is substituted with one or more groups each independently selected from the group consisting of C 1 -C 3 alkyl optionally substituted with NR 5 R 5 .
  • Z is aryl-heterocyclyl optionally substituted with fluoro or C 1 alkyl that is optionally substituted with OH. In embodiments, Z is aryl-heterocyclyl substituted with one or more fluoro. In embodiments, Z is aryl-heterocyclyl substituted with one or more C1 alkyl that is optionally substituted with OH.
  • R 5 is H or C1-C4 alkyl. In embodiments, R 5 is H. In embodiments, R 5 is C 1 alkyl. In embodiments, R 5 is C 2 alkyl. In embodiments, R 5 is C 3 alkyl. In embodiments, R 5 is C4 alkyl.
  • R 6 is H, C 1 -C 4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR 5 R 5 .
  • R 6 is H.
  • R 6 is C 1 alkyl substituted with one or more halogen.
  • R 6 is C1 alkyl substituted with one or more CN.
  • R 6 is C1 alkyl substituted with one or more NR 5 R 5 .
  • R 6 is C 2 alkyl substituted with one or more halogen.
  • R 6 is C2 alkyl substituted with one or more CN.
  • R 6 is C 2 alkyl substituted with one or more NR 5 R 5 . In embodiments, R 6 is C 3 alkyl substituted with one or more halogen. In embodiments, R 6 is C3 alkyl optionally substituted with one or more CN. In embodiments, R 6 is C3 alkyl substituted with one or more NR 5 R 5 . In embodiments, R 6 is C4 alkyl substituted with one or more halogen. In embodiments, R 6 is C4 alkyl substituted with one or more CN. In embodiments, R 6 is C4 alkyl substituted with one or more NR 5 R 5 .
  • R 7 is H or C 1 -C 5 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR 5 R 5 , heteroaryl, and heterocyclyl optionally substituted with C 1 -C 5 alkyl or CN, or R 7 is C 1 -C 5 alkyl substituted with C3-C6 cycloalkyl optionally substituted with a group selected from the group consisting of O-C 1 -C 5 alkyl, CN, NR 5 R 5 , and one or more fluoro, or R 7 is C 3 -C 5 cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH, or if R 6 and R 7 are attached to the same nitrogen atom, R 6 and R 7 together with their connecting nitrogen form a 3- to 6- membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C 1 -C 5 alkyl.
  • R 7 is H. In embodiments, R 7 is C1-C5 alkyl substituted with one or more hydroxyl. In embodiments, R 7 is C 1 -C 5 alkyl substituted with one or more, NR 5 R 5 . In embodiments, R 7 is C1-C5 alkyl substituted with one or more heteroaryl. In embodiments, R 7 is C 1 -C 5 alkyl substituted with one or more heterocyclyl substituted with C 1 -C 5 alkyl. In embodiments, R 7 is C1-C5 alkyl substituted with one or more heterocyclyl substituted with CN.
  • R 7 is C 1 -C 5 alkyl substituted with C 3 -C 6 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1-C5 alkyl, CN, NR 5 R 5 , and one or more fluoro.
  • R 7 is C 1 -C 5 alkyl substituted with C 3 -C 6 cycloalkyl substituted with O-C1-C5 alkyl.
  • R 7 is C1-C5 alkyl substituted with C3-C6 cycloalkyl substituted with CN.
  • R 7 is C1-C5 alkyl substituted with C3-C6 cycloalkyl substituted with NR 5 R 5 . In embodiments, R 7 is C 1 -C 5 alkyl substituted with C 3 -C 6 cycloalkyl substituted with one or more fluoro. [0069] In embodiments, R 7 is C3-C5 cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH. In embodiments, or R 7 is C 3 cycloalkyl optionally substituted with C1 alkyl optionally substituted with OH. In embodiments, or R 7 is C3 cycloalkyl substituted with C 1 alkyl optionally substituted with OH.
  • R 7 is C 4 cycloalkyl substituted with C1 alkyl optionally substituted with OH. In embodiments, or R 7 is C5 cycloalkyl substituted with C1 alkyl optionally substituted with OH. [0070] In certain embodiments, R 6 and R 7 are attached to the same nitrogen atom and together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1-C5 alkyl.
  • R 6 and R 7 are attached to the same nitrogen atom and together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is O and optionally substituted with C 1 -C 5 alkyl. In certain embodiments, R 6 and R 7 are attached to the same nitrogen atom and together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is N and optionally substituted with C1-C5 alkyl.
  • n is 1-4. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.
  • p is 1-2. In embodiments, p is 1. In embodiments, p is 2. [0073] In embodiments, the compounds are identified in Table 1. Table 1. Example N o Chemical Name Structure
  • the compounds of the present invention may contain asymmetric carbon atoms (sometimes as the result of a deuterium atom) and thereby can exist as either individual stereoisomers or mixtures of the enantiomers or mixtures of diastereomers. Accordingly, a compound of the present invention may exist as either a racemic mixture, a mixture of diastereomers, or as individual stereoisomers that are substantially free of other stereoisomers. Synthetic, separation, or purification methods to be used to obtain an enantiomer of a given compound are known in the art and are applicable for obtaining the compounds identified herein.
  • the compounds of the present invention may contain double bonds that may exist in more than one geometric isomer. Examples of such double bonds are carbon-carbon double bonds which form alkenes. In the case of carbon-carbon double bonds, the geometric isomers may be E or Z isomers.
  • hydrogen atoms may be replaced with deuterium.
  • the deuterium isotope content at a substituted position may be greater than the natural isotopic deuterium content (0.015%), more preferably greater than 50%, more preferably greater than 60%, more preferably greater than 75%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%. It will be understood that some variation of natural isotopic abundance may occur in any compound depending upon the source of the reagents used in the synthesis.
  • 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.
  • deuterated isotopologues such amounts being insignificant as compared to the degree of stable isotopic substitution of the deuterated compounds of the invention.
  • replacement of hydrogen with deuterium may affect the activity, toxicity, and pharmacokinetics (e.g., absorption, distribution, metabolism, and excretion (“ADME”)) of some drugs. For instance, such replacement may alter the chemical stability and biochemical reactivity of a compound through kinetic isotope effects.
  • ADME absorption, distribution, metabolism, and excretion
  • a partial list of abbreviations that may be used herein include: acetonitrile (CH 3 CN or MeCN or ACN), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf)Cl 2 complex with CH 2 Cl 2 ), bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium (II) (Pd(amphos)Cl2), calculated (Calcd.), cerium chloride (CeCl 3 ), cesium carbonate (Cs 2 CO 3 ), cesium fluoride (CsF), copper acetate (Cu(OAc)3), copper bromide (CuBr), copper (I) oxide (Cu2O), diethylaminosulfur trifluoride (DAST), degrees Celsius (°C), deuterium (d), dichloromethane (DCM, CH 2 Cl
  • Example 1 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-cyanophenyl)pyrazol-3- yl]urea [ ] p ( py y) ( ) pyrazol-3-amine (0.34 g, 4.13 mmol) in DMF (5 mL) was added cesium carbonate (1.34 g, 4.13 mmol) followed by copper (I) bromide (1.18 g, 0.82 mmol) at RT. To the resulting reaction mixture, 4-fluorobenzonitrile 1-2 (0.50 g, 4.13 mmol) was added and the reaction mixture was stirred at 110 °C for 16 h.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-cyanophenyl)pyrazol-3-yl]urea
  • Example 1 To a stirred solution of 4-(3-aminopyrazol-1-yl)benzonitrile 1-3 (0.07g, 0.40 mmol) in MeCN (2 mL) was added pyridine (0.06 g, 0.81 mmol) followed by N,N′- disuccinimidyl carbonate (0.10 g, 0.40 mmol). Reaction mixture was stirred at RT for 30 min.
  • Example 2 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methoxy-4- pyridyl)pyrazol-3-yl]urea bromo-2-methoxy-pyridine 2-1 (1.13 g, 6.02 mmol) in DMF (4 mL) was added copper (I) bromide (0.17 g, 1.20 mmol) and cesium carbonate (2.94 g, 9.03 mmol) followed by 1H- pyrazol-3-amine 2-2 (0.60 g, 7.22 mmol) at RT. Reaction mixture was stirred at 120 °C for 16 h. After completion, reaction mixture was diluted with EtOAc and filtered through Celite bed.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methoxy-4-pyridyl)pyrazol-3- yl]urea
  • Example 2 To a stirred solution of 1-(2-methoxy-4-pyridyl)pyrazol-3-amine 2-3 (0.10 g, 0.54 mmol) in MeCN (3 mL) was added N,N′-disuccinimidyl carbonate (0.13 g, 0.54 mmol) followed by pyridine (0.04 mL, 0.54 mmol) at RT. Reaction mixture was stirred at RT for 15 min.
  • reaction mixture N,N-diisopropylethylamine (0.28 mL, 1.63 mmol) was added followed by (4S)-8-chlorochroman-4-amine 2-4 (0.12 g, 0.54 mmol) and stirred at RT for 4 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • Step-1 3-(3-aminopyrazol-1-yl)benzonitrile (3-3): To a stirred solution of 1H- pyrazol-3-amine 3-1 (0.10 g, 1.20 mmol) in DMF (2 mL) was added 3-bromobenzonitrile 3-2 (0.50 g, 2.75 mmol) followed by Cs 2 CO 3 (0.16 g, 1.20 mmol) and Cu(I)Br (0.01 g, 0.12 mmol).
  • reaction mixture was stirred at 100 qC for 12 h. After completion, reaction mixture was quenched with H 2 O, and filtered through Celite pad. Aqueous layer was extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Product obtained was purified by CombiFlash (40 % EtOAc/hexane) to afford 3-(3-aminopyrazol-1-yl)benzonitrile 3-3 (0.15 g).
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-cyanophenyl)pyrazol-3-yl]urea (Example 3): To a stirred solution of 3-(3-aminopyrazol-1-yl)benzonitrile 3-3 (0.10 g, 0.54 mmol) in MeCN (4 mL) was added pyridine (0.04 mL, 0.54 mmol) followed by bis(2,5- dioxopyrrolidin-1-yl) carbonate (0.13 g, 0.54 mmol). Reaction mixture was stirred at RT for 30 min.
  • Step-1 N,N-dimethyl-2-(3-nitro-1H-pyrazol-1-yl) ethane-1-amine (4-3): To a stirred solution of 3-nitro-1H-pyrazole 4-1 (3.00 g, 26.50 mmol) in DMF (50 mL), K2CO3 (11.00 g, 79.6mmol) was added at 0 °C followed by 2-bromo-N,N-dimethylethan-1-amine hydrobromide 4-2 (7.42 g, 31.80 mmol) and the reaction mixture was stirred at 90 °C 8 h.
  • Step-2 1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-amine (4-4): To a stirred solution of N,N-dimethyl-2-(3-nitro-1H-pyrazol-1-yl) ethane-1-amine 4-3 (2.50 g, 13.6 mmol) in a mixture of MeOH (40 mL) and THF (40 mL), 10% Pd/C (1.00 g) was added and the reaction mixture was stirred under 50 psi hydrogen gas pressure at RT for 16 h. After completion of reaction, the reaction mixture was filtered through Celite bed and washed thoroughly with MeOH.
  • Step-3 Phenyl (1-(2-(dimethyl amino) ethyl)-1H-pyrazol-3-yl) carbamate (4-5): To a stirred solution of 4-4 (1.0 g, 6.55 mmol) in THF (10 mL), DIPEA (0.26 mL, 1.48 mmol) was added followed by phenyl chloroformate (2.36 g, 15.1 mmol) and the resulting reaction mixture was stirred at RT for 16 h. After completion of reaction, the reaction mixture was diluted with water, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-4 (S)-1-(8-chlorochroman-4-yl)-3-(1-(2-(dimethylamino)ethyl)-1H-pyrazol- 3-yl)urea (Example 4): To a stirred solution of (S)-8-chlorochroman-4-amine 4-6 (0.1 g, 0.54 mmol) in THF (5 mL), NaH (60% in mineral oil, 0.03 g, 1.09 mmol) was added at 0 °C followed by 4-5 (0.18 g, 0.65 mmol) and the reaction mixture was stirred at 80 °C for 2 h.
  • Example 4 (0.015 g).
  • Example 5 Synthesis of 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]-N,N-dimethyl-benzamide dimethyl-benzamide (Example 5): To a stirred solution of 4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]benzoic acid (0.05 g, 0.12 mmol) in DMF (1mL) was added DIPEA (0.08 mL, 0.48 mmol) followed by HATU (0.06 g, 0.182 mmol) and N- methylmethanamine hydrochloride (0.01 g, 0.18 mmol) at 0 °C.
  • Example 6 Synthesis of 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]benzamide yl]benzamide (Example 6): To a stirred solution of 4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]benzoic acid 6-1 (0.05 g, 0.12 mmol) in DMF (1 mL) was added DIPEA (0.08 mL, 0.48 mmol) followed by HATU (0.06 g, 0.182 mmol) and NH4Cl (0.009 g, 0.18 mmol) at 0 °C .
  • Example 7 Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chloro-5-fluoro-chroman-4-yl]urea [0095]
  • Step-1 tert-butyl N-[1-[4-[3-[[(4S)-8-chloro-5-fluoro-chroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]carbamate (7-3): To a stirred solution of tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 7-1 (0.20 g, 0.63 mmol) in MeCN (5 mL) was added pyridine (0.10 mL, 1.26 mmol) and N,N′- disuccin
  • reaction mixture was stirred at RT for 30 min.
  • N,N-diisopropylethylamine (0.33 mL, 1.90 mmol) and (4S)-8-chloro-5-fluoro-chroman-4-amine 7-2 (0.12 g, 0.63 mmol) were added and stirred at 25 °C for 4 h. After completion, the reaction mixture was diluted with water, extracted with EtOAc.
  • Step-2 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8-chloro-5- fluoro-chroman-4-yl]urea (Example 7): To a stirred solution of tert-butyl N-[1-[4-[3- [[(4S)-8-chloro-5-fluoro-chroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl- ethyl]carbamate 7-3 (0.13 g, 0.10 mmol) in DCM (3 mL) was added 4M HCl in 1,4-dioxane (2.3 mL, 64.8 mmol) at 0 °C.
  • Step-1 (E)-8-fluorochroman-4-oneoxime (8-2): To a stirred solution of 8- fluorochroman-4-one 8-1 (2.0 g, 12.0 mmol) in ethanol (100 mL), sodium acetate (2.47 g, 30.1 mmol) was added at 0 °C followed by hydroxylamine hydrochloride (1.67 g, 24.1 mmol) and the reaction mixture was stirred at 90 °C for 5 h.
  • Step-2 8-fluorochroman-4-amine (8-3): To a stirred solution of 8-2 (1.80 g, 9.9 mmol) in methanol (25 mL), 10% Pd/C (0.50 g) was added at RT and the reaction mixture was stirred under 50 psi hydrogen gas pressure at RT for 16 h. After completion of reaction, the reaction mixture was filtered through Celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to afford 8-3 (1.5 g).
  • Step-3 1-(1-ethyl-1H-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea (Example 8): To a stirred solution of 8-3 (0.15 g, 0.89 mmol) in DCM (5 mL), TEA (0.37 mL, 2.69 mmol) was added at 0 °C followed by triphosgene (0.16 g, 0.53 mmol) and the reaction mixture was stirred for 15 min. To the resulting reaction mixture 1-ethyl-1H-pyrazol-3-amine 8-4 (0.11 g, 0.98 mmol) was added and the reaction mixture was stirred at RT for 3 h.
  • Step-1 (E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide (9-3): To a stirred solution of 4-bromobenzaldehyde 9-1 (2.00 g, 10.8 mmol) in THF (25 mL) was added 2-methylpropane-2-sulfinamide 9-2 (1.57 g, 12.97 mmol) at 0 qC followed by titanium (IV) ethoxide (4.93 g, 21.61 mmol). Reaction mixture was stirred at 80 qC for 12 h. After completion, reaction was quenched with H2O and filtered the emulsion through Celite, which was washed with EtOAc.
  • Step-2 N-[1-(4-bromophenyl)but-3-enyl]-2-methyl-propane-2-sulfinamide (9-5): To a stirred solution of (E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide 9-3 (2.00 g, 6.94 mmol) in THF (25 mL) was added ally magnesium bromide 9-4 (1M in THF) (10 mL, 10.41 mmol) at 0 qC. Reaction mixture was stirred at RT for 12 h. After completion, reaction was quenched with aqueous ammonium chloride solution. Aqueous layer was extracted with EtOAc.
  • Step-3 1-(4-bromophenyl)but-3-en-1-amine (9-6): To a stirred solution of N-[1-(4- bromophenyl)but-3-enyl]-2-methyl-propane-2-sulfinamide 9-5 (5.00 g, 15.13 mmol) in 1,4- dioxane (25 mL) was added 4.0 M HCl in dioxane (20 mL, 75.70 mmol) at 0 qC. Reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure.
  • Step-4 N-[1-(4-bromophenyl)but-3-enyl]acetamide (9-7): To a stirred solution of 1-(4-bromophenyl)but-3-en-1-amine 9-6 (3.50 g, 15.47 mmol) in chloroform (50 mL) was added triethylamine (3.13 mL, 30.95 mmol) followed by acetic anhydride (1.89 g, 18.57 mmol) at 0 qC. Reaction mixture was stirred at RT for 1 h. After completion, reaction was quenched with aqueous sodium bicarbonate solution. Aqueous layer was extracted with EtOAc.
  • Step-5 [5-(4-bromophenyl)pyrrolidin-3-yl] acetate (9-8): To a stirred solution of N-[1-(4-bromophenyl)but-3-enyl]acetamide 9-7 (3.00 g, 11.18 mmol) in THF (20 mL) and water (5 mL) was added iodine (8.51 g, 33.56 mmol) at RT and the reaction mixture was stirred for 16 h. After completion, reaction was quenched with mixture of saturated sodium bicarbonate solution and saturated sodium thiosulfate solution. Aqueous layer was extracted with EtOAc.
  • Step-6 tert-butyl 4-acetoxy-2-(4-bromophenyl)pyrrolidine-1-carboxylate (9-9): To a stirred solution of [5-(4-bromophenyl)pyrrolidin-3-yl] acetate 9-8 (2.80 g, 9.85 mmol) in 1,4-dioxane (25 mL) and water (15 mL) was added BOC anhydride (2.57 g, 11.82 mmol) at 0 qC followed by 1M NaOH solution (0.24 g, 9.85 mmol) to make (pH-8) and reaction was stirred at RT for 1 h.
  • Step-7 tert-butyl 2-(4-bromophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (9- 10): To a stirred solution of tert-butyl 4-acetoxy-2-(4-bromophenyl)pyrrolidine-1-carboxylate 9-9 (3.00 g, 7.81 mmol) in methanol (25 mL) was added NaOH (0.34 g, 8.59 mmol) and water (5 mL) at RT. Reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was neutralized with 2N HCl and concentrated under reduced pressure. The product obtained was dissolved in ethyl acetate and washed with water and brine solution.
  • Step-8 tert-butyl 2-(4-bromophenyl)-4-oxo-pyrrolidine-1-carboxylate (9-11): To a stirred solution of oxalyl chloride (1.1 mL, 13.14 mmol) in dry DCM (10 mL), DMSO (1.86 mL, 26.29 mmol) was added at -78 °C under N2 atmosphere and the reaction mixture was stirred for 10 min.
  • tert-butyl 2-(4-bromophenyl)-4- hydroxy-pyrrolidine-1-carboxylate 9-10 (1.50 g, 4.38 mmol) in DCM (5 mL) was added over a period of 5 min and the reaction mixture was stirred at -78 °C for 15 min. The temperature was raised to -50 °C.
  • triethylamine (5.54 mL, 39.44 mmol) was added and allowed the temperature to warm at RT over 30 min. After completion of reaction, the reaction mixture was quenched with saturated NH4Cl solution at 0 °C and extracted with DCM.
  • Step-9 tert-butyl 2-(4-bromophenyl)-4,4-difluoro-pyrrolidine-1-carboxylate (9- 12): To a stirred solution of tert-butyl 2-(4-bromophenyl)-4-oxo-pyrrolidine-1-carboxylate 9- 11 (2.00 g, 5.88 mmol) in DCM (25 mL) was added DAST (1.89 g, 11.75 mmol) at 0 °C. Reaction mixture was stirred at RT for 5 h. After completion, reaction was quenched with saturated sodium bicarbonate solution. Aqueous layer was extracted with DCM.
  • Step-10 tert-butyl 2-[4-(3-aminopyrazol-1-yl)phenyl]-4,4-difluoro-pyrrolidine-1- carboxylate (9-14): To a stirred solution of tert-butyl 2-(4-bromophenyl)-4,4-difluoro- pyrrolidine-1-carboxylate 9-12 (1.50 g, 4.14 mmol) in DMSO (15 mL) was added 1H- pyrazol-3-amine 9-13 (0.69 g, 8.28 mmol) followed by cesium carbonate (4.05 g, 12.4 mmol) at RT.
  • Step-11 tert-butyl 2-[4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1-carboxylate (9-16): To a stirred solution of tert-butyl 2-[4-(3-aminopyrazol-1-yl)phenyl]-4,4-difluoro- pyrrolidine-1-carboxylate 9-14 (0.70 g, 1.92 mmol) in MeCN (10 mL) was added pyridine (0.15 g, 1.92 mmol) followed by N,N′-disuccinimidyl carbonate (0.49 g, 1.92 mmol) at RT.
  • Step-12 tert-butyl 2-[4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1-carboxylate (9-17) and tert-butyl 2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]phenyl]-4,4-difluoro-pyrrolidine-1-carboxylate (9-18): 200 mg of tert-butyl 2-[4-[3- [[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine- 1-carboxylate 9-16 was separated by chiral purification method to afford tert-butylate 9-16 was
  • Chiral method Chiral separation was performed on a Chiral Pack IK column (30 mm x 250 mm), 5 ⁇ , with a flow rate of 42 mL/min.
  • Mobile Phase 50% n-hexane + 50% ethanol/methanol (1:1), held isocratic with detection at a wavelength of 270 nm.
  • Step-13 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[4,4-difluoropyrrolidin-2- yl]phenyl]pyrazol-3-yl]urea (Example 9): To a stirred solution of tert-butyl 2-[4-[3-[[(4S)- 8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1- carboxylate 9-17 (0.02 g, 0.034 mmol) in ethyl acetate (2 mL) was added 4N HCl in ethyl acetate (5.0 mL) at 0 °C and the reaction mixture was stirred at RT for 4h.
  • Step-14 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[4,4-difluoropyrrolidin-2- yl]phenyl]pyrazol-3-yl]urea (Example 10): To a stirred solution of tert-butyl 2-[4-[3-[[(4S)- 8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-4,4-difluoro-pyrrolidine-1- carboxylate 9-18 (0.08 g, 0.13 mmol) in ethyl acetate (2 mL) was added 4N HCl in ethyl acetate (5.0 mL) at 0 °C and the reaction mixture was stirred at RT for 4h.
  • Step-2 tert-butyl N-[1-[4-(3-aminopyrazol-1-yl) phenyl] cyclopropyl] carbamate (11-4): To a stirred solution of tert-butyl N-[1-[4-(3-nitropyrazol-1- yl)phenyl]cyclopropyl]carbamate 11-3 (0.25 g, 0.72 mmol) in EtOH (8 mL) and water (2 mL) was added NH 4 Cl (0.50 g, 3.63 mmol) followed by iron powder (0.20 g, 3.63 mmol) at RT and the reaction mixture was stirred under 100 °C for 2 h.
  • reaction mixture was filtered through Celite. The aqueous layer was extracted with EtOAc. Organic layer was concentrated under reduced pressure. Product obtained was purified by reverse phase column chromatography to afford tert-butyl N-[1-[4-(3-aminopyrazol-1- yl)phenyl]cyclopropyl]carbamate 11-4 (0.15 g).
  • Step-3 tert-butyl N-[1-[4-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino]pyrazol-1-yl]phenyl]cyclopropyl]carbamate (11-6): To a stirred solution of tert- butyl N-[1-[4-(3-aminopyrazol-1-yl) phenyl] cyclopropyl] carbamate 11-4 (0.13 g, 0.41 mmol) in MeCN (5 mL) was added pyridine (0.03 mL, 0.41 mmol) and N,N′-disuccinimidyl carbonate (0.10 g, 0.41 mmol) at 0 °C.
  • reaction mixture was stirred at RT for 50 min. To this were added DIPEA (0.22 mL, 1.24 mmol) and (4S)-8-chlorochroman-4-amine hydrochloride 11-5 (0.09 g, 0.414 mmol) at 0 °C and reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure and product obtained was dissolved in EtOAc. Organic layer was washed with 2N HCl, H 2 O, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-4 1-[1-[4-(1-aminocyclopropyl) phenyl] pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 11): To a stirred solution of tert-butyl N-[1-[4-[3- [[(4S)-8-chlorochroman-4-yl] carbamoyl amino]pyrazol-1-yl]phenyl]cyclopropyl]carbamate 11-6 (0.13 g, 0.248 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (5.0 mL) at 0 °C and the reaction mixture was stirred at RT for 4 h.
  • Example 12 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2-(dimethylamino)-1,1- difluoro-ethyl]phenyl]pyrazol-3-yl]urea [0 ] Step : , d uoo [ (3 topyao y)p e y]acetc acd ( 3): o a stirred solution of 3-nitro-1H-pyrazole 12-2 (1.00 g, 8.84 mmol) in DMSO (15 mL) were added K 2 CO 3 (3.66 g, 26.5 mmol) and CuI (0.34 g, 1.77 mmol) followed by L-proline (0.20 g, 1.77 mmol) and ethyl 2-(4-bromophenyl)-2,2-difluoro-acetate 12-1 (2.96 g, 10.60 mmol) and the reaction mixture was stirred at 120 °C for
  • Step-2 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanol (12-4): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]acetic acid 12-3 (3.00 g, 10.60 mmol) in THF (5 mL) was added BH 3 . DMS (0.80 g, 21.2 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 2 h. After completion, reaction was quenched with H2O, extracted with EtOAc.
  • Step-3 [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate (12-5): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1- yl)phenyl]ethanol 12-4 (1.00 g, 2.53 mmol) in DCM (10 mL) was added Et 3 N (1.1 mL, 7.60 mmol) followed by p-toluene sulphonyl chloride (0.72 g, 3.80 mmol) portion wise and the reaction mixture was stirred at 25 °C for 16 h.
  • Step-4 1-[4-(2-azido-1,1-difluoro-ethyl)phenyl]-3-nitro-pyrazole (12-6): To a stirred solution of [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate 12-5 (0.50 g, 1.18 mmol) in DMF (3 mL) was added NaN 3 (0.15 g, 2.36 mmol) and the resulting reaction mixture was stirred at 100 °C for 16 h. After completion, reaction mixture was diluted with H 2 O and extracted with EtOAc.
  • Step-5 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine (12-7): To a stirred solution of 1-[4-(2-azido-1,1-difluoro-ethyl)phenyl]-3-nitro-pyrazole (0.60 g, 2.04 mmol) in THF (3 mL) and water (1 mL) was added TPP (1.07 g, 4.08 mmol) at 0 °C. Resulting reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc. Organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-6 2,2-difluoro-N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine (12-8): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine 12- 7 (0.06 g, 0.22 mmol) in formic acid (0.01 mL, 0.33 mmol) was added formaldehyde (0.01 mL, 0.33 mmol) at 0 °C. Resulting reaction mixture was stirred at 80 °C for 4 h. After completion, reaction mixture was diluted with H 2 O and extracted with EtOAc. Organic layer was concentrated under reduced pressure.
  • Step-7 1-[4-[2-(dimethylamino)-1,1-difluoro-ethyl]phenyl]pyrazol-3-amine (12- 9): To a stirred solution of 2,2-difluoro-N,N-dimethyl-2-[4-(3-nitropyrazol-1- yl)phenyl]ethanamine 12-8 (0.20 g, 0.67 mmol) in ethanol (8 mL) and water (2 mL) was added ammonium chloride (0.18 g, 3.38 mmol) followed by iron powder (0.18 g, 3.38 mmol). The reaction was stirred at 80 °C for 4 h.
  • Step-8 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2-(dimethylamino)-1,1-difluoro- ethyl]phenyl]pyrazol-3-yl]urea (Example 12): To a stirred solution of 1-[4-[2- (dimethylamino)-1,1-difluoro-ethyl]phenyl]pyrazol-3-amine 12-9 (0.15 g, 0.58 mmol) in MeCN (5 mL) was added pyridine (0.06 mL, 0.73 mmol) followed by N,N′-disuccinimidyl carbonate (0.12 g, 0.488 mmol).
  • Example 13 and Example 14 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1- (dimethylamino)ethyl]phenyl]pyrazol-3-yl]urea [ ] p [ ( py y )p y ] ( ) - [4-(3-nitropyrazol-1-yl)phenyl]ethanone 13-1 (0.50 g, 2.16 mmol) in a mixture of methanol (5 mL) and THF (5 mL) was added sodium borohydride (0.12 g, 3.24 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h.
  • Step-2 1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate (13-3): To a stirred solution of 1-[4-(3-nitropyrazol-1-yl)phenyl]ethanol 13-2 (0.40 g, 1.72 mmol) in DCM (10 mL) were added triethyl amine (0.35 g, 3.43 mmol) and 4-dimethylaminopyridine (0.04 g, 0.34 mmol) followed by 4-toluenesulfonyl chloride (0.49 g, 2.57 mmol) at 0 °C and the reaction mixture was stirred in a sealed tube at 30 °C for 18 h.
  • Step-3 N,N-dimethyl-1-[4-(3-nitropyrazol-1-yl) phenyl]ethanamine (13-4): To a stirred solution of 1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate 13-3 (0.40 g, 1.03 mmol) in MeCN (5 mL) was added potassium carbonate (0.42 g, 3.10 mmol) followed by 2M dimethylamine solution in THF (0.76 g, 6.19 mmol) at 0 °C and the reaction mixture was stirred in a sealed tube at 80 °C for 16 h.
  • Step-4 1-[4-[1-(dimethylamino) ethyl] phenyl] pyrazol-3-amine (13-5): To a stirred solution of N,N-dimethyl-1-[4-(3-nitropyrazol-1-yl) phenyl] ethanamine 13-4 (0.25 g, 0.96 mmol) in ethanol (5 mL) and water (2 mL) was added iron powder (0.32 g, 5.76 mmol) followed by ammonium chloride (0.31g, 5.76 mmol) and the reaction mixture was stirred at 80 °C for 2 h. After completion, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure.
  • Step-5 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1- (dimethylamino)ethyl]phenyl]pyrazol-3-yl]urea (Examples 13 and 14): To a stirred solution of 1-[4-[1-(dimethylamino)ethyl]phenyl]pyrazol-3-amine 13-5 (0.20 g, 0.86 mmol) in MeCN (5 mL) maintained at 0 °C was added pyridine (0.09 mL, 1.17 mmol) followed by N,N′-disuccinimidyl carbonate (0.24 g, 0.95 mmol).
  • Step-1 2-[3-(3-nitropyrazol-1-yl)phenyl]acetonitrile (15-3): To a stirred solution of 3-nitro-1H-pyrazole 15-1 (0.50 g, 4.42 mmol) in DCM (20 mL) were added [3- (cyanomethyl)phenyl]boronic acid 15-2 (1.42 g, 8.84 mmol) and copper (II) acetate (0.87 g, 8.84 mmol) followed by pyridine (0.78 mL, 8.84 mmol) at RT.
  • reaction mixture was stirred at 25 °C for 16 h. After completion of reaction, the reaction mixture was filtered through Celite bed and filtrate was concentrated under reduced pressure to yield product which was purified by CombiFlash (60% EtOAc/n-heptane) to afford 2-[3-(3-nitropyrazol-1- yl)phenyl]acetonitrile 15-3 (0.30 g).
  • Step-2 2-methyl-2-[3-(3-nitropyrazol-1-yl)phenyl]propanenitrile (15-4): To a stirred solution of 2-[3-(3-nitropyrazol-1-yl)phenyl]acetonitrile (1.00 g, 4.38 mmol) in THF (15 mL) were added sodium hydride (60% in mineral oil, 0.26 g, 11.00 mmol) and iodomethane (0.81 mL, 13.10 mmol) at 0 °C. The reaction mixture was stirred under 25 °C for 16 h. After completion of reaction, reaction mixture was quenched with ice cold water and extracted with ethyl acetate.
  • Step-3 2-methyl-2-[3-(3-nitropyrazol-1-yl)phenyl]propanamide (15-5): To a stirred solution of 2-methyl-2-[3-(3-nitropyrazol-1-yl)phenyl]propanenitrile 15-4 (0.80 g, 3.12 mmol) in EtOH (46 mL) were added K2CO3 (0.43 g, 3.12 mmol) and 30% H2O2 (66 mL, 3.12 mmol) at RT. The reaction mixture was stirred at 25 °C for 16 h. After completion of reaction, reaction mixture was diluted with water, aqueous layer was extracted with DCM.
  • Step-4 2-[3-(3-nitropyrazol-1-yl)phenyl]propan-2-amine (15-6): To a stirred solution of 2-methyl-2-[3-(3-nitropyrazol-1-yl)phenyl]propanamide 15-5 (0.50 g, 1.82 mmol) in MeCN (10 mL) and water (10 mL) was added (bis(trifluoroacetoxy)iodo)benzene (0.78 g, 1.82 mmol) at RT. The reaction mixture was stirred under 25 °C for 16 h. After completion of reaction, reaction mixture was diluted with water, aqueous layer was extracted with ethyl acetate.
  • Step-5 tert-butyl N-[1-methyl-1-[3-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate (15-7): To a stirred solution of 2-[3-(3-nitropyrazol-1-yl)phenyl]propan-2-amine 15-6 (0.55 g, 2.23 mmol) in DCM (15 mL) was added triethylamine (0.62 mL, 4.47 mmol) followed by di-tert-butyl dicarbonate (0.62 mL, 2.68 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 16 h.
  • reaction mixture was diluted with water, aqueous layer was extracted with DCM. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield product which was purified by flash column chromatography (50% EtOAc/n-heptane) to afford tert- butyl N-[1-methyl-1-[3-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 15-6 (0.18 g).
  • Step-6 tert-butyl N-methyl-N-[1-methyl-1-[3-(3-nitropyrazol-1- yl)phenyl]ethyl]carbamate (15-8): To a stirred solution of tert-butyl N-[1-methyl-1-[3-(3- nitropyrazol-1-yl)phenyl]ethyl]carbamate 15-7 (0.18 g, 0.52 mmol) in THF (5 mL) were added NaH (60% in mineral oil, 0.12 g, 3.12 mmol) and iodomethane (0.19 mL, 3.12 mmol) at 0 °C.
  • reaction mixture was stirred under 25 °C for 16 h. After completion of reaction, reaction mixture was quenched with ice cold water and extracted with ethyl acetate. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield product which was purified by CombiFlash to afford tert-butyl N-methyl-N-[1-methyl-1-[3-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 15- 8 (0.07 g).
  • Step-7 tert-butyl N-[1-[3-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]-N- methyl-carbamate (15-9): To a stirred solution of tert-butyl N-methyl-N-[1-methyl-1-[3-(3- nitropyrazol-1-yl)phenyl]ethyl]carbamate 15-8 (0.06 g, 0.16 mmol) in ethanol (3 mL) and water (1.5 mL) was added iron powder (0.04 g, 0.83 mmol) followed by ammonium chloride (0.04 g, 0.83 mmol) at RT.
  • Step-8 tert-butyl N-[1-[3-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]-N-methyl-carbamate (15-11): To a stirred solution of tert-butyl N-[1-[3-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]-N- methyl-carbamate 15-9 (0.04 g, 0.13 mmol) in MeCN (2 mL) was added pyridine (0.02 mL, 0.27 mmol) followed by N,N′-disuccinimidyl carbonate (0.03 g, 0.13 mmol) at 0 °C.
  • reaction mixture was stirred at RT for 1 h. To this was added (4S)-8- chlorochroman-4-amine;hydrochloride 15-10 (0.03 g, 0.13 mmol) followed by DIPEA (0.07 mL, 0.40 mmol) at RT and the reaction mixture was stirred at 25 °C for 1 h. After completion of reaction, reaction mixture was quenched with ice cold water and extracted with ethyl acetate.
  • Step-9 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-[1-methyl-1- (methylamino)ethyl]phenyl]pyrazol-3-yl]urea
  • Example 15 To a stirred solution of tert- butyl N-[1-[3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1- methyl-ethyl]-N-methyl-carbamate 15-11 (1.00 eq, 60 mg, 0.111 mmol) in DCM (1.5 mL), were added 2,6-lutidine (0.07 mL, 0.56 mmol) and trimethylsilyl trifluoromethanesulfonate (0.10 mL, 0.56 mmol) at 0 °C.
  • Example 16 Synthesis of 1-[1-[4-(azetidin-3-yl) phenyl] pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea ed solution of (4-bromophenyl) boronic acid 16-1 (0.53 g, 2.65 mmol) in IPA (10 mL) was added nickel (II) iodide (0.16 g, 0.53 mmol) followed by (1R,2R)-2-aminocyclohexan-1-ol (0.06 g, 0.53 mmol) and degassed with argon for 10 min.
  • (4-bromophenyl) boronic acid 16-1 (0.53 g, 2.65 mmol) in IPA (10 mL) was added nickel (II) iodide (0.16 g, 0.53 mmol) followed by (1R,2R)-2-aminocyclohexan-1-ol (0.06
  • Step-2 tert-butyl 3-[4-(3-aminopyrazol-1-yl) phenyl] azetidine-1-carboxylate (16- 5): To a stirred solution of 1H-pyrazol-3-amine 16-4 (0.47 g, 5.66 mmol) in DMF (5 mL) was added tert-butyl 3-(4-bromophenyl) azetidine-1-carboxylate 16-3 (1.94 g, 6.22 mmol) followed by cesium carbonate (4.60 g, 14.10 mmol) and copper (I) bromide (0.24 g, 1.70 mmol).
  • Step-3 tert-butyl 3-[4-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl] phenyl] azetidine-1-carboxylate (16-7): To a stirred solution of tert-butyl 3- [4-(3-aminopyrazol-1-yl) phenyl] azetidine-1-carboxylate 16-5 (0.50g, 1.59 mmol) in MeCN (5 mL) was added pyridine (0.26 mL, 3.18 mmol) followed by N,N′-disuccinimidyl carbonate (0.44 g, 1.75 mmol) at 0 °C.
  • reaction mixture was stirred at RT for 30 min. To this was added (4S)-8-chlorochroman-4-amine 16-6 (0.35 g, 1.91 mmol) followed by DIPEA (1.1 mL, 6.36 mmol) and reaction mixture was stirred at 30 °C for 2 h. After completion, reaction mixture was concentrated under reduced pressure. The product was quenched with H2O and extracted with 10% MeOH/DCM. Combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-4 1-[1-[4-(azetidin-3-yl) phenyl] pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4- yl]urea
  • Example 16 To a stirred solution of tert-butyl 3-[4-[3-[[(4S)-8-chlorochroman-4- yl] carbamoyl amino] pyrazol-1-yl] phenyl] azetidine-1-carboxylate 16-7 (0.10 g, 0.19 mmol) in DCM (2.5 mL) was added TFA (1.0 mL) at 0 °C and the reaction mixture was stirred at RT for 4 h.
  • Example 17 Synthesis of 2-(3-(3-(8-fluorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N,N- dimethylacetamide
  • 3-nitro-1H-pyrazole 17-1 0.5 g, 4.42 mmol
  • MeCN 8 mL
  • 2-bromo-N,N- dimethyl-acetamide 17-2 0.5 g, 0.97 mmol
  • K2CO3 0.18 g, 1.00 mmol
  • Step-2 2-(3-amino-1H-pyrazol-1-yl)-N,N-dimethylacetamide (17-4): To a stirred solution of 17-3 (0.52 g, 2.63 mmol) in ethanol/water (1:1, 14 mL), NH 4 Cl (0.14 g, 2.63 mmol) was added followed by iron powder (0.84 g, 15.0 mmol) at RT and stirred for 10 min. The reaction mixture was heated at 80 oC for 16 h. After completion of reaction, the reaction mixture was diluted with water, the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-3 2-(3-(3-(8-fluorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N,N- dimethylacetamide
  • Example 17 To a stirred solution of N,N'-disuccinimidyl carbonate (0.15 g, 0.60 mmol) in THF (4 mL), pyridine (0.05 mL, 0.60 mmol) was added followed by 17-4 (0.10 g, 0.60 mmol) and the reaction mixture was stirred at RT for 45 min.
  • Example 18 Synthesis of 1-[1-[4-(3-aminooxetan-3-yl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea [0152]
  • Step-1 N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl-propane-2-sulfinamide (18- 3): To a stirred solution of 1-bromo-4-iodo-benzene 18-1 (0.10 g, 0.35 mmol) in dry THF ( 3 mL) was added n-BuLi (1.6M in hexane, 0.26 mL, 0.42 mmol) drop wise at -78 °C under argon atmosphere and the reaction mixture was stirred for 10 min.
  • Step-2 N-[3-[4-(3-aminopyrazol-1-yl)phenyl]oxetan-3-yl]-2-methyl-propane-2- sulfinamide (18-5): To a stirred solution of N-[3-(4-bromophenyl)oxetan-3-yl]-2-methyl- propane-2-sulfinamide 18-3 (1.60 g, 4.82 mmol) in DMSO (20 mL) was added 1H-pyrazol-3- amine 18-4 (0.40 g, 4.82 mmol) followed by cesium carbonate (3.14 g, 9.63 mmol).
  • reaction mixture was purged with argon gas for 20 min and then was added trans-4-hydroxy- D-proline (0.31 g, 2.41 mmol) followed by copper (I) iodide (0.18 g, 0.96 mmol), purged with argon again for 10 min.
  • the reaction was stirred at 120 °C for 12 h. After completion, the reaction mixture was diluted with cold water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-3 1-[1-[4-[3-(tert-butylsulfinylamino)oxetan-3-yl]phenyl]pyrazol-3-yl]-3- [(4S)-8-chlorochroman-4-yl]urea (18-7): To a stirred solution of N-[3-[4-(3-aminopyrazol- 1-yl)phenyl]oxetan-3-yl]-2-methyl-propane-2-sulfinamide 18-5 (0.30 g, 0.89 mmol) in MeCN (5 mL) was added pyridine (0.14 mL, 1.79 mmol) followed by N,N′-disuccinimidyl carbonate (0.34 g, 1.35 mmol) and the reaction mixture was stirred at 25 °C for 45 min.
  • Step-4 1-[1-[4-(3-aminooxetan-3-yl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea
  • Example 18 To a stirred solution of 1-[1-[4-[3-(tert- butylsulfinylamino)oxetan-3-yl]phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 18- 7 (0.05 g, 0.09 mmol) in methanol (1 mL) was added 4M HCl in 1,4 dioxane (0.10 mL, 0.14 mmol) at -10 °C.
  • Example 19 and Example 20 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[(2R)- 1-methylpyrrolidin-2-yl] phenyl] pyrazol-3-yl]urea 2- (4-bromophenyl) pyrrolidine 19-1 (0.50 g, 2.21 mmol) in methanol (5 mL) was added formaldehyde (0.66 g, 22.1 mmol). The resulting solution was stirred at RT under nitrogen atmosphere for 2 h. To this was added sodium triacetoxyborohydride (0.93 g, 4.42 mmol) and the reaction mixture was stirred at RT under nitrogen atmosphere for 24 h.
  • Step-2 1-[4-(1-methylpyrrolidin-2-yl) phenyl] pyrazol-3-amine (19-4): To a stirred solution of 1H-pyrazol-3-amine 19-3 (0.06 g, 0.83 mmol) in DMF (2 mL) was added 2-(4-bromophenyl)-1-methyl-pyrrolidine 19-2 (0.20 g, 0.83 mmol) followed by cesium carbonate (0.54 g, 1.67 mmol) and copper (I) bromide (0.03 g, 0.25 mmol). The reaction mixture was stirred at 140 °C under microwave for 4 h. After completion, the reaction was quenched with ice cold water and extracted with DCM.
  • Step-3 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-(1-methylpyrrolidin-2-yl) phenyl] pyrazol-3-yl]urea (19-6): To a stirred solution of 1-[4-(1-methylpyrrolidin-2-yl) phenyl] pyrazol-3-amine 19-4 (0.10 g, 0.41 mmol) in MeCN (5 mL) was added N,N′-disuccinimidyl carbonate (0.10 g, 0.41 mmol) followed by pyridine (0.06 mL, 0.82 mmol). The resulting reaction mixture was stirred at RT for 45 min.
  • Step-4 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[(2R)-1-methylpyrrolidin-2-yl] phenyl]pyrazol-3-yl]urea
  • Example 19 and 20 The purified product of 1-[(4S)-8- chlorochroman-4-yl]-3-[1-[4-(1-methylpyrrolidin-2-yl)phenyl]pyrazol-3-yl]urea 19-6 was submitted for chiral prep HPLC separation to afford Example 19 (0.02 g) and Example 20 (0.02 g). The absolute stereochemistry for these examples was not determined.
  • Example 21 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1-methyl-1- (methylamino) ethyl] phenyl] pyrazol-3-yl]urea
  • Step-1 tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl) phenyl]ethyl]carbamate (21-3): To a stirred solution of 3-nitro-1H-pyrazole 21-1 (0.14 g, 1.24 mmol) in DCM (30 mL) were added [4-[1-(tert-butoxycarbonylamino)-1-methyl-ethyl] phenyl] boronic acid 21-2 (1.03 g, 3.71 mmol) and copper acetate (0.24 g, 2.48 mmol) followed by pyridine (0.20 mL, 2.48 mmol) and the reaction mixture was stirred at RT for
  • reaction mixture was filtered through Celite bed and the filtrate was concentrated under reduced pressure to yield product which was purified by CombiFlash (30% EtOAc/n- heptane) to afford tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 21-3 (0.30 g).
  • Step-2 tert-butyl N-methyl-N-[1-methyl-1-[4-(3-nitropyrazol-1-yl) phenyl] ethyl]carbamate (21-4): To a stirred solution of tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol- 1-yl) phenyl] ethyl]carbamate 21-3 (0.93 g, 2.68 mmol) in THF (10 mL) was added NaH (60% mineral oil, 0.64 g, 16.1 mmol) at 0 °C followed by MeI (1.0 mL, 16.1 mmol). Reaction mixture was stirred at RT for 24 h.
  • Step-3 tert-butyl N-[1-[4-(3-aminopyrazol-1-yl) phenyl]-1-methyl-ethyl]-N- methylcarbamate (21-5): To a stirred solution of tert-butyl N-methyl-N-[1-methyl-1-[4-(3- nitropyrazol-1-yl)phenyl]ethyl]carbamate 21-4 (0.26 g, 0.71 mmol) in ethanol (10 mL) and water (2.5 mL) was added NH 4 Cl (0.19 g, 3.59 mmol) followed by iron powder (0.20 g, 3.59 mmol) at RT and the reaction mixture was stirred under 80 °C for 2 h.
  • reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc and the combined organic layer was concentrated under reduced pressure to yield product which was purified by CombiFlash (50% EtOAc/n-heptane) to afford tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl- ethyl]-N-methyl-carbamate 21-5 (0.16 g, 0.45 mmol).
  • Step-4 N-[1-[4-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl] phenyl]-1-methyl-ethyl]-N-methyl-carbamate (21-7): To a stirred solution of tert-butyl N- [1-[4-(3-aminopyrazol-1-yl) phenyl]-1-methyl-ethyl]-N-methylcarbamate 21-5 (0.26 g, 0.51 mmol) in MeCN (5 mL) was added N,N′-disuccinimidyl carbonate (0.13 g, 0.514 mmol) followed by pyridine (0.04 mL, 0.51 mmol).
  • reaction mixture was stirred at RT for 1 h. After completion, reaction mixture was concentrated under reduced pressure. The residue was washed with ice-cold water and the precipitated solid was filtered under vacuum.
  • Step-5 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1-methyl-1-(methylamino) ethyl] phenyl] pyrazol-3-yl]urea
  • Example 21 To a stirred solution of tert-butyl N-[1-[4-[3- [[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]-N- methyl-carbamate 21-7 (0.02 g, 0.04 mmol) in DCM (0.5 mL) was added 2.6-lutidine (0.05 mL, 0.46 mmol) followed by TMS triflate (0.08 mL, 0.46 mmol) at 0 °C and the reaction mixture was stirred at RT for 1 h.
  • Example 22 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-(1-methylazetidin-3- yl)phenyl]pyrazol-3-yl]urea [0167]
  • Step-1 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-(1-methylazetidin-3- yl)phenyl]pyrazol-3-yl]urea
  • Example 22 To a stirred solution of 1-[1-[4-(azetidin-3- yl)phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea
  • Example 16 (0.10 g, 0.23 mmol) in methanol (5 mL) was added 37% formaldehyde (1.0 mL, 2.36 mmol) and the reaction mixture was stirred at RT for 2 h.
  • Example 22 (0.03 g).
  • Example 23 Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)-3-fluoro-phenyl]pyrazol-3- yl]-3-[(4S)-8-chlorochroman-4-yl]urea [068] Step : ( bo o uoop e y) et y popa e t e (3 ): o a st ed solution of 2-(4-bromo-2-fluoro-phenyl)acetonitrile 23-1 (2.00 g, 9.34 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 0.93 g, 23.4 mmol) at 0 °C and the reaction mixture was stirred for 1 h.
  • Step-2 [4-(1-cyano-1-methyl-ethyl)-3-fluoro-phenyl]boronic acid (23-3): To a stirred solution of 2-(4-bromo-2-fluoro-phenyl)-2-methyl-propanenitrile 23-2 (8.50 g, 35.1 mmol) in THF (95 mL) was added n-BuLi (23.00 mL, 246 mmol) at -78 °C and reaction mixture was stirred at -78 °C for 1 h. To this was added B(OMe)3 (6.80 mL, 45.60 mmol) and the reaction mixture was warmed to RT for 30 min.
  • Step-3 2-[2-fluoro-4-(3-nitropyrazol-1-yl)phenyl]-2-methyl-propanenitrile (23- 5): To a stirred solution of 3-nitro-1H-pyrazole 23-4 (0.50 g, 4.42 mmol) in DCM (16 mL) was added pyridine (1.1 mL, 13.3 mmol) at 0 °C followed by [4-(1-cyano-1-methyl-ethyl)-3- fluoro-phenyl]boronic acid 23-3 (2.29 g, 11.1 mmol). The reaction mixture was purged with oxygen for 20 min followed by addition of Cu(OAc) 2 (1.61 g, 8.84 mmol).
  • Step-4 2-[2-fluoro-4-(3-nitropyrazol-1-yl)phenyl]-2-methyl-propanamide (23-6): To a stirred solution of 1-[3-(1,1-dimethylprop-2-ynyl)phenyl]-3-nitro-pyrazole 23-5 (0.93 g, 3.39 mmol) in ethanol (22 mL), saturated K2CO3 (16 mL) was added followed by 30% H2O2 (32 mL). The reaction mixture was stirred at 25 °C for 16 h.
  • reaction mixture was filtered by Buchner funnel to obtain a white solid which was triturated with diethyl ether to afford 2-[2-fluoro-4-(3-nitropyrazol-1-yl)phenyl]-2-methyl-propanamide 23-6 (0.60 g).
  • LCMS: [M+H] + 293.
  • Step-5 2-[4-(3-aminopyrazol-1-yl)-2-fluoro-phenyl]-2-methyl-propanamide (23- 7): To a stirred solution of 2-[2-fluoro-4-(3-nitropyrazol-1-yl)phenyl]-2-methyl-propanamide 23-6 (0.60 g, 2.05 mmol) in ethanol (45 mL) and water (15 mL) was added NH 4 Cl (0.54 g, 10.3 mmol) followed by iron powder (0.57 g, 10.3 mmol) at RT. The resulting reaction mixture was stirred at 100 °C for 1 h.
  • reaction mixture was filtered through Celite bed and washed with 5% MeOH/DCM. Filtrate was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. Product was purified by column chromatography (100% EtOAc) to afford 2-[4-(3-aminopyrazol-1-yl)-2-fluoro-phenyl]-2-methyl-propanamide 23-7 (0.36 g, 66.86 %).
  • LCMS: [M+H] + 263.
  • Step-6 2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-2- fluoro-phenyl]-2-methyl-propanamide (23-9): To a stirred solution of 2-[4-(3- aminopyrazol-1-yl)-2-fluoro-phenyl]-2-methyl-propanamide 23-7 (0.18 g, 0.69 mmol) in MeCN (5 mL) was added pyridine (0.05 g, 0.69 mmol) followed by N,N′-disuccinimidyl carbonate (0.17 g,0.69 mmol).
  • reaction mixture was stirred at RT for 15 min.
  • (4S)-8-chlorochroman-4-amine hydrochloride 23-8 (0.12 g, 0.69 mmol) followed by DIPEA (0.26 g, 2.06 mmol) and reaction mixture was stirred at 25 °C for 3 h.
  • reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-7 1-[1-[4-(1-amino-1-methyl-ethyl)-3-fluoro-phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea
  • Example 23 To a stirred solution of 2-[4-[3-[[(4S)-8- chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-2-fluoro-phenyl]-2-methyl-propanamide 23-9 (0.12 g, 0.25 mmol) in MeCN (2 mL) and water (8 mL) was added KOH (0.07 g, 1.16 mmol) followed by 1,3-dibromo-5,5-dimethylhydantoin 23-10 (0.04 g, 0.13 mmol) and the reaction mixture was stirred at RT for 1 h.
  • Example 24 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2- (dimethylamino)acetyl]phenyl]pyrazol-3-yl]urea [ ] p ( [ ( py y )p y] ( ) f 3-nitro-1H-pyrazole 24-1 (3.00 g, 26.5 mmol) in DCM (35 mL) was added (4- acetylphenyl)boronic acid 24-2 (6.53 g, 39.80 mmol) followed by pyridine (7.00 mL, 79.60 mmol) and Cu(OAc)2 (9.60 g, 53.1 mmol).
  • Step-2 2-bromo-1-[4-(3-nitropyrazol-1-yl)phenyl]ethanone (24-4): To a stirred solution of 1-[4-(3-nitropyrazol-1-yl)phenyl]ethenone 24-3 (1.00 g, 4.33 mmol) in MeCN (15 mL) was added pTSA (0.08 g, 0.43 mmol) followed by NBS (0.76 g, 4.33 mmol). Resulting mixture was stirred at 80 °C for 12 h. After completion, reaction mixture was diluted with ice cold water, extracted with EtOAc. Organic layer was washed with NaHCO 3 solution, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-3 2-(dimethylamino)-1-[4-(3-nitropyrazol-1-yl)phenyl]ethanone (24-5): To a stirred solution of N,N-dimethyl amine (2M in THF, 0.36 g, 8.06 mmol) in MeCN (10 mL) was added K2CO3 (0.22 g, 1.61 mmol) and stirred for 15 min.
  • Step-4 1-[4-(3-aminopyrazol-1-yl)phenyl]-2-(dimethylamino)ethanone (24-6): To a stirred solution of 2-(dimethylamino)-1-[4-(3-nitropyrazol-1-yl)phenyl]ethanone 24-5 (0.15 g, 0.54 mmol) in ethanol (3 mL) and water (1 mL) was added NH4Cl (0.14 g, 2.73 mmol) followed by Fe powder (0.15 g, 2.73 mmol). The reaction mixture was stirred at 80 °C for 4 h. After completion, reaction mixture was filtered and filtrate was concentrated under reduced pressure.
  • Step-5 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2- (dimethylamino)acetyl]phenyl]pyrazol-3-yl]urea
  • Example 24 To a stirred solution of 1- [4-(3-aminopyrazol-1-yl)phenyl]-2-(dimethylamino)ethanone 24-6 (0.06 g, 0.24 mmol) in MeCN (3 mL) was added pyridine (0.03 mL, 0.36 mmol) followed by N,N′-disuccinimidyl carbonate (0.06 g, 0.24 mmol).
  • Step-1 2-fluoro-4-(3-nitropyrazol-1-yl)aniline (25-3): To a stirred solution of 3- nitro-1H-pyrazole 25-1 (1.00 g, 8.84 mmol) in THF (10 mL) was added (4-amino-3-fluoro- phenyl) boronic acid 25-2 (2.19 g, 14.2 mmol) followed by copper (I) chloride (0.12 g, 1.33 mmol) and sodium hydroxide (0.42 g, 10.6 mmol).
  • Step-2 2-[2-fluoro-4-(3-nitropyrazol-1-yl)anilino]ethanol (25-4): To a suspension of 2-fluoro-4-(3-nitropyrazol-1-yl)aniline 25-3 (0.30 g, 1.35 mmol) in THF (0.1 mL) was added 2-bromoethanol (0.16 g, 1.35 mmol) and stirred at 90 °C for 12 h. After completion, reaction mixture was diluted with EtOAc and filtered. Filtrate was concentrated under reduced pressure.
  • Step-3 2-[4-(3-aminopyrazol-1-yl)-2-fluoro-anilino]ethanol (25-5): To a stirred solution of 2-[2-fluoro-4-(3-nitropyrazol-1-yl)anilino]ethanol 25-4 (0.13 g, 0.48 mmol) in ethanol (4 mL) was added water (1 mL) followed by ammonium chloride (0.12 g, 2.44 mmol) and iron powder (0.13 g, 2.44 mmol) and the reaction mixture was stirred at 100 °C for 2 h. After completion, reaction was filtered and filtrate was concentrated under reduced pressure. Residue was dissolved in EtOAc and filtered.
  • Step-4 1-[1-[3-fluoro-4-(2-hydroxyethylamino)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea
  • Example 25 To a stirred solution of 2-[4-(3-aminopyrazol-1- yl)-2-fluoro-anilino]ethanol 25-5 (0.10 g, 0.45 mmol) in MeCN (8 mL) was added pyridine (0.04 mL, 0.45 mmol) followed by N,N′-disuccinimidyl carbonate (0.11 g, 0.454 mmol). Resulting reaction mixture was stirred at RT for 30 min.
  • Step-1 2-(5-bromo-2-pyridyl)propan-2-amine (26-2): To a stirred solution of 5- bromopyridine-2-carbonitrile 26-1 (5.00 g, 27.3 mmol) in toluene (5 mL) was drop wise added MeMgI (15.90 g, 95.6 mmol) at 0 °C. Reaction mixture was stirred at 100 °C for 16 h. After completion, reaction mixture was quenched with saturated NH4Cl solution, acidified with 1N HCl, aqueous layer was extracted with EtOAc. Then aqueous layer was basified with saturated NaOH solution, and the aqueous layer was extracted with DCM.
  • MeMgI 15.90 g, 95.6 mmol
  • Step-2 2-[1-(5-bromo-2-pyridyl)-1-methyl-ethyl]isoindoline-1,3-dione (26-3): To a stirred solution of 2-(5-bromo-2-pyridyl)propan-2-amine 26-2 (1.50 g, 6.97 mmol) in toluene (10 mL) was added isobenzofuran-1,3-dione (1.08 g, 7.32 mmol) and the reaction mixture was stirred at 110 °C for 16 h.
  • reaction mixture was concentrated under reduced pressure to obtain product which was purified by flash chromatography (20% EtOAc/heptane) to afford 2-[1-(5-bromo-2-pyridyl)-1-methyl-ethyl]isoindoline-1,3-dione 26- 3 (1.10 g).
  • Step-3 2-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- pyridyl]ethyl]isoindoline-1,3-dione (26-4): To a degassed solution of 2-[1-(5-bromo-2- pyridyl)-1-methyl-ethyl]isoindoline-1,3-dione 26-3 (2.70 g, 7.82 mmol) and bis(pinacolato)diboron (2.98 g, 11.7 mmol) in DMF (10 mL) was added potassium acetate (2.33 g, 23.5 mmol) and Pd(dppf)Cl 2 (0.57 g, 0.78 mmol) at RT and the resulting solution was stirred at 100 °C for 3 h.
  • Step-4 [6-[1-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethyl]-3-pyridyl]boronic acid (26-5): To a stirred solution of 2-[1-methyl-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-2-pyridyl]ethyl]isoindoline-1,3-dione 26-4 (3.80 g, 9.69 mmol) in THF (5 mL) and water (5 mL) was added sodium metaperiodate (6.19 g, 29.1 mmol) and the reaction mixture was stirred at 25 °C for 30 min.
  • Step-5 2-[1-methyl-1-[5-(3-nitropyrazol-1-yl)-2-pyridyl]ethyl]isoindoline-1,3- dione (26-7): To a stirred solution of 3-nitro-1H-pyrazole 26-6 (0.52 g, 4.60 mmol) in DCM (10 mL) were added [6-[1-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethyl]-3-pyridyl]boronic acid 26-5 (2.42 g, 7.82 mmol), copper acetate (1.66 g, 9.20 mmol) and pyridine (1.1 mL, 13.8 mmol) at RT.
  • Step-6 2-[1-[5-(3-aminopyrazol-1-yl)-2-pyridyl]-1-methyl-ethyl]isoindoline-1,3- dione (26-8): To a stirred solution of 2-[1-methyl-1-[5-(3-nitropyrazol-1-yl)-2- pyridyl]ethyl]isoindoline-1,3-dione 26-7 (0.14 g, 0.37 mmol) in EtOH (2 mL) and water (2 mL) was added ammonium chloride (0.14 g, 2.60 mmol) followed by iron powder (0.10 g, 1.86 mmol).
  • Step-7 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[6-[1-(1,3-dioxoisoindolin-2-yl)-1- methyl-ethyl]-3-pyridyl]pyrazol-3-yl]urea (26-10): To a stirred solution of N,N′- disuccinimidyl carbonate (0.13 g, 0.51 mmol) in MeCN (3 mL) were added pyridine (0.04 mL, 0.51 mmol) and 2-[1-[5-(3-aminopyrazol-1-yl)-2-pyridyl]-1-methyl-ethyl]isoindoline- 1,3-dione 26-8 (0.18 g, 0.51 mmol) and the reaction mixture was stirred at RT for 45 min.
  • Step-8 1-[1-[6-(1-amino-1-methyl-ethyl)-3-pyridyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea
  • Example 26 To a stirred solution of 1-[(4S)-8-chlorochroman- 4-yl]-3-[1-[6-[1-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethyl]-3-pyridyl]pyrazol-3-yl]urea 26- 10 (0.14 g, 0.251 mmol) in ethanol (1 mL) and methanol (1 mL) was added hydrazine hydrate (0.06 mL, 1.26 mmol) at RT.
  • Example 27 and Example 28 Synthesis of 1-[1-[4-[1-amino-2,2,2-trifluoro- ethyl]phenyl]pyrazol 3 yl] 3 [(4S) 8 chlorochroman 4 yl]urea [0192]
  • Step-1 2, 2-trifluoro-1-[4-(3-nitropyrazol-1-yl)phenyl]ethanone (27-3): To a stirred solution of 1-(4-bromophenyl)-2,2,2-trifluoro-ethanone 27-2 (0.84 g, 3.32 mmol) in DMF (2 mL) was added 3-nitro-1H-pyrazole 27-1 (0.25 g, 2.21 mmol) followed by addition of K2CO3 (0.76 g, 5.53 mmol), CuI (0.08 g, 0.44 mmol) and trans-N,N′-dimethylcyclohexane- 1,2-diamine (0.13 g, 0.88 mmol).
  • reaction mixture was stirred at 120 °C for 2 h. After completion of reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Organic layer was washed with brine and dried over anhydrous Na 2 SO 4 . The product obtained was concentrated under reduced pressure to afford 2, 2, 2-trifluoro-1-[4-(3- nitropyrazol-1-yl)phenyl]ethanone 27-3 (0.30 g).
  • Step-2 2-methyl-N-[2,2,2-trifluoro-1-[4-(3-nitropyrazol-1- yl)phenyl]ethyl]propane-2-sulfinamide (27-5): To a stirred solution of 2,2,2-trifluoro-1-[4- (3-nitropyrazol-1-yl)phenyl] ethanone 27-3 (1.70 g, 5.96 mmol) in THF (50 mL) was added 2-methylpropane-2-sulfinamide 27-4 (1.08 g, 8.94 mmol) followed by addition of titanium isopropaoxide (3.6 mL, 11.9 mmol). Reaction mixture was stirred at 80 °C for 16 h.
  • reaction mixture was cooled to RT and was added sodium borohydride (1.13 g, 29.8 mmol) portion wise at RT.
  • the reaction mixture was stirred at RT for 3 h.
  • reaction mixture was diluted with H 2 O and extracted with EtOAc. The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • the product was purified by CombiFlash to afford 2-methyl-N-[2,2,2-trifluoro-1-[4- (3-nitropyrazol-1-yl)phenyl]ethyl]propane-2-sulfinamide 27-5 (0.85 g).
  • LCMS: [M+H]+ 391.
  • Step-3 N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethyl]-2-methyl- propane-2-sulfinamide (27-6): To a stirred solution of 2-methyl-N-[2,2,2-trifluoro-1-[4-(3- nitropyrazol-1-yl)phenyl]ethyl]propane-2-sulfinamide 27-5 (0.65 g, 1.67 mmol) in ethanol (50 mL) was added 10% Pd/C (0.35 g) and the reaction mixture was stirred under 100 psi hydrogen gas pressure at 25 °C for 3 h.
  • Step-4 1-[1-[4-[1-(tert-butylsulfinylamino)-2,2,2-trifluoro-ethyl]phenyl]pyrazol- 3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea (27-8): To a stirred solution of N-[1-[4-(3- aminopyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethyl]-2-methyl-propane-2-sulfinamide 27-6 (0.55 g, 1.53 mmol) in MeCN (20 mL) was added pyridine (0.12 mL, 1.53 mmol) followed by N,N′-disuccinimidyl carbonate (0.39 g, 1.53 mmol).
  • Step-5 1-[1-[4-(1-amino-2,2,2-trifluoro-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (27-9): To a stirred solution of 1-[1-[4-[1-(tert- butylsulfinylamino)-2,2,2-trifluoro-ethyl]phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4- yl]urea 27-8 (0.40 g, 0.70 mmol) in DCM (15 mL) was added 4 M HCl in dioxane (0.20 mL, 3.51 mmol) at 0 °C and the reaction mixture was stirred at 25 °C for 1 h.
  • Step-6 1-[1-[4-[1-amino-2,2,2-trifluoro-ethyl]phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Examples 27 and 28): 0.35 g of 1-[1-[4-(1-amino-2,2,2- trifluoro-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 27-9 was submitted for chiral-HPLC separation to afford Example 27 (0.06 g) and Example 28 (0.04 g). The absolute stereochemistry of these products was not determined.
  • Example 29 and Example 30 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4- [pyrrolidin-2-yl] phenyl] pyrazol-3-yl]urea stirred solution of 2-(4-bromophenyl)pyrrolidine 29-1 (0.10 g, 0.44 mmol) in THF (5 mL) was added triethylamine (0.07 mL, 0.53 mmol) followed by (BOC) 2 (0.11 mL, 0.53 mmol) and stirred at RT for 2 h. After completion, the reaction mixture was concentrated under reduced pressure.
  • Step-2 tert-butyl 2-[4-(3-aminopyrazol-1-yl) phenyl] pyrrolidine-1-carboxylate (29-4): To a stirred solution of 1H-pyrazol-3-amine 29-3 (0.02 g, 0.27 mmol) in DMF (2 mL) was added tert-butyl 2-(4-bromophenyl) pyrrolidine-1-carboxylate 29-2 (0.09 g, 0.30 mmol) followed by cesium carbonate (0.13 g, 0.41 mmol) and copper (I) bromide (0.004 g, 0.02 mmol). The reaction was stirred at 120 °C for 18 h.
  • Step-3 tert-butyl 2-(4-(3-(3-((S)-8-chlorochroman-4-yl)ureido)-1H-pyrazol-1- yl)phenyl)pyrrolidine-1-carboxylate (29-6): To a stirred solution of tert-butyl 2-[4-(3- aminopyrazol-1-yl) phenyl] pyrrolidine-1-carboxylate 29-4 (0.01 g, 0.04 mmol) in MeCN (3 mL) was added N,N′-disuccinimidyl carbonate (0.01 g, 0.04 mmol). The resulting reaction mixture was stirred at RT for 45 min.
  • Step-4 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-pyrrolidin-2-ylphenyl) pyrazol-3- yl]urea hydrochloride (29-7): To a stirred solution of tert-butyl 2-(4-(3-(3-((S)-8- chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)phenyl)pyrrolidine-1-carboxylate 29-6 (0.15 g, 0.27 mmol) in 1,4-dioxane (2 mL) was added 4N HCl in 1,4-dioxane (2 mL) at 0 °C and the resulting reaction mixture was stirred at RT for 4 h.
  • Step-5 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[pyrrolidin-2-yl] phenyl] pyrazol- 3-yl]urea
  • Racemic 29-7 was purified by prep HPLC purification which was submitted for chiral prep HPLC separation to afford Example 29 (0.03 g, 0.07 mmol) and Example 30 (0.03 g, 0.06 mmol). The absolute stereochemistry of these compounds was not determined.
  • Example 31 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2- (dimethylamino)ethyl]phenyl]pyrazol-3-yl]urea [0 07] Step : et y [ (3 t opy a o y)p e y ]acetate (3 3): o a st ed sout on of 3-nitro-1H-pyrazole 31-2 (1.00 g, 8.84 mmol) in 1,4-dioxane (10 mL) was added potassium carbonate (2.44 g, 17.70 mmol) followed by copper (I) iodide (0.03 g, 0.17 mmol), trans-1,2-diaminocyclohexane (0.02 g, 0.17 mmol) and ethyl 2-(4-iodophenyl)acetate 31-1 (2.56 g, 8.84 mmol) at
  • Step-2 2-[4-(3-nitropyrazol-1-yl)phenyl]ethanol (31-4): To a stirred solution of ethyl 2-[4-(3-nitropyrazol-1-yl)phenyl]acetate 31-3 (1.50 g, 5.45 mmol) in THF (15 mL) maintained at 0 °C was added lithium borohydride solution 2M in THF (3.30 mL, 6.54 mmol) and reaction mixture was stirred at 26 °C for 4 h. After completion of reaction, reaction mixture was quenched with aqueous ammonium chloride solution, aqueous layer was extracted with EtOAc.
  • Step-3 2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate (31-5): To a stirred solution of 2-[4-(3-nitropyrazol-1-yl)phenyl]ethanol 31-4 (0.50 g, 2.14 mmol) in DCM (20 mL) was added triethylamine (0.90 mL, 6.43 mmol) followed by p-toluenesulfonyl chloride (0.49 g, 2.57 mmol) at 0 °C. Reaction mixture was stirred at 26 °C for 16 h. After completion, reaction mixture was quenched with H2O, extracted with DCM.
  • Step-4 N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine (31-6): To a stirred solution of 2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl 4-methylbenzenesulfonate 31-5 (0.60 g, 1.55 mmol) in DMF (10 mL) was added potassium carbonate (0.64 g, 4.65 mmol) followed by dimethyl amine hydrochloride (0.25 g, 3.10 mmol) at RT. The resulting solution was stirred at 110 °C for 12 h. After completion of reaction, the reaction mass was concentrated under reduced pressure.
  • Step-5 1-[4-[2-(dimethylamino)ethyl]phenyl]pyrazol-3-amine (31-7): To a stirred solution of N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine 31-6 (0.12 g, 0.46 mmol) and ammonium chloride (0.14 g, 2.77 mmol) in ethanol (5 mL) was added water (2 mL) followed by iron powder (0.07 g, 1.38 mmol) at RT. Reaction mixture was stirred at 100 °C for 2 h. After completion of reaction, reaction mixture was quenched with H 2 O, aqueous layer was extracted with EtOAc.
  • Step-6 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[2- (dimethylamino)ethyl]phenyl]pyrazol-3-yl]urea
  • Example 31 To a stirred solution of 1- [4-[2-(dimethylamino)ethyl]phenyl]pyrazol-3-amine 31-7 (0.10 g, 0.43 mmol) in MeCN (5 mL) was added pyridine (0.06 g, 0.86 mmol) followed by N,N′-disuccinimidyl carbonate (0.11 g, 0.43 mmol) at RT.
  • Example 32 and Example 33 Synthesis of 1-[1-[4-(1-amino-1-methyl- ethyl)phenyl]pyrazol-3-yl]-3-[(chroman-4-yl]urea [ ] p y [ y [ ( py y )p y ] y ] ate (32-3): To a stirred solution of 3-nitro-1H-pyrazole 32-2 (0.20 g, 1.79 mmol) in DCM (30 mL) were added [4-[1-(tert-butoxycarbonylamino)-1-methyl-ethyl]phenyl]boronic acid 32-1 (1.00 g, 3.58 mmol) and copper acetate (0.35 g, 3.58 mmol) followed by pyridine (0.29 mL, 3.58 mmol) at RT.
  • reaction mixture was stirred at RT for 16 h. After completion of reaction, the reaction mixture was filtered through Celite bed and the filtrate was concentrated under reduced pressure to get product which was purified by CombiFlash (30% EtOAc/n-heptane) to afford tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1- yl)phenyl]ethyl]carbamate 32-3 (0.40 g).
  • Step-2 tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl- ethyl]carbamate (32-4): To a stirred solution of tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol- 1-yl)phenyl]ethyl]carbamate 32-3 (0.40 g, 1.15 mmol) in ethanol (15 mL) and water (10 mL) was added ammonium chloride (0.30 g, 577 mmol) followed by iron powder (0.32 g, 5.77 mmol) at RT. The reaction mixture was stirred at 100 °C for 2 h.
  • Step-3 tert-butyl N-[1-[4-[3-(chroman-4-ylcarbamoylamino)pyrazol-1- yl]phenyl]-1-methyl-ethyl]carbamate (32-6): To a stirred solution of tert-butyl N-[1-[4-(3- aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 32-4 (0.40 g, 1.26 mmol) in MeCN (10 mL) was added pyridine (0.10 mL, 1.26 mmol) followed by N,N′-disuccinimidyl carbonate (0.32 g, 1.26 mmol) at RT.
  • reaction mixture was stirred at RT for 15 min. To this was added chroman-4-amine 32-5 (0.18 g, 1.26 mmol) followed by DIPEA (0.91 mL, 5.06 mmol) and reaction mixture was stirred at 30 °C for 12 h. After completion of reaction, reaction mixture was quenched with H2O and extracted with EtOAc.
  • Step-4 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-chroman-4- yl]urea (Examples 32 and 33): To a stirred solution of tert-butyl N-[1-[4-[3-(chroman-4- ylcarbamoylamino)pyrazol-1-yl]phenyl]-1-methyl-ethyl]carbamate 32-6 (0.10 g, 0.19 mmol) in 1,4-dioxane (1 mL) was added 4M HCl in 1,4-dioxane (0.30 mL) at 0 °C.
  • Step-1 chroman-4-one oxime (32-5B): To a stirred solution of chroman-4-one (2.00 g, 13.50 mmol) in EtOH (20 mL), sodium acetate (2.21 g, 27.00 mmol) was added at 0 °C followed by hydroxylamine hydrochloride (1.88 g, 27.00 mmol) at RT and the reaction mixture was stirred at 90 °C for 12 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water to form precipitate.
  • Step-2 chroman-4-amine (32-5): To a stirred solution of chroman-4-one oxime (32- 5B, 1.00 g, 6.13 mmol) in a mixture of methanol (10 mL) and THF (10 mL) was added 10% Pd/C (0.30 g) at RT. The reaction mixture was stirred under 50 psi hydrogen gas pressure in autoclave at RT for 16 h. After completion of reaction, the reaction mixture was filtered through Celite.
  • Example 35 Synthesis of 1-[(4S)-8-fluorochroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea
  • Step-1 To a stirred solution of 1-phenylpyrazol-3-amine 35-1 (0.13 g, 0.82 mmol) in DCM (6 mL) was added triphosgene (0.12 g, 0.41 mmol) at RT and the resulting reaction mixture was cooled to 0 °C. To this was added DIPEA (0.43 mL, 2.45 mmol) followed by (4S)-8-fluorochroman-4-amine 35-2 (0.14 g, 0.82 mmol) and reaction was stirred at RT for 3 h.
  • Example 36 Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)- 8-chlorochroman-4-yl]urea
  • Step-1 tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate (36-3): To a stirred solution of 3-nitro-1H-pyrazole 36-1 (0.06 g, 0.531 mmol) in DCM (6 mL) was added [4-[1-(tert-butoxycarbonylamino)-1-methyl-ethyl]phenyl]boronic acid 36-2 (0.44 g, 1.59 mmol) followed by copper acetate (0.10 g, 1.06 mmol) and pyridine ( 0.08 mL, 1.06 mmol).
  • reaction mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was filtered through Celite bed and the filtrate was concentrated under reduced pressure. Product was purified by flash chromatography (0-70% EtOAc/heptane) to afford tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate 36-3 (0.12 g).
  • Step-2 tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl- ethyl]carbamate (36-4): To a stirred solution of tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol- 1-yl)phenyl]ethyl]carbamate 36-3 (0.60 g, 1.56 mmol) in ethanol (8 mL) and water (4 mL) was added NH4Cl ( 1.07 g, 7.78 mmol) followed by iron powder (0.43 g, 7.78 mmol) at RT and the reaction mixture was stirred under 100 °C for 2 h.
  • Step-3 tert-butyl N-[1-[4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]carbamate (36-6): To a stirred solution of tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 36-4 (0.17 g, 0.53 mmol) in MeCN (5 mL) were added pyridine (0.043 mL, 0.53 mmol) and N,N′- disuccinimidyl carbonate ( 0.13 g, 0.53 mmol) at 0 °C and the reaction mixture was stirred for 10 min.
  • Step-4 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 36): To a solution of tert-butyl N-[1-[4-[3-[[(4S)-8- chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl-ethyl]carbamate 36-6 (0.17 g, 0.29 mmol) in DCM (1 mL) maintained at 0 °C was added 4M HCl in 1,4-dioxane (0.10 g, 2.91 mmol).
  • Example 37 Synthesis of 1-[(4S)-8-methylchroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea [ ] p p ypy ( g, mmol) in MeCN (5 mL) was added pyridine (0.05 mL, 0.69 mmol) followed by N,N′-disuccinimidyl carbonate (0.17 g, 0.69 mmol). The resulting mixture was stirred at RT for 30 min. To this was added (4S)-8-methylchroman-4-amine 37-2 (0.10 g, 0.63 mmol) followed by DIPEA (0.34 mL, 1.88 mmol) and reaction was stirred at 30 °C for 1 h.
  • Example 38 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-fluorophenyl) pyrazol- 3-yl]urea
  • Step-1 To a stirred solution of 1-(3-fluorophenyl) pyrazol-3-amine 38-1 (0.10 g, 0.56 mmol) in MeCN (5 mL) was added Pyridine (0.05 mL, 0.62 mmol) followed by N,N'- disuccinimidyl carbonate (0.16 g, 0.62 mmol). The resulting mixture was stirred at RT for 30 min.
  • Example 39 Synthesis of 1-[1-(3-fluorophenyl) pyrazol-3-yl]-3-[(4S)-8-methylchroman- 4-yl]urea [ ] p ( p y ) py ( ) pyrazol-4-amine 39-1 (1.00 g, 12.00 mmol) in DMSO (10 mL) was added Cu2O (0.17 g, 1.20 mmol) followed by KOH (1.35 g, 24.1 mmol) under Argon. To this was added 1-fluoro-3- iodo-benzene 39-2 (4.10 g, 18.10 mmol) and reaction was stirred at 110 °C for 12 h.
  • Step-2 1-[1-(3-fluorophenyl) pyrazol-3-yl]-3-[(4S)-8-methylchroman-4-yl]urea (Example 39): To a stirred solution of 39-3 (0.11 g, 0.61 mmol) in MeCN (3 mL) was added pyridine (0.54 mL, 0.67 mmol) followed by N,N′-disuccinimidyl carbonate (0.17 g, 0.67 mmol) at RT. The reaction mixture was stirred at RT for 15 min.
  • Example 40 Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)- 8-fluorochroman-4-yl]urea
  • Step-1 tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]carbamate (40-3): To a stirred solution of 3-nitro-1H-pyrazole 40-2 (0.14 g, 1.24 mmol) in DCM (30 mL) were added [4-[1-(tert-butoxycarbonylamino)-1-methyl-ethyl]phenyl]boronic acid 40-1 (1.03 g, 3.71 mmol) and copper acetate (0.24 g, 2.48 mmol) followed by pyridine (0.20 mL, 2.48 mmol) and the reaction mixture was stirred at RT for 16 h.
  • Step-2 tert-butyl N-[1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl- ethyl]carbamate (40-4): To a stirred solution of tert-butyl N-[1-methyl-1-[4-(3-nitropyrazol- 1-yl)phenyl]ethyl]carbamate 40-3 (0.15 g, 0.431 mmol) in ethanol (5 mL) and water (2.5 mL) was added NH4Cl (0.11 g, 2.15 mmol) followed by iron powder (0.12 g, 2.15 mmol) at RT and the reaction mixture was stirred under 80 °C for 2 h.
  • Step-3 (4S)-8-fluorochroman-4-amine (40-6): To a stirred solution of tert-butyl N- [1-[4-(3-aminopyrazol-1-yl)phenyl]-1-methyl-ethyl]carbamate 40-4 (0.05 g, 0.15 mmol) in MeCN (2 mL) were added N,N′-disuccinimidyl carbonate (0.04 g, 0.15 mmol) and pyridine ( 0.01 mL, 0.158 mmol) and the reaction mixture was stirred at RT for 45 min.
  • Step-4 1-[1-[4-(1-amino-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- fluorochroman-4-yl]urea (Example 40): To a stirred solution of tert-butyl N-[1-[4-[3- [[(4S)-8-fluorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-1-methyl- ethyl]carbamate 40-6 (0.03 g, 0.0738 mmol) in 1,4-dioxane (1 mL) was added 4M HCl in dioxane (1.0 mL, 0.74 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h.
  • Example 41 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(6-methoxy-3- pyridyl)pyrazol-3-yl]urea [ ] p ( y py y )py ( ) 1H-pyrazol-3-amine (0.10 g, 1.20 mmol) in DMF (5 mL) were added CuBr (0.03 g, 0.24 mmol) and Cs 2 CO 3 (0.59 g, 1.81 mmol) followed by 5-bromo-2-methoxy-pyridine 41-1 (0.22 g, 1.20 mmol). The reaction was stirred at 120 °C for 16 h.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(6-methoxy-3-pyridyl)pyrazol-3- yl]urea
  • Example 41 To a stirred solution of 1-(6-methoxy-3-pyridyl)pyrazol-3-amine 41-3 (0.09 g, 0.50 mmol) in MeCN (5 mL) was added pyridine (0.10 mL, 0.50 mmol) followed by N,N’-disuccinimidyl carbonate (0.12 g, 0.50 mmol). The resulting mixture was stirred at RT for 1 h.
  • Example 42 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-(1-tetrahydropyran-4- ylpyrazol-3-yl)urea [ ] p y py y ( ) tetrahydropyran-4-ol 42-1 (0.67 g, 4.42 mmol) in DCM (10 mL) at 0 °C was added triethylamine (3.20 mL, 23.00 mmol). To this was added methanesulfonyl chloride (1.50 mL, 19.50 mmol) slowly dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h.
  • Step-2 3-nitro-1-tetrahydropyran-4-yl-pyrazole (42-4): To a stirred solution of 3- nitro-1H-pyrazole 42-3 (0.30 g, 2.65 mmol) in MeCN (5 mL) was added Cs2CO3 (1.03 g, 3.18 mmol) followed by tetrahydropyran-4-yl methanesulfonate (0.47 g, 2.65 mmol). The reaction mixture was stirred at 80 °C for 2 h. After completion, the reaction was quenched with water and extracted with EtOAc. The combined organic layer was washed with H 2 O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-3 1-tetrahydropyran-4-ylpyrazol-3-amine (42-5): To a stirred solution of 3- nitro-1-tetrahydropyran-4-yl-pyrazole 42-4 (0.20 g, 1.01 mmol) in ethanol (8 mL) and water (2 mL) was added ammonium chloride (0.70 g, 5.07 mmol) and iron powder (0.28 g, 5.07 mmol) at RT. The reaction mixture was stirred at 100 °C for 2 h. After completion, reaction mixture was filtered and washed with EtOAc.
  • Step-4 1-[(4S)-8-chlorochroman-4-yl]-3-(1-tetrahydropyran-4-ylpyrazol-3- yl)urea
  • Example 42 To a stirred solution of 1-tetrahydropyran-4-ylpyrazol-3-amine 42-5 (0.15 g, 0.79 mmol) in MeCN (3 mL) was added pyridine (0.03 mL, 0.45 mmol) followed by N,N'-disuccinimidyl carbonate (0.11 g, 0.45 mmol) at RT. The reaction mixture was stirred at RT for 30 min.
  • Example 43 Synthesis of : 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol- 1-yl]benzamide [0 ] Step : et y 3 (3 t opy a o y )be oate ( 33): o a st ed sout o o 3- nitro-1H-pyrazole 43-1 (0.50 g, 4.42 mmol) in MeOH (10 mL) was added (4- methoxycarbonylphenyl)boronic acid 43-2 (0.95 g, 5.31 mmol) followed by NaOH (0.35 g, 8.84 mmol) and copper chloride (0.04 g, 0.44 mmol) at RT.
  • Step-2 methyl 3-(3-aminopyrazol-1-yl)benzoate (43-4): To a stirred solution of iron powder (0.54 g, 9.69 mmol) in THF (12 mL) were added methyl 3-(3-nitropyrazol-1- yl)benzoate 43-3 (0.50 g, 2.02 mmol) and NH 4 Cl (0.52 g, 9.69 mmol) at RT. The reaction was stirred at 80 °C for 4 h. After completion, reaction mixture was concentrated under reduced pressure and was extracted with EtOAc. Organic layer was washed with H 2 O, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get the product.
  • Step-3 methyl 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]benzoate (43-6): To a stirred solution of methyl 3-(3-aminopyrazol-1-yl)benzoate (0.04 g, 0.21 mmol) in MeCN (2 mL) was added pyridine (0.03 mL, 0.43 mmol) followed by bis(2,5- dioxopyrrolidin-1-yl)carbonate (0.05 g, 0.21 mmol). The resulting mixture was stirred at RT for 30 min.
  • Step-4 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]benzoic acid (43-7): To a stirred solution of methyl 3-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]benzoate 43-6 (0.07 g, 0.16 mmol) in methanol (1 mL), THF (4 mL) and water (1 mL) was added LiOH.H 2 O (0.02 g, 0.49 mmol) at RT. The reaction was stirred at RT for 12 h.
  • reaction mixture was concentrated and diluted with H 2 O (2 mL) and pH was adjusted with 2N HCl. Precipitated solid was filtered, dried under reduced pressure to afford 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol- 1-yl]benzoic acid 43-7 (0.05 g).
  • Step-5 3-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]benzamide
  • Example 43 To a stirred solution of 3-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]benzoic acid 43-7 (0.07 g, 0.17 mmol) in DMF (1 mL) were added DIPEA ( 0.12 mL, 0.678 mmol), HATU (0.09 g, 0.25mmol) and NH4Cl (0.01 g, 0.25 mmol) maintained at 0 °C.
  • Step-1 (4-(3-nitropyrazol-1-yl)phenol (44-3): To a stirred solution of 3-nitro-1H- pyrazole 44-1 (1.00 g, 8.84 mmol) in DCM (30 mL) were added (4-hydroxyphenyl)boronic acid 44-2 (1.83 g, 13.3 mmol), pyridine (2.3 mL, 26.5 mmol) and Cu(OAc) 2 (3.20 g, 17.7 mmol) and the reaction mixture was stirred at RT for 12 h under presence of oxygen.
  • Step-2 (N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenoxy]ethanamine (44-5): To a stirred solution of 4-(3-nitropyrazol-1-yl)phenol 44-3 (0.30 g, 1.46 mmol) in DMF (10 mL) were added Cs 2 CO 3 (1.18 g, 3.66 mmol) and 2-bromo-N,N-dimethylethanamine hydrobromide 44-4 (0.50 g, 2.19 mmol) and the reaction mixture was stirred at 100 °C for 12 h. After completion, reaction was quenched with H 2 O, extracted with EtOAc.
  • Step-3 (1-[4-[2-(dimethylamino)ethoxy]phenyl]pyrazol-3-amine (44-6): To a stirred solution of N,N-dimethyl-2-[4-(3-nitropyrazol-1-yl)phenoxy]ethanamine 44-5 (0.04 g, 0.145 mmol) in ethanol (4 mL) and water (2 mL) was added iron powder (0.02 g, 0.43 mmol) followed by NH 4 Cl (0.02 g, 0.43 mmol) and the reaction mixture was stirred at 100 °C for 12 h. After completion, reaction mixture was filtered to remove unwanted solid material. Reaction mixture was diluted with H 2 O, extracted with EtOAc.
  • Step-4 (1-[1-[4-[2-(dimethylamino)ethoxy]phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea
  • Example 44 To a stirred solution of 1-[4-[2- (dimethylamino)ethoxy]phenyl]pyrazol-3-amine 44-6 (0.09 g, 0.38 mmol) in MeCN (2 mL) was added pyridine (0.06 mL, 0.76 mmol) followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (DSC) (0.09 g, 0.38 mmol).
  • DSC bis(2,5-dioxopyrrolidin-1-yl) carbonate
  • Example 45 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1,1-difluoro-2 (methylamino)ethyl] phenyl] pyrazol-3-yl]urea
  • Step-1 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]acetic (45-3): To a stirred solution of 3-nitro-1H-pyrazole 45-2 (1.00 g, 8.84 mmol) in DMSO (15 mL) were added K 2 CO 3 (3.66 g, 26.5 mmol), CuI (0.34 g, 1.77 mmol) and L-proline (0.20 g, 1.77 mmol) followed by ethyl 2-(4-bromophenyl)-2,2-difluoro-acetate 45-1 (2.96 g, 10.6 mmol) and the reaction mixture was stirred for at 120 °C for 12
  • Step-2 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanol (45-4): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]acetic acid 45-3 (0.50 g, 1.77 mmol) in THF (5 mL) was added BH 3 . DMS (0.13 g, 3.53 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 2 h. After completion, reaction was quenched with H2O, extracted with EtOAc.
  • Step-3 [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate (45-5): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol-1- yl)phenyl]ethanol 45-4 (0.80 g, 2.97 mmol) in DCM (10 mL) was added triethylamine (1.20 mL, 8.92 mmol) followed by 4-toluenesulfonyl chloride (0.85 g, 4.46 mmol) drop wise at 25 °C. The reaction mixture was stirred for 25 °C at 16 h.
  • Step-4 1-[4-(2-azido-1,1-difluoro-ethyl)phenyl]-3-nitro-pyrazole (45-6): To a stirred solution of [2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl] 4- methylbenzenesulfonate 45-5 (1.10 g, 2.60 mmol) in DMF (5 mL) was added NaN3 (0.33 g, 5.20 mmol). Resulting reaction mixture was stirred at 100 °C for 16 h. After completion, reaction mixture was diluted with H2O and extracted with EtOAc.
  • Step-5 2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethanamine (45-7): To a stirred solution of 1-[4-(2-azido-1,1-difluoro-ethyl)phenyl]-3-nitro-pyrazole 45-6 (0.75 g, 2.55 mmol) in THF (3 mL) and water (1 mL) was added TPP (0.13 g, 5.10 mmol) at 0 °C. Resulting mixture was stirred at RT for 4 h. After completion, reaction mixture was diluted with H 2 O and extracted with EtOAc. Organic layer was concentrated under reduced pressure.
  • Step-6 tert-butyl N-[2,2-difluoro-2-[4-(3-nitropyrazol-1- yl)phenyl]ethyl]carbamate (45-8): To a stirred solution of 2,2-difluoro-2-[4-(3-nitropyrazol- 1-yl)phenyl]ethanamine 45-7 (0.25 g, 0.93 mmol) in DCM (5 mL) were added DIPEA (0.50 mL, 2.80 mmol) and DMAP (0.01 g, 0.09 mmol) followed by (Boc) 2 O (0.26 mL, 1.12 mmol). The reaction mixture was stirred for 25 °C at 16 h.
  • Step-7 tert-butyl N-[2,2-difluoro-2-[4-(3-nitropyrazol-1-yl)phenyl]ethyl]-N- methylcarbamate (45-9): To a stirred solution of tert-butyl N-[2,2-difluoro-2-[4-(3- nitropyrazol-1-yl)phenyl]ethyl]carbamate 45-8 (0.20 g, 0.54 mmol) in DMF (3 mL) were added NaH (60% in mineral oil, 0.02 g, 0.81 mmol) and methyl iodide (0.10 mL, 1.63 mmol) at 0 °C.
  • Step-8 tert-butyl N-[2-[4-(3-aminopyrazol-1-yl)phenyl]-2,2-difluoro-ethyl]-N- methylcarbamate (45-10): To a stirred solution of tert-butyl N-[2,2-difluoro-2-[4-(3- nitropyrazol-1-yl)phenyl]ethyl]-N-methylcarbamate 45-9 (0.10 g, 0.26 mmol) in ethanol (5 mL) and water (2 mL) were added NH4Cl (0.07 g, 1.31 mmol) and Fe powder (0.07 g, 1.31 mmol).
  • Step-9 tert-butyl N-[2-[4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]phenyl]-2,2-difluoro-ethyl]-N-methylcarbamate (45- 12): To a stirred solution of tert-butyl N-[2-[4-(3-aminopyrazol-1-yl)phenyl]-2,2-difluoro- ethyl]-N-methylcarbamate 45-10 (0.07 g, 0.19 mmol) in MeCN (3 mL) was added pyridine (0.02 mL, 0.29 mmol) followed by N,N′-disuccinimidyl carbonate (0.05 g, 0.19 mmol).
  • Step-10 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[1,1-difluoro-2- (methylamino)ethyl]phenyl]pyrazol-3-yl]urea
  • Example 45 To a stirred solution of tert- butyl N-[2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]phenyl]-2,2- difluoro-ethyl]-N-methylcarbamate 45-12 (0.10 g, 0.17 mmol) in DCM (3 mL) was added 4M HCl in dioxane (0.20 mL, 0.89 mmol) at 0 °C.
  • Example 45 (0.04 g).
  • Example 46 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-[2- (methylamino)ethoxy]phenyl]pyrazol-3-yl]urea [0261]
  • Step-1 1-(3-methoxyphenyl)-3-nitro-pyrazole (46-3): A stirred solution of (3- methoxyphenyl)boronic acid 46-1 (1.34 g, 8.84 mmol), 3-nitro-1H-pyrazole 46-2 (1.00 g, 8.84 mmol) and NaOH (0.42 g, 10.6 mmol) in methanol (15 mL) was purged with oxygen for 30 min.
  • Step-2 3-(3-nitropyrazol-1-yl)phenol (46-4): A solution of 1-(3-methoxyphenyl)-3- nitro-pyrazole 46-3 (1.00 g, 4.56 mmol) in hydrobromic acid (47-48% in aqueous solution, 15 mL) was stirred at 0 °C and the reaction mixture was stirred at 100 °C for 12 h. After completion of reaction, the reaction mixture was poured into cold water. The aqueous layer was extracted with DCM. Combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 3-(3-nitropyrazol-1-yl)phenol 46-4 (0.3 g).
  • LCMS: [M-H]- 205.
  • Step-3 N,N-dimethyl-2-[3-(3-nitropyrazol-1-yl)phenoxy]ethanamine (46-6): To a stirred solution of 3-(3-nitropyrazol-1-yl)phenol 46-4 (1.00 g, 4.87 mmol) in DMF (10 mL) was added sodium hydride (60% in mineral oil, 0.39 g, 9.75 mmol) at 0 °C followed by 2- chloro-N,N-dimethyl-ethanamine hydrochloride 46-5 (1.40 g, 9.75 mmol) and the reaction mixture was stirred at RT for 2 h. After completion of reaction, the reaction mixture was poured into cold water. The aqueous layer was extracted with DCM.
  • Step-4 1-[3-[2-(dimethylamino)ethoxy]phenyl]pyrazol-3-amine (46-7): To a stirred solution of N,N-dimethyl-2-[3-(3-nitropyrazol-1-yl)phenoxy]ethanamine 46-6 (0.80 g, 2.90 mmol) in ethanol (6 mL) was added iron powder (1.29 g, 23.2 mmol) followed by ammonium chloride (1.24 g, 23.2 mmol) in water (2 mL).
  • Step-5 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-[2-(methylamino)ethoxy]phenyl] pyrazol-3-yl]urea (Example 46): To a stirred solution of 1-[3-[2- (dimethylamino)ethoxy]phenyl]pyrazol-3-amine 46-7 (0.05 g, 0.21 mmol) in MeCN (5 mL) was added pyridine (0.03 mL, 0.43 mmol) at 0 °C followed by N,N′-disuccinimidyl carbonate (0.06 g, 0.23 mmol). Resulting mixture was stirred at RT for 30 min.
  • Example 47 and Example 48 Synthesis of 1-(8-chloro-2-(methoxymethyl)chroman-4- yl)-3-(1-phenyl-1H-pyrazol-3-yl)urea
  • Step-1 8-chlorochromen-4-one (47-3): To a stirred solution of 1-(3-chloro-2- hydroxy-phenyl)ethanone 47-1 (2.00 g, 11.70 mmol) in THF (20 mL) was added ethyl formate 47-2 (1.30 g, 17.60 mmol) at 0 °C followed by NaH (60 % in mineral oil, 1.69 g, 70.30 mmol) and the reaction was stirred at RT for 1 h.
  • Step-2 8-chloro-2-(hydroxymethyl)chroman-4-one (47-4): To a stirred solution of 8-chlorochromen-4-one 47-3 (1.00 g, 5.54 mmol) in methanol (10 mL) was added di-tert- butyl peroxide (3.0 mL, 16.60 mmol) at 0 °C. The reaction mixture was stirred at 140 °C in steel bomb for 15 h. Reaction mixture was cooled to RT. After completion, the reaction mixture was evaporated under reduced pressure to afford product.
  • Step-3 8-chloro-2-(methoxymethyl)chroman-4-one (47-5): To a stirred solution of 8-chloro-2-(hydroxymethyl)chroman-4-one 47-4 (2.00 g, 9.41 mmol) in MeCN (20 mL) was added silver carbonate (7.78 g, 28.20 mmol) at 0 °C followed by methyl trifluoromethanesulfonate (5.1 mL, 47.00 mmol). The reaction was stirred at 25 °C for 2 h.
  • Step-4 8-chloro-2-(methoxymethyl)chroman-4-one (47-6a and 47-6b): After prep- HPLC purification afforded 0.98 g of racemic product, the enantiomers were separated by chiral prep-HPLC purification to afford 8-chloro-2-(methoxymethyl)chroman-4-one 47-6a (0.48 g) and 47-6b 8-chloro-2-(methoxymethyl)chroman-4-one (0.50 g). The absolute stereochemistry of these compounds was not determined.
  • Step-5 8-chloro-2-(methoxymethyl)chroman-4-amine (47-7): To a stirred solution of 8-chloro-2-(methoxymethyl)chroman-4-one 47-6a (0.05 g, 0.22 mmol) in methanol (15 mL) was added ammonium acetate (0.25 g, 3.31 mmol) at 0 °C followed by sodium cyanoborohydride (0.04 g, 0.66 mmol) and the reaction mixture was stirred at 80 °C for 16 h. After completion, the reaction mixture was cooled to 0 °C, diluted with H2O and extracted with DCM.
  • Step-6 1-(8-chloro-2-(methoxymethyl)chroman-4-yl)-3-(1-phenyl-1H-pyrazol-3- yl)urea (47-9): To a stirred solution of 1-phenylpyrazol-3-amine 47-8 (0.20 g, 1.26 mmol) in MeCN (15 mL) was added pyridine (0.10 mL, 1.26 mmol) followed by N,N′-disuccinimidyl carbonate (0.32 g, 1.26 mmol). Resulting reaction mixture was stirred at RT for 15 min.
  • Step-7 1-(8-chloro-2-(methoxymethyl)chroman-4-yl)-3-(1-phenyl-1H-pyrazol-3- yl)urea (Examples 47 and 48): Prep-HPLC afforded 0.08 g of racemic product.
  • Example 52 and Example 53 Synthesis of 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]- 3-(1-phenylpyrazol-3-yl)urea
  • Step-1 ethyl 4-(3-chloro-2-hydroxy-phenyl)-2,4-dioxo-butanoate (49-3): To a stirred solution of 1-(3-chloro-2-hydroxy-phenyl)ethanone 49-1 (8.00 g, 46.90 mmol) in THF (60 mL) was added sodium hydride (60% in mineral oil, 4.50 g, 188.00 mmol) at 0 °C followed by diethyl oxalate 49-2 (16.00 mL, 117.00 mmol).
  • Step-2 ethyl 8-chloro-4-oxo-chromene-2-carboxylate (49-4): To a stirred solution of ethyl 4-(3-chloro-2-hydroxy-phenyl)-2,4-dioxo-butanoate 49-3 (4.00 g, 14.80 mmol) in toluene (35 mL) was added p-toluene sulphonic acid (0.64 g, 3.69 mmol). The reaction mixture was stirred at 120 °C for 12 h. After completion, the reaction mixture was quenched with H 2 O and extracted with EtOAc.
  • Step-3 8-chloro-2-(hydroxymethyl)chroman-4-ol (49-5): To a stirred solution of ethyl 8-chloro-4-oxo-chromene-2-carboxylate 49-4 (3.00 g, 11.90 mmol) in methanol (30 mL) was added sodium borohydride (2.25 g, 59.40 mmol) at 0 °C and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was quenched with ice cold H 2 O and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-4 8-chloro-2-(hydroxymethyl)chroman-4-one (49-6): To a stirred solution of 8-chloro-2-(hydroxymethyl)chroman-4-ol 49-5 (2.00 g, 9.32 mmol) in DCM (20 mL) was added pyridinium chlorochromate (2.01 g, 9.32 mmol) at 0 °C and the reaction mixture was stirred at RT for 3 h. After completion, the reaction mixture was quenched with H2O and extracted with DCM.
  • Step-5 8-chloro-2-(hydroxymethyl)chroman-4-one (49-7a) and 8-chloro-2- (hydroxymethyl)chroman-4-one (49-7b): Chiral prep-HPLC purification of 3 g of racemic 8-chloro-2-(hydroxymethyl)chroman-4-one 49-6 afforded 8-chloro-2- (hydroxymethyl)chroman-4-one (49-7a) (0.45 g) and 8-chloro-2-(hydroxymethyl)chroman-4- one (49-7b) (0.52 g). The absolute stereochemistry of these compounds was not determined.
  • Step-6 [4-amino-8-chloro-chroman-2-yl]methanol (49-8): To a stirred solution of 8-chloro-2-(hydroxymethyl)chroman-4-one 49-7a (0.45 g, 2.12 mmol) in methanol (10 mL) was added ammonium acetate (2.44 g, 31.7 mmol) at 0 °C followed by sodium cyanoborohydride (0.39 g, 6.35 mmol). The reaction mixture was stirred at 80 °C for 16 h. Reaction mixture was cooled to 0 °C, quenched with H2O and pH was adjusted to 13 with 2N NaOH solution. Aqueous layer was extracted with DCM.
  • Step-7 [4-amino-8-chloro-chroman-2-yl]methanol hydrochloride (49-9): To a stirred solution of [4-amino-8-chloro-chroman-2-yl]methanol 49-8 (0.30 g, 1.40 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (1.6 mL, 4.21 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was concentrated under reduced pressure.
  • Step-8 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1-phenylpyrazol-3- yl)urea (49-11): To a stirred solution of [4-amino-8-chloro-chroman-2-yl]methanol hydrochloride 49-9 (0.30 g, 1.20 mmol) in MeCN (3 mL) was added pyridine (0.09 mL, 1.20 mmol) followed by N,N′-disuccinimidyl carbonate (0.30 g, 1.20 mmol). Resulting reaction mixture was stirred at RT for 15 min.
  • Example 51 Synthesis of 1-[(4S)-8-fluorochroman-4-yl]-3-[1-(3-fluorophenyl) pyrazol- 3-yl]urea
  • Step-1 1-(3-fluorophenyl) pyrazol-3-amine (51-3): To a stirred solution of 1H- pyrazol-3-amine 51-1 (1.00 g, 12.00 mmol), was added Cu2O (0.17 g, 1.20 mmol) followed by KOH (1.35 g, 24.10 mmol) in DMSO (10 mL) under Argon.
  • Step-2 1-[(4S)-8-fluorochroman-4-yl]-3-[1-(3-fluorophenyl) pyrazol-3-yl]urea
  • Example 51 To a solution of 1-(3-fluorophenyl) pyrazol-3-amine 51-3 (0.15 g, 0.85 mmol) in DCM (3 mL), was added triphosgene (0.13 g, 0.42 mmol) at 0 °C followed by DIPEA (0.44 mL, 2.54 mmol). The reaction was stirred at RT for 30 min.
  • Example 52 and Example 53 Synthesis of 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]- 3-(1-phenylpyrazol-3-yl)urea
  • Step-1 [4-amino-8-chloro-chroman-2-yl]methanol (52-2): To a stirred solution of 8-chloro-2-(hydroxymethyl)chroman-4-one 49-7b (0.30 g, 1.41 mmol) in methanol (10 mL) was added ammonium acetate (1.63 g, 21.2 mmol) at 0 °C followed by sodium cyanoborohydride (0.26 g, 4.23 mmol). The reaction was stirred at 80 °C for 16 h.
  • Step-2 [4-amino-8-chloro-chroman-2-yl]methanol hydrochloride (52-3): To a stirred solution of [4-amino-8-chloro-chroman-2-yl]methanol 52-2 (0.30 g, 1.40 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (1.6 mL, 4.21 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was concentrated under reduced pressure.
  • Step-3 1-[8-chloro-2-(hydroxymethyl)chroman-4-yl]-3-(1-phenylpyrazol-3- yl)urea (52-5): To a stirred solution of [4-amino-8-chloro-chroman-2-yl]methanol hydrochloride 52-3 (0.30 g, 1.20 mmol) in MeCN (3 mL) was added pyridine (0.09 mL, 1.20 mmol) followed by N,N′-disuccinimidyl carbonate (0.30 g, 1.20 mmol). Resulting reaction mixture was stirred at RT for 15 min.
  • Example 54 Synthesis of 2-(3-amino-1H-pyrazol-1-yl)-N,N-dimethylacetamide [02 ] p , y ( py y ) ( ) f 3- nitro-1H-pyrazole 54-1 (0.50 g, 4.42 mmol) in DMF (8 mL) was added K 2 CO 3 (1.22 g, 8.84 mmol) at 0 °C followed by 2-chloro-N,N-dimethyl-acetamide 54-2 (0.91 mL, 8.84 mmol). The reaction was stirred at 90 °C for 16 h. After completion, the reaction was quenched with H2O, extracted with ethyl acetate.
  • Step-2 2-(3-amino-1H-pyrazol-1-yl)-N,N-dimethylacetamide (54-4): To a stirred solution of 54-3 (0.50 g, 2.01 mmol) in MeOH (10 mL), 10% Pd/C (0.25 g) was added and the reaction mixture was stirred under 50 psi hydrogen pressure at RT for 2 h. After completion, the reaction mixture was filtered through Celite bed. The filtrate was concentrated under reduced pressure to yield 54-4, which was used directly for the next reaction.
  • Step-3 (S)- N,N-dimethyl-2-(3-(3-(8-methylchroman-4-yl) ureido)-1H-pyrazol-1- yl) acetamide
  • Example 54 To a stirred solution of 54-4 (0.15 g, 0.89 mmol) in ACN (5 mL) was added pyridine (0.07 mL, 0.89 mmol) followed by N,N'-disuccinimidyl carbonate (0.23 g, 0.89 mmol). The resulting mixture was stirred at RT for 30 min.
  • Example 55 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4- [(dimethylamino)methyl]phenyl]pyrazol-3-yl]urea stirred solution of [4-(3-nitropyrazol-1-yl)phenyl]methanol 55-1 (0.18 g, 0.84 mmol) in DCM (2 mL) was added DIPEA (0.59 mL, 3.38 mmol) followed by methanesulfonyl chloride (0.09 mL, 1.27 mmol) at -78 o C and the reaction mixture was stirred at -78 °C for 2 h.
  • Step-2 N,N-dimethyl-1-[4-(3-nitropyrazol-1-yl)phenyl]methanamine (55-3): To a stirred solution of [4-(3-nitropyrazol-1-yl)phenyl]methyl methanesulfonate 55-2 (0.33 g, 1.11 mmol) in DMF (3 mL) was added K 2 CO 3 (0.94 g, 4.44 mmol) followed by N- methylmethanamine hydrochloride (0.22 g, 2.78 mmol) and the reaction mixture was stirred at 70 °C for 12 h. After completion, the reaction mixture was quenched with H2O, extracted in EtOAc.
  • Step-3 1-[4-[(dimethylamino)methyl]phenyl]pyrazol-3-amine (55-4): A mixture of N,N-dimethyl-1-[4-(3-nitropyrazol-1-yl)phenyl]methanamine 55-3 (0.25 g, 1.02 mmol) and Pd/C (0.10 g) in methanol (3.5 mL) was stirred at 50 psi H 2 pressure for 8 h. After completion, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to afford 1-[4-[(dimethylamino)methyl]phenyl]pyrazol-3-amine 55-4 (0.15 g).
  • Step-4 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4- [(dimethylamino)methyl]phenyl]pyrazol-3-yl]urea (Example 55): To a stirred solution of 1-[4-[(dimethylamino)methyl]phenyl]pyrazol-3-amine 55-4 (0.14 g, 0.67 mmol) in MeCN (5 mL) was added pyridine (0.11 mL, 1.34 mmol) followed by N,N′-disuccinimidyl carbonate (0.17 g, 0.67 mmol).
  • Example 56 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methoxypyrimidin-5- yl)pyrazol-3-yl]urea of 1H-pyrazol-3-amine 56-2 (0.44 g, 5.29 mmol) in DMF (5 mL) was added Cs2CO3 (3.45 g, 10.60 mmol) followed by 5-bromo-2-methoxy-pyrimidine 56-1 (1.00 g, 5.29 mmol) and CuBr (0.07 g, 0.52 mmol) at RT. The reaction was stirred at 120 °C for 16 h.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methoxypyrimidin-5-yl)pyrazol-3- yl]urea
  • Example 56 To a stirred solution of 1-(2-methoxypyrimidin-5-yl)pyrazol-3-amine 56-3 (0.10 g, 0.52 mmol) in MeCN (5 mL) was added pyridine (0.04 mL, 0.52 mmol) followed by N,N′-disuccinimidyl carbonate (0.13 g, 0.52 mmol) at RT. The resulting reaction mixture was stirred at RT for 30 min.
  • Example 57 Synthesis of 5-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]-N-methyl-pyridine-2-carboxamide: [ ] p y py ( ) f methyl 5-bromopyridine-2-carboxylate 57-1 (0.40 g, 1.85 mmol) in methanol (3 mL) was added methylamine (25% solution in MeOH, 9.30 mL, 9.26 mmol) at 0 °C. The resulting mixture was stirred at 80 °C for 8 h.
  • Step-2 5-(3-aminopyrazol-1-yl)-N-methyl-pyridine-2-carboxamide (57-4): To a stirred solution of 5-bromo-N-methyl-pyridine-2-carboxamide 57-2 (0.30 g, 1.40 mmol) in DMF (7 mL) were added 1H-pyrazol-3-amine 57-3 (0.14 g, 1.67 mmol) and Cs 2 CO 3 (0.90 g, 2.79 mmol) followed by copper (II) bromide (0.06 g, 0.27 mmol) at RT. The reaction was stirred in microwave at 180 °C for 30 min. After completion, reaction was quenched with ice cold water , extracted with DCM.
  • Step-3 5-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-N- methyl-pyridine-2-carboxamide
  • Example 57 To a stirred solution of product 5-(3- aminopyrazol-1-yl)-N-methyl-pyridine-2-carboxamide 57-4 (0.10 g, 0.46 mmol) in MeCN (5 mL) was added pyridine (0.03 g, 0.46 mmol) followed by N,N′-disuccinimidyl carbonate (0.11 g, 0.46 mmol) at RT. The reaction mixture was stirred at RT for 15 min.
  • Example 58 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-methylsulfonylphenyl) pyrazol-3-yl]urea [03 0] Step : (3 et y su o y p e y ) py a o 3 a e (583): o a st ed so ut o o 1H-pyrazol-3-amine 58-1 (0.20 g, 2.41 mmol) and 1-bromo-3-methylsulfonyl-benzene 58-2 (0.62 g, 2.65 mmol) in DMSO (3 mL) was added cesium carbonate (1.57 g, 4.81 mmol) followed by copper (II) bromide (0.06 g, 0.48 mmol).
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-methylsulf yl]urea
  • Example 58 To a stirred solution of 1-(3-methylsulfonylphenyl) pyrazol-3-amine 58-3 (0.18 g, 0.75 mmol) in MeCN (5 mL) was added pyridine (0.12 mL, 1.52 mmol) followed by N,N′-disuccinimidyl carbonate (0.21 g, 0.83 mmol). Resulting reaction mixture was stirred at RT for 30 min.
  • Step-1 4-(3-aminopyrazol-1-yl)-2-fluoro-N-methyl-benzamide (59-3): To a stirred solution of 1H-pyrazol-3-amine 59-2 (0.25 g, 3.01 mmol) in DMF (4 mL) were added 2- fluoro-4-iodo-N-methyl-benzamide 59-1 (1.25 g, 4.51 mmol) and CuBr 2 (0.13 g, 0.60 mmol) followed by cesium carbonate (0.98 g, 3.01 mmol).
  • reaction mixture was stirred under microwave at 180 °C for 30 min. After completion, reaction mixture was quenched with H2O, extracted with EtOAc. Combined organic layer was washed with H 2 O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash (0.05% formic acid in H 2 O:ACN) to afford 4-(3-aminopyrazol-1-yl)-2-fluoro-N- methyl-benzamide 59-3 (0.12 g).
  • Step-2 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-2- fluoro-N-methyl-benzamide
  • Example 59 To a stirred solution of N,N′-disuccinimidyl carbonate (0.13 g, 0.51 mmol) in CH 3 CN (5 mL) was added pyridine (0.04 mL, 0.51 mmol) and 4-(3-aminopyrazol-1-yl)-2-fluoro-N-methyl-benzamide 59-3 (0.12 g, 0.51 mmol) at RT. Reaction mixture was stirred for 45 min.
  • Step-1 1-(2-methylpyridin-4-yl)-1H-pyrazol-3-amine (60-3): To a stirred solution of 1H-pyrazol-3-amine 60-1 (0.50 g, 6.02 mmol) in DMF (5 mL) was added copper (I) bromide (0.17 g, 1.20 mmol) and cesium carbonate (2.94 g, 9.03 mmol) followed by 4- bromo-2-methyl-pyridine 60-2 (1.14 g, 6.62 mmol).
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methyl-4-pyridyl) pyrazol-3- yl]urea (Example 60): To a stirred solution of 60-3 (0.10 g, 0.57 mmol) in MeCN (5 mL) was added pyridine (0.05 g, 0.69 mmol) followed by N,N’-disuccinimidyl carbonate (0.16 g, 0.63 mmol). The resulting mixture was stirred at RT for 30 min.
  • Example 61 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3,4-dimethoxyphenyl) pyrazol-3-yl]urea
  • Step-1 1-(3,4-dimethoxyphenyl) pyrazol-3-amine (61-3): To a stirred solution of 1H-pyrazol-3-amine 61-1 (0.40 g, 4.81 mmol) in DMSO (8 mL) was added potassium hydroxide (0.27 g, 4.81 mmol) and copper (II) oxide (0.07 g, 0.48 mmol) followed by 4-iodo- 1,2-dimethoxy-benzene 61-2 (1.91 g, 7.22 mmol) at RT.
  • reaction mixture was degassed under argon atmosphere for 30 min and stirred at 120 °C for 12 h. After completion, the reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to afford a product. The product was purified by CombiFlash column chromatography to afford 61-3 (0.30 g).
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3,4-dimethoxyphenyl) pyrazol-3- yl]urea
  • Example 61 To a stirred solution of product (4S)-8-chlorochroman-4-amine 61-4 (0.06 g, 0.30 mmol) in MeCN (3 mL) was added pyridine (0.024 mL, 0.30 mmol) followed by N,N′-disuccinimidyl carbonate (0.04 mL, 0.30 mmol) at RT and the reaction mixture was stirred at RT for 15 min.
  • Example 62 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-pyridyl) pyrazol-3- yl]urea -3- amine 62-1 (0.50 g, 6.02 mmol) in DMSO (6 mL) was added KOH (0.68 g, 12.00 mmol), Cu 2 O (0.09 g, 0.60 mmol) followed by 4-iodopyridine 62-2 (1.48 g, 7.22 mmol) at RT. The reaction mixture was degassed under argon atmosphere for 20 min and stirred at 120 °C for 12 h. After completion, the reaction mixture was quenched with H 2 O and extracted with EtOAc.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-pyridyl) pyrazol-3-yl]urea
  • Example 62 To a stirred solution of 1-(4-pyridyl) pyrazol-3-amine 62-3 (0.50 g, 0.31 mmol) in MeCN (5 mL) was added pyridine (0.025 mL, 0.31 mmol) followed by N,N'- disuccinimidyl carbonate (0.08 g, 0.31 mmol). The resulting mixture was stirred at RT for 30 min.
  • Example 63 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-pyridyl) pyrazol-3- yl]urea 3-1 (0.05 g, 0.24 mmol) in MeCN (3 mL) was added pyridine (0.02 mL, 0.24 mmol) and N,N’- disuccinimidyl carbonate (0.06 g, 0.24 mmol) at 0 °C. The reaction mixture was stirred at RT for 10 min.
  • Example 63 (0.04 g).
  • Example 64 Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(1-(3-fluoro-4- methoxyphenyl)-1H-pyrazol-3-yl)urea solution of 3-nitro-1H-pyrazole 64-1 (0.70 g, 6.19 mmol) in MeOH (10 mL) was added (3- fluoro-4-methoxy-phenyl) boronic acid 64-2 (1.05 g, 6.19 mmol) followed by sodium hydroxide (0.74 g, 18.6 mmol). The reaction mixture was purged under oxygen atmosphere for 30 min.
  • Step-2 1-(3-fluoro-4-methoxy-phenyl) pyrazol-3-amine (64-4): To a solution of 64-3 (0.50 g, 2.11 mmol) in ethanol (3 mL) and water (2 mL) was added iron powder (0.59 g, 10.5 mmol) followed by NH 4 Cl (0.50 g, 9.36 mmol).
  • Step-3 (S)-1-(8-chlorochroman-4-yl)-3-(1-(3-fluoro-4-methoxyphenyl)-1H- pyrazol-3-yl)urea (Example 64): To a stirred solution of N,N′-disuccinimidyl carbonate (0.12 g, 0.48 mmol) in CH3CN (2 mL) was added pyridine (0.038 mL, 0.48 mmol) and (4S)- 8-chlorochroman-4-amine 64-5 (0.09 g, 0.48 mmol) at RT. The reaction mixture was stirred for 45 min.
  • Example 64 (0.04 g).
  • Example 65 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-(1-tetrahydropyran-4- ylpyrazol-3-yl)urea stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate 65-1 (0.16 g, 0.79 mmol) in DCM (5 mL) at 0 °C was added triethylamine (0.33 mL, 2.38 mmol). To this was added methanesulfonyl chloride (0.1 mL, 1.19 mmol) slowly dropwise at 0 °C. The reaction mixture was stirred at RT for 2 h.
  • reaction mixture was quenched with aqueous NH4Cl and extracted with DCM.
  • the combined organic layer was washed with H2O and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford tert- butyl 4-methylsulfonyloxypiperidine-1-carboxylate 65-2 (0.20 g).
  • Step-2 tert-butyl 4-(3-nitropyrazol-1-yl)piperidine-1-carboxylate (65-4): To a stirred solution of 3-nitro-1H-pyrazole 65-3 (1.00 g, 8.84 mmol) in DMF (10 mL) was added Cs2CO3 (4.32 g, 13.30 mmol) followed by tert-butyl 4-methylsulfonyloxypiperidine-1- carboxylate 65-2 (2.47 g, 8.84 mmol) at RT. The reaction mixture was stirred at 90 °C for 16 h. After completion, the reaction was quenched with water and extracted with EtOAc.
  • Step-3 tert-butyl 4-(3-aminopyrazol-1-yl)piperidine-1-carboxylate (65-5): To a stirred solution of tert-butyl 4-(3-nitropyrazol-1-yl)piperidine-1-carboxylate 65-4 (0.50 g, 1.69 mmol) in EtOH (5 mL) and water (3 mL) was added ammonium chloride (0.45 g, 8.44 mmol) followed by iron powder (0.47 g, 8.44 mmol) at RT. The reaction mixture was stirred at 90 °C for 2 h. After completion, reaction mixture was filtered and washed with EtOAc.
  • Step-4 tert-butyl 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]piperidine-1-carboxylate (65-7): To a stirred solution of tert-butyl 4-(3-aminopyrazol-1- yl)piperidine-1-carboxylate 65-5 (0.20 g, 0.75 mmol) in DCM (5 mL) was added triphosgene (0.15 g, 0.52 mmol) at RT. The reaction mixture was stirred at RT for 30 min.
  • Step-5 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-piperidyl)pyrazol-3-yl]urea (Example 65): To a stirred solution of tert-butyl 4-[3-[[(4S)-8-chlorochroman-4- yl]carbamoylamino]pyrazol-1-yl]piperidine-1-carboxylate 65-7 (0.40 g, 0.84 mmol) in DCM (4 mL) was added TFA (0.45 mL, 5.88 mmol) at 0 °C. The reaction mixture was stirred at RT for 4 h. After completion, reaction mixture was concentrated under reduced pressure.
  • Example 66 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[1-(2-hydroxyethyl)-4- piperidyl]pyrazol-3-yl]urea piperidyl]pyrazol-3-yl]urea (Example 66): To a stirred solution of 1-[(4S)-8- chlorochroman-4-yl]-3-[1-(4-piperidyl)pyrazol-3-yl]urea Example 65 (0.15 g, 0.39 mmol) in THF (3 mL) was added triethylamine (0.17 mL, 1.20 mmol) followed by 2-bromoethanol (0.10 g, 0.79 mmol) at RT.
  • reaction mixture was stirred at 70 °C for 5 h. After completion, reaction mixture was quenched with H2O and extracted with EtOAc. The c ombined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain product. The product was purified by prep HPLC to afford Example 66 (0.01 g).
  • Example 67 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-pyridyl) pyrazol-3- yl]urea pyrazol-3-amine 67-1 (0.05 g, 0.60 mmol) in DMSO (0.5 mL) was added KOH (0.07 g, 1.20 mmol), copper (II) oxide (0.01 g, 0.06 mmol) followed by 3-iodopyridine 67-2 (0.19 g, 0.90 mmol) at RT. The reaction mixture was degassed under argon atmosphere for 20 min. Then, the reaction mixture was stirred at 120 °C for 12 h.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3-pyridyl) pyrazol-3-yl]urea
  • Example 67 To a stirred solution of 67-3 (0.75 g, 0.47 mmol) in MeCN (2 mL) was added pyridine (0.08 mL, 0.94 mmol) followed by N,N′-disuccinimidyl carbonate (0.12 g, 0.47 mmol) at RT and the reaction mixture was stirred at RT for 45 min.
  • Example 68 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3,4-difluorophenyl) pyrazol-3-yl]urea - pyrazol-3-amine 68-1 (0.50 g, 5.90 mmol) in DMSO (5 mL) was added KOH (0.42 g, 7.31 mmol), Cu2O (0.05 g, 0.35 mmol) followed by 1,2-difluoro-4-iodo-benzene 68-2 (0.86 mL, 8.85 mmol) at RT. The reaction mixture was degassed under argon atmosphere for 30 min and stirred at 120 °C for 14 h.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(3,4-difluorophenyl) pyrazol-3- yl]urea
  • Example 68 To a stirred solution of 68-3 (0.11 g, 0.51 mmol) in MeCN (4 mL) was added N,N′-disuccinimidyl carbonate (0.13 g, 0.51 mmol) followed by pyridine (0.04 mL, 0.51 mmol). The resulting reaction mixture was stirred at RT for 20 min.
  • Example 69 Synthesis of 1-[1-[4-(1-amino-1-methyl-ethyl)-2-fluoro-phenyl]pyrazol-3- yl]-3-[(4S)-8-chlorochroman-4-yl]urea [033 ] Step : ( b o o 3 uo o p e y ) et y p opa e t e (69 ): o a st ed solution of 2-(4-bromo-3-fluoro-phenyl)acetonitrile 69-1 (5.00 g, 23.36 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 2.80 g, 116.81 mmol) at 0 °C and the reaction mixture was stirred for 1 h.
  • Step-2 2-[4-(3-aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl-propanenitrile (69- 4): To a stirred solution of 1H-pyrazol-3-amine 69-3 (0.15 g, 1.81 mmol) in DMF (5 mL) was added 2-(4-bromo-3-fluoro-phenyl)-2-methyl-propanenitrile 69-2 (0.43 g, 1.81 mmol) followed by potassium carbonate (0.49 g, 3.61 mmol).
  • reaction mixture was purged with argon for 20 min and then added trans-N,N'-dimethylcyclohexane-1,2-diamine (0.05 g, 0.36 mmol) followed by copper (I) bromide (0.10 g, 0.72 mmol).
  • the reaction mixture was purged with argon for 10 min.
  • the reaction mixture was stirred at 120 °C for 12 h on microwave irradiation. After completion, the reaction mixture was cooled to RT and filtered through Celite. The filtrate was diluted with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
  • Step-3 2-[4-(3-aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl-propanamide (69- 5): To a stirred solution of 2-[4-(3-aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl- propanenitrile 69-4 (0.50 g, 2.05 mmol) in ethanol (4 mL) was added potassium carbonate (0.56 g, 4.09 mmol) in water (2 mL) followed by 30% H2O2 (0.13 g, 4.09 mmol). Reaction mixture was stirred at 25 °C for 12 h. After completion, reaction mixture was diluted with H2O, extracted with EtOAc.
  • Step-4 2-[4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-3- fluoro-phenyl]-2-methyl-propanamide (69-7): To a stirred solution of 2-[4-(3- aminopyrazol-1-yl)-3-fluoro-phenyl]-2-methyl-propanamide 69-5 (0.40 g, 1.53 mmol) in MeCN (8 mL) was added N,N′-disuccinimidyl carbonate (0.39 g, 1.53 mmol) followed by pyridine (0.12 mL, 1.53 mmol).
  • reaction mixture was stirred at RT for 45 min.
  • (4S)-8-chlorochroman-4-amine hydrochloride 69-6 (0.40 g, 1.83 mmol) followed by N,N-diisopropylethylamine (0.80 mL, 4.58 mmol) and stirred at RT for 4 h.
  • reaction mixture was diluted with H 2 O and extracted with EtOAc. Combined organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-5 1-[1-[4-(1-amino-1-methyl-ethyl)-2-fluoro-phenyl]pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea (Example 69): To a stirred solution of 2-[4-[3-[[(4S)-8- chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-3-fluoro-phenyl]-2-methyl-propanamide 69-7 (0.30 g, 0.63 mmol) in MeCN (2 mL) and water (8 mL) was added potassium hydroxide (0.16 g, 2.86 mmol) followed by 1,3-dibromo-5,5-dimethylhydantoin (0.09 g, 0.31 mmol) and reaction mixture was stirred at RT for 12 h.
  • Example 70 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2- methylsulfonylphenyl)pyrazol-3-yl]urea
  • Step-1 1-(2-methylsulfonylphenyl)pyrazol-3-amine (70-3): To a stirred solution of 1-bromo-2-methylsulfonyl-benzene 70-2 (0.50 g, 2.13 mmol) in DMSO (10 mL) were added 1H-pyrazol-3-amine 70-1 (0.21 g, 2.55 mmol) and Cs 2 CO 3 (1.38 g, 4.25 mmol) followed by copper (II) bromide (0.09 g, 0.42 mmol) at RT.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-methylsulfonylphenyl)pyrazol-3- yl]urea
  • Example 70 To a stirred solution of 1-(2-methylsulfonylphenyl)pyrazol-3-amine 70-3 (0.10 g, 0.42 mmol) in MeCN (5 mL) was added pyridine (0.03 g, 0.42 mmol) followed by N,N′-disuccinimidyl carbonate (0.10 g, 0.42 mmol) at RT. The reaction mixture was stirred at RT for 15 min.
  • Example 71 Synthesis of 1-[(4S)-5-fluorochroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea
  • Step-1 To a stirred solution of 1-phenylpyrazol-3-amine 71-1 (0.10 g, 0.59 mmol) in MeCN (3 mL) was added pyridine (0.05 mL, 0.59 mmol) followed by N,N′-disuccinimidyl carbonate (0.15 g, 0.59 mmol) at RT. The reaction mixture was stirred at RT for 15 min.
  • Example 72 Synthesis of 1-[1-[5-(1-amino-1-methyl-ethyl)-2-pyridyl]pyrazol-3-yl]-3- [(4S)-8-chlorochroman-4-yl]urea [0342]
  • Step-1 2-(6-chloro-3-pyridyl) propan-2-amine (72-2): To a stirred suspension of anhydrous cerium (III) chloride (7.36 g, 29.9 mmol) in THF (40 mL) was added methyl lithium (1.6 M in diethyl ether) (19.00 mL, 29.9 mmol) at -78 °C and the reaction mixture was stirred at same temperature for 30 min.
  • III cerium
  • Step-2 tert-butyl (2-(6-chloropyridin-3-yl)propan-2-yl)carbamate (72-3): To a stirred solution of 2-(6-chloro-3-pyridyl) propan-2-amine 72-2 (1.00 g, 5.86 mmol) in THF (10 mL) was added triethylamine (1.6 mL, 11.7 mmol) followed by BOC anhydride (1.6 mL, 7.03 mmol) and stirred at RT for 12 h. After completion, the reaction mixture was concentrated under reduced pressure.
  • Step-3 2-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3-yl)propan-2-amine (72-5): To a stirred solution of 3-nitro-1H-pyrazole 72-4 (0.20 g, 1.85 mmol) in DMSO (3 mL) was added tert-butyl (2-(6-chloropyridin-3-yl)propan-2-yl)carbamate 72-3 (0.50 g, 1.85 mmol) followed by tripotassium phosphate (0.78 g, 3.69 mmol) and reaction mixture was degassed with argon for 20 min.
  • trans-N,N'-dimethylcyclohexane-1,2-diamine (0.10 g, 0.74 mmol) followed by copper (I) iodide (0.07 g, 0.36 mmol) and reaction mixture was further degassed with argon for 10 min. Then the reaction mixture was stirred at 125 °C for 16 h. After completion, the reaction mixture was quenched with ice cold water. Aqueous layer was extracted with EtOAc. Combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 2-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3- yl)propan-2-amine 72-5 (0.90 g).
  • Step-4 tert-butyl (2-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3-yl)propan-2- yl)carbamate (72-6): To a stirred solution of 2-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3- yl)propan-2-amine 72-5 (0.90 g, 3.64 mmol) in THF (10 mL) was added triethylamine (1.0 mL, 7.28 mmol) followed by BOC anhydride (1.0 mL, 4.37 mmol) and the reaction mixture was stirred at RT for 4 h.
  • Step-5 tert-butyl N-[1-[6-(3-aminopyrazol-1-yl)-3-pyridyl]-1-methyl-ethyl] carbamate (72-7): To a stirred suspension of tert-butyl (2-(6-(3-nitro-1H-pyrazol-1- yl)pyridin-3-yl)propan-2-yl)carbamate 72-6 (0.40 g, 1.15 mmol) in ethanol (12 mL) and water (3 mL) solvent mixture, was added ammonium chloride (0.30 g, 5.76 mmol) followed by iron powder (0.32 g, 5.76 mmol) and the reaction mixture was stirred at 80 °C for 3 h.
  • Step-6 tert-butyl N-[1-methyl-1-[6-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl]-3-pyridyl] ethyl]carbamate (72-9): To a stirred solution of tert-butyl N-[1-[6-(3-aminopyrazol-1-yl)-3-pyridyl]-1-methyl-ethyl] carbamate 72-7 (0.20 g, 0.63 mmol) in MeCN (8 mL) was added pyridine (0.05 mL, 0.63 mmol) followed by N,N′- disuccinimidyl carbonate (0.16 g, 0.63 mmol).
  • Step-7 1-[1-[5-(1-amino-1-methyl-ethyl)-2-pyridyl] pyrazol-3-yl]-3-[(4S)-8- chlorochroman-4-yl]urea
  • Example 72 To a stirred solution of tert-butyl N-[1-methyl-1- [6-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl]-3-pyridyl] ethyl]carbamate 72-9 (0.10 g, .19 mmol) in 1,4-dioxane (1 mL) was added 4 N HCl in dioxane (0.40 mL ) and stirred at RT for 1 h.
  • Example 73 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-pyridyl) pyrazol-3- yl]urea
  • Step-1 1-(2-pyridyl) pyrazol-3-amine (73-3): To a solution of 1H-pyrazol-3-amine 73-1 (0.60 g, 7.22 mmol) in DMSO (10 mL) was added Cu2O (0.10 g, 0.72 mmol) followed by KOH (0.81 g, 14.4 mmol) at RT. The reaction mixture was degassed under argon atmosphere for 30 min.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2-pyridyl) pyrazol-3-yl]urea
  • Example 73 To a stirred solution of N,N′-disuccinimidyl carbonate (0.16 g, 0.62 mmol) in MeCN (5 mL) was added pyridine (0.05 mL, 0.62 mmol) and 73-3 (0.10 g, 0.62 mmol) at RT. The reaction mixture was stirred for 45 min.
  • Example 74 Synthesis of 1-[(4S)-7-fluorochroman-4-yl]-3-(1-phenylpyrazol-3-yl)urea
  • Step-1 To a stirred solution of 1-phenylpyrazol-3-amine 74-1 (0.10 g, 0.59 mmol) in MeCN (3 mL) was added pyridine (0.10 mL, 1.19 mmol) followed by N,N′-disuccinimidyl carbonate (0.61 g, 2.39 mmol) at RT and the reaction mixture was stirred at RT for 15 min.
  • Example 75 Synthesis of (S)-3-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N- methylbenzamide
  • Step-1 N-methyl-3-(3-nitro-1H-pyrazol-1-yl)benzamide (75-2): To a stirred solution of 3-(3-nitropyrazol-1-yl)benzoic acid 75-1 (0.30 g, 1.29 mmol) in DMF (5 mL) was added DIPEA (0.92 mL, 5.15 mmol), methylamine hydrochloride (0.13 g, 1.93 mmol) and HATU (0.73 g, 1.93 mmol) and the reaction mixture was stirred at RT for 2 h.
  • Step-2 3-(3-amino-1H-pyrazol-1-yl)-N-methylbenzamide (75-3): To a solution of 75-2 (0.20 g, 0.81 mmol) in THF/MeOH/water (3:1:1, 10 mL) was added ammonium chloride (0.13 g, 2.44 mmol) and iron powder (0.14 g, 2.44 mmol) and the reaction mixture was heated at 80 °C for 6 h. After completion, the reaction mixture was quenched with water and filtered through a Celite bed. The aqueous layer was extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-3 (S)-3-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N- methylbenzamide (Example 75): To a solution of 75-3 (0.05 g, 0.23 mmol) in MeCN (2 mL) was added pyridine (0.02 mL, 0.23 mmol) followed by N,N′-disuccinimidyl carbonate (0.06 g, 0.23 mmol) and the resulting reaction mixture was stirred at RT for 30 min.
  • Example 76 Synthesis of (S)-4-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N- methylbenzamide
  • Step-1 ethyl 4-(3-nitro-1H-pyrazol-1-yl)benzoate (76-3): To a stirred solution of 3- nitro-1H-pyrazole 76-1 (0.10 g, 0.88 mmol) in DMSO (2 mL) was added potassium carbonate (0.15 g, 1.06 mmol) followed by ethyl 4-fluorobenzoate 76-2 (0.16 g, 0.97 mmol) and the reaction mixture was stirred at 90 °C for 12 h.
  • Step-2 4-(3-nitro-1H-pyrazol-1-yl)benzoic acid (76-4): To a stirred solution of 76- 3 (0.40 g, 1.53 mmol) in THF (6 mL) and MeOH (3 mL) was added LiOH.H 2 O (0.19 g, 4.59 mmol) in water (1 mL) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, pH ⁇ 3 was adjusted with 2N HCl. The precipitated solid was filtered, dried under reduced pressure to afford 76-4 (0.30).
  • Step-3 N-methyl-4-(3-nitro-1H-pyrazol-1-yl)benzamide (76-5): To a stirred solution of 76-4 (0.20 g, 0.86 mmol) in DMF (3 mL) was added HATU (0.49 g, 1.29 mmol) and methylamine hydrochloride (0.09 g, 1.29 mmol) followed by DIPEA (0.60 mL, 3.43 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-4 4-(3-amino-1H-pyrazol-1-yl)-N-methylbenzamide (76-6): To a stirred solution of 76-5 (0.30 g, 1.22 mmol) in EtOH (3 mL) and water (1 mL) was added iron powder (0.34 g, 6.09 mmol) and ammonium chloride (0.33 g, 6.09 mmol) and the reaction mixture was stirred at 100 °C for 4 h. After completion of the reaction, the mixture was filtered through a Celite bed.
  • Example 77 Synthesis of (S)-3-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)- N,N-dimethylbenzamide of 3-nitro-1H-pyrazole 77-1 (0.50 g, 4.42 mmol) in DCM (10 mL) was added (3- methoxycarbonylphenyl)boronic acid 77-2 (1.19 g, 6.63 mmol), pyridine (1.10 mL, 13.30 mmol) and copper acetate (1.61 g, 8.84 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was quenched with water and extracted with DCM.
  • Step-3 N,N-dimethyl-3-(3-nitro-1H-pyrazol-1-yl)benzamide (77-5): To a stirred solution of 77-4 (0.40 g, 1.72 mmol) in DMF (5 mL) was added DIPEA (1.20 mL, 6.86 mmol), dimethylamine hydrochloride (0.21 g, 2.57 mmol) and HATU (0.98 g, 2.57 mmol) and the reaction mixture was stirred at RT for 12 h. After completion, the reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc.
  • Step-4 3-(3-amino-1H-pyrazol-1-yl)-N,N-dimethylbenzamide (77-6): To a stirred solution of 77-5 (0.40 g, 1.54 mmol) in THF/MeOH/water (3:1:1, 10 mL) was added iron powder (0.26 g, 4.61 mmol) and ammonium chloride (0.25 g, 4.61 mmol) and the reaction mixture was heated at 80 °C for 2 h.
  • Step-5 (S)-3-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N,N- dimethylbenzamide (Example 77): To a stirred solution of 77-6 (0.05 g, 0.22 mmol) in MeCN (2 mL) was added pyridine (0.02 mL, 0.22 mmol) followed by N,N′-disuccinimidyl carbonate (0.06 g, 0.22 mmol) at 0 °C and the resulting reaction mixture was stirred at RT for 30 min.
  • Example 78 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4,4-difluorocyclohexyl) pyrazol-3-yl]urea
  • Step-1 4,4-difluorocyclohexanol (78-2): To a stirred solution of 4,4- difluorocyclohexanone 78-1 (1.50 g, 11.2 mmol) in MeOH (15 mL) was added sodium borohydride (0.51 g, 13.4 mmol) at 0 °C and the reaction mixture was stirred at RT for 4 h. After completion, the reaction mixture was quenched with H 2 O and concentrated under reduced pressure.
  • Step-2 (4,4-difluorocyclohexyl) methane sulfonate (78-3): To a stirred solution of 78-2 (0.50 g, 3.67 mmol) in DCM (7 mL) was added triethylamine (1.30 mL, 9.18 mmol) at 0 °C followed by methane sulfonyl chloride (0.34 mL, 4.41 mmol). The reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was quenched with H2O. The aqueous layer was extracted with 5% MeOH/DCM.
  • Step-3 1-(4,4-difluorocyclohexyl)-3-nitro-pyrazole (78-5): To a stirred solution of 3-nitro-1H-pyrazole 78-4 (0.38 g, 3.36 mmol) in DMF (10 mL) was added cesium carbonate (1.83 g, 5.60 mmol) at 0 °C followed by 78-3 (0.60 g, 2.80 mmol). The reaction was heated at 90 °C for 12 h. After completion, the reaction mixture was quenched with H2O, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 78-5 (0.40 g).
  • Step-4 1-(4,4-difluorocyclohexyl) pyrazol-3-amine (78-6): To a stirred solution of 78-5 (0.35 g, 1.51 mmol) in EtOH (5 mL) and water (3 mL), ammonium chloride (0.35 g, 6.54 mmol) and iron powder (0.42 g, 7.57 mmol) were added at RT and the reaction mixture was stirred at 80 °C for 2 h. After completion, the reaction mixture was filtered through a Celite bed. The filtrate was concentrated, diluted with cold water and extracted with EtOAc.
  • Step-5 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4,4-difluorocyclohexyl) pyrazol-3- yl]urea (Example 78): To a stirred solution of 78-6 (0.11 g, 0.55 mmol) in MeCN (3 mL) was added pyridine (0.04 mL, 0.55 mmol) followed by N,N′-disuccinimidyl carbonate (0.14 g, 0.55 mmol) at RT. The reaction mixture was stirred at RT for 15 min.
  • Example 79 Synthesis of (S)-2-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)- N,N-dimethylbenzamide [ ] p ( py y ) ( ) nitro-1H-pyrazole 79-1 (0.20 g, 1.77 mmol) in DMF (3 mL) was added K 2 CO 3 (0.73 g, 5.31 mmol) followed by 2-fluorobenzonitrile 79-2 (0.21 g, 1.77 mmol) and the reaction mixture was stirred at 100 °C for 16 h. After completion, the reaction mixture was quenched with ice cold water.
  • Step-2 2-(3-nitro-1H-pyrazol-1-yl)benzoic acid (79-4): To a stirred solution of 79- 3 (0.70 g, 3.27 mmol) in EtOH/water (1:1, 30 mL) was added NaOH (0.26 g, 6.54 mmol) and the reaction mixture was stirred at 100 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water.2N HCl was added until the pH was adjusted to pH ⁇ 3. The precipitated solid was filtered and dried under reduced pressure to afford 79-4 (0.50 g).
  • Step-3 N,N-dimethyl-2-(3-nitro-1H-pyrazol-1-yl)benzamide (79-5): To a stirred solution of 79-4 (0.06 g, 0.26 mmol) in DMF (3 mL) was added HATU (0.10 g, 0.26 mmol) and DIPEA (0.09 mL, 0.52 mmol) at 0 °C followed by dimethylamine hydrochloride (0.02 g, 0.26 mmol) and the reaction mixture was stirred at RT for 16 h. After completion, the reaction mixture was quenched with ice cold water. The precipitated solid was filtered and dried under reduced pressure to afford 79-5 (0.06 g).
  • Step-4 2-(3-amino-1H-pyrazol-1-yl)-N,N-dimethylbenzamide (79-6): To a stirred solution of 79-5 (0.06 g, 0.23 mmol) in EtOH/water (1:1, 6 mL), was added ammonium chloride (0.05 g, 0.92 mmol) followed by iron powder (0.05 g, 0.92 mmol) and the reaction mixture was heated at 90 °C for 4 h. After completion, the reaction mixture was quenched with water and filtered through a Celite bed. The aqueous layer was extracted with EtOAc.
  • Example 79 (0.03 g).
  • Example 80 Synthesis of (S)-1-(8-chlorochroman-4-yl)-3-(1-(4- (trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)urea solution of 3-nitro-1H-pyrazole 80-1 (2.50 g, 22.10 mmol) in methanol (50 mL), [4- (trifluoromethoxy)phenyl] boronic acid 80-2 (5.46 g, 26.5 mmol) was added followed by CuCl2 (1.48 g, 11.00 mmol) and the reaction mixture was stirred at 80 °C for 24 h under oxygen atmosphere. After completion of the reaction, the mixture was concentrated under reduced pressure.
  • Step-2 1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-amine (80-4): To a stirred solution of 80-3 (0.70 g, 2.56 mmol) in methanol (8 mL) and water (2 mL), was added ammonium chloride (1.10 g, 20.50 mmol) followed by iron powder (0.57 g, 10.30 mmol) at RT and the reaction mixture was stirred at 100 °C for 2 h. After completion of reaction, the reaction mixture was filtered through a Celite bed. The filtrate was diluted with cold water and extracted with ethyl acetate.
  • Step-3 (S)-1-(8-chlorochroman-4-yl)-3-(1-(4-(trifluoromethoxy)phenyl)-1H- pyrazol-3-yl)urea
  • Example 80 To a stirred solution of (4S)-8-chlorochroman-4-amine 80- 5 (0.05 g, 0.27 mmol) in MeCN (2 mL) was added pyridine (0.04 g, 0.55 mmol) followed by N,N'-disuccinimidyl carbonate (0.07 g, 0.27 mmol) and the reaction mixture was stirred at RT for 15 min.
  • Example 80 (0.07 g, 0.27 mmol) followed by DIPEA (0.14 g, 1.09 mmol) and the resulting reaction mixture was stirred at RT for 4 h. After completion, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by preparative HPLC to afford Example 80 (0.08 g).
  • Example 81 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4- methylsulfonylphenyl)pyrazol-3-yl]urea
  • Step-1 1-(4-methylsulfonylphenyl)-3-nitro-pyrazole (81-3): To a stirred solution of (4-methylsulfonylphenyl)boronic acid 81-1 (0.20 g, 1.00 mmol) in DCM (2 mL) was added 3-nitro-1H-pyrazole 81-2 (0.13 g, 1.00 mmol) followed by pyridine (0.17 mL, 2.00 mmol) and Cu(OAc) 2 (0.01 g, 1.00 mmol) under oxygen gas at RT.
  • reaction was stirred at 25 °C for 12 h. After completion of reaction, the reaction mixture was filtered over Celite bed. Filtrate was washed with water and brine, organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product was purified by column chromatography (20% EtOAc/heptane) to afford 1-(4-methylsulfonylphenyl)-3-nitro-pyrazole 81-3 (0.20 g).
  • Step-2 1-(4-methylsulfonylphenyl)pyrazol-3-amine (81-4): To a stirred solution of 1-(4-methylsulfonylphenyl)-3-nitro-pyrazole 81-3 (0.20 g, 0.74 mmol) in methanol (5 mL) and THF (5 mL) was added 10% Pd/C (0.05 g) at RT. The reaction was stirred under 50 psi hydrogen gas pressure in autoclave at RT for 12 h.
  • Step-3 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-methylsulfonylphenyl)pyrazol-3- yl]urea
  • Example 81 To a stirred solution of 1-(4-methylsulfonylphenyl)pyrazol-3-amine 81-4 (0.05 g, 0.21 mmol) in MeCN (2 mL) was added pyridine (0.01 mL, 0.21 mmol) followed by N,N′-disuccinimidyl carbonate (0.05 g, 0.21 mmol). Resulting mixture was stirred at RT for 30 min.
  • Example 82 and Example 83 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[2- (hydroxymethyl)-2,3-dihydrobenzofuran-5-yl]pyrazol-3-yl]urea [ ] p , y y ( ) solution of 2,3-dihydrobenzofuran-2-carboxylic acid 82-1 (1.50 g, 9.14 mmol) in acetic acid (4 mL) was added bromine (0.47 mL, 9.14 mmol) at 25 °C. Reaction mixture was stirred at same temperature for 16 h. After completion, reaction mixture was quenched with cold water.
  • Step-2 ethyl 5-bromo-2,3-dihydrobenzofuran-2-carboxylate (82-3): To a stirred solution of 5-bromo-2,3-dihydrobenzofuran-2-carboxylic acid 82-2 (0.25 g, 1.03 mmol) in ethanol (3 mL) was added H 2 SO 4 (0.10 mL) at 0 °C and the reaction mixture was stirred at 60 °C for 16 h. After completion, reaction mixture was quenched with H2O, extracted with EtOAc.
  • Step-3 (5-bromo-2,3-dihydrobenzofuran-2-yl)methanol (82-4): To a stirred solution of ethyl 5-bromo-2,3-dihydrobenzofuran-2-carboxylate 82-3 (1.00 g, 3.69 mmol) in ethanol (25 mL) was added NaBH 4 (0.28 g, 7.38 mmol) at 0 °C and the reaction mixture was stirred at RT for 16 h. After completion, reaction mixture was quenched with H2O, extracted with EtOAc.
  • Step-4 (5-bromo-2,3-dihydrobenzofuran-2-yl)methoxy-tert-butyl-dimethyl- silane (82-5): To a stirred solution of (5-bromo-2,3-dihydrobenzofuran-2-yl)methanol (0.75 g, 3.27 mmol) in DCM (25 mL) was added imidazole (0.44 g, 6.55 mmol) followed by tert- butyldimethylsilyl chloride (0.98 g, 6.55 mmol) and the reaction mixture was stirred at RT for 2 h. After completion, reaction mixture was quenched with H2O and extracted with the EtOAc.
  • Step-5 [2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3-dihydrobenzofuran-5- yl]boronic acid (82-6): To a stirred solution of (5-bromo-2,3-dihydrobenzofuran-2- yl)methoxy-tert-butyl-dimethyl-silane 82-5 (0.50 g, 1.46 mmol) in dry THF (10 mL), n-BuLi (1.6M in hexane) (1.8 mL, 2.91 mmol) was added drop wise at -78 °C under N 2 atmosphere and the reaction mixture was stirred for 10 min.
  • n-BuLi 1.6M in hexane
  • Step-6 tert-butyl-dimethyl-[[5-(3-nitropyrazol-1-yl)-2,3-dihydrobenzofuran-2- yl]methoxy]silane (82-8): To a stirred solution of 3-nitro-1H-pyrazole 82-7 (0.15 g, 1.33 mmol) in DCM (25 mL) were added [2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3- dihydrobenzofuran-5-yl]boronic acid 82-6 (0.40 g, 1.33 mmol), copper (II)acetate (0.36 g, 1.99 mmol) and pyridine (0.21 g, 2.65 mmol) at RT.
  • reaction mixture was stirred at RT for 12 h under oxygen atm. After completion, reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The product was purified by flash column chromatography (10-20% EtOAc/n-heptane) to afford tert-butyl-dimethyl-[[5-(3- nitropyrazol-1-yl)-2,3-dihydrobenzofuran-2-yl]methoxy]silane 82-8 (0.30 g).
  • Step-7 1-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3-dihydrobenzofuran-5- yl]pyrazol-3-amine (82-9): To a stirred solution of tert-butyl-dimethyl-[[5-(3-nitropyrazol-1- yl)-2,3-dihydrobenzofuran-2-yl]methoxy]silane 82-8 (0.30 g, 0.79 mmol) in ethanol (15 mL), ammonium chloride (0.25 g, 4.79 mmol) in water (2 mL) and iron powder (0.22 g, 3.99 mmol) were added at RT and the reaction mixture was stirred at 80 °C for 3 h.
  • Step-8 1-[1-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3-dihydrobenzofuran-5- yl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea (82-11): To a stirred solution of 1-[2- [[tert-butyl(dimethyl)silyl]oxymethyl]-2,3-dihydrobenzofuran-5-yl]pyrazol-3-amine 82-9 (0.25 g, 0.72 mmol) in MeCN (5 mL) was added pyridine (0.11 g, 1.45 mmol) followed by N,N′-disuccinimidyl carbonate (0.18 g, 0.72 mmol).
  • reaction mixture was stirred at RT for 30 min.
  • (4S)-8-chlorochroman-4-amine hydrochloride 82-10 (0.15 g, 0.72 mmol) followed by DIPEA (0.39 mL, 2.17 mmol) and reaction mixture was stirred at 30 °C for 1 h.
  • reaction mixture was concentrated under reduced pressure and product obtained was dissolved in EtOAc.
  • Organic layer was washed with H 2 O and brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-9 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[2-(hydroxymethyl)-2,3- dihydrobenzofuran-5-yl]pyrazol-3-yl]urea (Examples 82 and 83): To a stirred solution of 1-[1-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3-dihydrobenzofuran-5-yl]pyrazol-3-yl]-3- [(4S)-8-chlorochroman-4-yl]urea 82-11 (0.20 g, 0.36 mmol) in THF (5 mL) was added TBAF(1M in THF) (0.72 mL, 0.72 mmol) at 0 °C and the reaction mixture was stirred for 1 h.
  • Example 84 Synthesis of (S)-4-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N- methylbenzenesulfonamide [ ] p y ( ) - bromobenzenesulfonyl chloride 84-1 (1.00 g, 3.91 mmol) in DCM (8 mL) was added triethylamine (1.60 mL, 11.70 mmol) followed by methanamine (0.74 mL, 15.70 mmol) and the reaction mixture was stirred at 27 °C for 2 h. The reaction mixture was quenched with water, aqueous layer was extracted with DCM.
  • Step-2 4-(3-aminopyrazol-1-yl)-N-methyl-benzenesulfonamide (84-4): To a stirred solution of 4-bromo-N-methyl-benzenesulfonamide 84-2 (0.82 g, 3.31 mmol) in DMSO (5 mL) was added Cs2CO3 (1.96 g, 6.02 mmol) followed by 1H-pyrazol-3-amine 84-3 (0.03 g, 0.36 mmol) and CuBr (I) (0.08 g, 0.60 mmol) and the reaction mixture was stirred at 120 °C for 12 h. The reaction mixture was quenched with water, aqueous layer was extracted with EtOAc.
  • Step-3 (S)-4-(3-(3-(8-chlorochroman-4-yl)ureido)-1H-pyrazol-1-yl)-N- methylbenzenesulfonamide (Example 84): To a stirred solution of 4-(3-aminopyrazol-1- yl)-N-methyl-benzenesulfonamide 84-4 (0.05 g, 0.19 mmol) in MeCN (2 mL) was added pyridine (0.01 mL, 0.19 mmol) followed by N,N′-disuccinimidyl carbonate (0.05 g, 0.19 mmol) at RT.
  • Example 85 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-(methylsulfamoyl) phenyl] pyrazol-3-yl]urea - bromobenzenesulfonyl chloride 85-1 (2.00 g, 7.83 mmol) in THF (10 mL) was added 2M methyl amine in THF (10 mL) at 0 °C. Reaction mixture was stirred at RT for 16 h. After completion, reaction was quenched with H 2 O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
  • Step-2 3-(3-aminopyrazol-1-yl)-N-methyl-benzenesulfonamide (85-4): To a stirred solution of 1H-pyrazol-3-amine 85-3 (0.39 g, 4.80 mmol) and 3-bromo-N-methyl- benzenesulfonamide 85-2 (1.00 g, 4.00 mmol) in DMSO (15 mL) was added cesium carbonate (2.61 g, 8.00 mmol) followed by copper (II) bromide (0.17 g, 0.80 mmol).
  • Step-3 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-(methylsulfamoyl) phenyl]pyrazol- 3-yl]urea
  • Example 85 To a stirred solution of 3-(3-aminopyrazol-1-yl)-N-methyl- benzenesulfonamide 85-4 (0.13 g, 0.51 mmol) n MeCN (5 mL) was added pyridine (0.08 mL, 1.03 mmol) followed by N,N′-disuccinimidyl carbonate (0.14 g, 0.56 mmol). Resulting reaction mixture was stirred at RT for 30 min.
  • Example 86 Synthesis of 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]-N,3-dimethyl-benzamide [0398]
  • Step 1 4 iodo N,3 dimethyl benzamide (862): To a stirred solution of methyl 4 iodo-3-methyl-benzoate 86-1 (1.00 g, 3.62 mmol) in EtOH (10 mL) was added 27% methylamine in MeOH (30 mL, 29.00 mmol) at 0 °C. The reaction mixture was stirred at 100 °C for 12 h.
  • Step-2 4-(3-aminopyrazol-1-yl)-N,3-dimethyl-benzamide (86-4): To a stirred solution of 4-iodo-N,3-dimethyl-benzamide 86-2 (0.10 g, 0.36 mmol) in DMSO (5 mL) were added 1H-pyrazol-3-amine 86-3 (0.03 g, 0.43 mmol) and Cs 2 CO 3 (0.29 g, 0.90 mmol) followed by Cu2O (0.02 g, 0.07 mmol) at RT. The reaction was stirred in a sealed tube at 120 °C for 16 h. After completion, reaction was quenched with ice cold water, extracted with EtOAc.
  • Step-3 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-N,3- dimethyl-benzamide
  • Example 86 To a stirred solution of 4-(3-aminopyrazol-1-yl)-N,3- dimethyl-benzamide 86-4 (0.10 g, 0.43 mmol) in MeCN (5 mL) was added pyridine (0.1 mL, 0.86 mmol) at 0 °C followed by N,N′-disuccinimidyl carbonate (0.12 g, 0.47 mmol) at RT. Resulting reaction mixture was stirred at RT for 30 min.
  • Example 87 Synthesis of (1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4- methoxyphenyl)pyrazol-3-yl]urea [0401]
  • Step-1 (1-(4-methoxyphenyl)-3-nitro-pyrazole (87-3): To a stirred solution of 2-(4- methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 87-1 (3.11 g, 13.30 mmol) and 3- nitro-1H-pyrazole 87-2 (1.00 g, 8.84 mmol) in DCM (20 mL) was added pyridine (2.30 mL, 26.50 mmol) maintained at 0 °C followed by Cu(OAc)2 (3.25 g, 17.70 mmol) at RT.
  • reaction mixture was stirred at RT for 12 h. After completion, reaction mixture was filtered. Filtrate was diluted with H2O and extracted with EtOAc. Combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash (30% EtOAc/n-hexane) to afford (1-(4- methoxyphenyl)-3-nitro-pyrazole 87-3 (1.80 g).
  • Step-2 (1-(4-methoxyphenyl)pyrazol-3-amine (87-4): To a stirred solution of 1-(4- methoxyphenyl)-3-nitro-pyrazole 87-3 (1.50 g, 6.84 mmol) in MeOH (15 mL), THF (45 mL) and H2O (15 mL) were added iron powder (1.15 g, 20.50 mmol) and NH4Cl (1.15 g, 20.50 mmol) at RT. The reaction mixture was heated at 100 °C for 12 h.
  • Step-3 (1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-methoxyphenyl)pyrazol-3-yl]urea
  • Example 87 To a stirred solution of 1-(4-methoxyphenyl)pyrazol-3-amine 87-4 (0.05 g, 0.26 mmol) in MeCN (2 mL) was added pyridine (0.04 mL, 0.52 mmol) followed by bis(2,5- dioxopyrrolidin-1-yl)carbonate (0.06 g, 0.26 mmol) at RT. The resulting reaction mixture was stirred at RT for 30 min.
  • Example 88 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-(1-hydroxy-1-methyl- ethyl)phenyl]pyrazol-3-yl]urea [0404]
  • Step-1 1-[4-(3-aminopyrazol-1-yl)phenyl]ethanone (88-3): To a stirred solution of 1H-pyrazol-3-amine 88-1 (0.25 g, 3.01 mmol) in DMF (10 mL) was added cesium carbonate (1.63 g, 5.02 mmol) followed by 2-pyridinol-1-oxide (0.14 g, 1.26 mmol) and copper (I) iodide (0.10 g, 0.50 mmol) at RT.
  • Step-2 1-[1-(4-acetylphenyl)pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea (88-5): To a stirred solution of 1-[4-(3-aminopyrazol-1-yl)phenyl]ethanone 88-3 (0.05 g, 0.24 mmol) in MeCN (3 mL) was added pyridine (0.04 g, 0.49 mmol) followed by (4S)-8- chlorochroman-4-amine 88-4 (0.06 g, 0.24 mmol) at RT. Resulting mixture was stirred at RT for 30 min.
  • Step-3 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-(1-hydroxy-1-methyl- ethyl)phenyl]pyrazol-3-yl]urea
  • Example 88 To a stirred solution of 1-[1-(4- acetylphenyl)pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 88-5 (0.05 g, 0.12 mmol) in THF (2 mL) was added methyl magnesium bromide 1M solution in THF (0.02 g, 0.18 mmol) at 0 °C. Reaction was stirred at RT for 2 h.
  • Step-1 1-(2,2-difluoro-1,3-benzodioxol-5-yl)pyrazol-3-amine (89-3): To a stirred solution of 1H-pyrazol-3-amine 89-2 (0.50 g, 6.02 mmol) in DMF (5 mL) were added CuBr 2 (0.26 g, 1.20 mmol) and Cs2CO3 (1.96 g, 6.02 mmol) followed by 5-bromo-2,2-difluoro-1,3- benzodioxole 89-1 (1.85 g, 7.82 mmol).
  • reaction mixture was irradiated in microwave at 180 °C for 30 min. After completion, reaction was quenched with H 2 O, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get product which was purified by comb flash column (0.05% formic acid in H2O:ACN ) to afford 1-(2,2-difluoro-1,3-benzodioxol-5-yl)pyrazol-3- amine 89-3 (0.26 g).
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(2,2-difluoro-1,3-benzodioxol-5- yl)pyrazol-3-yl]urea
  • Example 89 To a stirred solution of 1-(2,2-difluoro-1,3- benzodioxol-5-yl)pyrazol-3-amine 89-3 (0.07 g, 0.29 mmol) in MeCN (5 mL) was added pyridine (0.02 mL, 0.29 mmol) followed by N,N’-disuccinimidyl carbonate (0.07 g, 0.50 mmol).
  • Example 90 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(1-methyl-4- piperidyl)pyrazol-3-yl]urea
  • Step-1 tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (90-2): To a suspension of tert-butyl 4-hydroxypiperidine-1-carboxylate 90-1 (0.16 g, 0.79 mmol) in DCM (5 mL) was added triethylamine (0.33 mL, 2.38 mmol) at 0 °C followed by methane sulfonyl chloride (0.09 mL, 1.19 mmol) drop wise and the reaction mixture was stirred at RT for 2 h.
  • Step-2 tert-butyl 4-(3-nitropyrazol-1-yl) piperidine-1-carboxylate (90-4): To a stirred solution of 3-nitro-1H-pyrazole 90-3 (1.00 g, 8.84 mmol) in DMF (10 mL) was added cesium carbonate (4.32 g, 13.3 mmol) followed by tert-butyl 4-methylsulfonyloxypiperidine- 1-carboxylate 90-2 (2.47 g, 8.84 mmol) and the reaction mixture was stirred at 90 °C for 16 h. After completion, reaction mixture was quenched with ice cold water and extracted with EtOAc.
  • Step-3 1-methyl-4-(3-nitropyrazol-1-yl) piperidine (90-5): To a stirred solution of tert-butyl 4-(3-nitropyrazol-1-yl)piperidine-1-carboxylate 90-4 (1.00 g, 3.37 mmol) in THF (8 mL) was added paraformaldehyde (1.40 g, 46.6 mmol) followed by acetic acid (0.3 mL) and stirred at RT for 30 min. To this was added sodium triacetoxyborohydride (2.14 g, 10.1 mmol) and stirred at 80 °C for 2 h.
  • Step-4 1-(1-methyl-4-piperidyl) pyrazol-3-amine (90-6): To a stirred solution of 1- methyl-4-(3-nitropyrazol-1-yl)piperidine 90-5 (0.65 g, 3.09 mmol) in ethanol (10 mL) and water (2 mL) was added ammonium chloride (0.81 g, 15.5 mmol) followed by iron powder (0.85 g, 15.5 mmol) portion wise. The reaction mixture was stirred at 100 °C for 2 h. After completion, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water and brine.
  • Step-5 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(1-methyl-4-piperidyl)pyrazol-3- yl]urea
  • Example 90 To a stirred solution of 1-(1-methyl-4-piperidyl) pyrazol-3-amine 90- 6 (0.10 g, 0.55 mmol) in DMSO (4 mL) was added N,N′-disuccinimidyl carbonate (0.14 g, 0.55 mmol) followed by pyridine (0.04 mL, 0.55 mmol). The resulting reaction mixture was stirred at RT for 15 min.
  • Example 91 Synthesis of 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1- yl]-3-fluoro-N-methyl-benzamide [0414]
  • Step-1 3-fluoro-4-iodo-N-methyl-benzamide (91-2): To a stirred solution of 3- fluoro-4-iodo-benzoic acid 91-1 (1.00 g, 376 mmol) in DMF (10 mL) were added DIPEA (2.8 mL, 15.0 mmol) and HATU (2.14 g, 5.64 mmol) followed by methanamine (0.18 g, 5.64 mmol) in THF maintained at 0 °C.
  • Step-2 4-(3-aminopyrazol-1-yl)-3-fluoro-N-methyl-benzamide (91-4): To a stirred solution of 3-fluoro-4-iodo-N-methyl-benzamide 91-2 (0.50 g, 1.79 mmol) in DMSO (5 mL) were added 1H-pyrazol-3-amine 91-3 (0.18 g, 2.15 mmol) and Cs 2 CO 3 (1.46 g, 4.48 mmol) followed by Cu2O (0.13 g, 0.89 mmol) at RT. Reaction mixture was stirred in a sealed tube at 120 °C for 16 h. After completion, reaction was quenched with ice cold water, extracted with EtOAc.
  • Step-3 4-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-3- fluoro-N-methyl-benzamide
  • Example 91 To a stirred solution of 4-(3-aminopyrazol-1- yl)-3-fluoro-N-methyl-benzamide 91-4 (0.20 g, 0.85 mmol) in MeCN (5 mL) was added pyridine (0.14 mL, 1.71 mmol) followed by N,N′-disuccinimidyl carbonate (0.24 g, 0.93 mmol) maintained at 0 °C.
  • Example 92 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4- hydroxyphenyl)pyrazol-3-yl]urea [0417]
  • Step-1 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4-hydroxyphenyl)pyrazol-3-yl]urea
  • Example 92 To a stirred solution of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(4- methoxyphenyl)pyrazol-3-yl]urea
  • Example 87 (0.09 g, 0.22 mmol) in DCM (5mL) was added BBr3 in DCM (0.10 mL) maintained at 0 °C and the reaction mixture was stirred at RT for 4 h.
  • Example 93 Synthesis of 1-[(4S)-chroman-4-yl]-3-[1-(3-methylsulfonylphenyl)pyrazol- 3-yl]urea
  • Step-1 1-(3-methylsulfonylphenyl)pyrazol-3-amine (93-3): To a stirred solution of 1H-pyrazol-3-amine 93-1 (0.50 g, 6.02 mmol) in DMSO (10 mL) were added cesium carbonate (3.92 g, 12.0 mmol) and 1-bromo-3-methylsulfonyl-benzene 93-2 (1.55 g, 6.62 mmol) followed by copper (II) bromide (0.17 g, 1.20 mmol) at RT.
  • Step-2 1-[(4S)-chroman-4-yl]-3-[1-(3-methylsulfonylphenyl)pyrazol-3-yl]urea
  • Example 93 To a stirred solution of 1-(3-methylsulfonylphenyl)pyrazol-3-amine 93-3 (0.15 g, 0.63 mmol) in MeCN (3 mL) was added pyridine (0.05 mL, 0.63 mmol) followed by N,N′-disuccinimidyl carbonate (0.16 g, 0.63 mmol) at RT. The resulting reaction mixture was stirred at RT for 15 min.
  • Example 94 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-(1-hydroxy-1-methyl- ethyl)phenyl]pyrazol-3-yl]urea
  • Step-1 1-[3-(3-aminopyrazol-1-yl)phenyl]ethanone (94-3): To a stirred solution of 1H-pyrazol-3-amine 94-1 (0.50 g, 6.02 mmol) in DMF (5 ml) was added cesium carbonate (5.88 g, 18.10 mmol) followed by pyrolidine-1-oxide (0.33 g, 3.01 mmol), CuI (0.22 g, 1.20 mmol) and 1-(3-bromophenyl)ethanone 94-2 (1.79 g, 9.03 mmol) at RT.
  • Step-2 1-[1-(3-acetylphenyl)pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea (94-5): To a stirred solution of 1-[3-(3-aminopyrazol-1-yl)phenyl]ethanone 94-3 (0.20 g, 0.99 mmol) in MeCN (5 mL) was added N,N′-disuccinimidyl carbonate (0.25 g, 0.99 mmol) followed by pyridine (0.23 g, 2.98 mmol) at RT. Reaction mixture was stirred at RT for 30 min.
  • Step-3 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-(1-hydroxy-1-methyl- ethyl)phenyl]pyrazol-3-yl]urea
  • Example 94 To a stirred solution of 1-[1-(3- acetylphenyl)pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea 94-5 (0.05 g, 0.12 mmol) in THF (1 mL) was added methyl magnesium bromide, 1M solution in THF (0.19 mL, 0.18 mmol) at 0 °C. Reaction was stirred at RT for 2 h.
  • Example 95 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(5,6-dimethoxy-3- pyridyl)pyrazol-3-yl]urea
  • Step-1 1-(5,6-dimethoxy-3-pyridyl)pyrazol-3-amine (95-3): To a stirred solution of 1H-pyrazol-3-amine 95-1 (0.20 g, 2.41 mmol) in DMF (5 mL) were added Cs 2 CO 3 (1.56 g, 4.81 mmol) and CuI (0.09 g, 0.48 mmol) at RT.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-(5,6-dimethoxy-3-pyridyl)pyrazol-3- yl]urea
  • Example 95 To a stirred solution of 1-(5,6-dimethoxy-3-pyridyl)pyrazol-3-amine 95-3 (0.02 g, 0.11 mmol) in MeCN (2 mL) were added pyridine (0.01 g, 0.11 mmol) and DSC (0.03 g, 0.11 mmol) at RT. The reaction mixture was stirred at 27 °C for 1 h.
  • Example 96 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-fluoro-4-(methylamino) phenyl]pyrazol-3-yl]urea
  • Step-1 tert-butyl N-(4-bromo-2-fluoro-phenyl) carbamate (96-2): To a stirred solution of 4-bromo-2-fluoro-aniline 96-1 (2.50 g, 13.2 mmol) in THF (8 mL) was added di- tert-butyl dicarbonate (3.3 mL, 14.5 mmol) and the reaction mixture was stirred at 50 °C for 12 h.
  • Step-2 tert-butyl N-(4-bromo-2-fluoro-phenyl)-N-methylcarbamate (96-3): To a stirred solution of tert-butyl N-(4-bromo-2-fluoro-phenyl)carbamate 96-2 (1.00 g, 3.45 mmol) in THF (20 mL) was added sodium hydride (60% in mineral oil, 0.20 g, 4.31 mmol) at 0 °C and the reaction mixture was stirred at same temperature for 10 min. To this was added iodomethane (0.34 mL, 5.51 mmol) and stirred at RT for 4 h. After completion, the reaction mixture was concentrated under reduced pressure.
  • Step-3 tert-butyl N-[4-(3-aminopyrazol-1-yl)-2-fluoro-phenyl]-N- methylcarbamate (96-5): To a stirred solution of 1H-pyrazol-3-amine 96-4 (0.20 g, 2.41 mmol) in DMF (5 mL) was added tert-butyl N-(4-bromo-2-fluoro-phenyl)-N- methylcarbamate 96-3 (0.80 g, 2.65 mmol) followed by cesium carbonate (0.29 g, 0.90 mmol) and copper (I) bromide (0.01 g, 0.06 mmol).
  • Step-4 tert-butyl N-[2-fluoro-4-[3-[[(4S)-8-chlorochroman-4-yl] carbamoyl amino] pyrazol-1-yl] phenyl]-N-methyl-carbamate (96-7): To a stirred solution of tert- butyl N-[4-(3-aminopyrazol-1-yl)-2-fluoro-phenyl]-N-methylcarbamate 96-5 (0.09 g, 0.31 mmol) in MeCN (5 mL) was added pyridine (0.03 mL, 0.32 mmol) followed by N,N′- disuccinimidyl carbonate (0.08 g, 0.31 mmol).
  • Step-5 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[3-fluoro-4-(methylamino) phenyl] pyrazol-3-yl]urea (Example 96): To a stirred solution of tert-butyl N-[4-[3-[[(4S)-8- chlorochroman-4-yl]carbamoyl amino]pyrazol-1-yl]-2-fluoro-phenyl]-N-methyl-carbamate 96-7 (0.08 g, 0.15 mmol) in DCM (5 mL) was added TFA (0.04 mL, 0.62 mmol) and the reaction mixture was stirred at RT for 4 h.
  • Example 97 Synthesis of 1-[(4S)-chroman-4-yl]-3-[1-[4- (methylsulfamoyl)phenyl]pyrazol-3-yl]urea bromobenzenesulfonyl chloride 97-1 (2.00 g, 7.83 mmol) in DCM (10 mL) at 0 °C, was added TEA (2.2 mL, 15.7 mmol). To this was added methanamine (0.72 g, 23.50 mmol) at 0 °C and the reaction mixture was stirred at RT for 4 h. After completion, the reaction mixture was quenched with aqueous NH 4 Cl solution and extracted with DCM.
  • Step-2 4-(3-aminopyrazol-1-yl)-N-methyl-benzenesulfonamide (97-4): To a stirred solution of 1H-pyrazol-3-amine 97-3 (0.40 g, 4.80 mmol) in DMF (10 mL) was added Cs 2 CO 3 (2.61 g, 8.00 mmol) followed by 4-bromo-N-methyl-benzenesulfonamide 97-2 (1.00 g, 4.00 mmol) and CuBr2 (0.23 g, 1.60 mmol) at RT. The reaction mixture was stirred at 120 °C for 12 h. After completion, the reaction was quenched with water and extracted with EtOAc.
  • Step-3 1-[(4S)-chroman-4-yl]-3-[1-[4-(methylsulfamoyl)phenyl]pyrazol-3-yl]urea
  • Example 97 To a stirred solution of 4-(3-aminopyrazol-1-yl)-N-methyl- benzenesulfonamide 97-4 (0.10 g, 0.39 mmol) in MeCN (2 mL) was added pyridine (0.06 mL, 0.79 mmol) followed by N,N'-disuccinimidyl carbonate (0.10 g, 0.39 mmol) at RT. The reaction mixture was stirred at RT for 30 min.
  • Step-1 5-(3-aminopyrazol-1-yl)-N-methyl-pyridin-2-amine (98-3): To a stirred solution of 5-bromo-N-methyl-pyridin-2-amine 98-1 (0.50 g, 2.67 mmol) in DMF (5 mL) were added 1H-pyrazol-3-amine 98-2 (0.27 g, 3.21 mmol) and cesium carbonate (2.18 g, 6.68 mmol) followed by copper (II) bromide (0.30 g, 1.34 mmol) at RT.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[6-(methylamino)-3-pyridyl]pyrazol- 3-yl]urea
  • Example 98 To a stirred solution of 5-(3-aminopyrazol-1-yl)-N-methyl-pyridin- 2-amine 98-3 (0.06 g, 0.31 mmol) in MeCN (2 mL) maintained at 0 °C was added pyridine (0.05 mL, 0.63 mmol) followed by N,N′-disuccinimidyl carbonate (0.08 g, 0.34 mmol). Resulting reaction mixture was stirred at RT for 30 min.
  • Example 99 and Example 100 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4- [2,2,2-trifluoro-1-hydroxy-ethyl]phenyl]pyrazol-3-yl]urea
  • Step-1 1-[4-(3-aminopyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethanol (99-3): To a stirred solution of 1-(4-bromophenyl)-2,2,2-trifluoro-ethanol 99-1 (0.05 g, 0.19 mmol) in DMF (2 mL) were added cesium carbonate (0.19 g, 0.59 mmol) and CuBr 2 (0.01 g, 0.04 mmol) followed by 1H-pyrazol-3-amine 99-2 (0.01 g, 0.19 mmol) and the reaction mixture was stirred at 120 °C for 12 h.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[1-[4-[(1S)-2,2,2-trifluoro-1-hydroxy- ethyl]phenyl]pyrazol-3-yl]urea (Examples 99 and 100): To a stirred solution of 1-[4-(3- aminopyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethanol 99-3 (0.20 g, 0.77 mmol) in MeCN (10 mL) were added pyridine (0.06 mL, 0.77 mmol) and N,N'-disuccinimidyl carbonate (0.19 g, 0.77 mmol) and the reaction mixture was stirred at 27 °C for 1 h.
  • Example 101 Synthesis of 6-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol- 1-yl]-N-methyl-pyridine-3-carboxamide ed solution of methyl 6-chloropyridine-3-carboxylate 101-1 (2.00 g, 11.65 mmol) in DMF (50 mL) was added 3-nitro-1H-pyrazole 101-2 (1.97 g, 17.48 mmol) followed by cesium carbonate (7.59 g, 23.31 mmol) at RT. Reaction was stirred at 100 °C for 4 h.
  • Step-2 methyl 6-(3-aminopyrazol-1-yl)pyridine-3-carboxylate (101-4): To a stirred solution of methyl 6-(3-nitropyrazol-1-yl)pyridine-3-carboxylate 101-3 (0.20 g, 0.80 mmol) in methanol (20 mL) was added 10% Pd/C (0.10 g) at RT.
  • Step-3 methyl 6-[3-[(8-chlorochroman-4-yl)carbamoylamino]pyrazol-1- yl]pyridine-3-carboxylate (101-6): To a stirred solution of methyl 6-(3-aminopyrazol-1- yl)pyridine-3-carboxylate 101-4 (0.20 g, 0.92 mmol) in DMSO (5 mL) was added N,N'- disuccinimidyl carbonate (0.23 g, 0.92 mmol) followed by pyridine (0.07 mL, 0.91 mmol) at RT. Reaction was stirred at 25 °C for 45 min.
  • Step-4 6-[3-[[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]-N- methyl-pyridine-3-carboxamide (Example 101): To a stirred solution of methyl 6-[3- [[(4S)-8-chlorochroman-4-yl]carbamoylamino]pyrazol-1-yl]pyridine-3-carboxylate 101-6 (0.10 g, 0.23 mmol) in methylamine in methanol (10 mL) was stirred at 25 °C for 4 h.
  • Example 101 (0.01 g).
  • Step-1 5-methyl-1-(3-methylsulfonylphenyl)pyrazol-3-amine (102-3): To a stirred solution of 5-methyl-1H-pyrazol-3-amine 102-1 (0.40 g, 4.12 mmol) in DMSO (6 mL) were added CuBr 2 (0.18 g, 0.82 mmol) and Cs 2 CO 3 (2.01 g, 6.18 mmol) followed by 1-bromo-3- methylsulfonyl-benzene 102-2 (0.96 g, 4.12 mmol).
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[5-methyl-1-(3- methylsulfonylphenyl)pyrazol-3-yl]urea (Example 102): To a stirred solution of 5-methyl- 1-(3-methylsulfonylphenyl)pyrazol-3-amine 102-3 (0.10 g, 0.39 mmol) in MeCN (7 mL) was added pyridine (0.03 mL, 0.39 mmol) followed by N,N’-disuccinimidyl carbonate (0.10 g, 0.39 mmol). The reaction mixture was stirred at RT for 45 min.
  • Example 103 Synthesis of 1-[(4S)-8-chlorochroman-4-yl]-3-[4-methyl-1-(3- methylsulfonylphenyl) pyrazol-3-yl]urea stirred solution of 4-methyl-1H-pyrazol-3-amine 103-1 (0.50 g, 5.15 mmol) and 1-bromo-3- methylsulfonyl-benzene 103-2 (1.21 g, 5.15 mmol) in DMSO (6 mL) was added cesium carbonate (2.51 g, 7.72 mmol) followed by copper bromide (0.14 g, 1.03 mmol). Reaction mixture was stirred at 180 °C for 30 min in microwave irradiation.
  • Step-2 1-[(4S)-8-chlorochroman-4-yl]-3-[4-methyl-1-(3-methylsulfonylphenyl) pyrazol-3-yl]urea (Example 103): To a stirred solution of 4-methyl-1-(3- methylsulfonylphenyl) pyrazol-3-amine 103-3 (0.09 g, 0.35 mmol) in MeCN (7 mL) was added N,N′-disuccinimidyl carbonate (0.09 g, 0.36 mmol) followed by pyridine (0.03 mL, 0.36 mmol). The resulting reaction mixture was stirred at RT for 15 min.
  • Example 104 and Example 105 Synthesis of 1-(8-cyanochroman-4-yl)-3-(1-phenyl-1H- pyrazol-3-yl)urea and 1-(8-cyanochroman-4-yl)-3-(1-phenyl-1H-pyrazol-3-yl)urea hydroxybenzonitrile 104-1 (4.20 mL, 42.00 mmol) and 3-bromopropanoic acid 104-2 (4.40 mL, 42.00 mmol) in H2O (30 mL) was added NaOH (3.77 g, 92.30 mmol). The reaction was stirred at 100 °C for 12 h.
  • reaction mixture was quenched with H 2 O, acidified with concentrated HCl and extracted with EtOAc. The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford 3-(2- cyanophenoxy)propanoic acid 104-3 (3.30 g) which was used directly for the next reaction.
  • Step-2 3-(2-cyanophenoxy)propanoyl chloride (104-4): To a stirred solution of 3- (2-cyanophenoxy)propanoic acid 104-3 (3.67 g, 17.30 mmol) in DCM (20 mL) maintained at 0 °C was added oxalyl chloride (2.30 mL, 25.90 mmol).
  • Step-3 4-oxochromane-8-carbonitrile (104-5): To a stirred solution of 3-(2- cyanophenoxy)propanoyl chloride 104-4 (3.47 g, 15.70 mmol) in DCM (6 mL) maintained at 0 °C was added AlCl 3 (2.56 g, 18.90 mmol) at RT. The reaction was stirred at RT for 12 h.
  • Step-4 (Z)-N-(8-cyanochroman-4-ylidene)-2-methylpropane-2-sulfinamide (104- 7): To a stirred solution of 4-oxochromane-8-carbonitrile 104-5 (0.50 g, 2.60 mmol) in THF (8 mL) was added titanium (IV) ethoxide (1.80 mL, 6.50 mmol) followed by 2- methylpropane-2-sulfinamide 104-6 (0.64 g, 5.20 mmol). The reaction mixture was stirred at 90 °C for 16 h. After completion, reaction mixture was concentrated under reduced pressure and quenched with H2O and extracted with EtOAc.
  • Step-5 N-(8-cyanochroman-4-yl)-2-methyl-propane-2-sulfinamide (104-8): To a stirred solution of (Z)-N-(8-cyanochroman-4-ylidene)-2-methylpropane-2-sulfinamide 104-7 (0.60 g, 1.76 mmol) in MeOH (8 mL) maintained at 0 °C was added sodium borohydride (0.08 g, 2.29 mmol). The reaction mixture was stirred at RT for 12 h. After completion, reaction was quenched with H2O and extracted with EtOAc.
  • Step-6 4-aminochromane-8-carbonitrile hydrochloride (104-9): To a stirred solution of N-(8-cyanochroman-4-yl)-2-methyl-propane-2-sulfinamide 104-8 (0.70 g, 1.66 mmol) in EtOAc (8 mL) maintained at 0 °C was added HCl in EtOAc (2.50 mL). The reaction mixture was stirred at 0 °C for 6 h. After completion, reaction mixture was concentrated under reduced pressure to get the product which was triturated using EtOAc to afford 4-aminochromane-8-carbonitrile hydrochloride 104-9 (0.02 g) which was used directly for the next reaction.
  • Step-7 1-(8-cyanochroman-4-yl)-3-(1-phenyl-1H-pyrazol-3-yl)urea (104-11): To a stirred solution of 1-phenylpyrazol-3-amine 104-10 (0.15 g, 0.94 mmol) in DCM (4 mL) was added triphosgene (0.14 g, 0.47 mmol) at RT. The reaction mixture was maintained at 0 °C for 10 min.
  • BIOLOGICAL/BIOCHEMICAL EVALUATION DNA polymerization assay to monitor effects on human POL ⁇ and five disease-causing mutant variants of human POL ⁇ .
  • the ability of small molecules to stimulate the polymerase activity of POL ⁇ was analyzed in a quantitative fluorescence SYBR Green I assay with fluorescence intensity (FI) readout.
  • FI fluorescence intensity
  • POL ⁇ and mutant derivatives thereof will extend the primer and use the M13mp18 molecule as a template to synthesize long stretches of double-stranded DNA.
  • SYBR Green I which is a double- stranded DNA-binding dye, was used to quantify formation of double-stranded DNA in the reaction. When bound to double-stranded DNA, SYBR Green I fluorescence increases by up to 100-fold. [0460] The assay was performed in the 384-well plate format. Upon addition of compounds, changes in double-stranded DNA synthesis activity can be monitored by following effects on fluorescent intensity.
  • Proteins used in the polymerization assays were wild type POL ⁇ A (POL ⁇ A:WT) and mutant derivatives thereof in which an Alanine in position 467 of the amino acids sequence had been changed to Threonine (POL ⁇ A:A467T), a Glycine in position 848 of the amino acids sequence had been changed to Serine (POL ⁇ A:G848S), an Arginine in position 309 of the amino acids sequence had been changed to Cysteine (POL ⁇ A:R309C), or a Tyrosine in position 955 of the amino acid sequence had been changed to Cysteine (POL ⁇ A:Y955C).
  • W748S mutant Another mutant derivative used in the assay was the W748S mutant, which arises as a result of the substitution of a G to C mutation at position 2243 in exon 13.
  • the W748S mutation is generally found in cis with the E1143G polymorphism, which is caused by an A to G transition at nucleotide 3428 in exon 21 of POL ⁇ .
  • the reactions also contained the accessory POL ⁇ B subunit, and the human mitochondrial single stranded DNA binding protein (mtSSB).
  • the protein mixture used in the assays contained POL ⁇ A or a mutant derivative (1 nM), POL ⁇ B (1.3 nM, concentration calculated as a dimer), 25 mM Tris-HCl (pH 8.0), 0.1 mg/mL bovine serum albumin, 1 mM TCEP solution (pH 7), 25 mM NaCl, and 0.02% Triton X-100.
  • the primed circular single-stranded DNA template used in the polymerization assay was generated by hybridizing circular, single-stranded DNA from M13mp18 with a 20 nucleotides long oligonucleotide (5'-GTA AAA CGA CGG CCA GTG CC-3') using a Bio- Rad T100 Thermal Cycler.
  • the DNA template mixture used in the assay contained 0.5 nM primed M13 mp18 single-stranded DNA, 400 nM mtSSB, 0.1 mM Tris-HCl (pH 8.0), 100 ⁇ M dNTP, 10 mM MgCl2, 0.1 mg/mL BSA, 1 mM TCEP solution, and 0.02% Triton X-100.
  • the DNA template mixture for the wild type protein contained either 100 ⁇ M dNTP or 0.1 ⁇ M dNTP, the latter being designated with an * in Table 2.
  • Microplates with compounds (0.1 ⁇ L in each well) to be tested in the assay were prepared from 10 mM compound stocks in 100% DMSO, and equal amounts of DMSO without any compound were added to positive and negative control wells.
  • the protein mixture was dispensed (5 ⁇ L into each well) into compound plates and incubated at 37 °C for 15 minutes. After incubation, 5 ⁇ L of the DNA template mixture was dispensed into each well. The plates were then incubated at 37 °C for 2 hours.
  • a combined stop buffer and detection reagent solution was prepared.
  • the buffer contained 25 mM EDTA (pH 8.0), 0.02% Triton X-100, and SYBR Green I diluted 10,000 X (for fluorescent readout). EDTA will stop the enzymatic reaction by chelating magnesium ions.
  • SYBR Green I solution was added (10 ⁇ L) to the screening plates and the plates were incubated at room temperature in the dark for 20 minutes before the fluorescent signal was read between 485-520 nM on a microtiter plate reader.
  • the compound concentrations for half maximum activity (AC 50 ) are provided in Table 2 Table 2: AC 50 Values for POL ⁇ Activators on Human POL ⁇ and Human Mutant POL ⁇ .

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Abstract

La présente invention concerne des composés de formule (I), leurs sels pharmaceutiquement acceptables, et des compositions pharmaceutiques de ceux-ci, qui se rapportent à de nouveaux modulateurs de l'ADN polymérase γ (POL γ).
PCT/US2024/037620 2023-07-11 2024-07-11 Modulateurs de la réplication d'adn mitochondrial Pending WO2025015178A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020082264A1 (en) * 2000-09-06 2002-06-27 Susanne Nikolic Medicaments for viral diseases
WO2023034346A1 (fr) * 2021-08-30 2023-03-09 Pretzel Therapeutics, Inc. Composés de chromèn-2-one modulateurs de polrmt

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020082264A1 (en) * 2000-09-06 2002-06-27 Susanne Nikolic Medicaments for viral diseases
WO2023034346A1 (fr) * 2021-08-30 2023-03-09 Pretzel Therapeutics, Inc. Composés de chromèn-2-one modulateurs de polrmt

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE 5 January 2023 (2023-01-05), XP093266862, Database accession no. 333886390 *

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